This invention relates to nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS.
This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Since the recognition that cyclic adenosine tri-phosphate (cAMP) is an intracellular second messenger, inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized and their selective inhibition has led to improved drug therapy. More particularly, it has been recognized that inhibition of PDE4 can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation. Thus, compounds that inhibit PDE4, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
Recent molecular cloning has revealed a complexity and diversity of PDE4 enzymes. It is now known that there are four distinct PDE4 isozymes (A, B, C and D), each encoded for by a separate gene. Kinetic studies of human recombinant materials suggest that these four isozymes may differ in their Km""s and Vmax""s for hydrolysis of cAMP. Analysis of tissue distribution of PDE4 mRNAs suggests that each isozyme may be localized in a cell-specific pattern. For example, unlike human skeletal muscle human peripheral blood leukocytes do not express PDE4C message, and guinea pig eosinophils express predominantly PDE4D message. The structural and distribution diversity of PDE4 isozymes offers an opportunity to discover an isozyme selective inhibitor that blocks the function of inflammatory cells only. Using PDE4D isozyme selective inhibitors, we have demonstrated that the PDE4D isozyme plays a key role in regulating the activation and degranulation of human eosinophils. In a primate model of asthma, PDE4D isozyme selective compounds inhibit antigen-induced pulmonary eosinophilia. Therefore, by selectively blocking the D isozyme, PDE4D inhibitors exhibit reduced side effects and retain anti-asthmatic (anti-inflammatory) efficacy.
The present invention relates to a compound of the formula 
or the pharmaceutically acceptable salt thereof, wherein the broken line represents an optional double bond;
m is 0 or 1;
n is 0 or 1;
o is 0, 1, 2, 3or 4;
p is 0 or 1;
q is 0, 1, 2 or 3;
r is 0, 1, 2, 3, or 4;
t is 0 or 1;
A is oxygen,  greater than NH or sulfur;
B is oxygen or NH;
D is oxygen or NR9, wherein R9 is hydrogen or (C1-C6)alkyl;
E is CH2, O, NH or S(O)a wherein a is 0, 1 or 2;
R1 is hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C6-C10)aryl, bridged(C7-C9)bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group;
wherein said saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above;
wherein said R1 cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, (C1-C6)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, ((C1-C6)alkyl2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, aminosulfonyl, (C1-C6)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C3-C7) heterocycle;
wherein said saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle substituents on said R1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups contain from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above, and wherein the heterocycles are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
wherein said alkyl, alkoxy or cycloalkyl substituents on said R1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally further independently substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or said R1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are additionally optionally independently substituted with from one to three substituents of the formula 
wherein R10 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, (C6-C10)arylamino, (C6-C10)aryl, bridged(C7-C9)bicycloalkyl or a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle;
wherein said R10 saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above;
wherein said R10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocycle groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, (C1-C6)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle;
wherein said saturated or unsaturated cyclic or bicyclic (C3-C7) heterocycle contains from one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above; wherein the heterocycle is optionally substituted by from one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
wherein the alkyl, alkoxy or cycloalkyl substituents on said R10 alkyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or R1 is a group of the formula 
wherein u is 0 or 1; and
G, J, K and L are each independently oxygen, sulfur, nitrogen, NR9, wherein R9 is as defined above, carbonyl or CHR16; wherein the dashed lines represent optional double bonds and where it is understood that when a double bond exists between G and J, J and K or K and L that R9 is absent,  greater than CHR16 is  greater than CR16 and G, J, K or L cannot be carbonyl; wherein R16 is hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, (C1-C6)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C3-C7) heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above, wherein said heterocycle is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
wherein said R16 alkyl, alkoxy or cycloalkyl substituents are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6) alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
wherein each R2, R3 and R4 is independently hydrogen, hydroxy, halo, cyano, carboxy, nitro, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, hydroxyamino, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, or a group of the formula 
wherein R10 is as defined above;
or R2 and R3 can be taken together with the carbon to which they are attached to form a carbonyl group or R2 and R3 taken together with the carbon to which they are attached form a (C3-C7)cycloalkyl ring;
or when m is 1, n is 1, o is 1 and p is 0, A and R2 can be taken together to form a group of the formula 
wherein the broken lines represent optional double bonds and q, A, B, R1, R3 and R4 are as defined above and when a double bond contains the carbon atom to which R3 is attached then R3 is absent;
or when m is 1, n is 1, o is 1 and p is 0, A and R2 are taken together and R3 and xe2x80x94[R4]qxe2x80x94R1 are taken together to form a group of the formula 
R5 is a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above; wherein the heterocyclic group is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, difluoro trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, ((C1-C6)alkyl)2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, aminosulfonyl, (C1-C6)alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above;
wherein the heterocycle substituent on said R5 saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group is optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
wherein the alkyl, alkoxy or cycloalkyl substituents on said R5 saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group, are optionally substituted by one to three sub-substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or said R5 saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group is additionally optionally substituted by a group of the formula 
wherein R10 is as defined above;
or R5 is a group of the formula 
wherein R11, R12, R13, R14 and R15 are each substituents independently selected from the group consisting of hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C1-C6)acylamino, (C6-C10)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94(Cxe2x95x90O), (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)acyloxy, (C1-C6alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90Oxe2x80x94, ((C1-C6)alkyl)2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or a saturated or unsaturated cyclic or bicyclic (C3-C7)heterocycle containing one to four heteroatoms independently selected from oxygen, sulfur, nitrogen and NR9, wherein R9 is as defined above, and wherein said heterocycle is optionally substituted by one to three substituents independently selected from the group consisting of halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or , R11, R12, R13, R14 and R15 are optionally independently a group of the formula 
wherein R10 is as defined above;
wherein the alkyl, alkoxy or cycloalkyl groups of said R11, R12 , R13, R14 and R15 groups are optionally substituted by one to three substituents independently selected from halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy( C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or R12 and R13 can be taken together with the carbons to which they are attached to form a group of the formula 
wherein u, G, J, K and L are as defined above;
R6, R7, and R8 are each independently hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)acyl, (C6-C10)aryl, (C1-C6)acylamino, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylsulfonyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C9)alkyl)2aminosulfonyl or (C2-C9)heteroaryl;
or R7 and R8 may be taken together with the carbons to which they are attached to form a fused bicyclic ring of the formula 
wherein the dashed lines represent optional double bonds; and M, P, Q and T are each independently oxygen, nitrogen or CR17 wherein R17 is hydrogen or (C1-C6)alkyl;
with the proviso that when m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A is oxygen, B is NH; R2 and R3 are hydrogen; R1 is phenyl substituted by methyl, methoxy, chloro or fluoro; E is oxygen and R5 is phenyl optionally substituted by one or two fluoro or chloro; then R1 must be at least di-substituted by substituents other than methyl, methoxy or halo;
with the proviso that when t is one that the compound of formula I is a zwiterionic N-oxide, with the proviso that adjacent positions defined by G, J, K and L cannot both be defined by oxygen; and
with the proviso that when the broken line of formula I represents a double bond, p is 0 and R3 is absent.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The term xe2x80x9ca saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is as defined abovexe2x80x9d, as used herein, unless otherwise indicated, includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzothiadiazole, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl. Preferably, heterocyclic refers to furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-thiadiazolyl, pyridyl, benzoxazolyl or indolyl.
The term xe2x80x9cacylxe2x80x9d, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d are as defined above.
The term xe2x80x9cacyloxyxe2x80x9d, as used herein, includes O-acyl groups wherein xe2x80x9cacylxe2x80x9d is defined above.
The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A is oxygen or nitrogen; B is NH; R2 is hydrogen or (C1-C6)alkyl; R3 is hydrogen; R1 is (C6-C10)aryl, (C3-C7)cycloalkyl or a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl wherein the aryl, cycloalkyl and heterocyclic groups are optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
More preferred compounds of formula I are those wherein R1 is optionally substituted (C6-C10)aryl wherein said substituents are hydroxy(C1-C6)alkyl or wherein at least one of R11, R12, R13, R14 or R15 is halo or wherein R12 and R13 are taken together to form a fused bicyclic ring wherein u is zero, G and L are oxygen and J is CH2.
Other preferred compounds of formula I include those wherein m is 0; n is 0; o is 3; p is 0; q is 0; r is 0; R2 and R3 are hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 0; o is 2; p is 0; q is 0; r is 0; A is oxygen; R2 and R3 are hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 0; n is 0; 0 is 1; p is 1; q is 1; r is 0; R2 and R3 are hydrogen; D is oxygen; R4 is hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 0; n is 0, o is 3; p is 0; q is 0; r is 0; R2 is hydrogen or hydroxy, R3 is hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 0; o is 1; p is q is 0; r is 0; A is oxygen; R2 and R3 are hydrogen; D is oxygen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl,
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A is oxygen; B is oxygen; R2 and R3 are hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 0; p is 1; q is 0; r is 0; A is oxygen; B is NH; D is NR8 wherein R8 is hydrogen or (C1-C6)alkyl; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 0; n is 1; o is 1; p is 0; q is 1; r is 0; B is NH; R2and R3 are taken together to form a carbonyl group; R4 is hydrogen; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A and R2 are taken together to form a group of the formula 
wherein A is nitrogen; B is NH; R is (C1-C6)alkyl or (C1-C10)aryl wherein the aryl group is optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 0; n is 0; o is 1; p is 0; q is 2; r is 0; R2 is hydrogen or hydroxy; R3 is hydrogen; R4 is independently hydrogen or hydroxy; R1 is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1, 2, 3 or 4; p is 0; q is 1, 2 or 3; r is 0; A is oxygen; B is oxygen; R2, R3, R4 and R1 are hydrogen; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A and R2 are taken together to form a group of the formula 
wherein A is nitrogen; B is oxygen; R1 is (C1-C6)alkyl or (C6-C10)aryl wherein the aryl group is optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 1; p is 0; q is 0; r is 0; A and R2 are taken together to form a group of the formula 
wherein A is oxygen; B is oxygen; R1 is (C1-C6)alkyl or (C6-C10)aryl wherein the aryl group is optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)lkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 0; o is 0; p is 0; q is 0; r is 0; A is oxygen; R1 is (C6-C10)aryl or a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is a hydrogen or (C1-C6)alkyl wherein the aryl or heterocyclic groups are optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein m is 1; n is 1; o is 0; p is 0; q is 1; r is 0; A is oxygen; B is NH; R4 is hydroxy (C1-C6)alkyl; R1 is (C1-C6)alkyl; E is oxygen and R5 is a group of the formula 
or R5 is a saturated or unsaturated, cyclic or bicyclic (C3-C7) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen and NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Specific preferred compounds of formula I include the following:
N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-methyl-benzo(d)isoxazol-7-yloxy)-nicotinamide;
N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-oxo-indan-5-yloxy)-nicotinamide;
2-(3-(1-Hydroxyimino-ethyl)-phenoxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-nicotinamide;
N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(4-oxo-chroman-6-yloxy)-nicotinamide;
(xc2x1) 2-(3-Acetyl-phenoxy)-N-(1-hydroxy-indan-5-ylmethyl)-nicotinamide;
2-(2,3-Dihydro-benzo(1,4)dioxin-6-yloxy)-N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-nicotinamide;
N-(4-(1-Hydroxy-1-methyl-ethyl)-benzyl)-2-(3-(1-methoxyimino-ethyl)-phenoxy)-nicotinamide;
N-(2-Chloro-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide;
N-(5-Chloro-thiophen-2-ylmethyl)-2-(pyridin-3-yloxy)-nicotinamide;
2-(4-Fluoro-phenoxy)-N-[4-(3-hydroxy-azetidin-1-yl)-benzyl]-nicotinamide;
N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-nitro-phenoxy)-nicotinamide;
2-(4-Fluoro-phenoxy)-N-(2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-nicotinamide;
N-[2-(3-Acetyl-phenoxy)-pyridin-3-yl]-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-acetamide;
3-{3-[4-(1-Hydroxy-1-methyl-ethyl)-benzylcarbamoyl]-pyridin-2-yloxy}-benzoic acid methyl ester;
2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
2-(4-Fluoro-phenoxy)-N-(1-thiophen-2-yl-ethyl)-nicotinamide;
N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-phenoxy)-nicotinamide;
2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3,4-difluoro-phenoxy)-nicotinamide;
(+)-2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide;
(xe2x88x92)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide;
(+)-2-(3-Cyano-4-fluoro-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide;
(+)-2-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide;
(xe2x88x92)-2-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide;
2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide,
2-(Benzo[1,3]dioxol-5-yloxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide;
2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-ethyl)-cyclohexylmethyl]-nicotinamide; and
2-(3-Cyano-4-fluoro-phenoxy)-N-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
N-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-2-(3-cyano-4-fluoro-phenoxy)-nicotinamide;
2-(3-Acetyl-phenoxy)-N-[2-chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide;
2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
2-(3,4-Difluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide;
2-(4-Fluoro-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide;
2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohexylmethyl]-nicotinamide;
N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(3-methoxy-phenoxy)-nicotinamide;
2-(3-Cyano-phenoxy)-N-[4-(1-hydroxy1-methyl-ethyl)-benzyl]-nicotinamide;
N-[4-(1-Hydroxy-1-methyl-ethyl)-benzyl]-2-(pyridin-3-yloxy)-nicotinamide; and
2-(3-Acetyl-phenoxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide.
The present invention also relates to a pharmaceutical composition for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such preventions or treatment and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such treatment
The present invention also relates to a pharmaceutical composition for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosinophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment and a pharmaceutically acceptable carrier.
The present invention also relates to a method for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosinophils useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a PDE4 D isozyme inhibiting compound or a pharmaceutically acceptable salt thereof, effective in such treatment.
The following reaction Schemes illustrate the preparation of compounds of the present invention. 
In reaction 1 of Scheme 1, the 2-chloropyridine compound of formula IV is converted to the corresponding compound of formula III by reacting IV with a compound of the formula, R5(CH2)rxe2x80x94OH, in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 3 hours to about 20 hours, preferably about 4 hours.
In reaction 1 of Scheme 2, the 3-carboxylic acid compound of formula IV is converted to the corresponding ethyl ester pyridine compound of formula VI by reacting IV with ethanol in the presence of thienyl chloride. The reaction mixture is heated to reflux for a time period between about 1 hour to about 3 hours, preferably about 1.5 hours.
In reaction 2 of Scheme 2, the 2-chloropyridine compound of formula VI is converted to the corresponding compound of formula V by reacting IV with a compound of the formula, R5(CH2)rxe2x80x94OH, in the presence of cesium carbonate and a polar aprotic solvent, such as; dimethylformamide. The reaction is carried out at a temperature between about 65xc2x0 C. to about 90xc2x0 C., preferably about 65xc2x0 C., for a time period between about 10 hours to about 18 hours, preferably about 10 hours.
In reaction 3 of Scheme 2, the ethyl ester pyridine compound of formula V is converted to the corresponding 3-carboxylic acid compound of formula III by reacting V with ethanol in the presence of sodium hydroxide. The reaction mixture is heated to reflux for a time period between about 3 hours to about 5 hours, preferably about 4 hours.
In reaction 1 of Scheme 3, the 3-carboxylic acid compound of formula IV is converted to the corresponding benzyl ester pyridine compound of formula X by reacting IV with benzyl bromide in the presence of potassium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 10 hours.
In reaction 2 of Scheme 3, the 2-chloropyridine compound of formula X is converted to the corresponding compound of formula IX by reacting X with 3-iodophenol in the presence of cesium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at a temperature between about 70xc2x0 C. to about 80xc2x0 C., preferably about 75xc2x0 C., for a time period between about 1 hours to about 6 hours, preferably about 2 hours.
In reaction 3 of Scheme 3, the (3-iodo-phenoxy) pyridine compound of formula IX is converted to the corresponding compound of formula VIII by reacting IX with carbon monoxide and methanol in the presence of palladium acetate, 1,1-bix(diphenylphosphino)-ferrocene, triethylamide and a polar aprotic solvent, such as dimethylformamide. The reaction mixture is heated to a temperature between about 50xc2x0 to about 70xc2x0 C., preferably about 60xc2x0 C., for a time period between about 2 hours to about 4 hours, preferably about 4 hours.
In reaction 4 or Scheme 3, the benzyl ester pyridine compound of formula VIII is converted to the corresponding compound of VIII by hydrogenating VIII in the presence of palladium on carbon, methanol and ethyl acetate. The reaction is carried out at room temperature for a time period between about 1 hour to about 2 hours, preferably about 2 hours.
In reaction 1 of Scheme 4, the carboxylic acid pyridine compound of formula III is converted to the corresponding compound of formula XI by reacting III with a compound of the formula 
by one of four different synthetic methods.
In the first method, the compound of formula III is reacted with XII in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-hydroxybenzotriazole hydrate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 10 hours. In the second method, III is reacted a chloroformate such as isobutylchloroformate, in the presence of N-methylmorpoline and a polar aprotic solvent, such as methylene chloride, at a temperature between about 0xc2x0 C. to about xe2x88x9220xc2x0 C., preferably about xe2x88x9210xc2x0 C., for a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The reaction mixture is warmed to room temperature and the compound of formula XII is added. The resulting reaction mixture is stirred for a time period between about 1 hour to about 24 hours, preferably about 10 hours.
In the third method, the compound of formula III is heated to reflux in the presence of thionyl chloride for a time period between about 1 hour to about 24 hours, preferably about 1 hours. The resulting acid chloride is then reacted with the compound of formula XII in the presence of pyridine and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 0xc2x0 C. to about room temperature, preferably about 0xc2x0 C.
In the fourth method, the compound of formula II is reacted with XII in the presence of BOP, diisopropyl ethyl amine and a polar aprotic solvent,such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 3 hours to about 4 hours, preferably about 4 hours.
In reaction 1 of Scheme 5the 3-carboxylic acid pyridine compound of formula III is converted to the corresponding compound of formula XIII by reacting III with a compound of the formula 
in the presence of 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, pyridine and diethyl ether. The reaction is carried out at room temperature for a time period between about 1 hour to about 3 hours, preferably about 1 hours.
In reaction 1 of Scheme 6, the compound of formula XVI is converted to the corresponding compound of formula XV by reacting XVI with acetonitrile in the presence of formaldehyde and sodium cyanoborohydride. The reaction is carried out at room temperature for a time period between about 14 hours to about 16 hours, preferably about 16 hours.
In reaction 1 of Scheme 7, the compound of formula XVII is converted to the corresponding compound of formula XVI by first reacting XVII with phosphorus oxychloride in an aprotic solvent, such as toluene, then treating the compound so formed with sodium hydroxide in a polar protic solvent, such as methanol. The reaction is carried out at a temperature between about 0xc2x0 C. to room temperature, preferably about 22xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 12 hours.
In reaction 1 of Scheme 8, the compound of formula XIX is converted to the corresponding compound of formula XVIII by a method to that described in reaction 1 of Scheme 7.
In reaction 1 of Scheme 9, the 3-aminopyridine compound of formula XXI is converted to the corresponding compound of formula XX by reacting XXI with a compound of the formula 
in the presence of 1-hydroxybenzotriazole hydrate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 16 hours.
In reaction 1 of Scheme 10, the compound of formula XXIII is converted to the corresponding compound of formula XXII by reacting XXIII with a compound of the formula 
in the presence of p-toluenesulfonic acid and an aprotic solvent, such as toluene. The reaction is mixture heated to reflux for a time period between about 1 hour to about 48 hours, prefereably about 24 hours.
In reaction 1 of Scheme 11, the compound of formula XXVI is converted to the corresponding compound of formula XXV by reacting XXVI with methyl lithium in an aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 75xc2x0 C. to about xe2x88x9285xc2x0 C., preferably about xe2x88x9278xc2x0 C., for a time period between about 1 hour to about 6 hours, preferably about 2 hours.
In reaction 1 of Scheme 12, the compound of formula XXVII by reacting XXVIII with boron tribromide in a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about xe2x88x9278xc2x0 C. to room temperature, preferably about 0xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 16 hours.
In reaction 1 of Scheme 13, the compound of formula XXX is converted to the corresponding compound of formula XXIX by reacting XXX with a compound of the formula 
in the presence of triethylamine and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about 0xc2x0 C. to room temperature, preferably about 0xc2x0 C., for a time period between about 30 minutes to about 2 hours, prefereably about 1 hours.
In reaction 1 of Scheme 14, the compound of formula XXX is converted to tie corresponding compound of formula XXXII by reacting XXX with methanesulfonic anhydride in the presence of triethylamine. The reaction is carried out at room temperature for a time period between about 30 minutes to about 24 hours, preferably about 12 hours.
In reaction 1 of Scheme 15, the compound of formula XXXV is converted to the corresponding compound of formula XXXIV by reacting XXXV with sodium hydroxide in a polar aprotic solvent, such as ethanol. The reaction is heated to reflux for a time period between about 1 hour to about 24 hours, preferably about 9 hours.
In reaction 1 of Scheme 16, the compound of formula XXXVII is converted to the corresponding compound of formula XXXVI by oxidizing XXXVII with tetrapropylammonium perruthenate and 4-methylmorpholine N-oxide in a polar aprotic solvent, such as methylene chloride. The reaction is carried out at room temperature for a time period between about 2 hours to about 6 hours, perferably about 4 hours.
In reaction 1 of Scheme 17, the 2-aminopyridine compound of formula XXXIX is converted to the corresponding compound of formula XXXVIII by reacting XXXIX with a compound of the formula, R5xe2x80x94Nxe2x95x90Cxe2x95x90O. The reaction is heated to reflux for a time period between about 1 hour to about 24 hours, preferably about 16 hours.
In reaction 1 of Scheme 18, the 2-nitropyridine compound of formula XLI is converted to the correspond 2-aminopyridine compound of formula XL by reducing XLI with 10% platinum oxide on carbon, methanol and tetrahydrofuran. The reaction is carried out at room temperature for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 1 of Scheme 19, the compound of formula XLIII is converted to the corresponding compound of formula XLII by reacting XLIII with MCPBA in a polar aprotic solvent, such as methylene chloride. The reaction is carried out at room temperature for a time period between about 1 hour to about 4 hours, prefereably about 1 hours.
In reaction 1 of Scheme 20, the 2-chloropyridine compound of formula XLV is converted to the corresponding compound of formula XLVI by reacting XLV with a compound of the formula, R5(CH2)rOH, in the presence of cesium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction is carried out at a temperature between about 65xc2x0 C. to about 90xc2x0 C., preferably about 80xc2x0 C., for a time period between about 10 hours to about 18 hours, preferably about 16 hours.
In reaction 2 of Scheme 20, the 3-cyanopyridine compound of formula XLVI is converted to the corresponding compound of formula XLVII by reacting XLVI with hydrogen peroxide in the presence of potassium hydroxide and a polar protic solvent, such as ethanol. The reaction is carried out at room temperature for a time period between about 1 hour to about 24 hours, preferably about 12 hours.
In reaction 3 of Scheme 20, the compound of formula XLVII is converted to the corresponding compound of formula XLIV by reacting XLVII with a compound of the formula 
wherein X is chloro, bromo or iodo, in the presence of potassium hydroxide and a polar aprotic solvent, such as dimethyl sulfoxide. The reaction is carried at room temperature for a time period between about 1 hour to about 24 hours, preferably about 1 hours.
In reaction 1 of Scheme 21, the compound of formula XLIX is converted to the corresponding compound of formula L by reacting XLIX with a compound of the formula 
in a polar aprotic solvent, such a tetrahydrofuran. The reaction is carried out at a temperature between about xe2x88x9285xc2x0 C. to about xe2x88x9275xc2x0 C., preferably about 78xc2x0 C., for a time period between about 0.5 hours to about 16 hours, preferably about 2 hours.
In reaction 2 of Scheme 21, the compound of formula L is converted to the corresponding compound of formula XLVIII by reacting L with chromic acid, sulfuric acid and water in a polar aprotic solvent, such as acetone. The reaction is carried out at a temperature between about 0xc2x0 C. to about 25xc2x0 C., preferably about 0xc2x0 C., for a time period between about 0.5 hours to about 16 hours, preferably 2 hours.
In reaction 1 of Scheme 22, the compound of formula LIII is converted to the corresponding compound of formula LIV by reacting LIII with a compound of the formula 
in the presence of sodium hydride and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 0xc2x0 C. to about 60xc2x0 C., preferably about 0xc2x0 C., for a time period between about 1 hours to about 16 hours, preferably about 4 hours.
In reaction 2 of Scheme 22, the compound of formula LIV is converted to the corresponding compound of formula LII by reacting LIV with trifluoroacetic acid neat for a time period between about 1 hours to about 16 hours, preferably about 4 hours.
In reaction 1 of Scheme 23, the compound of formula LVI is converted to the corresponding compound of formula LV by reacting LVI with a compound of the formula, R1CHO, in the presence of lithium diisopropylamide and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about xe2x88x9275xc2x0 C. to about xe2x88x9285xc2x0 C., preferably about xe2x88x9278xc2x0 C., for a time period between about 1 hour to about 6 hours, preferably about 1 hours.
In reaction 1 of Scheme 24, the compound of formula LVIII is converted to the corresponding compound of formula LVII by reacting LVIII with sodium borohydride in the presence of a polar protic solvent, such as methanol. The reaction is carried out at a temperature between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably about 0xc2x0 C., for a time period between about 0.5 hours to about 16 hours, preferably about 1 hours.
In reaction 1 of Scheme 25, the compound of formula LX is converted to the corresponding compound of formula LIX by reacting LX with a compound of the formula 
wherein X is chloro, bromo or iodo, in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide.
In reaction 1 of Scheme 26, the 2-fluoropyridine compound of formula LXII is converted to the corresponding compound of formula LXIII, by reacting LXII, with a compound of the formula 
in the presence of lithium diisopropylamide and a polar aprotic solvent, such as tetrahydrofuran.
In reaction 2 of Scheme 26, the compound of formula LXIII is converted to the corresponding compound of formula XLVIII, by reacting LXIII with a compound of the formula, HExe2x80x94(CH2)rxe2x80x94R5, in the presence of sodium hydride and a polar aprotic solvent, such as dimethylformamide.
In reaction 1 of Scheme 27, the compound of formula LXV is converted to the corresponding compound of formula LXVI, by reacting LXV with the Burgess reagent, CH3OOCNSO2NCH2CH3, in the presence of benzene.
In reaction 2 of Scheme 27, the compound of formula LXVI is converted to the corresponding compound of formula LXIV, by reacting LXVI with osminum tetroxide in the presence of tert-butanol, NMO and actone.
In reaction 1 of Scheme 28, the compound of formula LXVI is converted tot he corresponding compound of formula LXVII by hydrogenating LXVI in the presence of pallidium on carbon and ethanol.
The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to humans or animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is readily obtained. The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Pharmaceutically acceptable salts of amino groups include hydrochloride (preferred), hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. Cationic salts of the compounds of formula I are similarly prepared except through reaction of a carboxy group, such as where R6 is carboxy, with an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,Nxe2x80x2-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg). The active compounds can be administered in single or divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The ability of the compounds of formula I or the pharmaceutically acceptable salts thereof to inhibit PDE4 may be determined by the following assay.
Inhibition of Eosinophil Degranulation and Activation in Human Whole Blood
Human Blood Eosinophil Degranulation and Activation Measurement
Blood Collection and Compound Incubation
One hundred ml blood is obtained from normal volunteers in Vacutainer tube #6480 (14.3 USP units sodium heparin/ml blood). Heparinized blood is pooled in 50 ml conical centrifuge tubes at 22xc2x0 C. On ml blood is placed in a 12xc3x9775 mm siliconized glass tube containing 1 ul DMSO or 1 ul test compound in triplicate. After mixing, tubes are placed in a shaking water bath at 37xc2x0 C. for 15 minutes. One ul PGE1 in DMSO is added to all tubes to give a final concentration of 1 uM. After mixing, 100 ul PBS (negative control) or Sephadex G-15 beads in PBS (8.25-16.5 mg/ml final concentration) is added to tubes. After mixing, all tubes are incubated in a shaking water bath at 37xc2x0 C. for 1-2 hours.
Preparation of Plasma Samples
At the end of incubation, 20 ul of 15% EDTA in PBS is added to each assay tube. After mixing, the samples are centrifuged at 2,000 rpm (Sorvall 6000B centrifuge) at 22xc2x0 C. for 5 minutes.
EDN (or EPX) and LTE4 Measurements and the Effect of Compounds
All plasma samples are tested for EDN (eosinophil derived neurotoxin) and LTE4 (leukotriene E4) levels. Extensive studies suggest that Sephadex beads trigger cosinophil-mediated EDN and LTE4 release in human whole blood. The levels of EDN and LTE4 are determined by a RIA (Kabi Pharmacia Diagnostics) and EIA (Cayman Chemical), respectively. EDN and LTE4 levels are calculated by comparison to a standard curve using Microsoft Excel or other appropriate software. Percent of control EDN or LTE4 release is calculated by:
% Control EDN=[EDN(compound)xe2x88x92EDN(blank)]/[EDN(total)xe2x88x92EDN(blank)]
% Control LTE4=[LTE4(compound)xe2x88x92LTE4(blank)]/[LTE4(total)xe2x88x92LTE4(blank)]
where the blank is the level of EDN or LTE4 in the absence of Sephadex beads and the total is the level of EDN or LTE4 in the presence of Sephadex beads. An IC30 or IC50 value is defined as the concentration of a compound that inhibits specific EDN or LTE 4 release by 30 or 50%, respectively.
Inhibition of PDE4 Isozyme and Eosinophil Activation by (+) and (xe2x88x92) Enantiomers
To assess pharmacologically which PDE4 isozyme(s) is responsible for eosinophil activation, we have prepared enantiomers of PDE4 inhibitors and compare the inhibitory effect of these enantiomers on PDE activity and eosinophil activation. PDE4 activity is assessed by measuring hydrolysis of 1 uM cAMP by individual human recombinant PDE4 isozymes (PDE4A, 4B, 4C or 4D). Eosinophil activation is estimated by measuring Sephadex beads-induced release of eosinophil derived neurotoxin (EDN) and leukotriene E4 in human whole blood. Table 1 illustrates comparison of one example of (xe2x88x92) and (+) enantiomers on the activity of individual PDE4 isozymes and on the release of END and LTE4. (+) Enantiomer ((S)-(xe2x88x92)2(4-Fluoro-phenoxy)-N-[1-(4-methoxy-phenyl)-ethyl]nictinamide) is 22 times more potent in inhibiting PDE4D than (xe2x88x92) enantiomer ((R)2-(4-Fluoro-phenoxy)-N-[1-(4-metoxy-phenyl)-ethyl]-nicotinamide); however, they are approximately equipotent in inhibiting the other 3 isozymes, i.e., PDE4A, 4B and 4C. Importantly, the (+) enantiomer is 20-37 fold more effective against the EDN and LTE4 response. These results indicate that the differential effect of (+) and (xe2x88x92) enantiomers on PDE4D isozyme inhibition is identical to their effects on eosinophil EDN/LTE4 release, demonstrating that the PDE4D isozyme plays a key role in regulating eosinophil.
Including the aforementioned enantiomer, a total of 8 pairs of (+) and (xe2x88x92) enantiomers has been prepared. As illustrated in Table 2, the enantioselective effect of these compounds on PDE4D isozyme inhibition correlates significantly with those on the EDN and LTE4 response.
Inhibition of Pulmonary Eosinophilia
To evaluate these compounds for pulmonary efficacy, we have used a well-characterized monkey model of asthma (Turner et al., Am. J. Respir. Crit. Care Med. 149, 1153-1159, 1994). Exposure of atopic Macaca fascicularis monkeys to antigen causes a significant influx of inflammatory cells observed in the bronchoalveolar (BAL) fluid of these monkeys at 4-24 hours post antigen challenge. In this model, PDE4D isozyme selective compounds given subcutaneously significantly inhibit pulmonary eosinophil infiltration by 59-76% at 24 h post antigen challenge. These compounds, however, do not affect neutrophil or lymphocyte infiltration, demonstrating selective inhibition of the eosinophil response by these compounds.
Inhibition of TNF Production in Isolated Human-Monocytes
The ability of the compounds I or the pharmaceutically acceptable salts thereof to inhibit the production TNF and, consequently, demonstrate their effectiveness for treating disease involving the production of TNF is shown by the following In vitro assay:
Peripheral blood (100 mls) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by FICOLL/Hypaque and washed three times in incomplete HBSS. Cells are resuspended in a final concentration of 1xc3x97106 cells per ml in pre-warmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1xc3x97106 cells in 1.0 ml in 24-well plates. The cells are incubated at 37xc2x0 C. (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10ml) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10ml) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37xc2x0 C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (RandD Quantikine Kit). IC50 determinations are made for each compound based on linear regression analysis.
Mass spectra were determined by the GC-MS, AMPI, APCI or thermospray method.
All 1H NMR were taken on a 400 MHz instrument.
To a stirred solution of 4-fluorophenol (5.0 grams, 44.6 mmole) in dimethylformamide (40 ml) at room temperature was added 60% sodium hydride (3.6 grams, 89.0 mmole) portionwise and stirred for 30 minutes. 2-Chloronicotinic acid (7.1 grams, 45.0 mmole) was added portionwise and the mixture was refluxed for 3 hours. The solution was poured into 300 ml water and washed with diethyl ether. The aqueous was poured into 400 ml ice/water and acidified to pH 3 with acetic acid. The resulting precipitate was isolated by filtration to give an off-white solid (5.2 g). M.P. 180-182xc2x0 C.; MW 233.21; MS (m/e) 234 (M++1).
The compounds of Preparation 2-5 were prepared according to the procedure of Preparation 1 substituting the corresponding alcohol for 4-fluorophenol. The duration of reaction was between 1 and 24 hours.
MW 233.21; MS (m/e) 233 (M+).
MW 251.19; MS (m/e) 252 (M++1).
MW 249.65; MS (m/e) 250 (M++1).
MW 245.23; MS (m/e) 261 (M++18).
A solution of 2-(Pyridin-3-yloxy)-nicotinic acid ethyl ester (0.419 grams, 1.71 mmole) in ethanol (10 ml) and 1 N sodium hydroxide (4 ml) was refluxed for 4 hours. The mixture was poured into 100 ml water, acidified to pH 4 with 1 N hydrochloric acid and concentrated to dryness to give a solid (0.643 g). MW 216.21; MS (m/e) 217 (M++1).
The compounds of Preparations 7-22 were prepared according to the procedure of Preparation 6 substituting the corresponding ester for 2-(Pyridin-3-yloxy)-nicotinic acid ethyl ester. The duration of reaction was between 1 and 24 hours.
MW 250.65; MS (m/e) 251 (M++1).
M.P. 172-174xc2x0 C.; MW 260; MS (m/e) 261 (M++1) Anal. calcd. for C12H8N2O5; C, 55.39; H, 3.10; N, 10.77. Found: C, 54.71; H, 3.15; N, 10.65.
M.P. 220-222xc2x0 C.; MW 240.22; MS (m/e) 240 (M+).
MW 258.27; MS (m/e) 259 (M++1).
M.P. 273-275xc2x0 C.; MW 272.26; MS (m/e) 273 (M++1).
MW 254; MS (m/e) 255 (M++1).
M.P. 148-150xc2x0 C.; MW 283.05; Anal. calcd. for C13H8NO3F3: C, 55.10; H, 2.85; N, 4.95. Found: C, 54.71; H, 2.51; N, 4.83.
M.P. 185-188xc2x0 C.; MW 283.2; MS (m/e) 282 (M+xe2x88x921).
MW 261.302; MS (m/e) 262 (M++1).
MW 257.248; MS (m/e) 256 (M+xe2x88x921).
MW 299.208; MS (m/e) 300 (M++1).
MW 251.20; MS (m/e) 251 (M+). 
MW 251.20; MS (m/e) 252 (M++1).
M.P. 135-137xc2x0 C.; Anal. calcd. for C12H8NO3F: C, 61.79; H, 3.46; N, 6.01. Found: C, 61.51; H, 3.69; N, 5.78.
M.P. 162-164xc2x0 C.; 1H NMR (DMSO-d6) d 6.0 (2H, s), 6.5-8.3 (6H, m).
1H NMR (DMSO-d6) d 2.88 (3H, s), 2.93 (3H, s), 7.08 (4H, m), 7.42 (1H, m), 8.22 (2H, m).
A solution 2-Chloro-nicotinic acid ethyl ester (0.53 grams, 2.85 mmole), cesium carbonate (2.326 grams, 6.73 mmole) and Pyridin-3-ol (0.271 grams, 2.85 mmole) in dimethylformamide (20 ml) was heated to 65xc2x0 C. for 10 hours. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated to an oil (0.55 g). MW 244.25; MS (m/e) 244 (M+).
The compounds of Preparations 24-43 were prepared according to the procedure of Preparation 23 substituting the corresponding alcohol for Pyridin-3-ol. The duration of reaction was between 1 and 24 hours.
A solution of 2-Chloro-nicotinic acid ethyl ester (2.07 grams, 11.2 mmole), Cesium carbonate (7.27 grams, 22.3 mmole) and 5-chloro-3-pyridinol (1.45 grams, 11.2 mmole) in dry dimethylformamide (40 ml) was stirred at 90xc2x0 C. overnight. The suspension was cooled to room temperature, poured into water and extracted with diethyl ether. The combined organics were washed with water and brine, dried over MgSO4, and concentrated to a tan solid. Recrystalization from hexane gave a yellow solid (1.0 g). M.P. 65-69xc2x0 C.; Anal. calcd. for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C, 56.14; H, 4.04; N, 10.16.
MW 278.72; MS (m/e) 279 (M++1).
M.P. 70-72xc2x0 C.; MW 288.26; MS (m/e) 289 (M++1).
MW 268; 1H NMR (CDCl3) d 1.4 (3H, t), 4.39 (2H, q), 7.12-8.4 (7H, m).
MW 286.33; MS (m/e) 287 (M++1).
MW 268; MS (m/e) 268 (M+).
MW 300.32; MS (m/e) 301 (M++1).
MW 277.71; MS (m/e) 278 (M++1).
MW 282; 1H NMR (DMSO-d6) d 5.9 (1H, s), 6.4-8.4 (7H, m), 11.20 (1H, bs).
M.P. 46-48xc2x0 C.; MW 311; MS (m/e) 312 (M++1).
M.P. 100-102xc2x0 C.; MW 311.27; MS (m/e) 312 (M++1).
MW 289.356; MS (m/e) 290 (M++1).
MW 285.302; MS (m/e) 286 (M++1).
MW 327.262; MS (m/e) 328 (M++1).
MW 279.26; MS (m/e) 279 (M+).
MW 279.26; MS (m/e) 279 (M+).
MW 261.26 MS (m/e) 262 (M+).
MW 286.28 MS (m/e) 286 (M+).
MW 287, 1H NMR (DMSO-d6) d 1.2 (3H, t), 4.30 (2H, q), 6.0 (2H, s), 6.5-8.4 (6H, m).
1H NMR (CDCL3) d 1.36 (3H, t), 3.00 (3H, s), 3.07 (3H, s), 4.38 (2H, q), 7.06 (1H, m), 7.19 (1H, m), 7.24 (2H, m), 7.42 (1H, m), 8.24 (2H, dd).
MW 271.29 MS (m/e) 271 (M+).
To a solution 2-Chloro-nicotinic acid (12.5 g) in Ethanol (250 ml) was added thionyl chloride (5.77 ml) dropwise and refluxed for 1.5 hours. The mixture was concentrated to remove ethanol and diluted with 300 ml water. Solid sodium bicarbonate was added to adjust the solution to pH 8.0. This was extracted with ethyl acetate, washed with water, saturated bicarbonate solution, water and brine, dried over Na2SO4, filtered and concentrated to a yellow liquid (10.0 g). MW 185.61; MS (m/e) 185 (M+).
A solution of 2-(4-Cyano-phenoxy)-nicotinic acid methyl ester (0.200 grams, 0.787 mmole) in tetrahydrofuran (3 ml) and 1 M LiOH.H2O (1.97 ml) was stirred over night. The mixture was diluted with 25 ml water, acidified to pH 1 with 2 N hydrochloric acid and filtered to give a white solid (0.144 g). MW 240; 1H NMR (DMSO-d6) d 7.2 (3H, m), 7.90 (2H, m), 8.35 (2H, m), 13.5 (1H, bs).
The compounds of Preparations 46 was prepared according to the procedure of Preparation 45 substituting the corresponding ester for 2-(4-Cyano-phenoxy)-nicotinic acid methyl ester. The duration of reaction was between 1 and 24 hours.
MW 258.22 MS (m/e) 258, 257 (M+).
To a stirred solution of 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile (20.9 g, 0.13 mol.) in dry tetrahydrofuran (300 mL) at 0xc2x0 C. was added slowly dropwise 1.0M lithium aluminium hydride in tetrahydrofuran (388 mL, 0.39 mol.). The mixture was refluxed for 30 min. then cooled to 0xc2x0 C. and quenched with methanol (50 mL) added slowly dropwise. The mixture was concentrated in vacuo to half volume and diluted with chloroform (1200 mL) then washed with water (300 mL). The resulting suspension was filtered through Celite and the filtrate layers seperated. The organic extract was dried (MgSO4) and concentrated to give 16.2 g as a light yellow solid mp 64-6xc2x0 C. NMR (CDCl3): 7.45 (d, 2H), 7.26 (d, 2H), 3.83 (s, 2H), 1.57 (s, 6H). GC-MS (m/e, %): 164 (M+, 15), 150 (80), 132 (75), 106 (100).
A solution of 2-(4-Cyano-phenoxy)-nicotinic acid ethyl ester (0.90 grams, 2.44 mmole) in methanol (10 ml) and potassium carbonate (1.01 grams, 7.33 mmole) was refluxed for 20 minutes. The mixture was diluted with 100 ml water, acidified to pH 1 and filtered to give a solid (0.200 g). MW 254; MS (m/e) 254 (M+).
A solution of 2-(3-Chloro-phenoxy)-nicotinonitrile (7.81 grams, 33.9 mmole), 3% hydrogen peroxide (190 ml, 169 mmole) and 50% potassium hydroxide (380 ml, 3.39 mmole) in ethanol (100 ml) was stirred at 70xc2x0 C. over night. The mixture was concentrated to 250 ml and cooled to 0xc2x0 C. A solid was isolated by filtration, dissolved in ethyl acetate, dired over magnesium sulfate and concentrated to a white solid (6.51 g). M.P. 225-228xc2x0 C.; MW 248.67; MS (m/e) 250 (M++1).
A solution 2-Chloro-nicotinonitrile (5.0 grams, 36.1 mmole), cesium carbonate (23.5 grams, 72.2 mmole) and 3-chlorophenol (4.65 grams, 36.1 mmole) in dimethylformamide (100 ml) was heated to 80xc2x0 C. over night. The mixture was cooled and poured into 500 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a white solid (8.21 g). M.P. 88-90xc2x0 C.; Anal. calcd. for C12H7N2OCl: C, 62.49; H, 3.06; N, 12.15. Found: C, 62.43; H, 3.00; N, 12.13.
To a solution 2-(4-Fluoro-phenoxy)-3-nitro-pyridine (3.00 grams, 12.81 mmole) in ethyl acetate (100 ml) was added 10% palladium on carbon (0.600 g). This was shaken under 50 psi hydrogen for 1 hour. The catalyst was removed by filtration, and the solution was concentrated to give a white solid (2.49 g). M.P. 92-94xc2x0 C.; MW 204.20; MS (m/e) 204 (M+).
The compound of Preparation 10a was prepared according to the procedure of Preparation 10 substituting the corresponding nitro for 2-(4-Fluoro-phenoxy)-3-nitro-pyridine. The duration of reaction was between 1 and 24 hours.
MW 187; MS (m/e) 188 (M++1).
A solution 2-Chloro-3-nitro-pyridine (5.0 grams, 31.54 mmole), cesium carbonate (25.7 grams, 78.85 mmole) and 4-fluorophenol (3.6 grams, 34.69 mmole) in dimethylformamide (85 ml) was stirred for 2 hours at room temperature. The mixture was diluted with 250 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N NaOH, water and brine, dried over Na2SO4, filtered, and concentrated to a yellow solid (7.16 g). M.P. 87-89xc2x0 C.; MW 234.1; MS (m/e) 234 (M+).
The compound of Preparation 54 was prepared according to the procedure of Preparation 53 substituting the corresponding alcohol for 4-fluorophenol. The duration of reaction was between 1 and 24 hours.
MW 217.186; MS (m/e) 218 (M++1).
To a solution of methyl sulfoxide (0.23 ml, 3.3 mmole) and methylene chloride (10 ml) at xe2x88x9270xc2x0 C. was added oxalyl chloride (0.20 ml, 2.3 mmole) dropwise over 5 minutes and stirred for 1 hour. A solution of [2-(3-Chloro-phenoxy)-pyridin-3-yl]-methanol (0.39 grams, 1.7 mmole) in methylene chloride (10 ml) was added to the stirring mixture dropwise and stirred at xe2x88x9270xc2x0 C. for 1 hour. It was warmed to xe2x88x9235xc2x0 C. for 15 minutes and cooled down to xe2x88x9270xc2x0 C. at which time triethylamine (1.15 ml, 8.3 mmole) was added and the mixture was warmed to 0xc2x0 C. The mixture was diluted with 20 ml methylene chloride and washed with saturated sodium hydrogencarbonate and brine, dried over Na2SO4, filtered, and concentrated to an orange oil which was which was purified by chromatography on silica gel eluting with 1/3 ethyl acetate/hexane to give a yellow oil (0.180 g). MW 233.65; MS (m/e) 234 (M++1).
The compound of Preparation 56 was prepared according to the procedure of Preparation 55 substituting the corresponding alcohol for [2-(3-Chloro-phenoxy)-pyridin-3-yl]-methanol. The duration of reaction was between 1 and 24 hours.
MW 200.20; MS (m/e) 201 (M++1).
To a solution of 2-(3-Chloro-phenoxy)-nicotinic acid ethyl ester (0.5 g) and tetrahydrofuran (10 ml) at 0xc2x0 C. was added lithium aluminum hydride (0.4 g) in two portions and stirred for 30 minutes. The solution was allowed to warm to room temperature and stirred over night. The mixture was quenched with 1 N sodium hydroxide (0.5 ml) and diluted with water. The mixture was filtered through celite which was washed with ethyl acetate to extract the product. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil (0.39 g). MW 235.67; MS (m/e) 236 (M++1).
The compound of Preparation 58 was prepared according to the procedure of Preparation 57 substituting the corresponding ester for 2-(3-Chloro-phenoxy)-nicotinic acid ethyl ester. The duration of reaction was between 1 and 24 hours.
MW 202.21; MS (m/e) 203 (M++1).
To a solution 1-(3-Benzyloxy-phenyl)-1H-tetrazole (0.640 grams, 2.54 mmole) in ethanol (15 ml) was added 10% palladium on carbon (xcx9c0.100 g). This was stirred under hydrogen balloon over night. The catalyst was removed by filtration, and the solution was concentrated to give a white solid (0.364 g). M.P. 171-172xc2x0 C.; MW 162.12; MS (m/e) 163 (M++1).
To a solution of 3-Benzyloxy-phenylamine (1.50 grams, 7.53 mmole) and acetic acid (15 ml) at 70xc2x0 C. was added a solution of ethyl orthoformate (1.116 g, 7.53 mmole) in acetic acid (4 ml) and stirred for 4 hours. To the solution was added sodium azide (1.468 g, 22.6 mmole) in two portions and stirred for 20 hours at 70xc2x0 C. The mixture was extracted with ethyl acetate. The combined extracts were washed with saturated sodium hydrogencarbonate and brine, dried over Na2SO4, filtered, and concentrated. The product was purified via flash chromatography on silica using 3/1 hexane/ethyl acetate as eluent to give white crystals (0.650 g). M.P. 85-86xc2x0 C.; MW 252.25; MS (m/e) 252.8 (M+).
To a solution of acetic acid (200 ml) was cooled to xe2x88x9250xc2x0 C. was bubbled in HBr gas (20 g). m-Methoxyphenylmethylsulfide (20 grams, 130 mmole) and 48% aqueous HBr (10 ml) was added and the mixture was refluxed for 3 hours. The acetic acid was removed, and the oil was poured into 150 ml ice water. It was extracted with diethyl ether. The combined extracts were washed with 15% KOH, and the aqueous was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The combined extracts were dried over Na2SO4, filtered, and concentrated to an oil (11.5 g). MW 140.205; MS (m/e) 141 (M++1).
To a suspension of magnesium (7.2 grams, 296 mmole) and iodine (100 ml) in diethyl ether (250 ml) m-Bromoanisole (47.0 grams, 250 mmole) was added slowly with spontaneous refluxing. Methyl disulfide (16.0 grams, 160 mmole) was added and stirred for 1 hour. A solution of water (100 ml) and concentrated hydrochloric acid (30 ml) was added as the mixture was being cooled. The layers were separated and the aqueous was extracted with diethyl ether. The combined extracts were dried over MgSO4, filtered and concentrated to an oil which was purified by distilation (20 mm Hg) at 130-135xc2x0 C. (23.5 g).
To a solution of Pyridin-3-yl-methanol (0.59 grams, 5.4 mmole) in dimethylformamide (20 ml) sodium hydride (0.259 grams, 6.5 mmole) was added and stirred for 30 minutes. 2-Chloro-nicotinic acid ethyl ester (1.0 grams, 5.4 mmole) was added via syringe and stirred at room temperature over night. The mixture was diluted with water (150 ml) and extracted by diethyl ether and ethyl acetate. The combined extracts were washed with 1N NaOH, water and brine, dried over Na2SO4, filtered, and concentrated to an oil (1.3 g). MW 258.28; MS (m/e) 259 (M++1).
To a solution 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid benzyl ester (1.1 g) in methanol (15 ml) and ethyl acetate (15 ml) was added 10% palladium on carbon (0.2 g). This was shaken under 30 psi hydrogen for 2 hours. The catalyst was removed by filtration, and the solution was concentrated to give a solid which was triturated in methylene chloride/hexane to give a white solid (0.630 g). MW 273.26; MS (m/e) 274 (M++1).
Into a solution of 2-(3-Iodo-phenoxy)-nicotinic acid benzyl ester (1.7 grams, 3.94 mmole), dppf (0.131 grams, 0.24 mmole), Pd(OAc)2 (0.027 grams, 0.12 mmole) and triethylamine (0.797 grams, 7.9 mmole) in methanol (10 ml) was bubbled in carbon monoxide gas for 5 minutes. The mixture was heated to 60xc2x0 C. for 4 hours, poured into 200 ml water, and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% ethyl acetate/hexane as eluent (1.2 g). MW 363.39; MS (m/e) 364 (M++1).
A solution 2-Chloro-nicotinic acid benzyl ester (1.7 grams, 6.86 mmole), cesium carbonate (4.5 grams, 13.7 mmole) and 3-iodophenol (1.7 grams, 7.54 mmole) in dimethylformamide (20 ml) was stirred for 2 hours at 70-80xc2x0 C. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent (2.32 g). MW 431.24; MS (m/e) 432 (M++1).
A solution 2-Chloro-nicotinic acid (3.0 grams, 19.0 mmole), potassium carbonate (6.5 grams, 48.0 mmole) and benzyl bromide (2.8 ml, 24.0 mmole) in dimethylformamide (20 ml) was stirred at room temperature over night. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent (2.8 g). MW 247.69; MS (m/e) 247 (M+).
To a solution of 5-Chloro-furan-2-carbaldehyde oxime (1.38 grams, 9.5 mmole) in tetrahydrofuran (30 ml) was added dropwise 1.0 M lithium aluminum hydride (21 ml, 21 mmole) and refluxed for 30 minutes. The mixture was cooled to 0xc2x0 C. and quenched with 5 ml methanol and 5 ml saturated NH4Cl. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil (0.403 g). MW 131.57; MS (m/e) 130/131 (M+).
The compounds of Preparations 69-71 were prepared according to the procedure of Preparation 68 substituting the corresponding oxime for 5-Chloro-furan-2-carbaldehyde oxime. The duration of reaction was between 30 minutes and 24 hours.
MW 111.16; MS (m/e) 111 (M+).
MW 147.64.
MW 114.19.
To a solution 5-Chloro-furan-2-carbaldehyde (1.3 grams, 9.96 mmole) and NaOAc (1.8 grams, 21.9 mmole) in methylene chloride (30 ml) and water (30 ml) was added NH2OH.HCl (0.761 grams, 10.96 mmole) and stirred at room temperature over night. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid (1.38 g). MW 145.55; MS (m/e) 145/147 (M+).
The compounds of Preparations 73-75 were prepared according to the procedure of Preparation 72 substituting the corresponding aldehyde for 5-Chloro-furan-2-carbaldehyde. The duration of reaction was between 1 and 24 hours.
Mixture of E/Z isomers; MW 125.11; 1H NMR (CDCl3) d 2.32 (3H, s), 6.03 (1H, d), 6.12 (1H, d), 6.0 (2H, s), 6.48 (1H, d), 7.22 (1H, d), 7.42 (1H, s), 7.91 (1H, s).
MW 161.62.
MW 128.17.
A solution of 5-Nitro-furan-2-carbaldehyde (14.1 g) in concentrated hydrochloric acid (60 ml) was steam distilled until xcx9c150 ml liquid was collected. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO3, water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 20% ethyl acetate/hexane as eluent to give a white solid (1.3 g). MW 130.53; MS (m/e) 129/131 (M++1 ).
A solution of 2-Bromomethyl-1,3,5-trifluoro-benzene (2.0 g, 8.9 mmole) and HMTA (3.1 grams, 22.2 mmole) in chloroform (35 ml) was refluxed for 18 hours. A resulting precipitate was isolated by filtration and taken up into methanol (10 ml), water (5 ml) and concentrated hydrochloric acid (5 ml) and refluxed for 4 hours. The mixture was poured into 200 ml water and washed with diethyl ether. The aqueous was basified with 5 N sodium hydroxide and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which solidified on standing (1.32 g). MW 161.14; MS (m/e) 145 (M+xe2x88x92NH2).
The compounds of Preparation 78-79 were prepared according to the procedure of Preparation 77 substituting the corresponding halide for 2-Bromomethyl-1,3,5-trifluoro-benzene. The duration of reaction was between 1 and 24 hours.
MW 147.64; MS (m/e) 147 (M+).
MW 182.08; MS (m/e) 181-186 (M+).
To a solution 3,4-Dichloro-thiophene-2-carboxylic acid amide (0.640 grams, 3.3 mmole) in tetrahydrofuran (20 ml) was added dropwise 1.0 M lithium aluminum hydride (7 ml, 7 mmole) and stirred at room temperature for 30 minutes. The mixture was cooled to 0xc2x0 C. and quenched with 3 ml methanol and 5 ml saturated NH4Cl added dropwise. The mixture was poured into 100 ml water and extracted with diethyl ether. This was then filtered through celite. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give an oil (0.335 g). MW 182.08; 1H NMR (CDCl3) d 4.01 (2H, s), 7.09 (1H, s).
The compounds of Preparations 81-88 were prepared according to the procedure of Preparation 80 substituting the corresponding amide for 3,4-Dichloro-thiophene-2-carboxylic acid amide. The duration of reaction was between 30 minutes and 24 hours.
MW 147.64; 1H NMR (CDCl3) d 3.99 (2H, s), 6.86 (1H, d), 7.16 (1H, d).
MW 163.26; MS (m/e) 163 (M+).
MW 181.20; MS (m/e) 181 (M+).
MW 171.29.
MW 205.73; 1H NMR (CDCl3) d 1.69 (6H, s), 3.92 (2H, s), 6.69 (1H, s).
MW 155.22; 1H NMR (CDCl3) d 1.56 (6H, s), 3.77 (2H, s), 6.02 (1H, d), 6.06 (1H, d).
MW 199.35; 1H NMR (CDCl3) d 0.85 (6H, t), 1.82 (4H, q), 3.97 (2H, s), 6.67 (1H, d), 6.73 (1H, d).
MW 205.73; 1H NMR (CDCl3) d 1.60 (6H, s), 3.92 (2H, s), 6.71 (1H, s).
To a stirred suspension of 3,4-Dichloro-thiophene-2-carboxylic acid (1.0 grams, 5.08 mmole) in methylene chloride (20 ml) and dimethylformamide (0.2 ml) was added thionyl chloride (1.9 ml, 25.3 mmole) and refluxed for 3 hours. The mixture was concentrated to give an oil. The oil was taken up in methylene chloride (15 ml), cooled to 0xc2x0 C. and NH3 gas was bubbled in for 5 minutes and stirred for 20 minutes. The mixture was diluted with methylene chloride (150 ml) washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid which was purified via flash chromatography on silica using 2.5% methanol/methylene chloride as eluent to give a solid which was triturated in methylene chloride to give a white solid (0.475 g). MW 196.06; MS (m/e) 195/197 (M+).
The compounds of Preparations 90-92 were prepared according to the procedure of Preparation 89 substituting the corresponding acid for 3,4-Dichloro-thiophene-2-carboxylic acid. The duration of reaction was between 1 and 24 hours.
MW 161; MS (m/e) 161/163 (M+).
MW 195.18; MS (m/e) 196 (M++1).
MW 169.18; 1H NMR (DMSO-d6) d 1.40 (6H, s), 5.20 (1H, d), 6.26 (1H, d), 6.93 (1H, d), 7.24 (1H, bs), 7.58 (1H, bs).
To a solution 4-(2,2,2-Trifluoro-ethoxy)-benzonitrile (0.5 grams, 2.48 mmole) in tetrahydrofuran (10 ml) was added 1.0 M lithium aluminum hydride (6.2 ml, 6.2 mmole) and refluxed for 40 minutes. The mixture was cooled to 0xc2x0 C. and quenched with 5 ml methanol added dropwise and diluted with saturated NH4Cl (50 ml). The mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give an oil (0.230 g ). MW 205.18; MS (m/e) 206(M++1).
The compounds of Preparations 94-106 were prepared according to the procedure of Preparation 93 substituting the corresponding nitrile for 4-(2,2,2-Trifluoro-ethoxy)-benzonitrile. The duration of reaction was between 30 minutes and 24 hours.
MW 173.18; 1H NMR (CDCl3) d 3.85 (2H, s), 6.48 (1H, t), 7.09 (2H, m), 7.30 (2H, m).
MW 146.21; MS (m/e) 146 (M+).
1H-NMR (CDCl3): d 6.47 (m, 1H), 6.26 (m, 1H), 3.91 (m, 2H). GC-MS (m/e, %) 131 (M+, 100).
MW 235; MS (m/e) 235 (M+).
MW 143.14.
MW 199.70; MS (m/e) 199/201 (M+).
MW 199.70; MS (m/e) 198/200 (M++1).
1H NMR (CDCl3) d 1.54 (6H, s), 3.89 (2H, s), 7.31 (2H, m), 7.48 (1H, d).
MW 177.27; MS (m/e, %) 177 (M+, 3), 160 (45),148 (100).
MW 161.22; MS (m/e, %) 160(M+, 15), 115 (20), 106 (100).
MW 193.248; MS (m/e) 178 (M+xe2x88x92NH3).
MW 171.241; MS (m/e) 172 (M++1).
MW 151.21; MS (m/e) 152 (M++1).
1H NMR (CDCl3) d 1.54 (6H, s), 3.89 (2H, s), 7.30 (2H, m), 7.48 (1H, s).
To a stirred solution of 4-cyanoacetophenone (49.5 g, 0.34 mol.) in dry tetrahydrofuran (400 mL) at xe2x88x9278xc2x0 C. was added dropwise 3.0 M methylmagnesium chloride (150 mL, 0.45 mol.). The mixture was allowed to slowly warm to 0xc2x0 C. over 3.5 h then quenched with methanol (80 mL) added dropwise. The mixture was poured into water (1000 mL) and acidified to pHxcx9c3 with oxalic acid then extracted with ethyl acetate (2xc3x97500 mL). The organic extracts were combined and washed with water (2xc3x97100 mL), brine (100 mL), dried (MgSO4) then concentrated to give a white residue. Flash Chromatography on Silica Gel eluting with 20% ethyl acetate/hexanes yielded 13.5 g clear oil which solidified upon standing mp 45-7xc2x0 C.
To a solution 4-cyanophenol (5.0 grams, 42.0 mmole) in HMPT (40 ml) was added sodium hydride (1.68 grams, 42.0 mmole) and stirred for 15 minutes at room temperature. Via syringe 2,2,2-trifluoroethyl methane sulphonate (8.98 grams, 50.4 mmole) was added and the mixture was stirred at 140xc2x0 C. over night. The mixture was cooled to room temperature, diluted with 300 ml ice water and 50 ml 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water, 1N sodium hydroxide and brine, dried over Na2SO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% diethyl ether/hexane as eluent to give an oil (2.68 g). Synthesis 727 (1980).
A solution of 1-(5-Chloro-thiophen-2-yl)-ethanone (5.0 grams, 31.0 mmole) in formamide (6 ml, 150.0 mmole) was stirred at 160xc2x0 C. for 18 hours. The mixture was poured into 200 ml and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 20% ethyl acetate/hexane as eluent to give an oil. The oil was taken up in 26 ml 6 N NaOH, 20 ml methanol and 5 ml tetrahydrofuran and refluxed for three hours. The mixture was poured into 200 ml and extracted with diethyl ether. The combined extracts were concentrated to give a dark oil (2.3 g). MW 161.67; MS (m/e) 161 (M+).
The compounds of Preparation 110-111 were prepared according to the procedure of Preparation 109 substituting the corresponding aldehyde or ketone for 1-(5-Chloro-thiophen-2-yl)-ethanone. The duration of reaction was between 30 minutes and 24 hours.
MW 127.23; MS (m/e) 127 (M+).
MW 127.23; MS (m/e) 127 (M+).
To a solution of 2-Oxo-2,3-dihydro-1H-indole-5-carbonitrile (1.3 g) in methanol (30 ml) was added 10% PtO2 (0.200 g). This was shaken under 44 psi hydrogen over night. The catalyst was removed by filtration, and the mixture was dried over Na2SO4. The solution was concentrated to give a yellow solid, (1.1 g). MW 162; MS (m/e) 162 (M+).
A solution of 3,3-Dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (10.5 grams, 33.3 mmole) and Zn dust (22.0 grams, 338.5 mmole) in acetic acid (250 ml) was stirred at room temperature for 45 minutes. The mixture was filtered through celite and concentrated to dryness. The resulting oil was diluted with 300 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide and brine, dried over MgSO4, filtered, and concentrated to give a white solid (1.9 g). MW 158.
To a solution of 1H-Indole-5-carbonitrile (5.0 grams, 35.2 mmole) in t-Butanol (300 ml) was added pyridinium bromide perbromide (37.5 grams, 105.6 mmole) over 10 minutes and stirred at room temperature for 2 hours. The mixture was concentrated to an orange oil. The resulting oil was diluted with 500 ml water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a yellow solid (10.37 g). MW 315.95; MS (m/e) 316 (M++1).
A solution of 6-Nitro-3H-benzooxazol-2-one (8.4 grams, 46.0 mmole) and Tin (16.0 g) in concentrated hydrochloric acid (100 ml) was stirred at 60xc2x0 C. for 2 hours. The mixture was diluted with water, basified to pH 12 and extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated to give an orange solid (2.45 g). MW 150; MS (m/e) 151 (M++1).
A solution of 3H-Benzooxazol-2-one (10.0 g) in concentrated HNO3 (100 ml) was stirred at 40xc2x0 C. A precipitate formed and the reaction temperature rose. It was cooled below 50 xc2x0 C. in an ice bath. The mixture was diluted with ice water, and the precipitate was isolated by filtration. The product was washed with water to give a white solid. (8.4 g). M.P. 239-241.
A solution of 5-Cyano-1H-indole-2carboxylic acid ethyl ester (1.8 grams, 8.4 mmole) and Bu4N+BH3xe2x88x92 in methylene chloride (80 ml) was refluxed for 4 hours. The mixture was concentrated to a brown oil which was dissolved in 10% hydrochloric acid (50 ml) and refluxed for 1 hour. The mixture was extracted with ethyl acetate (discarded) and the pH was neutralized. The aqueous was extracted with ethyl acetate. The combined extracts were dried over Na2SO4, filtered, and concentrated to give a solid. (0.920 g). MW 218.258; MS (m/e) 218 (M+).
A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde oxime (3.0 grams, 8.4 mmole) in acetic anhydride (6 ml) was was refluxed for 2 hours. The mixture was cooled to 0xc2x0 C. and saturated sodium hydrogencarbonate was added. The mixture was extracted with methylene chloride. The combined extracts were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to give a solid. This was dissolved in diethyl ether and extracted with 1 N sodium hydroxide which was then acidified to pH 1 and extracted with ethyl acetate. The extract was dried and concentrated to a yellow solid which was recrystalized from ethyl acetate/hexane to give white crystals (1.05 g). MW 231; MS (m/e) 249 (M++NH4+).
A solution of 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde (10.0 grams, 42.67 mmole), NH2OH.HCl (14.83 grams, 213.3 mmole) and 40% KOH (80 ml) in methanol (100 ml) was stirred at room temperature over the weekend. The mixture was concentrated to remove methanol. The aqueous phase was acidified and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a yellow solid. (8.9 g). M.P. 122-124xc2x0 C.; MW 249; MS (m/e) 249 (M+).
The compound of Preparation 120 was prepared according to the procedure of Preparation 119 substituting the corresponding aldehyde for 3,5-Di-tert-butyl-4-hydroxy-benzaldehyde. The duration of reaction was between 1 and 48 hours.
MW 165; MS (m/e) 166 (M++1).
A solution of 4-Hydroxy-3,5-dimethyl-benzaldehyde oxime (1.0 grams, 6.06 mmole) in acetic acid (30 ml) and Zn dust (4.0 grams, 61.2 mmole) was stirred at xcx9c60xc2x0 C. for 2 hours. The mixture was filtered through celite, basified by aqueous ammonium hydroxide and extracted with chloroform. The combined extracts were dried over MgSO4, filtered, and concentrated to give a foam (0.90 g). MW 151; MS (m/e) 151 (M+).
To a vigrouosly stirred mixture of AD-mix (1.4 g) in water (5 ml) and t-butanol (5 ml) at 0xc2x0 C. was added 1-Chloro-2-vinyl-benzene (0.140 grams, 1.0 mmole) and stirred at 0xc2x0 C. for 2 hours. To the mixture sodium sulfite (1.5 g) was added and allowed to warm to room temperature for 1 hour. The mixture was extracted with methylene chloride. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give a colorless oil (0.190 g). MW 172.61; MS (m/e) 190 (M++18).
A solution of 4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid methyl ester (2.4 g) in condensed NH3 (20 ml) and methanol (10 ml) was stirred at room temperature in a sealed tube for 3 days. The solvent was evaporated to give a solid which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give a tan solid. This was triturated in diethyl ether to give a white solid (1.6 g). MW 219.71; MS (m/e) 237 (M++18) 220 (M++1) .
The compounds of Preparations 124-125 were prepared according to the procedure of Preparation 123 substituting the corresponding ester for 4-Chloro-5-(1-hydroxy-1-methyl-ethyl)-thiophene-2-carboxylic acid methyl ester. The duration of reaction was between 1 and 72 hours.
MW 213.33; MS (m/e) 213 (M+).
MW 186.63; 1H NMR (CDCl3) d 1.63 (6H, s), 6.85 (1H, s).
To a solution of diisopropyl amine (6 ml, 38.9 mmole) in tetrahydrofuran (15 ml) at 0xc2x0 C. was added dropwise 2.5 M nBuLi (16 ml) and stirred at 0xc2x0 C. for 10 minutes. The mixture was cooled to xe2x88x9278xc2x0 C. and 4-Chloro-thiophene-2-carboxylic acid (3.0 grams, 18.5 mmole) in tetrahydrofuran (15 ml) was added dropwise and stirred for 20 minutes then acetone (1.6 mL, 22.2 mmol.) was added and the mixture was allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water and extracted with diethyl ether. The aqueous was acidified to pH 4 with oxalic acid and extracted with methylene chloride. The combined extracts were washed with water dried over MgSO4, filtered, and concentrated to a solid. This was taken up in diethyl ether (100 ml) and treated with CH2N2 at 0xc2x0 C. The reaction was quenched with acetic acid, diluted with diethyl ether (300 ml) and washed with saturated NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/hexane as eluent to give a solid (2.42 g). MW 234.72; MS (m/e) 234/236 (M++1).
The compounds of Preparations 127-129 were prepared according to the procedure of Preparation 126 substituting the corresponding acid for 4-Chloro-thiophene-2-carboxylic acid. The duration of reaction was between 1 and 24 hours.
MW 184.21; MS (m/e) 184 (M+).
MW 228.34; MS (m/e) 228 (M+).
MW 234.70; 1H NMR (CDCl3) d 1.62 (6H, s), 3.85 (3H, s), 6.84 (1H, s).
A solution of 5-Amino-pentanoic acid (1.06 grams, 9.0 mmole) and thionyl chloride (20.0 ml) was stirred at room temperature for 2 hours. The solvent was evaporated and ethanol (26.5 ml) was added and gently warmed. After 2 hours the solution was concentrated to give a yellow solid (0.580 g). MW 145.22; MS (m/e) 146 (M++1).
The compound of Preparations 131 was prepared according to the procedure of Preparation 130 substituting the corresponding acid for 5-Amino-pentanoic acid. The duration of reaction was between 1 and 24 hours.
MW 185.28; MS (m/e) 186 (M++1).
To a solution of diisopropylamine (7.6 ml, 54.0 mmole) in tetrahydrofuran (20 ml) at 0xc2x0 C. was added 2.5 M nButyl lithium (22 ml, 54.0 mmole). The mixture was cooled to xe2x88x9278xc2x0 C. and a solution of Furan-2-carboxylic acid (3.0 grams, 27.0 mmole) in tetrahydrofuran (20 ml) was added dropwise and stirred for 20 minutes and acetone (2.4 ml, 32.0 mmole) was added. The mixture was stirred at xe2x88x9278xc2x0 C. for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water, acidified with oxalic acid to pH 2 and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give a solid. (0.580 g). MW 145.22; MS (m/e) 146 (M++1).
To a solution of 3-Chloro-4-cyano-benzoic acid methyl ester (2.0 grams, 10.0 mmole) in tetrahydrofuran (30 ml) at xe2x88x9240xc2x0 C. was added 3.0 M CH3MgCl (8 ml, 22.0 mmole) dropwise. The mixture was allowed to warm to room temperature over one hour. The reaction was quenched with 10 ml methanol added dropwise, poured into 200 ml water, acidified with oxalic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil. (2.1 g). MW 195.60; MS (m/e) 195/197 (M30).
The compound of Preparation 134 was prepared according to the procedure of Preparation 133 substituting the corresponding ester for 3-Chloro-4-cyano-benzoic acid methyl ester. The duration of reaction was between 1 and 24 hours.
MW 195.60; MS (m/e) 195/197 (M+).
A solution of 4-Bromo-2-chloro-benzoic acid methyl ester (3.1 grams, 12.0 mmole), Zn(CN)2 0.875 grams, 7.0 mmole) and PH(PPh3)4 (0.555 grams, 48.0 mmole) in dimethylformamide (30 ml) was heated to 90xc2x0 C. over night. The reaction was poured into 200 ml saturated sodium hydrogencarbonate and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/hexane as eluent to give a white solid. (2.1 g). MW 195.61; MS (m/e) 195/197 (M+).
The compounds of Preparation 136 was prepared according to the procedure of Preparation 135 substituting 3-chloro-4trifluoromethane sulfonyloxy-benzoic acid methyl ester for 4-Bromo-2-chloro-benzoic acid methyl ester. The duration of reaction was between 1 and 24 hours.
MW 199.13; MS (m/e) 199 (M+).
Prepared in an analogous manner to that of Preparation 253 from (S)-(+)-(trans-4-(1-Hydroxy-ethyl-)cyclohexylmethyl)carbamic acid benzyl ester which was obtained from (trans-4-Acetyl-cyclohexylmethyl)-carbamic acid benzyl ester using (R)-2-Methyl-CBS-oxazaborolidine monohydrate in an analogous fashion as that of Preparation 254.
To a solution of 4Trifluoroacetyl-benzonitrile (0.840 grams, 4.49 mmole) in tetrahydrofuran (20 ml) was added 1.0 M lithium aluminum hydride (15 ml, 14.8 mmole) dropwise, stirred at 0xc2x0 C. for 10 minutes and refluxed for 30 minutes. The mixture was cooled to 0xc2x0 C., quenched with 10 ml methanol added dropwise and diluted with chloroform (300 ml). The mixture was washed with water, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give a solid (0.350 g). MW 205.20; MS (m/e) 205(M+).
The compound of Preparation 139 was prepared according to the procedure of preparation 138 substituting the corresponding nitrile for 4-Trifluoroacetyl-benzonitrile. The duration of reaction was between 30 minutes and 24 hours.
MW 179.24; MS (m/e) 179 (M+).
A solution of Trifluoro-methanesulfonic acid 4-oxo-chroman-7-yl ester (2.0 grams, 6.80 mmole), Zn(CN)2 (0.476 grams, 4.1 mmole) and Pd(PPh3)4 (0.314 grams, 0.27 mmole) in dimethylformamide (20 ml) was heated to 80xc2x0 C. over night. The reaction was poured into 200 ml 1/1 saturated NaHCO3/water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid. (1.02 g). MW 173.20; MS (m/e) 173 (M+).
The compound of Preparation 141 was prepared according to the procedure of Preparation 140 substituting the corresponding triflate for Trifluoro-methanesulfonic acid 4-oxo-chroman-7-yl ester. The duration of reaction was between 30 minutes and 24 hours.
MW 195.61 MS (m/e, %) 195(M+, 25), 164 (100).
To a solution of 4-Bromo-benzonitrile (2.0 grams, 10.99 mmole) in tetrahydrofuran (30 ml) at xe2x88x92100xc2x0 C. was added dropwise 2.5 M nBuLi (4.8 ml) and stirred at xe2x88x92100xc2x0 C. for 15 minutes. Cyclobutanone (0.965 grams, 13.19 mmole) was added dropwise and stirred for 10 minutes and allowed to warm to room temperature over 1 hour. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 40% ethyl acetate/hexane as eluent to give a clear oil (1.5 g). MW 173.23; MS (m/e) 173 (M+).
To a solution of 4-Formyl-benzonitrile (1.5 grams, 10.0 mmole) in tetrahydrofuran (20 ml) at xe2x88x9278xc2x0 C. was added 0.5 M ethynyl magnesium bromide (26 ml, 13.0 mmole) dropwise. The mixture was stirred at xe2x88x9278xc2x0 C. for 30 minutes and allowed to warm to room temperature over one hour. The reaction was cooled to 0xc2x0 C., quenched with 10 ml methanol, poured into 200 ml water, acidified with oxalic acid and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid. (1.6 g). MW 157.18; MS (m/e) 157 (M+).
To a solution of 3-Chloro-4-hydroxy-benzoic acid methyl ester (15.0 grams, 80.0 mmole), triethylamine (20.2 grams, 200 mmole) and DMAP (1.0 grams, 8.0 mmole) in methylene chloride (200 ml) at 0xc2x0 C. was added triflic anhydride (17 ml, 100.0 mmole) dropwise. The mixture was allowed to warm to room temperature and stirred for four hours. It was diluted with methylene chloride (600 ml), washed with water, dried over MgSO4, filtered, and concentrated to give an oil which was purified via flash chromatography on silica using 20% ethyl acetate/hexane as eluent to give an oil. (20.9 g). MW 322.05; MS (m/e) 322 (M+).
A mixture of 6.34 9 (52.5 mmol) of 4-fluorobenzonitrile, 3.00 g (52.5 mmol) of azetidine, 7.26 g (52.5 mmol) of K2CO3, and 50 mL of methyl sulfoxide was heated to 60xc2x0 C. for 16 h. The cooled mixture was diluted with 200 mL of water and extracted with EtOAc (2xc3x97150 mL). The combined organic extracts were washed with water (1xc3x97150 mL), brine (1xc3x97150 mL), dried (Na2SO4), and evaporated to 5.65 g of a white solid. Trituration in hexane gave 3.85 g (56% yield) of the title compound as a white solid, mp 98-99xc2x0 C. 1H NMR (CDCl3) d 2.39-2.45 (2H, m), 3.96 (4H, t, J=7 Hz), 6.32 (2H, d, J=9 Hz), 7.41 (2H, d, J=9 Hz); AMPI MS (m/e) 159 (M++1).
The compounds of Preparations 146-151 were prepared according to the procedure of Preparation 145 substituting the corresponding amine for azetidine. Temperatures ranged from 90-115xc2x0 C. For preparations of the amines used in Preparations 54a and 54f, see: Rosenberg, S. H. et al. J. Med. Chem., 1993, 36, 460 and Goldberg, S. D.; J. Am. Chem. Soc., 1939, 61, 3526, respectively. Temperatures ranged from 90-115xc2x0 C. Mass spectra were determined by the AMPI method.
M.P. 75-78xc2x0 C.; 1H NMR (CDCl3) d 2.37 (1H, d, J=7 Hz), 4.04 (4H, ABX pattern, JAB=8 Hz, JAX=7 Hz, JBX=4 Hz), 4.77-4.88 (1H, m), 6.36 (2H, d, J=8 Hz), 7.41 (2H, d, J=8 Hz); MS (m/e) 175 (M++1).
M.P. 75-76xc2x0 C.; 1H NMR (CDCl3) d 2.01-2.04 (4H, m), 3.29-3.33 (4H, m), 6.49 (2H, d, J=8 Hz), 7.43 (2H, d, J=8 Hz); MS (m/e) 173 (M++1).
1H NMR (CDCl3) d 1.63-1.69 (6H, m), 3.29-3.33 (4H, m), 6.83 (2H, d, J=9 Hz), 7.44 (2H, d, J=9 Hz).
M.P. 81-82xc2x0 C.; 1H NMR (CDCl3) d 3.25-3.27 (4H, m), 3.82-3.85 (4H, m), 6.85 (2H, d, J=9 Hz), 7.49 (2H, d, J=9 Hz); MS (m/e) 189 (M++1).
M.P. 133-134xc2x0 C.; Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 69.21; H, 6.64; N, 11.61.
1H NMR (CDCl3) d 1.27 (6H, s), 1.56 (1H, s), 3.09 (3H, s), 3.39 (2H, s),6.79 (2H, d, J=9 Hz), 7.44 (2H, d, J=9 Hz); MS (m/e) 205 (M++1).
To a solution of 2.00 g (12.6 mmol) of the compond of Preparation 145 in 50 mL of tetrahydrofuran was added portionwise 479 mg (12.6 mmol) of lithium aluminum hydride. When the addition was complete, the mixture was stirred for 4 h at rt. The mixture was quenched by the sequential addition of 2 mL of water, 2 mL of aqueous 15% sodium hydroxide solution, and 6 mL of water. The precipitate was removed by filtration washing well with THF. The filtrate was dried (Na2SO4) and evaporated to a yellow solid, which was purified by flash chromatography using EtOAc followed by 76:20:4 CHCl3:MeOH: conc. NH3 (aq.) as eluants to give 1.22 g of a semisolid. Trituration in hexane afforded 815 mg (40% yield) of the title compound as a yellow solid, mp 58-60xc2x0 C. 1H NMR (CDCl3) d 1.60 (2H, s), 2.29-2.37 (2H, m), 3.73 (2H, s), 3.83 (4H, t, J=7 Hz), 6.42 (2H, d, J=8 Hz), 7.13 (2H, d, J=8 Hz).
The compounds of Preparations 153-158 were prepared according to the procedure of Preparation 55 substituting the appropriate substrate for the compound of Preparation 145. Mass spectra were determined by the AMPI method.
1H NMR (CDCl3) d 2.65 (3H, br s), 3.54-3.61 (2H, m), 3.70 (2H, s), 4.08-4.12 (2H, m), 4.68-4.79 (1H, m), 6.40 (2H, d, J=8 Hz), 7.09 (2H, d, J=8 Hz); MS (m/e) 162 (M++2xe2x88x9218 (H2O)).
M.P.108-110xc2x0 C.; 1H NMR (CDCl3) d 1.87 (2H, s), 1.96-1.99 (4H, m), 3.25 (4H, t, J=7 Hz), 3.73 (2H, s), 6.52 (2H, d, J=8 Hz), 7.15 (2H, d, J=8 Hz); MS (m/e) 160 (M++2xe2x88x9218)).
M.P.108-110xc2x0 C.; 1H NMR (CDCl3) d 1.52-1.58 (2H, m), 1.68-1.72 (4H, m), 1.80 (2H, s), 3.08-3.12(4H, m), 3.76(2H, s), 6.89(2H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz).
M.P.53-54xc2x0 C; 1H NMR (CDCl3) d 1.51 (2H, s), 3.11-3.14 (4H, m), 3.78 (2H, s), 3.83-3.86(4H, m), 6.88(2H, d, J=8 Hz), 7.22(2H, d, J=8 Hz).
M.P.107-110xc2x0 C.; 1H NMR (CDCl3) d 1.81 (4H, t, J=6 Hz), 3.07 (2H, br s), 3.29 (4H, t, J=6 Hz), 3.80 (2H, s), 3.98 (4H, s), 6.89 (2H, d, J=8 Hz), 7.22 (2H, d, J=8 Hz).
1H NMR (CDCl3) d 1.26 (6H, s), 1.97 (3H, br s), 2.97 (3H, s), 3.25 (2H, s), 3.78 (2 H, s),6.80 (2H, d, J=9 Hz), 7.20(2H, d, J=9 Hz).
A mixture of 20.0 g (89.6 mmol) of 2-(4-fluorophenoxy)-3-pyridinecarboxylic acid (for preparation, see: Villani, F. J. et al. J. Med. Chem., 1975, 18,3), 300 mL of methanol, and 5.5 mL of concentrated sulfuric acid was heated to reflux for 2 h. The cooled mixture was poured onto 500 mL of ice cold saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was filtered, washed with water, and dreid under vacuum to give 12.9 g (64% yield) of the title compound as a white solid, mp 97-99xc2x0 C. Anal. Calcd for C13H10NO3F: C, 63.16; H, 4.08; N, 5.67. Found: C, 62.80; H, 4.08; N, 5.50.
A solution of 10.00 g (40.45 mmol) of the compound of Preparation 56 in 200 mL of anhydrous toluene was cooled to xe2x88x9278xc2x0 C. and treated dropwise with 84.95 mL (84.95 mmol) of a 1 M solution of diisobutylaluminum hydride in CH2Cl2. When the addition was complete, 200 mL of water was added followed by 200 mL of EtOAc, and the mixture was allowed to warm to rt. Following adjustment of the aqueous layer to pH 4 with aqueous 1N hydrochloric acid solution, the organic layer was separated and combined with a 200 mL backwash of the aqueous layer. The organic extracts were washed with saturated aqueous sodium hydrogencarbonate solution, brine, dried (Na2SO4), and evaporated to give 9.00 g (90% yield) of the title compound as an off-white solid, mp 70-72xc2x0 C. 1H NMR (CDCl3) d 1.59 (1H, s), 4.84 (2H, d, J=6 Hz), 6.99-7.13 (5H, m), 7.76-7.80 (1H, m), 8.07 (1H, dd, J=2.5 Hz).
A mixture of 932 mg (4.25 mmol) of the compound of Preparation 57, 2.00 g (23.0 mmol) of manganese dioxide, and 30 mL of benzene was heated to reflux for 3 h with water separation. The cooled mixture was filtered, evaporated to a white solid, and purified by flash chromatography using 15% EtOAc-hexane as eluant to provide 735 mg (80% yield) of the title compound as a white solid, mp 61-62 xc2x0 C. 1H NMR (CDCl3) d 7.08-7.21 (5H, m), 8.19-8.32 (2 H, m), 10.55 (1H, s).
At xe2x88x9278 xc2x0 C., 115.3 mL (115.3 mmol) of a solution of 1 M lithium bis(trimethylsilyl)amide, in tetrahydrofuran was treated dropwise with 15.43 mL (13.39 grams, 115.3 mmol) of t-butyl acetate. When the addition was complete, the mixture was stirred for 15 min and then treated with a solution of 9.500 g (38.43 mmol) of the compound of Preparation 56 in 50 mL of THF. When the addition was complete, the mixture was stirred for 15 min and then quenched by the addition of 230 mL of aqueous 1N hydrochloric acid solution. After warming to rt, the organic layer was extracted with ether (2xc3x97500 mL) and the combined organic layers were washed with saturated aqueous sodium hydrogencarbonate solution (1xc3x97100 mL), brine (1xc3x97200 mL.), dried (Na2SO4), and evaporated to 13.8 g of a pale yellow oil. Purification by flash chromatography using 15 to 85% ether-hexane as eluant gave 11.7 g of a semi-solid, which was triurated with hexane to give 6.124 g (48% yield) of the title compound as a white solid, mp 87-89xc2x0 C. 1H NMR (CDCl3) d 1.54 (9H, s), 6.12 (1H, s), 7.01-7.16 (5H, m), 8.14 (1H, dd, J=2.5 Hz), 8.30 (1H, dd, J=2.8 Hz), 12.99 (1H, s). The NMR also showed the presence of  less than 10% of the keto tautomer. After standing for 12 days, the concentrated mother liquor crystallized and was triurated in hexane to give an additional 2.21 g (17% yield) of the title compound.
The sodium hydride obtained after washing 28.9 mg (0.604 mmol) of 50% sodium hydride dispersion in mineral oil with pentane (3xc3x975 mL) was suspended in 5 mL of THF, cooled to 0xc2x0 C., and treated dropwise with a solution of 200 mg (0.604 mmol) of the compound of preparation 59 in 5 mL of THF. After stirring for 15 min, 0.078 mL (124 mg, 0.604 mmol) of 2-chlorobenzyl bromide was added, and the mixture was allowed to warm to rt, stirred for 4 h, and then heated to reflux for 16 h. The cooled mixture was partitioned between 100 mL of saturated aqueous NH4Cl solution and 200 mL of EtOAc. The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (100 mL), brine (100 mL), dried (Na2SO4), and evaporated to an oil. Purification by flash chromatography using 60% CH2Cl2-hexane as eluant gave 226 mg (82% yield) of the title compound as an oil. 1H NMR (CDCl3) d 1.54 (9H, s), 3.32-3.52 (2H, m), 5.09 (1H, dd, J=7.8 Hz), 7.02-7.30 (9H, m), 8.05 (1H, dd, J=2.8 Hz), 8.22 (1H, dd, J=2.5 Hz). The NMR also showed the presence of  less than 10% of the enol tautomer.
The compounds of Preparations 164-168 were prepared according to the procedure of Preparation 163 substituting the indicated benzyl halide for 2-chlorobenzyl bromide. In the cases of Preparations 165-168 one equivalent of KI was added immediately after the addition of the benzyl halide. All compounds were oils. Mass spectra were determined by the thermospray method.
MS (m/e) 440 (M++1); 1H NMR (CDCl3) d 1.27 (9H, s), 3.17-3.44 (2H, m), 4.80 (1H, dd, J=7.8 Hz), 6.85-7.30 (9H, m), 8.08 (1H, dd, J=2.8 Hz), 8.23-8.25 (1H, m).
MS (m/e) 490 (M++1); 1H NMR (CDCl3) d 1.24 (9H, s), 3.36 (2H, ABX pattern, JAB=14 Hz, JAX=7 Hz, JBX =8 Hz), 4.83 (1H, dd, J=7.8 Hz), 6.99-7.50 (9H, m), 8.02-8.22 (2H, m).
MS (m/e) 506 (M++1); 1H NMR (CDCl3) d 1.25 (9H, s), 3.32-3.46 (2H, m), 4.82 (1H, t, J=7), 7.03-7.28 (9H, m), 8.09 (1H, dd, J=2,8 Hz), 8.24 (1H, dd, J=2.5 Hz).
MS (m/e) 458(M++1); 1H NMR (CDCl3) d 1.25 (9H, s), 3.28 (2H, ABX pattern, JAB=14 Hz, JAX=7 Hz, JBX=8 Hz), 4.79(1H, dd, J=7,8 Hz), 6.55-7.18 (8H, m), 8.09 (1H, dd, J=2,8 Hz), 8.23(1H, dd, J=2,4 Hz).
MS (m/e) 476(M++1); 1H NMR (CDCl3) d 1.22 (9H, s), 3.22-3.35 (2H, m), 4.82 (1H, J=8 Hz), 6.56 (2H, t, J=8 Hz), 7.02-7.12 (5H, m), 8.11 (1H, dd, J=2.8 Hz), 8.22 (1H, dd, J=2.5 Hz).
A mixture of 12.61 g (224.7 mmol) of KOH, 73 mL of water, and 425 mL of ethanol was combined with 15.00 g (68.10 mmol) of 3-[4-(1-oxyethyl)phenyl]propionic acid ethyl ester (for preparation, see: Marechal, E.; Quere, J.-P. Bull. Chem. Soc. Fr., 1971, 2227), and the resulting mixture was stirred at rt for 2 h. The mixture was concentrated, and the residue was dissolved in 100 mL of water, cooled to 0xc2x0 C., and acidified with concentrated aqueous hydrochloric acid solution. The precipitate was filtered and recrystallized from methanol-water to give 10.11 g (77% yield) of 3-[4-(1-oxoethyl)phenyl]propionic acid as a white solid, mp 118-119xc2x0 C. Anal. Calcd for C11H12O3: C, 68.52; H, 6.06. Found: C, 68.74; H, 6.29.
A solution of 5.000 g (26.01 mmol) of the above acid in 500 mL of tetrahydrofuran was cooled to xe2x88x9217xc2x0 C. and treated dropwise with 21.67 mL (65.03 mmol) of a 3 M solution of methylmagnesium iodide in ether. Additional Griganrd reagent solution was added in three portions, 5, 5, and 10 mL, respectively, over several hours, as the course of the reaction was monitored by NMR. The mixture was cooled to xe2x88x9230xc2x0 C., quenched by the addition of 200 mL of saturated aqueous NH4Cl solution, and allowed to warm to rt. The aqueous layer was adjusted to pH 1 with aqueous 1 N hydrochloric acid solution, and the organic layer was extracted with EtOAc (2xc3x97200 mL). The combined organic layers were washed with brine (3xc3x97500 mL), dried (Na2SO4), and evaporated to 5.62 g of a yellow solid. Recrystallization from hexane-EtOAc gave 2.20 g (40% yield) of the title compound as a pale yellow solid, mp 92-94xc2x0 C. 1H NMR (DMSO-d6) d 1.36 (6H, s), 2.47 (2H, t, J=7 Hz), 2.74 (2H, t, J=7 Hz), 4.90 (1H, s), 7.21 (4H, AB quartet, J=7 Hz), 12.09 (1H, s).
A suspension of 10.00 g (59.46 mmol) of 3-(4-fluorophenyl)propionic acid, 12.54 g (65.41 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 6.381 g (65.41 mmol) of N,O-dimethylhydroxylamine hydrochloride in 300 mL of CH2Cl2 was cooled to 0xc2x0 C. and treated with 18.23 mL (13.23 grams, 130.8 mmol) of triethylamine. The mixture was stirred for 16 h with slow warming to rt. The mixture was concentrated, and the residue was partitioned between 300 mL of EtOAc and 200 mL of aqueous 1 N hydrochloric acid solution. The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (1xc3x97100 mL), saturated aqueous sodium hydrogencarbonate solution (2xc3x97200 mL), brine (1xc3x97100 mL), dried (Na2SO4), and evaporated to give 9.56 g (76% yield) of the title compound as an oil. 1H NMR (CDCl3) d 2.70(2H, t, J=8 Hz), 2.91 (2H, t, J=8 Hz), 3.15 (3H, s), 3.59 (3H, s), 6.92-6.97 (2H, m), 7.15-7.19 (2H, m). APCI MS (m/e) 212 (M++1).
The compounds of Preparations 171-180 were prepared according to the procedure of Preparation 170 substituting the corresponding carboxylic acid for 3-(4-fluorophenyl)propionic acid. The carboxylic acid used in Preparation 174 was the compound of Preparation 163, whereas all other carboxylic acids were commercially available. Mass spectra were determined by the APCI method.
Anal. Calcd for C11H15NO2: C, 68.37,H, 7.82; N, 7.25. Found: C, 68.65; H, 8.11; N,
1H NMR (CDCl3) d 1.16 (3H, d, J=7 Hz), 2.83-3.28 (2H, ABX pattern, JAB=13 Hz, JAX=7 Hz, JBX=8 Hz), 3.08-3.18 (1H, m), 3.14 (3H, s), 3.48 (3H, s), 7.15-7.32 (5H, m); MS (m/e) 208 (M++1).
1H NMR (CDCl3) d 1.31 (3H, d, J=7 Hz), 2.59-2.78 (2H, m), 3.14 (3H, s), 3.32-3.44 (1H, m), 3.58 (3H, s), 7.14-7.32 (5H, m); MS (m/e) 208 (M++1).
1H NMR (CDCl3) d 1.56 (6H, s), 1.71 (1H, s), 2.72 (2H, t, J=8 Hz), 2.93 (2H, t, J=8 Hz), 3.17 (3H, s), 3.60 (3H, s), 7.30 (4H, AB quartet, J=8 Hz); MS (m/e) 234(M++1-18 (H2O)).
1H NMR (CDCl3) d 3.18 (3H, s), 3.54 (3H, s), 3.78 (2H, s), 7.20-7.34 (5 H, m); MS (m/e) 180 (M++1).
1H NMR (CDCl3) d 3.22 (3H, s), 3.74 (3H, s), 4.79 (2H, s), 6.92-6.97 (3 H, m), 7.24-7.29 (2H, m); MS (m/e) 196 (M++1).
M.P. 40-42xc2x0 C.; 1H NMR (CDCl3) d 3.30 (3H, s), 3.76 (3H, s), 7.02 (1H, d, J=16 Hz), 7.34-7.39 (3H, m), 7.55-7.57 (2H, m), 7.72 (1H, d, J=16 Hz); MS (m/e) 192 (M++1).
1H NMR (CDCl3) d 3.41 (3H, s), 3.82 (3H, s), 7.24-7.43 (2H, m), 7.50 (1 H, s), 7.59 (1H, dd, J=1.8 Hz), 7.66 (1H, dd, J=1.8 Hz); MS (m/e) 206 (M++1).
M.P. 136-137xc2x0 C.; Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.94; N, 13.72. Found: C, 64.97; H, 5.81; N, 13.65.
1H NMR (CDCl3) d 3.21 (3H, s), 3.74 (3H, s), 4.88 (2H, s), 6.89-6.93 (2 H, m), 7.15-7.19 (1H, m), 7.34-7.36 (1H, m).
A solution of 5.90 mL (4.56 grams, 45.0 mmol) of diisopropylamine in 20 mL of tetrahydrofuran was cooled to xe2x88x9278xc2x0 C. and treated dropwise with 18.0 mL (45.0 mmol) of a solution of 2.5 M n-butyllithium in hexane. When the addition was complete, the mixture was stirred for 0.5 h at xe2x88x9278xc2x0 C. and treated dropwise with 3.88 mL (4.37 grams, 45.0 mmol) of freshly distilled 2-fluoropyridine. After the addition was complete, the resulting yellow suspension was stirred for 0.5 h at xe2x88x9278xc2x0 C. To the suspension was added dropwise a solution of 9.51 g (45.0 mmol) of the compound of Preparation 62 in 200 mL of tetrahydrofuran dropwise. The mixture was stirred for 16 h with slowing warming to rt as the dry ice/acetone bath melted. The mixture was quenched by the addition of 50 mL of aqueous 1 N hydrochloric acid solution, and the THF was removed by partial evaporation. The residue was partitioned between EtOAc (300 mL) and aqueous 1 N hydrochloric acid solution (100 mL). The separated organic layer was washed with aqueous 1 N hydrochloric acid solution (100 mL), saturated aqueous sodium hydrogencarbonate solution (100 mL), brine (100 mL), dried (Na2SO4), and evaporated to 12.6 g of a yellow oil. Purification by flash chromatography using 25% EtOAc-hexane as eluant gave 7.11 g of a yellow which solidified on standing. Trituration in hexane gave 6.87 g (62% yield) of the title compound as a light yellow solid, mp 73-74xc2x0 C. 1H NMR (CDCl3) d 3.02 (2H, t, J=7 Hz), 3.29-3.36 (2H, m), 6.91-6.99 (2H, m), 7.17-7.33 (3 H, m), 8.29-8.38 (2H, m); APCI MS (m/e) 248 (M++1).
The compounds of Preparations 182-190 were prepared according to the procedure of Preparation 191 substituting the corresponding N-methoxy-N-methylamide or ester substrate for the compound of Preparation 170 In the case of Preparations 185 and 191, an additional equivalent of in situ-prepared 2-fluoro-3-lithiopyridine was utilized. Products were purified by direct trituration and/or flash chromatography. Mass spectra were determined by the APCI method.
1H NMR (CDCl3) d 3.05 (2H, t, J=7 Hz), 3.32-3.64 (2H, m), 7.17-7.33 (6 H, m), 8.29-8.38 (2H, m).
1H NMR (CDCl3) d 1.18 (3H, d, J=7 Hz), 2.88 (2H, ABX pattern, JAB=14 Hz, JAX=6 Hz, JBX=8 Hz), 3.63-3.72 (1H, m), 7.14-7.29 (6H, m), 8.14-8.19 (1H, m), 8.33-8.35 (1H, m); MS (m/e) 244 (M++1).
M.P. 51-53xc2x0 C.; Anal. Calcd for C15H14FNO: C, 74.06; H, 6.00; N, 5.76. Found: C, 73.82; H, 5.83; N, 5.90.
1H NMR (CDCl3) d 1.56 (6H, s), 3.03 (2H, t, J=7 Hz), 3.31-3.36 (2H, m), 7.20-7.25 (2H, m), 7.30-7.34 (1H, m), 7.40-7.42 (2H, m), 8.30-8.38 (2H, m); MS (m/e) 270 (M++1xe2x88x9218 (H2O)).
1H NMR (CDCl3) d 4.31 (2H, s), 7.19-7.34 (6H, m), 8.27-8.37 (2H, m); MS (m/e) 216 (M++1).
M.P. 82-83xc2x0 C.; 1H NMR (CDCl3) d 5.21 (2H, d, J=3 Hz), 6.91-7.01 (3H, m), 7.27-7.31 (2H, m), 7.37-7.40 (1H, m), 8.41-8.45 (2H, m); MS (m/e) 232 (M++1).
M.P. 84-86xc2x0 C.; 1H NMR (CDCl3) d 5.34 (2H, d, J=3 Hz), 6.85-7.45 (5H, m), 8.42-8.50 (2H, m); MS (m/e) 266, 268 (M++1).
M.P. 83-84xc2x0 C.; 1H NMR (CDCl3) d 7.34-7.37 (1H, m), 7.41-7.47 (4H, m), 7.62-7.65 (2H, m), 7.90 (1H, d, J=15 Hz), 8.29-8.31 (1H, m), 8.38-8.41 (1H, m).
M.P. 110-111xc2x0 C.; Anal. Calcd for C14H8FNO2: C, 69.71; H, 3.34; N, 5.81. Found: C, 69.64; H, 3.36; N, 6.12.
M.P. 195-198xc2x0 C.; Anal. Calcd for C14H9FN2O2: C, 70.00; H, 3.78; N, 11.66. Found: C, 69.69; H, 3.60; N, 11.59.
1H NMR (CDCl3) d 2.67 (3H, d, J=0.5 Hz),), 7.30-7.33 (1H, m), 8.30-8.38 (2H, m).
1H NMR (CDCl3) d 3.10 (3H, s), 4.72 (2H, d, J=3 Hz), 6.63-6.74 (3H, m), 7.18-7.24 (2H, m), 7.32-7.36 (1H, m), 8.30-8.42 (2H, m); MS (m/e) 245 (M++1).
1H NMR (CDCl3) d 2.75 (3H, s), 7.07-7.12 (5H, m), 8.20 (1H, dd, J 2, 7 Hz), 8.24 (1H, dd, J=2.5 Hz).
1H NMR (CDCl3) d 2.76 (3H, s), 7.13-7.15 (1H, m), 7.39 (1H, dd, J=5.9 Hz), 7.53-7.56 (1H, m), 8.22-8.24 (2H, m), 8.50-8.53 (2H, m).
1H NMR (CDCl3) d 2.61 (1H, br s), 6.03 (1H, s), 7.14-7.38 (6H, m), 7.97-8.08 (2H, m).
1H NMR (CDCl3) d 7.32-7.38 (1H, m), 7.47-7.50 (2H, m), 7.61-7.67 (1H, m), 7.78-7.82 (2H, m), 7.98-8.07 (1H, m), 8.38-8.42 (1H, m).
To a stirred suspension of anhydrous cerium (III) chloride (3.8 g, 16 mmol) in 20 mL dry tetrahydrofuran at 0xc2x0 C. was added slowly dropwise a solution of 3.0M methyl magnesium chloride in tetrahydrofuran (10 mL, 31 mmol). The mixture was stirred at 0xc2x0 C. for 30 min. then a solution of Methyl 4-cyanobenzoate (2.0 g, 12.4 mmol) in 20 mL dry tetrahydrofuran slowly dropwise. The mixture was stirred for an additional 30 min. at 0xc2x0 C. then quenched with 2.0 M acetic acid (xcx9c10 mL) added slowly dropwise. The mixture was poured into 200 mL water and extracted with ethyl acetate (2xc3x97200 mL). The organic extracts were combined, washed with sodium bicarbonate solution (1xc3x9740 mL), water (2xc3x9740 mL), brine (1xc3x9740 mL), dried (MgSO4) and concentrated in vacuo to give an oil. The oil was absorbed onto Silica Gel (10 g) and washed with ethyl acetate/hexane (1:2, 1500 mL). Concentration of the washings in vacuo afforded 1.75 g (88%) 4-(1-hydroxy-1-methyl-ethyl)-benzonitrile as a clear oil. 1H-NMR (CDCl3): xcex47.60 (m, 4H), 1.58 (m, 6H). GC-MS (m/e, %): 161 (M+, 2), 146 (100).
To a solution of 2-Fluoro-5-methoxy-benzonitrile (4.0 grams, 26.5 mmole) in CH2Cl2 (100 ml) at 0xc2x0 C. was added 1.0 M BBr3 (29 ml, 29 mmole) dropwise, warmed to room temperature and stirred over night. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride, and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+).
The compound of Preparation 200 was prepared according to the procedure of Preparation 199 substituting the corresponding ether for 2-Fluoro-5-methoxy-benzonitrile. The duration of reaction was between 1 and 24 hours.
MW 165.21 MS (m/e, %) 165(M+, 30), 121 (100).
A solution of 2-Chloro-1-fluoro-4-methoxy-benzene (10.4 grams, 65.0 mmole), CuCN (6.4 grams, 71.0 mmole) and N-methylpyrrolidinone (100 ml) was refluxed for 18 hours. An additional 2.3 g CuCN was added, and the mixture was refluxed for 40 hours. The mixture was poured into 300 ml ice water and stirred for 10 minutes. This was poured into 100 ml methylene chloride and the layers were separated. The mixture was washed with water, dried over MgSO4, filtered, and concentrated to a solid (2.8 g). MW 137.12; MS (m/e) 137(M+).
To a solution of 1,4-Dioxa-spiro[4,5]decan-8-one (2.0 grams, 12.8 mmole) and tosyl-methyl isocyanate (5.0 grams, 25.6 mmole) in dimethylformamide (25 ml) at 0xc2x0 C. was added 1.0 M tBuOK in tButanol (25.6 ml) and stirred at 0xc2x0 C. for 1 hour and room temperature over night. The mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a solid (1.45 g). MW 167.209; MS (m/e) 168 (M++1).
To a stirred suspension of 2-(4,5-Dichloro-thiophen-2-ylmethyl)-isoindole-1,3-dione (0.770 grams, 2.47 mmole) in methanol (30 ml) and tetrahydrofuran (10 ml) at room temperature was added hydrazine hydrate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. A precipitate formed, and the mixture was concentrated to about 15 ml and filtered. The filtrate was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 5% methanol/methylene chloride as eluent to give an oil (0.341 g). MW 182.08; MS (m/e) 183 (M++1).
To a stirred solution of (4,5-Dichloro-thiophen-2-yl)-methanol (0.660 grams, 3.60 mmole), Phthalimide (0.636 grams, 4.32 mmole), and triphenyl phosphene (1.1 grams, 4.32 mmole) in tetrahydrofuran (20 ml) at room temperature was added diethyl azodicarboxylate (0.395 grams, 12.3 mmole) and stirred at room temperature over night. The mixture was poured into 100 ml water and extracted with diethyl ether. The combined extracts were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered, and concentrated to an oil from which triphenylphosphine was crystalized out using diethyl ether/hexane. The mother liquor was concentrated to give a solid which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give a yellow solid. This was triturated in hexane to give a white solid (0.772 g). MW 312.18; MS (m/e) 313 (M++1).
To a solution of 4,5-Dichloro-thiophene-2-carboxylic acid (0.500 grams, 2.53 mmole) and thionyl chloride (1.0 ml) in methylene chloride (10 ml) was refluxed for 3 hours. The mixture was concentrated to remove solvent and diluted with 15 ml dioxane and sodium borohydride (0.143 grams, 3.8 mmole) and refluxed for 3 hours. The mixture was cooled to 0xc2x0 C. and 3 ml water was added dropwise. The mixture was poured into 100 ml water. This was extracted with diethyl ether, washed with 1N NaOH, water, and brine, dried over MgSO4, filtered and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give an oil (0.671 g). MW 183.06; MS (m/e) 184 (M++1).
Into a solution of sodium hydroxide (19.2 grams, 48.0 mmole) in water (30 ml) and ice (120 g) at xe2x88x9210xc2x0 C. was bubbled Cl2 gas until 14.4 g was obtained. The solution was warmed to 50xc2x0 C. and 1-(4,5-Dichloro-thiophen-2-yl)-ethanone (8.5 0 grams, 40.0 mmole) in dioxane (40 ml) was added dropwise as the temperature rose to 80-90xc2x0 C. This temperature was maintained for 30 minutes. The mixture was poured into 500 ml water. This was extracted with diethyl ether, and the aqueous was treated with NaHSO3, then acidified to pH 1 with concentrated HCl. The resultant precipitate was filtered, and dried to give a white solid. (5.7 g). MW 197.04; 1H NMR (DMSO-d6) d 7.731 (1H, s).
To a solution of 1-Thiophen-2-yl-ethanone (5.0 grams, 40.0 mmole) in chloroform (50 ml) at 20xc2x0 C. was added portionwise aluminum chloride (15.9 grams, 119.0 mmole). The mixture was stirred at 20xc2x0 C. for 10 minutes and 1 M Cl2 in carbon tetrachloride (120 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes and diluted with methylene chloride (300 ml) and washed with 1 N sodium hydroxide and water and dried over magnesium sulfate and concentrated to give a solid (8.5 g). MW 195.07; MS (m/e) 196 (M++1).
A solution of 3,5-Dichloro-2-methyl-thiophene (1.3 grams, 7.8 mmole), NBS (1.4 grams, 7.8 mmole) and benzoyl peroxide (0.065 g) in carbon tetrachloride (40 ml) was refluxed for 18 hours. The mixture was cooled to 0xc2x0 C., diluted with 40 ml hexane and filtered. The filtrate was concentrated to an oil which was purified via flash chromatography on silica using hexane as eluent to give an oil (1.06 g). MW 245.95; MS (m/e) 246 (M++1).
To a solution of 2-methylthiophene (7.0 grams, 70.0 mmole), in methylene chloride (50 ml) at room temperature was added SO2Cl2 dropwise. The mixture was stirred at room temperature over night, diluted with hexane (300 ml), washed with 1N NaOH, water and brine, dried over MgSO4, filtered and concentrated to an oil which was purified via vacuum distillation to give an oil. This was further purified via chromatography on silica using hexane as eluent to give an oil (1.32 g). MW 167.06; MS (m/e) 166 (M+xe2x88x921).
A solution of 2-(3-Carbamoyl-phenoxy)-N-(2-chloro-benzyl)-nicotinic acid ethyl ester (4.31 grams, 16.08 mmole) in ethanol (100 ml) and 1 N sodium hydroxide (40.21 ml) was refluxed for 4 hours. The mixture was concentrated to 1/3 volume, diluted to 300 ml with water, acidified to pH 3 with 1 N hydrochloric acid and filtered to isolate a white solid which was recrystalized from ethyl acetate/hexane (3.8 g). M.P. 220-224xc2x0 C.; Anal. calcd. for C13H10N2O4: C, 60.45; H, 3.91; N, 10.85. Found: C, 61.70; H, 3.61; N, 10.69.
Into a solution of 3-Methoxy-benzoyl chloride (5.0 g) in methylene chloride (50 ml) at 0xc2x0 C. was bubbled in dimethylamine gas for 5 minutes. The mixture was stirred at 0xc2x0 C. for 30 minutes, diluted with 300 ml methylene chloride, washed with water, dried over MgSO4, filtered and concentrated to give an oil (4.8 g). MW 179.24; MS (m/e) 179 (M+).
To a solution of 2-(3-Formyl-phenoxy)-nicotinic acid ethyl ester (2.0 grams, 7.4 mmole) in 0.5 M trimethyl(trifluoromethyl)silane (18 ml) in tetrahydrofuran (20 ml) at 0xc2x0 C. was added tetrabutyl ammonium fluoride (0.050 g). The mixture was stirred at 0xc2x0 C. for 1 hour. To the mixture was added 1.0 N hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The mixture was poured into 200 ml water and extracted with diethyl ether. The combined extracts were washed with saturated NaHCO3, and water, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 60% ethyl acetate/hexane as eluent to give an oil (1.97 g). MW 341.31; MS (m/e) 341 (M+).
To a stirred suspension of CeCl3 (4.7 grams, 19.0 mmole) in tetrahydrofuran (30 ml) at 0xc2x0 C. was added dropwise 3.0 M methyl magnesium chloride (6.0 ml, 19.0 mmole). The mixture was stirred at 0xc2x0 C. for 45 minutes and 4-Acetyl-2-fluoro-benzonitrile (2.5 grams, 15.0 mmole) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred at 0xc2x0 C. for 1 hour and quenched with 5 ml 2 N acetic acid added dropwise. The mixture was poured into 200 ml water, acidified to pH 2 with 2 N acetic acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 50% ethyl acetate/hexane as eluent to give an oil (1.95 g). MW 179.21; MS (m/e) 179 (M+).
A mixture of 4-Bromo-2-fluoro-benzonitrile (5.0 grams, 20.0 mmole), butyl vinyl ether (12.5 grams, 124.0 mmole), triethylamine (4.0 grams, 40.0 mmole), dppp (0.453 grams, 1.1 mmole), Thallium acetate (5.8 grams, 22.0 mmole) and Pd(OAc)2 (0.224 grams, 1.0 mmole) in dimethylformamide (50 ml) under N2 was heated to 90xc2x0 C. for 3 hours. An additional 0.453 g dpp and 0.244 g Pd(OAc)2 was added and the mixture was heated to 90xc2x0 C. for 4 hours. The mixture was cooled to room temperature, 25 ml 2 N hydrochloric acid was added and the mixture was stirred at room temperature for 30 hours. The mixture was poured into 300 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent to give an oil (2.5 g). 1H-NMR (CDCl3): xcex42.63 (s, 3H), 7.73 (m, 2H), 7.81 (m, 1H).
A solution of 1,4-Dioxa-spiro[4.5]decane-8-carbonitrile (2.0 grams, 12.8 mmole) and 2 N hydrochloric acid (21.0 grams, 42.0 mmole) in tetrahydrofuran (30 ml) at room temperature was stirred over night. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 10% ethyl acetate/hexane as eluent to give an oil (0.800 g). MW 123.15.
To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2xc3x97100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M+xe2x88x9218).
A solution 2-Chloro-nicotinic acid ethyl ester (5.0 grams, 27.0 mmole), cesium carbonate (2.96 grams, 67.5 mmole) and Benzo[1,3]dioxol-5-ol (4.19 grams, 29.7 mmole) in dimethylformamide (80 ml) was heated to 65xc2x0 C. for 10 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to a solid (7.0 g). MW 287.275.
To a stirred solution of 2-(4-Hydroxymethyl-cyclohex-3-enyl)-propan-2-ol (5.765 grams, 34.270 mmole), Phthalimide (6.50 grams, 44.208 mmole), and triphenyl phosphene (11.60 grams, 44.208 mmole) in tetrahydrofuran (200 ml) at room temperature was added DIAD (9.010 grams, 44.552 mmole) dropwise, and the peach mixture was stirred at room temperature over night. The mixture was quenched with 150 ml water and extracted with 2xc3x97100 ml ethyl acetate. It was then concentrated to a yellow residue. This was taken up in diethyl ether, diluted with hexane, chilled and filtered. The crude product was purified via flash chromatography on silica using 50% ethyl acetate/hexane as eluent to give a yellow gum (5.73 g). MW 299.373; MS (m/e) 279 (M+xe2x88x9218).
A solution of 0.3 M methanolic hydrazine hydrate was prepared by adding hydrazine hydrate (1.96 g) to 204 ml methanol. This was added to 2-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl]-isoindole-1,3-dione (5.73 g, 19.140 mmole) and stirred at room temperature over night. 5% hydrochloric acid was added and a precipitate was formed over two hours, which was filtered through celite and washed with water. The filtrate was poured into water and extracted with diethyl ether. The aqueous layer was basified to pH=9 with sodium hydroxide and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which solidified on. standing (0.188 g ). M.P. 95-97xc2x0 C.; MW 169.269.
The compounds in Preparations 220-228 were synthesized in a manner analogous to that of Preparation 23 substituting the indicated phenol.
Prepared using 2-methyl-5-benzothiazolol. MS (m/e): 314 (M+)
Prepared using 2-methyl-6-benzothiazolol (Tardieu et. al. Helv. Chim. Acta, 75, 4, 992, 1185-1197). MS (m/e): 314 (M+).
Prepared using benzothiazol-6-ol (El""tsov et. al. J. Gen. Chem. USSR 51, 1981, 1822-831). MS (m/e): 301 (M++1, 100).
Prepared using benzoxazol-6-ol (Cole et. al. Aust. J. Chem. 39, 2, 1986, 295-301). MS (m/e): 284 (M+)
Prepared using 3-acetyl-4-chlorophenol. MS (m/e): 319 (M+)
Prepared using 1-(3-chloro-5-hydroxy-phenyl)-ethanone. MS (m/e): 319 (M+)
Prepared from 5-hydroxy-3-methyl-benzo(d)isoxazole. MS (m/e): 299 (M++1, 100).
Prepared from 7-hydroxy-3-methyl-benz(d)isoxazole. MS (m/e): 298 (M+)
Prepared from 2,3-Dihydro-benzo[1,4]dioxin-6-ol (Biosci. Biotech. Biochem., 56(4), 1992, 630-635)
MS: m/e 302 (M++1)
A mixture of 3-acetyl-4-chloroanisole (6.3 g, 0.03 mol.), (Atkinson et. al. J. Med. Chem. 26, 10, 1983, 1353-1360) and pyridine hydrochloride (19.4 g, 0.17 mol.) was heated at 220xc2x0 C. for 2 hrs. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2xc3x97200 mL). The organic extracts were combined, washed with water (40 mL), brine (40 mL), dried (MgSO4) and concentrated to give an oil. Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:1) gave 5.1 g oil. MS (m/e): 172/170 (M+, 100).
A mixture of 7-methoxy-3-methyl-benz(d)isoxazole (2.9 g, 0.017 mmol.) (Borsche et. al. Justus Liebigs Ann. Chem. 570, 1950, 155, 163) in glacial acetic acid (15 mL) and 48% hydrobromic acid (15 mL) was refluxed for 6 hrs. The mixture was concentrated to give 4.0 g solid. MS (m/e): 227/229 (M++HBr), 149(M+).
A mixture of 1-(3-chloro-5-methoxy-phenyl)-ethanone (14.3 g, 0.08 mol.) and pyridine hydrochloride (44.8 g, 0.39 mol.) was heated at 220xc2x0 C. for 2 hrs. The mixture was poured into water (200 mL) and extracted with ethyl acetate (2xc3x97200 mL). The organic extracts were combined, washed with water (40 mL), brine (40 mL) and concentrated to give an oil. Flash Chromatography on Silica Get eluting with ethyl acetate/hexanes (1:1) gave 6.6 g solid. MS (m/e): 170/172 (M+).
A mixture of trifluoromethanesulfonic acid 3-chloro-5-methoxy-phenyl ester (26.5 g, 0.091 mol.), butyl vinyl ether (59 mL, 0.46 mol.), 1,3-Bis(diphenyl-phosphinopropane) (1.1 g, 0.003 mol.), palladium acetate (0.51 g, 0.002 mol.) and triethylamine (28 mL, 0.20 mol.) in dimethylforamide (90 mL) was heated at 80xc2x0 C. for 4 hrs. The mixture was poured into water (400 mL) and extracted with diethyl ether (2xc3x97400 mL). The organic extracts were combined, washed with 1N hydrochloric acid (80 mL), 1N sodium hydroxide (80 mL), water (80 mL), brine (80 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:9) gave 14.3 g solid. MS (m/e): 184/186 (M+).
To a stirred solution of 3-chloro-5-methoxyphenol (15 g, 0.09 mol.), triethylamine (31 mL, 0.23 mol.) and 4-dimethylaminipyridine (1.1 g, 0.009 mol.) in methylene chloride (200 mL) at xe2x88x9278xc2x0 C. was added dropwise, trifluoromethanesulfonic anhydride (20 mL, 0.118 mol.). The mixture was allowed to slowly warm to room temperature over 2 hrs., then diluted with methylene chloride (400 mL) and washed with water (100 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:9) gave 26.6 g oil. MS (m/e): 290 (M+).
A mixture of 5-Methoxy-3-methyl-benzo(d)isoxazole (4.9 g, 0.03 mol.) in 48% hydrobromic acid (20 mL) and acetic acid (20 mL) was refluxed for 4 hrs. The mixture was concentrated to give 6.2 g solid. MS (m/e): 149 (M+).
A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone-O-acetyl oxime (15.3 g, 0.069 mol.) in pyridine (50 mL) was refluxed for 4 hrs. The mixture was poured into water (800 mL), acidified with concentrated hydrochloric acid to pH 1, then extracted with ethyl acetate (2xc3x97800 mL). The organic extracts were combined, washed with 1 N hydrochloric acid (100 mL), 1N sodium hydroxide (100 mL), water (100 mL), brine (100 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:2) gave 5.9 g solid. MS (m/e): 163 (M+).
A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone oxime (13.7 g, 0.076 mol.) and acetic anhydride (50 mL) was heated at 50xc2x0 C. for 10 min. The mixture was cooled to 0xc2x0 C., filtered, and the filtrant washed with water (50 mL) and dried to give 15.5 g solid. MS (m/e): 224 (M++1), 164 (100).
A mixture of 2-Hydroxy-5-methoxyacetophenone (15.0 g, 0.09 mol.), potassium hydroxide (23.6 g, 0.36 mol.) and hydroxylamine hydrochloride (9.4 g, 0.14 mol.) in water (300 mL) was refluxed for 2 hrs. The mixture was poured into ice and acidified with 1N hydrochloric acid to pH 1. The resulting precipitate was filtered and dried to give 13.7 g solid. MS (m/e): 182 (M++1, 100).
The compounds in Preparations 238-247 were synthesized in a manner analogous to that of Preparation 45.
MS (m/e): 269 (M+)
MS (m/e): 287 (M++1, 100)
MS (m/e): 287 (M++1, 100)
MS (m/e): 273 (M++1)
MS (m/e): 256 (M+), 211 (100)
MS (m/e): 292/290 (M+, 100)
MS (m/e): 292/290 (M+, 100)
MS (m/e): 270 (M++1, 100)
MS (m/e): 270 (M++1, 100)
MS: m/e274 (M++1)
To a stirred solution of (S)-(xe2x88x92)-4-(1-Hydroxy-ethyl)-benzonitrile (2.2 g, 0.015 mol.) in tetrahydrofuran (20 mL) at 0xc2x0 C. was added dropwise a 1.0M solution of lithium aluminium hydride in tetrahydrofuran (45 mL, 0.045 mol.). The mixture was refluxed for 30 min. then cooled to 0xc2x0 C. then quenched with methanol (5 mL) added dropwise. The mixture was diluted with chloroform (300 mL) and washed with water (40 mL). The resulting suspension was filtered through Celite and the organic extract of the filtrate separated, dried (MgSO4) and concentrated to give 2.0 g solid. xcex1D (CHCl3) xe2x88x9240.3xc2x0.
To a stirred solution of 4-acetylbenzonitrile (3.0 g, 0.021 mol.) and a solution of 1.0 M (R)-2-Methyl-CBS-oxazaborolidine in toluene (1.0 mL, 0.001 mol.) in tetrahydrofuran (50 mL) at room temperature was added dropwise a solution of 2.0M Borane-Dimethylsulfide complex in tetrahydrofuran (9.0 mL, 0.017 mol.) over 30 min, The mixture was stirred at room temperature for 1 hr., cooled to 0xc2x0 C., then quenched with methanol (10 mL) added dropwise. The volume was reduced by half, diluted with diethyl ether (300 mL) and washed with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dried (MgSO4) then concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexane (2:3) to give 2.2 g clear oil. xcex1D (CHCl3) xe2x88x9240.0xc2x0.
Prepared in an analogous manner to that of Preparation 247 starting with (R)-(+)-4-(1-Hydroxy-ethyl)-benzonitrile which is obtained from 4-acetylbenzonitrile using 1.0 M (S)-2-Methyl-CBS-oxazaborolidine in toluene in an analogous fashion as in Preparation 248.
A mixture of trans-(4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylmethyl)-carbamic acid benzyl ester (8.3 g, 0.027 mole) and Pearlman""s catalyst (400 mg) in ethyl acetate (100 mL) and methanol (25 mL) was shaken in a Parr Apparatus under 40 psi hydrogen at room temperature for 1 hr. The mixture was filtered through Celite and the filtrate concentrated to give 5.1 g white solid. MS (m/e): 171 (M+, 100).
A mechanically stirred suspension of anhydrous cerium (III) chloride (29.8 g, 0.12 mol.) in tetrahydrofuran was refluxed for 10 min., cooled to 0xc2x0 C., and a solution of trans-4-(Benzyloxycarbonylamino-methyl)-cyclohexanecarboxylic acid ethyl ester (35.8 g, 0.11 mol.) in tetrahydrofuran (200 mL) was added dropwise followed by a solution of 3.0 M methylmagnesium chloride (121 mL, 0.363 mol.) in tetrahydrofuran added dropwise. The mixture was stirred at 0xc2x0 C. for 1 hr., then quenched with 2N acetic acid added dropwise. The mixture volume was reduced by half, poured into water (800 mL) and acidified with 2N acetic acid to pH 3. then extracted with ethyl acetate (2xc3x97800 mL). The organic extracts were combined, washed with sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (2:3) gave 8.34 g solid. MS (m/e): 323 (M++NH3, 100).
To a stirred solution of trans-4-Aminomethyl-cyclohexanecarboxylic acid ethyl ester (23.8 g, 0.11 mol.) and triethylamine (34 mL, 0.24 mol.) in dioxane (100 mL) at room temperature was added N-(Benzyloxycarbonyloxy)succinimide (26.7 g, 0.11 mol.). The mixture was stirred at room temperature for 18 hr., poured into water (800 mL) and extracted with ethyl acetate (2xc3x97800 mL). The organic extracts were combined, washed with 0.5 N sodium hydroxide (100 mL). 0.5 N hydrochloric acid (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated to give 36.0 9 solid. MS (m/e): 337 (M++NH3, 100).
A mixture of (R)-(xe2x88x92)-(trans-4-(1-Hydroxy-ethyl-)cyclohexylmethyl)carbamic acid benzyl ester (870 mg, 2.98 mmol.) and Pearlman""s Catalyst (100 mg) in ethyl acetate (100 mL) and methanol (25 mL) was shaken in a Parr Apparatus under 40 psi hydrogen at room temperature for 1 hr. The mixture was filtered through Celite and the filtrate concentrated to give 484 mg oil. xcex1D (CHCl3) xe2x88x921.6xc2x0.
To a stirred solution of (trans-4-Acetyl-cyclohexylmethyl)-carbamic acid benzyl ester (1.0 g, 3.46 mmol.) and (S)-2-Methyl-CBS-oxazaborolidine monohydrate (102 mg, 0.34 mmol.) in tetrahydrofuran (15 mL) at 0xc2x0 C. was added dropwise a 2.0 M solution of Borane-Dimethylsulfide complex (1.4 mL, 2.77 mmol.) in tetrahydrofuran over 20 min. The mixture was stirred at 0xc2x0 C. for 30 min., then quenched with methanol (10 mL). the mixture volume was reduced by half, poured into water (200 mL) and extracted with ethyl acetate (2xc3x97200 mL). The organic extracts were combined, washed with pH 4 buffer (40 mL), water (40 mL), brine (40 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica ,Gel eluting with ethyl acetate/hexanes (1:1) gave 870 mg solid xcex1D (CHCl3) xe2x88x920.8xc2x0.
To a stirred solution of (trans-4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl)-carbamic acid benzyl ester (5.8 g, 0.017 mol.) in tetrahydrofuran (100 mL) at 0xc2x0 C., was added dropwise a solution of 3.0M Methylmagnesium chloride in tetrahydrofuran (13 mL, 0.038 mol.). The mixture was stirred at 0xc2x0 C. for 1 hr., then quenched with 2 N acetic acid added dropwise. The mixture was poured into water (300 mL) and extracted with ethyl acetate (2xc3x97300 mL). The organic extracts were combined, washed with 0.5 N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (2:3) gave 2.0 g solid. MS (m/e): 307 (M++NH3, 100).
To a stirred solution of trans-4-(Benzyloxycarbonylamino-methyl)-cyclohexane carboxylic acid (16.7 g, 0.057 mol.), N,O-dimethylhydroxylamine hydrochloride (6.2 g, 0.063 mol.), triethylamine (9 mL, 0.063 mol.) and 1-hydroxy-benzotriazole hydrate (8.5 g, 0.063 mol.) in dimethylformamide (200 mL) at room temperature was added 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (13.1 g, 0.068 mol.). The mixture was stirred at room temperature for 72 hrs., poured into water (800 mL) and extracted with ethyl acetate (2xc3x97800 mL). The organic extracts were combined, washed with 1N sodium hydroxide (80 mL), 1N hydrochloric acid (80 mL), water (80 mL), brine (80 mL), dried (MgSO4) and concentrated to give an oil. Flash Chromatography on Silica Gel eluting with ethyl acetate/hexanes (3:2) gave 5.8 g oil. MS (m/e): 352 (M++NH3, 100).
To a stirred solution of trans-4-(Aminomethyl)-cyclohexane carboxylic acid (10.0 g, 0.063 mol.) and potassium carbonate (30.5 g, 0.22 mol.) in dioxane (200 mL) and water (200 mL) at room temperature was added benzyl chloroformate (11 mL, 0.08 mol.). The mixture was stirred at room temperature for 18 hrs., poured into water (800 mL) and washed with diethyl ether (800 mL). The aqueous extract was acidified and the resulting precipitate filtered and dried to give 16.7 g white solid. MS (m/e): 309 (M++NH3, 100).
Mass spectra were determined by the GC-MS, AMPI, APCI or thermospray method.
All 1H NMR were taken on 400 MHz instruments.