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Taxanes with a side chain intermediate compounds, methods of obtaining
C07D413/12 - linked by a chain containing hetero atoms as chain links
C07D305/14 - condensed with carbocyclic rings or ring systems
C07D263/16 - with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
C07C233/30 - having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
C07C233/17 - with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
A61K31/335 -
(57) Abstract:
The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained in these ways. Taxanes with oxazolinone side chain of the formula III, where R1is phenyl, alkyl, alkenyl, alkoxy, R4- N; R3is phenyl, benzyl, or furyl, R8and R9- N., HE, or R14O - group, R10and R11- independent - atom H, alkyl, alkenyl, C3-7- cycloalkyl, phenyl, R14- hidroxizina group and their salts exhibit antitumor activity. 22 c. and 52 C.p. f-crystals, 3 PL.
This application is a partial continuation of simultaneously applying 07/995443 data of applicants, filed December 23, 1992, which is incorporated in this description by reference.
The present invention relates to methods for taxan with side chain and their intermediates and to new compounds obtained by these methods.
Taxanes are diterpene compounds, which have found application in the manufacture of dosage forms. For example, it was found that effective antitumor agent is Taxol Texan with structurally materials and select them from there. But in plant materials such taxanes may be present in relatively small quantities, and because in the case of, for example, Taxol may require a large number of trees are slow-growing yew, which is the source for this connection. Thus continued the quest synthetic, including semi-synthetic, get taxan, such as Taxol and its analogs, as well as ways to obtain intermediate products (intermediates) used in obtaining these compounds.
In accordance with the present invention we propose a new General method of obtaining new taxan with a side chain that includes the following stages (a)-(e):
(a) obtaining oxazoline compounds of the following formula I or salts thereof:
< / BR>
R1> R5, R7-O-, R7- or (R5)(R6)N-;
R2- R7-O-, R7- or (R5)(R6)N-;
R3and R4- independent R5, R5-O-C(O)- or (R5)(R6)N-C(O)-;
R5and R6is independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl or heterocycle; and
R7- alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl or heterocycle;
1, R3and R4such as indicated above;
(c) a combination of oxazoline formula II or its salt with taxonom having a hydroxyl group directly associated with its atom C-13, or its salt for the formation of the bearing oxazolinone side chain texana the following formula III or its salt:
R1, R3and R4such as mentioned above,
T - taxonomy fragment, preferably the compound of formula IX, directly connected through C-13 of the above-mentioned fragment;
(d) contacting the carrier oxazolinone side chain taxane formula III or its salt with aqueous acid, is able to break oxazolinone ring of compounds of formula III or its salts, to form bearing a side chain texana the following formula X or salt:
R1, R3, R4and T - such as above, and the acid salt of the amino group in the above formula X is formed in contact with said tearing ring acid; and
(e) contacting the bearing side chain taxane formula X or its salt with a basis for forming the bearing side chain taxane of the following formula IV or its salt:
R1, R3, R4ividually how each of the stages (a)-(e), which new ways, and new compounds of formulas I, II, III, IV, IX and X and their salts and hydrates, such as described below. There are also new drug precursors of these compounds.
The terms "alkyl" or "ALK" as used herein alone or as part of another group denote optionally substituted unbranched and branched saturated hydrocarbon groups, preferably having 1-10 carbon atoms in the normal chain, most preferably lower alkyl groups. Examples of unsubstituted such groups are methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4 - trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc., Exemplary substituents can be one or more of the following groups: halogen, alkoxy, alkylthio, alkenyl, quinil, aryl (e.g., for the formation of benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (-COOH), allyloxycarbonyl, alkylcarboxylic, alkylsulphonyl, carbarnoyl (NH2-CO-), substituted carbarnoyl (R5)(R6)N-CO-, where R5or R6such as above, except when at least one of the radicals R
The terms "lower alkyl" or "lower ALK" when used in this specification means such optionally substituted groups as those described above for alkyl having 1-4 carbon atoms in the normal chain.
The terms "alkoxy" or "alkylthio" means such as described above, the alkyl group attached through an oxygen (-O) or sulfur (-S-) bridge, respectively. The term "allyloxycarbonyl" when used in this description means alkoxygroup attached through a carbonyl group. The term "alkylaryl" when used in this description means an alkyl group attached through a carbonyl group. The term "alkylaryl" when used in this description means an alkyl group attached through a carbonyl group, which is in turn attached through an oxygen bridge. The terms "monoalkylamines" or "dialkylamino" means an amino group substituted by one or two above-described alkyl groups, respectively.
The term "alkenyl" when used in this specification, individually or as part of a group means optionally substituted hydrocarbon group with unbranched and branched chain, containing at least the I. Examples of unsubstituted such groups include ethynyl, propenyl, Isobutanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanal, etc., Examples of the substituents can be one or more of the following groups: halogen, alkoxy, alkylthio, alkyl, quinil, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (-COOH), allyloxycarbonyl, alkylcarboxylic, alkylsulphonyl, carbarnoyl (NH2-CO-), substituted carbarnoyl ((R5)(R6)N-CO-, where R5or R6like stated above, if at least one of the radicals R5or R6are not hydrogen), amino (-NH2), heterocycle, mono - or alkylamino or thiol (-SH).
The term "quinil" when used in this specification, individually or as part of another group, denotes optionally substituted unbranched or branched hydrocarbon groups containing at least one carbon-carbon triple bond in the chain and preferably has 2 to 10 carbon atoms in the normal chain. Examples of unsubstituted such groups include ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, octenyl, nonini, decenyl, etc., Examples of the substituents can disable one or more of the following groups: ha is boxel (-COOH), allyloxycarbonyl, alkylcarboxylic, alkylsulphonyl, carbarnoyl (NH2-CO-), substituted carbarnoyl ((R5)(R6)N-CO-, where R5or R6like stated above, if at least one of R5or R6is not a conduit amino (-NH2), heterocycle, mono - or dialkylamino or thiol (-SH).
The term "cycloalkyl" when used in this specification, individually or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbon atoms in the ring. Examples of unsubstituted such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and substituted. Examples of the substituents include one or more of these, as described above, the alkyl groups or one or more groups described above as alkyl substituents.
The term "cycloalkenyl" when used in this specification, individually or as part of another group means such optionally substituted groups as those described above for cycloalkyl, but additionally containing at least one carbon-carbon double bond, obrazlo or as part of another group, denotes optionally substituted homozygotes aromatic group, preferably containing 1 or 2 ring of 6-12 carbon atoms in the ring. Examples of unsubstituted such groups are phenyl, biphenyl and naphthyl. Examples of the substituents include one or more, preferably three or less nitro groups, alkyl groups, such as described above or the groups described above as alkyl substituents.
The terms "heterocycle" or "heterocyclic" as used in this specification, individually or as part of another group denote optionally substituted, fully unsaturated or unsaturated aromatic or non-aromatic cyclic group having at least one heteroatom in at least one ring, preferably monocyclic or bicyclic group having 5 or 6 atoms in each ring. Heterocyclic group may have 1 or 2 oxygen atoms, 1 or 2 atoms and/or 1 to 4 nitrogen atom in the ring. Each heterocyclic group may be attached through any carbon atom or heteroatom of the ring system. Exemplary heterocyclic groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepine, indolyl, isoindolyl, chinoline, ethenolysis, benzothiazolyl several such as described above, the alkyl groups or by one or more groups described above as alkyl substituents. Such examples are also smaller heterocycles, such as epoxides and aziridines.
The terms "halogen", "halo" or "Gal" when used in this specification, individually or as part of another group means chlorine, bromine, fluorine and iodine.
The term "taxonomy fragment" when used in this specification, individually or as part of another group means the fragments containing the structure of the nucleus:
which may be substituted and may contain ethylene unsaturated in the ring system.
The term "taxon" when used in this specification means a compound containing the above-described taxonomy fragment.
The term "hydroxy(or a hydroxyl protective group" as used in this specification means any group capable of protecting a free hydroxyl group and may be removed after performing the reaction without destroying the rest of the molecule. Information about these groups, their synthesis can be found in "Protective Groups in Organic Synthesis" oy T. W. Greene, John Wiley and Sons, 1991, or Fieser and Fieser. Examples of replacement groups include methoxymethyl, 1-ethoxyethyl, 1-label the pet-butyl (diphenyl)silyl, trialkylsilyl, trichloromethylcarbnol and 2,2,2-trichloroacetyl.
The term "salt" includes acid and/or basic salts formed with inorganic and/or organic acids and bases. Examples of acid salts include salts formed with mineral acids such as HCl, H2SO4or HNO3or carboxylic acids, such as triperoxonane acid or acetic acid. Examples of basic salts include salts formed amines, such as triethylamine, diisopropylethylamine or pyridine, or amino acids such as arginine or guanidine. "Salts" in this description to consider, and salts of hydroxyl groups, such as alkoxides of metals such as alkali or alkaline earth metal). The alkoxides of the metals may be, for example, formed by contacting a hydroxyl group with metallorum agent.
The reference compound used in accordance with the present invention or obtained by these methods, covers and its salts and hydrates, unless otherwise indicated.
Getting oxazoline compounds of formula I and their salts
In accordance with the present invention offers new ways of getting oxazolinone soediniajtes with the present invention are also new oxazolinone the compounds of formula I and their salts, including all stereoisomers or essentially free from other stereoisomers, or in a mixture with other selected or all other stereoisomers, provided that when R1is phenyl and one of the radicals R3or R4is hydrogen, or R2not methoxy when the other of R3or R4- pentadecyl, benzyl or methoxycarbonyl, or R2- not ataxi when the other of the radicals R3or R4- etoxycarbonyl; when R1is methyl and one of the radicals R3or R4is hydrogen, R2- no 8-phenylmethoxy when the other of the radicals R3or R4- methylpropyl; and when R1- acetylethyl and R3and R4is hydrogen, R2- not ethoxy or NH2.
Preferred are oxazoline of the formula Ia and their salts, described below, especially the compounds of formula Ia having the substituents listed below in the section entitled "Preferred connection".
The method of dehydration
Oxazolinone the compounds of formula I or their salts can be obtained by the process of dehydration, including the stage of contacting compounds of the following formula V or its salt:
R1, R2, R3and R< the salt, for the formation of compounds of formula I or its salts.
The initial compounds of formula V and their salts can be obtained as described in the application N 07/975453 on U.S. patent, filed November 12, 1992, on behalf of Patel and others; Ojima et al., J. Org. Chem., 56, 1681-1683 (1991); Georg et al., Tetrahedron Lett., 32, 3151-3154 (1991); Denis et al., J. Org. Chem. , 51, 46-50 (1986); Corey et al., Tetrahedron Lett., 32, 2857-1860 (1991); Deng et al., J. Org. Chem., 57, 4320-4323 (1992); Ojima et al., Tetrahedron, 48 6985-7012 (1992); Commercon et al., Tett. Lett., 33, 5185-5188 (1992); Denis et al., J.Org. Chem., 56(24), 6939-6942 (1991) (for example, with the subsequent esterification and acid treatment); and Denis et al., J. Org. Chem., 55, 1957-1959 (1990), all of these materials are included in this description by reference.
In the method of dehydration in accordance with the present invention can be used any acid capable of dehydration. Exemplary acids are sulfonic acids, such as pyridine, paratoluenesulfonyl, paratoluenesulfonyl, camphorsulfonate and methansulfonate, carboxylic acids, such as triperoxonane or acetic acid, or mineral acids such as HCl, H2SO4or HN3. The molar ratio of acid:the compound of formula V is preferably from about 1: 100 to about 1:1.
The reaction preferably is about 5 atmospheres. The reaction is preferably carried out in an inert gas, such as argon.
As a solvent, preferably an inert organic solvents, such as toluene, tetrahydrofuran, acetonitrile, benzene, or xylene. The amount of solvent preferably provides the contents of the source compounds of the formula V to about 2.5% by weight of the total weight of the solvent and the compounds of formula V.
Oxazolinone ring of compounds of formula I are numbered as follows:
In respect of carbon atoms in the 4 and 5 positions oxazolinone the compounds of formula I can exist as four stereoisomers Ia, Ib, Ic and Id, are presented below:
The compounds of formula V can also exist as four stereoisomers with respect to the carbon atoms in the relevant provisions. These stereoisomers are compounds Va, Vb, Vc and Vd:
The desired stereoisomer of the compounds of formula I may, for example, be obtained by the proposed method of dehydration using the appropriate stereoisomer of starting compound of the formula V. Thus, the use of compounds Va will give compound Ia, using the I Id give compound Ib. It is preferred to use the proposed method of dehydration of a single stereoisomer of starting compound V, although can be used and mixtures of stereoisomers. Especially preferred is the use of compounds Va to obtain the compounds Ia, in particular for obtaining compounds Ia, having the substituents listed below in the section "Preferred connection".
The way to replace
Oxazolinone the compounds of formula I or their salts can also be obtained by the method of substitution, which includes a stage of contacting the compounds of formula V or its salts (in the presence of a base) with an activating substance capable of activating the hydroxyl group of compounds of formula V or its salt to allow intramolecular substitution and formation of the compounds of formula I or its salts, provided that when R1is phenyl and one of the radicals R3or R4is hydrogen, or R2- not ataxi when the other of the radicals R3or R4- etoxycarbonyl, or R2not methoxy when the other of the radicals R3or R4- benzyl.
As the activating substance in the way of substitution in accordance with nastawienia formula V and implement intramolecular substitution. Examples of activators are sulphoselenide, such as alkylhalogenide (e.g., methylsulfonate), or arylsulfonate (e.g., benzosulphochloride or paratoluenesulfonyl), phosphoroxychloride (POCl3), postcentral (PCl5) or thionyl chloride (SOCl2). The molar ratio of activator: compound of formula V is preferably from about 1:1 to about 2:1.
Activating the hydroxyl group of the compounds of formula V or its salt can result in the new intermediate compound of formula VI or its salt:
R1, R2, R3and R4such as above, and L is a leaving group such as alkylsulfonate (e.g., methylsulfonate), arylsulfonate (e.g. benzosulfimide or paratoluenesulfonyl), chlorine or phosphoroscope (PO2or PO). The present invention provides the above new compounds of formula VI and their salts, including all stereoisomers, or essentially free of other stereoisomers, or any other selected or all other stereoisomers, provided that when R1- phenyl, R2- methoxy and one of the radicals R3or R4is hydrogen and the other is benzyl, then L is not chlorine (e.g., pyridine, triethylamine, diisopropylethylamine, lutidine or 1.8-diazabicyclo- [5.4.0]undec-7-ene) or hexamethyldisilazide lithium, or inorganic bases, such as carbonates of alkali metals (e.g. potassium carbonate). The molar ratio of base: a compound of formula V, preferably greater than about 2:1.
The reaction is preferably carried out at a temperature from about -20oC to about 100oC, in particular 0oC and at a pressure of about 1 atmosphere. The reaction is preferably carried out in an inert gas, such as argon.
As a solvent, preferably an inert organic solvents, such as chloroform, methylene chloride, toluene, tetrahydrofuran, acetonitrile, or, most preferably, the basic organic solvent capable of acting as a solvent, and the Foundation for the method, such as pyridine, triethylamine or lutidine. The amount of solvent preferably provides the content of the source materials of the formula V to about 10% by weight of the total weight of the solvent and the compounds of formula V.
The desired stereoisomer of the compounds of formula I may, for example, be obtained prelim the use of compounds Va will give the connection Ic, using the connection Vb will give the Ib connection, using the connection Vc will give compound Ia and use connections Vd will give the connection Id. It is preferred to use in the proposed method, substitution of a single stereoisomer of starting compound of the formula V, although can be used and mixtures of stereoisomers. Especially preferred is the use of connection Vc for the formation of compounds Ia, in particular for obtaining compounds Ia, having the substituents listed below in the section entitled "Preferred connection".
Oxazolinone the compounds of formula I, where R1- R1'such as listed below, or their salts can also be obtained by way of exchange, including the stage of contacting compounds of the following formula VII or its salt:
R2, R3and R4such as above, with a compound of the following formula VIII or its salt:
R1'and E is independently alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl or heterocycle; provided that when E is ethyl, one of R3or R4is hydrogen and R1'- phenyl, R2not methoxy when another of radiocarbon, and when R1'is methyl, R2- no 8-phenylmethoxy when the other of R3or R4- 2-methylpropyl.
When using both parent compounds VII and VIII as acid salts with groups NH2and HN, respectively, for the formation of a free group NH2and/or HN (respectively) can be used amine base, such as ammonia or an organic amine base, to ensure the effective continuation of the reaction. This can be used any amine base, capable of forming free(s) group(s) NH2and/or HN. Preferred are tertiary amine base, such as triethylamine, diisopropylethylamine, lutidine, pyridine or 1,8-diazabicyclo [5.4.0]under-7-ene. The molar ratio of amine base to the compound of formula VII is preferably from about 1:1 to about 10:1.
The initial compounds of the formula VII and their salts can be obtained by such methods as those described in the application N 07/975453 on U.S. patent, filed on behalf of Patel and others 12 November 1992; Commercon et al., Tetrahedron Lett., 33 (36), 5185-5188 (1992); Corey et al., Tetrahedron Lett., 32, 2857-1860 (1991); Ojima et al. , Tetrahedron, 48, 6985-7012 (1992); and Ojima et al., Tetrahedron Lett., 33, 5737-5740 (1992); all of these mA the ways, as those described in Kimball et al., Org. Synth. Coll., so 11, page 284 (1943). The use of acid salts of compounds of formula VIII, for example, salts formed with carbon, sulfo or mineral acids as raw materials is preferred, since such compounds are relatively stable and easy to handle. The above salt can be neutralized upon contact with the ground, such as described above. The molar ratio of the compounds of formula VIII to the compound of formula VII is preferably from about 1:1 to about 2: 1.
The reaction is preferably carried out at a temperature from about 0oC to about 100oC and at a pressure of approximately 1 atmosphere. The reaction is preferably carried out in an inert atmosphere, e.g. argon or nitrogen.
Used solvents are preferably inert organic solvents, such as toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane or chloroform. The amount of solvent preferably provides the contents of the source compounds of the formula VII about 6% by weight of the total weight of the solvent and the compounds of formula VII.
The compounds of formula VII can, as seeding positions. These stereoisomers are the following compounds VIIa, VIIb, VIIc and VIId:
The desired stereoisomer of the compounds of formula I may, for example, be obtained by the proposed method exchange using the appropriate stereoisomer of starting compound of the formula VII. Thus, the use of compounds VIIa give compound Ia, the use of compounds VIIb will give the connection Id, the connection VIIc will give the Ic connection and use connections VIId will give the Ib connection. It is preferred to use a single stereoisomer of starting compound VII in the proposed exchange method, although can be used and mixtures of stereoisomers. Especially preferred is the use of compounds VIIa for obtaining compounds Ia, in particular for obtaining compounds Ia, with a substituent listed below in the section entitled "Preferred connection".
Getting oxazoline compounds of formula II and their salts
Oxazolinone the compounds of formula II and their salts can be obtained from oxazoline compounds of formula I and their salts by conversion of the group-C(O)-R2in group-C(O)-OH.
Can be used any substance that is able to videopom is its salt can be deaccelerate for the formation of compounds of formula II by using an appropriate nucleophilic substances, such as metanolovye salts of alkali and alkaline earth metals. In accordance with another option you can use hydrogenation, for example, transformation groups, such as benzyloxycarbonyl in carboxyl, through the use of moisturizing substances, for example, hydrogen and hydrogenation catalyst, such as palladium.
The transformation of the group-C(O)-R2the carboxy group is preferably carried out by hydrolysis. At the same time as gidrolizuemye agent is carried out by hydrolysis. At the same time as gidrolizuemye agent can be any compound capable of acting hydrolysis. Examples gidroliznaya agents include aqueous base, such as hydroxides (for example, metal hydroxides such as barium hydroxide, or preferably the hydroxides of alkali metals such as lithium hydroxide, sodium or potassium). The molar ratio of the base to the compound of formula I is preferably from about 1:1 to about 3:1. The molar ratio of water to the compound of formula I is preferably from about 1:1 to about 100:1.
The reaction is preferably carried out at a temperature from about -20oC to about 100oC and at a pressure practicelink carried out at higher temperatures above the range of temperatures or at temperatures close to or equal to the temperature of heating under reflux, used liquid medium. The reaction is preferably carried out in an atmosphere of nitrogen, argon or air.
The solvents can be selected from inorganic or organic liquids, such as water, alcohols, toluene, tetrahydrofuran, dioxane, acetonitrile or dimethylformamide or mixtures thereof. It is preferred to use as the solvent a mixture of water with an organic liquid, such as tetrahydrofuran. The amount of solvent preferably provides the content of the source compounds of formula I of about 7% by weight of the total weight of the solvent and the compounds of formula I.
In accordance with the present invention are also new compounds of formula II and their salts, including all stereoisomers, or essentially free of other stereoisomers, or in a mixture with other selected or all other stereoisomers, provided that when R1is phenyl and one of the radicals R3or R4is hydrogen, the other of the radicals R3or R4not COOH. As oxazoline formula I, oxazoline formula II may exist as four stereoisomers with respect to BR>< / BR>
Preferred are oxazoline formula IIa and their salts, in particular, the compounds of formula IIa having the substituents listed below in the section entitled "Preferred connection".
Stereoconfiguration starting compound of the formula I or its salt can be in the proposed method, stored and/or inverted. For example, the hydrolysis of the compounds of formula I, having the substituents in the CIS-position relative to each other in positions 4 and 5, can give the compound of formula II with the corresponding CIS-configuration, the compound of formula II with the corresponding TRANS-configuration, where the carboxyl substituent in position 5 is inverted relative to the parent compound, or a mixture of the above CIS - and TRANS-compounds. The base, which when used for hydrolysis deprive proton carbon atom through which joined the group-C(O)-R2and who then return the proton above the carbon atom on the opposite side of the ring system, provide inversion (treatment) stereoconfiguration. Examples of such bases are the reasons described above, or carbonates of alkali metals, such as carbon is(alkoxides) can be formed prior to their accession or in situ (e.g., by joining metalliser agent, such as n-utility, together with alkanols such as ethanol).
When contacting stereoconfiguration, as described above, during the implementation of this method, may be the formation of an intermediate product of the compounds of formula I with inverted (reversed) stereoconfiguration relative to the starting compound of the formula I (i.e., the epimerization). For example, when the source compound of formula I has the substituents in positions 4 and 5, located in the CIS-position relative to each other, the corresponding TRANS compound of the formula I, where the Deputy-C(O)-R2in position 5 is inverted relative to the parent compound, may be formed as an intermediate compound in the reaction of hydrolysis. The above method of treatment (inversion) is also included within the scope of the present invention.
Mix to obtain bearing oxazolinone side chain of formula III and their salts
Bearing a side chain Texan formula III or its salt can be obtained by a process comprising a stage of contacting oxazolinone the compounds of formula II or its salt with taxonom having a hydroxyl group directly sustained fashion to use in this way oxazoline formula IIa or their salts, in particular the compounds of formula IIa having the substituents listed below in the section "Preferred connection".
Taxanes are compounds having the structure of the kernel
which may be substituted and may have, as described above, the ethylene unsaturation in the ring system. This method can be used any taxon containing a hydroxyl group directly attached to the carbon atom C-13, or its salt (such as a metal alkoxide on the hydroxyl group at C-13). Taxonomy source material used in the method according to the present invention, there may be a connection, such as those described in the publication N 400971 European patent included in this description by reference, and the compound containing taxonomy fragment described (and obtained by methods described or similar) in the application N 07/907261 on U.S. patent, filed July 1, 1992, on behalf of Chen and others, or in the application N 07/981151 on U.S. patent, filed November 24, 1992, on behalf Ueda, etc. that are included in this description by reference. Examples of such taxan are taxanes having the following formula IX:
R8is hydrogen, hydroxyl, R14-O-, R15-C(O)-O - or 10 and R11is independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, R16-O-, aryl or heterocycle;
R14- hidroxizina group;
R15is hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl or heterocycle; and
R16- alkyl;
or their salts.
It is proposed to use in the way that the combination of the present invention all stereoconfiguration unregulated chiral centers of the compounds of formula IX. Preferred is the use of a single stereoisomer, but can be used and mixtures of stereoisomers. Used as starting material the compounds of formula IX are preferably 7-trialkylsilanes III, and most preferably 7-trimethylsilylcyanation III or 7-triethylcitrate III.
Another group of compounds of formula IX, serving as the preferred starting materials are compounds in which R8- OC(O)CH3, R9is hydroxyl or hydroxylamine group, such as O-trimethylsilyl or O-triethylsilyl, R10such as the one above, except for methyl, and R11- aryl, for example, benzyl. The last connection as new as the ways in which R10- cycloalkyl or or16.
The above connections will receive the following General scheme
R14- same as above
R14such as the one above, and X trimethylsilane or dimethylsilane
R20is hydrogen or R14and R - same as above
R - C(O)R10and R14and X - such as above
Stage F
Protect baccatin III at the C-7 and C-13 by reaction with a suitable agent, such as galadrielleallman, for example, trimethyl or triethyl, 2,2,2-trihloretilamina or carbobenzoxy. Can be used any inert organic solvent which is soluble baccatin III, for example, THF (tetrahydrofuran), DMF (dimethylformamide), MeCl2and dioxane. The reaction is carried out in the presence of a tertiary amine base such as pyridine or imidazole. The reaction temperature can be varied from -30oC to room temperature, and the substitution at C-7 is preferably at a temperature of from -30oC and 0oC, at C-13 is at a temperature of from 0oC to room temperature. The concentration of the reagent with a protective group, preferably taken in a molar excess (1-10) at C-1 by reaction with trimethylsilanol or preferably by dimethylsilanol, for example, chlorotrimethylsilane or preferably by chlorodimethylsilane in, for example, DMF, THF, dioxane, and various ethers. As in stage F, the reaction is preferably carried out in the presence of a tertiary amine base such as imidazole or pyridine. Temperatures can range from -30oC to room temperature, and preferably 0oC.
Stage H
(A) Then restore intermediate XII C-4 to hydroxy by reaction with a suitable reducing agent such as Red-AI or alumoweld lithium. The reducing agent is typically present in a molar excess (1-5 equivalents). The solvent can be THF, dioxane or a different suitable ethers, and the reaction temperature may be in the range from -30oC and 0oC, and preferably 0oC.
(B) Intermediate XIII(A), where group at C-4 - hydroxy, turn to the appropriate substituent at C-4 by reaction with a suitable acylchlorides, acid anhydride or mixed anhydride, for example by acrylsilicone, benzoyl chloride, cycloalkylcarbonyl, alkylchlorosilanes, in the presence of the anion of the alkali metal (Li, Na or K) a secondary amine base. Dissolve the temperature, and preferably equal to about 0oC.
Stage I
(A) Then remove the protection from the intermediate stage XIII H(B) by the reaction with pyridinethiol (aqueous formotorola in pyridine) in acetonitrile, and then tetrabutylammonium in THF or cesium fluoride in THF. Next, the mixture was diluted in alcohol, washed with an organic or inorganic acid and separated.
(B) Then, in the compound XIV may be, as in stage F, the introduced protective group for the hydroxy at C-7 when the parameters of the reaction, enabling the above-described substitution at C-7.
Next may be inserted a suitable side chain at C-13 in accordance with the new method, disclosed in this specification, or according to the method of nolton as disclosed in U.S. patent N 5227400, N 5175315 and N 5229526, descriptions of which are included in this description by reference.
New end-products in accordance with the present invention are therefore compounds of the formula
R1- R5, R7-O - or (R5)(R6)-;
R3and R4- independent R5, R5-O-C(O)- or (R5)(R6)-C(O)-;
R5and R6is independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, collaterall;
T is a
R8is hydrogen, hydroxyl, R14-O-, R15-C(O)- or R15-O-C(O)-O-;
R9is hydrogen, hydroxyl, fluorine, R14-O-, R15-C(O)-O - or R15-O-C(O)-O-;
R10and R11is independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, R16-O-, aryl or heterocycle;
R14- hydroxylamine group; and
R16- alkyl, provided that R10is not methyl;
or their salts or hydrates.
Preferred compounds
Particularly preferred among the novel compounds of formula IV are those compounds in which R10- cycloalkyl or or16. The most preferred novel compounds of formula IV are compounds in which R10- cycloalkyl; R1- aryl, preferably phenyl, or alkoxy, preferably tert-Butylochka; R3- aryl, preferably phenyl, heterocycle, preferably 2 - or 3-furanyl or thienyl, Isobutanol, 2-propenyl, isopropyl or (CH3)2CH-; R4is hydrogen; R8- preferably hydroxyl or alkylcarboxylic, for example, the atomic charges; R9 the person can be used in any connection, capable of esterification of the hydroxyl group at C-13 (or its salts) source taxane through the carboxyl group oxazoline formula II or its salt. Examples of combining agents include those compounds that form the activated complex oxasolinone ether (for example, 1-hydroxybenzotriazole or N-hydroxysuccinimide) or anhydride (e.g., acid chloride, such as pivaloyloxy or bis(2-oxo-3-oxazolidinyl)fosinopril) in contact with the oxazoline of formula II, in particular combining agents containing compound, such as carbodiimide (for example, dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) bis(2-oxo-3-oxazolidinyl)fosinopril), carbonyldiimidazole (CDI), pivaloyloxy or 2,4,6-trichlorobenzoyl, and the above compounds preferably used in conjunction with this compound, 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HO-S4), or an amine, such as triethylamine, pyridine or pyridine, substituted in position 4 by-N(R16)(R17), where R16and R17is independently selected from alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl or heterocycle (for education what have they are attached, form heterologous (for the formation of compounds such as 4-morpholinopropan or 4-pyrrolidinedione). The molar ratio combining agent to the original taxane is preferably from about 1:1 to about 2: 1. The molar ratio of oxazoline formula 11 to the original taxane is preferably from about 1:1 to about 2:1.
The reaction is preferably carried out at a temperature from about 0oC to about 140oC and at a pressure of approximately 1 ATM. Preferably the reaction is carried out in an inert gas, such as argon.
Preferably used solvents are inert organic liquids such as toluene, acetonitrile, 1,2-dichloroethane, chloroform, tetrahydrofuran, pyridine, methylene chloride or dimethylformamide. The amount used of the solvent is preferably provided by content source taxane about 20% by weight of the total weight of solvent and tecknologi connection.
Stereoconfiguration substituents in positions 4 and 5 of the original oxazoline the product of a combination of formula III may be stored and/or inverted, for example, it is assumed that may be the epimerization of CIS - to TRANS when Zam the invention are also new bearing oxazolinone side chain of taxanes of the formula III and their salts, including all stereoisomers, or essentially free of other stereoisomers, or in a mixture with other selected or all other stereoisomers.
Gap rings for education taxan formula X or salt
Bearing a side chain Texan formula X or its salt can be obtained from the supporting oxazolinone side chain taxane formula III or its salts by a process comprising a stage of contacting taxane formula III or its salt with aqueous acid, is able to break (open) ring oxazoline group that is attached through the C-13 tecknologi fragment mentioned tecknologi compounds for the formation of the above-mentioned compounds of formula X or salt.
In the method according to the present invention can be used in any aqueous acid capable of the above-mentioned gap rings. Examples tearing ring acids include carboxylic acids such as acetic or triperoxonane acid, or preferably, mineral acids such as hydrochloric, hydrofluoric, or sulfuric acid, in water. The molar ratio of tearing the ring of the acid to the compound of formula III is preferably from about 1:1 to about 10:1. The molar unctio disclosure ring preferably carried out at a temperature from about -20oC to about 40oC and at a pressure of approximately 1 atmosphere. The reaction is preferably carried out in an atmosphere of nitrogen, argon or air.
Preferably used solvents are inert organic liquids separately or in a mixture with water, such as tetrahydrofuran, alcohols, preferably lower alcohols, such as methanol, dioxane, toluene, acetonitrile or mixtures thereof. The amount of solvent preferably provides the contents of the source compounds of the formula III about 5% by weight of the total weight of the solvent and the compounds of formula III.
The preferred implementation of the present invention additionally includes a step of removing the protection of one or more groups, in particular to free hydroxyl groups on taksanova fragment to obtain taxan formula X. Removing protection may, for example, be carried out before or after (or simultaneously with) the aforementioned gap rings by using removing the protecting agent. As removing the protecting agent may be used any compound capable of removing the protective group. For example, to remove the silyl protective groups, you can use acid, tatera-n-butylammonium; benzyl protective group can be removed by hydrogenation; trichlorocarbanilide protective group can be removed by contacting with zinc; and acetylene or Catalunya protective group can be removed by using petievich acids or Lewis acids.
The preferred implementation of the present invention includes both the implementation gap the rings and unprotect one or more hydroxyl groups on taxanomy ring structure, in particular at C-7. Especially preferred option includes a step simultaneous rupture of the ring and remove the protection by the use of acid (for example, mineral acids such as hydrochloric), capable of both reactions. For example, the use of acid under the reaction conditions described above for the break ring, can provide simultaneous fracturing of the ring and remove tseplyaesh acid hydroxylamine groups at C-7, such as trialkylsilyl (for example, trimethylsilyl or triethylsilyl).
In accordance with the present invention are also new intermediate compounds (intermediates) of the formula X and their salts, education is Wu, free from other stereoisomers or in a mixture with other selected or all other stereoisomers.
Contact Foundation for education taxan formula IV and their salts
Treatment of compounds of formula X or salt base gives compound of formula IV or its salt. In the method according to the present invention can be used any basis, allowing the movement of acyl group-C(O)-R1the amino group-NH2in the resulting compound of formula IV or its salt. Examples of such bases are the bicarbonates of an alkali metal such as sodium bicarbonate or potassium bicarbonate. The molar ratio of the base to the compound of formula X is preferably from about 1:1 to about 5:1.
The reaction is preferably carried out at a temperature from about -20oC to about 80oC and at a pressure of 1 atmosphere. Preferably the reaction is carried out in argon, nitrogen or air.
Preferably used solvents are inert organic liquids separately or in a mixture with water, such as tetrahydrofuran, alcohols, preferably lower alcohols, such as ethanol, toluene, acetonitrile, dioxane or the s X from about 1% to about 5% by weight of the total weight of the solvent and the compounds of formula X.
Removing the protection from the protected groups can be carried out simultaneously using a base or after, but preferably the removal of the protection is carried out, as described above, prior to contacting with the base, in particular, simultaneously with opening of the ring.
The products obtained by the methods in accordance with the present invention, can be isolated and purified by such methods as extraction, distillation, crystallization and the column chromatography was carried out.
Products from taxan with the side chain
Bearing a side chain taxanes of formula IV and their salts obtained by methods in accordance with the present invention are themselves pharmacologically active or are compounds which can be converted into pharmacologically active products. Pharmacologically active taxanes, such as Taxol, can be used as anticancer agents for the treatment of patients with cancer, such as breast cancer, ovarian, colon or lung, melanoma or leukemia. The usefulness of such taxan with the side chain are described, for example, N 400971 European patent, U.S. patent N 4876399, and N 4857653, N 4814470, N 4924012, N 4924011, application N 07/907261 on U.S. patent, filed 1 the materials included in this description by reference.
The resulting ultimately preferred bearing side chain takanami formula IV are particularly preferred Taxol, have shown above structure, and Taxotere, having the structure shown below:
When necessary, can be used or obtained in any manner in accordance with the present invention is a solvate (such as hydrates) of the reactants or products.
In the scope of the present invention includes water-soluble drug precursor compounds of the formula IV. Such drug precursor compounds of the formula IV are obtained by the introduction of the C-7 or C-10 and/or 2' position of the side chain of phototoxicity General formula
-OCH2(OCH2)mOP(O)(OH)2,
m is O or an integer from 1 to 6, inclusive.
New drug precursors have the formula
R1- R5, R7-O - or (R5)(R6)N-;
R3and R4- independent R5, R5-O-C(O)- or (R5)(R6) N-C(O)-;
R7- alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ari15-C(O)-O-, R15-O-C(O)-O -, or-OCH2(OCH2)mOR(O)(OH)2;
R20- hydrogen, -OCH2(OCH2)mOR(O)(OH)2, -OC(O)R21or-OC(O)R21where R21- C1-C6- alkyl, optionally substituted with one to six halogen atoms, C3-C6cycloalkyl, C2-C6alkenyl or a radical of the formula
D - link or C1-C6alkyl, and Ra, Rband Rcis independently hydrogen, amino, C1-C6mono - or dialkylamino, halogen, C1-C6alkyl or C1-C6alkoxy;
R30is hydrogen, hydroxy, fluorine, -OCH2(OCH2)mOR(O)(OH)2or-OC(O)OR21where R21such as specified above;
R15is hydrogen, alkyl, alkenyl, quinil, cycloalkenyl, cycloalkyl, aryl or heterocycle;
m is O or an integer from 1 to 6 inclusive, provided that at least one of the radicals R8, R20and R30-OCH2(OCH2)mOR(O)(OH)2and R10is not methyl;
and their basic salt loukil or OME or OEt; R1- aryl, preferably phenyl or alkoxy, preferably tert-Butylochka;
R3- aryl, preferably phenyl, or heterocycle, preferably furyl, or thienyl, or alkenyl, preferably propenyl or isobutyl; R4is hydrogen; R3is hydroxy or alkylcarboxylic, preferably the atomic charges; R11- aryl, preferably phenyl;
R20- -OCH2(OCH2)mOR(O)(OH)2or-OC(O)OR21where R21- ethyl or N-propyl; R30- -OCH2(OCH2)mOR(O)(OH)2and m = 0 or 1.
Phosphoroscope imposed by the synthesis of the final products of formula IV by methods described in the application N 08/108015 on U.S. patent, filed August 17, 1993, which is incorporated in this description by reference.
In the course of obtaining the above-mentioned new drug precursors are formed of different intermediate products in the reaction conditions described in General in the above-mentioned application N 08/108015. The compounds of formula IV used as starting substances, in which unnecessary hydroxy-group is protected. Appropriately protected compound of formula IV, in which reactive hydroxy-group or in the 2' position or in positions 7 IL2)mSCH3. Then, depending on the values of m, the ether can be attached to a secure postexertional ether in accordance with the various stages described in the aforementioned application. Phosphonoamidate(s) group(s) and hydroxyamine group can then be removed by traditional methods.
Then the free acid may be converted into the required basic salt by conventional methods, including contacting the free acid with a metal base or amine. Suitable metal bases are the hydroxides, carbonates and bicarbonates of sodium, potassium, lithium, calcium, barium, magnesium, zinc and aluminum, and suitable amines are triethylamine, ammonia, lysine, arginine, N-methylglucamine, ethanolamine, procaine, benzathine, dibenzylamine, tromethamine (TRIS), chloroprocaine, choline, diethanolamine, triethanolamine, etc., the Basic salt can be further purified by chromatography followed by lyophilization or by crystallization.
Drug precursors can be administered orally or parenterally in accordance with the fact, as described in the aforementioned application N 08/108015. Compounds of formulas IV and IV' are new antitumor substances, pinii M cell lung cancer.
Below the present invention is described by way of examples, which should be considered only as illustrative and in no way limit the present invention defined by the attached claims.
Obtaining the ethyl ester of (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5 - oxazolidinone acid
In kiln dried flask with a capacity of 10 ml, purged with argon, was added (2R, 3S)-N-benzoyl-3-phenylisocyanate ester (0.104 g g, of 0.332 mmol) and suspended in toluene (5.0 ml). Added pyridinium paratoluenesulfonyl (42 mg, 0,167 mmol). After stirring at room temperature for about 1 hour the mixture was heated under reflux. When heated, the received light homogeneous solution. After about 1 hour of heating, the reaction mixture was mutela. TLC (thin-walled chromatography) after 16.5 hours of heating showed that the reaction was completed (ethyl acetate /EtOAc/hexane 1:1, PMK (phosphorus molybdenum acid/ethanol, ultraviolet light (UV)).
The reaction mixture was diluted with 10 ml of chloroform, washed with 5 ml saturated aqueous solution of NaHCO3, dried over N2SO4was filtered and concentrated, resulting in of 97.8 mg of a yellowish oil (VNIIM (< 5%) impurities, none of which was relevant CIS-oxazoline.
In dried over a flame flask with a capacity of 5 ml, purged with argon, was added (2S, 3S)-N-benzoyl-3-phenylisocyanate ether (0,100 g, 0,319 mmol) dissolved in pyridine (1.0 ml), and cooled to 0oC. was Added dropwise methylsulfonylamino (38 mg, 0,335 mmol and yellowish solution was stirred at 0oC for 1 3/4 hours, then was heated to room temperature. After 1 1/2 hours at room temperature, thin layer chromatography (TLC) showed that the reaction was completed (ethyl acetate: hexane = 1:1, PMK/ethanol, UV).
The heterogeneous mixture was diluted with 5 ml ethyl acetate and washed 1/3 saturated aqueous CuSO4(10 ml). The aqueous fraction was extracted with ethyl acetate (2x5 ml). The combined organic fractions washed with 5 ml saturated aqueous NaCl, dried over Na2SO4was filtered and concentrated, resulting in 0.12 g of a yellowish oil.
Specified in the header of the product was purified by chromatography on silica gel (column diameter 20 mm and length 50 mm) in ethyl acetate:gay, what has been specified in the header of the TRANS-oxasolinone product. Specific rotation (c = 0,1, CHCl3: []D= +15,6, []578= +16,3, []546= +18,7, []436= +33,1.
The original compound (2S,3S)-N-benzoyl-3-phenylisocyanate broadcast received separately as follows:
in a flask with a capacity of 500 ml, containing a solution of (4S-CIS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid ethyl ester (0.79 in) to 2.67 mmol) in methanol (MeOH) (57 ml) at 0oC, was added 1 N. HCl (57 ml) with stirring for 10 minutes. While adding HCl had the precipitate, which was dissolved by adding tetrahydrofuran (THF). Then was added THF (57 ml) for clarification of the solution, and the resulting mixture was stirred at 0oC for 2 hours and 15 minutes. Saturated NaHCO3(120 ml) regulate the pH of the solution to 9.0, after which the mixture was allowed to mix at room temperature for 18 hours. (The reaction was monitored by TLC (silica gel) using as eluent a mixture of EtOAc:hexane = 4:6, and the Rf for the source material = 0,71, Rffor product = 0,42, UV manifestation).
The reaction mixture was diluted with ethyl acetate (200 ml) and separating the aqueous layer, e), dried over Na2SO4was filtered and concentrated, obtaining as a result of the crude (2S,3S)-N-benzoyl-3-phenylisocyanate ether in the form of solids (0.810 g). Dissolved it in hot MeOH (15 ml) and left to stand at room temperature for 30 minutes and then at 4oC for 1 hour. Filtered the solid, washed it with cold MeOH (2 ml) and dried under vacuum, resulting in 0,43 g of (2S,3S)-N - benzoyl-3-phenylisocyanate ether as the first portion. The second portion (0.24 g) was obtained in the same way as described above, which gave the total of 0.67 g (80%) (2S,3S)-N-benzoyl-3-phenylisocyanate ether (white matter: so pl. = 160-161oC []D= -40,3(c = 1, CHCl3)).
Elemental analysis: C18H19NO40,03 H2O
Calculated: C - 68,86; H - 6,12; N - 4,46; H2O - 0,20
Found: C - 68,99; H, 6.7; in N - 4,60; H2O - 20.
Obtaining the ethyl ester of (4-TRANS)- and (4-CIS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid
In kiln dried flask with a capacity of 10 ml, purged with argon, was added (2S, 3S)-N-benzoyl-3-phenylisocyanate ether (66,88 mg, 0,213 mmol) and suspended him in toluene (4 ml). Added pyridine partywall the Angstrom). The reaction mixture was heated under reflux (most of the solids were dissolved by heating). Five-hour TLC showed that the reaction was nearly complete (EtOAc: hexane = 1:1, PMK/EtOH, UV).
The reflux was continued overnight. After 22 hours of heating, the reaction mixture was cooled to room temperature. From the solution precipitated oily substance. Upon further cooling to room temperature, this oil hardened. Adding about 5 ml of EtOAc, the solid does not appreciably dissolve. To dissolve all the solid substance was added about 3 ml of CHCl3. Thin layer chromatography showed no starting material.
Then the solution is washed with 5 ml saturated aqueous solution of NaHCO3, dried over Na2SO4was filtered and concentrated, resulting in 64,3 mg partially crystallized yellow oil.1H and13C NMR showed that the ratio indicated in the title CIS-oxasolinone product: specified in the header of the TRANS-oxasolinone product: admixture is approximately 5: traces: 1. Specified in the header of the TRANS-oxasolinone product was attributed to trace amounts of (2R,3S)-N-benzoyl-3-the gel when the relationship EtOAc/hexane = 1:1 and 2:1 (Rf= 0,57 (EtOAc : hexane = 1:1) and obtained as a result of 49.3 mg of an oily yellow solid (yield = 78,4; );1H NMR showed that the ratio (CIS:TRANS) specified in the header of CIS - and TRANS-oxazolinone products is approximately 10:1.
Obtaining methyl ester (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid
Hydrochloride ethyl ester benzoperoxide acid
In dried over a flame and purged with argon, the flask with a capacity of 100 ml was added benzonitrile (30,3 g, 294 mmol) and ethanol (14.2 g, 308 mmol) and cooled to 0oC. HCl was barbotirovany through peremeshivayte solution over a 20 minute period at the end of which the weighing containers showed that it was added to 17.5 g of HCl. The addition of HCl ceased, and the solution was stirred at 0oC. After about 1 hour the precipitate began to form.
After stirring at 0oC for about 2 1/2 hours heterogeneous mixture was transferred into a cold (4oC) placing. After 3 1/2 days of staying at the 4oC solid mass was crushed and triturated with 150 ml of cold (4oC) diethyl ether. The mixture was allowed to stand at 4oC for 6 hours. The mixture was filtered in a vacuum filter is in), receiving a result of 51.6 g (95,5%) of a white granular powder specified in the connection header.
Methyl ester of (4S-TRANS)4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid
Dissolved (2R,3S)-3-phenylisocyanate ester hydrochloride (USD 5.76 g, 24,9 mmol) in 1,2-dichloroethane (75 ml). Was added triethylamine (2,77 g and 27.3 mmol) and the resulting mixture was stirred for 15 minutes before adding one portion obtained in the above stage (a) benzimidate (4,62 g, 24,9 mmol). The mixture was stirred 10 minutes, then was heated under reflux. After 4 1/2 hours of heating TLC showed that the reaction was completed (ethyl acetate:hexane = 1:1, PMK/ethanol, UV).
The reaction mixture was diluted with 150 ml dichloromethane and 150 ml of 10% aqueous K2CO3and which. Separated the layers and the aqueous fraction was extracted with 3 x 50 ml of CH2Cl2. The combined organic fractions were washed with 50 ml saturated NaCl solution, dried over Na2SO4was filtered and concentrated, resulting in a yellow oil, which was purified on a column of silica gel (dry volume of about 750 ml; filled column: diameter 100 ml and a length of 110 mm) with respect to the ethyl acetate: hexane = 1:2, resulting in a received 6,05 g specified the Noah temperature. Output = 86.4% of
Obtaining the ethyl ester of (4S-CIS)-4,5-dihydro-2,4-diphenyl-5 - oxazolidinone acid
In a 100 ml flask containing a solution of (2R,3S)-N-benzoyl-3-phenylisocyanate ester (2.00 g, 6.38 mmol) in pyridine (20 ml) at 0oC, was added dropwise methanesulfonanilide (0,52 ml, 6,70 mmol) for 2 minutes. The solution was stirred at 0-4oC for 90 minutes and then at 65 to 70oC for 18 hours (the reaction was monitored by TLC using as eluent a mixture of ethyl acetate with toluene in the ratio of 1:2, Rffor the original material = 0,48 and Rf for the specified header CIS-product = 0,78, UV manifestation).
The reaction mixture was cooled to room temperature and was diluted with ethyl acetate (80 ml) and 1/3 saturated solution of CuSO4(80 ml (1/3 saturated solution of CuSO4was obtained by dilution of a saturated solution of CuSO4up to 1/3 of its original concentration). The aqueous layer was separated and was extracted with ethyl acetate (40 ml x 1). Then the combined ethyl acetate solution was washed with brine (80 ml x 1), dried over Na2SO4was filtered , concentrated and azeotropically heptane (20 ml x 2), resulting in untreated specified in the header bavlyali hexane (4 ml). Crystallizing the mixture was stirred at room temperature for 20 minutes and then at 4oC for 30 minutes. The solid was filtered off, washed with cold ethyl acetate (10%) in hexane, and dried in the air, receiving a result of 1.34 g (71.3 per cent) specified in the header CIS-oxazoline product, having a melting point 135oC. []D= -9,25(c = 1,0,CHCl3).
Receipt of (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid
Ethyl ester (92 mg, 0,311 mmol) of (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid was transferred into a vial for 1 drachma (3,888 g) was dissolved in tetrahydrofuran (THF) (0.8 ml). Was added dropwise LiOH (waters. , 1 N., 0,343 mmol) and the resulting biphasic mixture was intensively stirred at room temperature. Within 5 minutes there was obtained a homogeneous solution. After about 45 minutes, thin layer chromatography showed the absence of starting material (ethyl acetate:hexane = 1:1, PMK/ethanol (EtOH), UV).
The solution was cooled to 0oC and then diluted to 2.0 ml THF. Abruptly stopped the reaction of 0.34 ml of 1 N. HCl (1.1 EQ). After heating to room temperature the solution was diluted with 5 ml EtOAc and 5 ml of H2O and which. Shared layers. The aqueous fraction extrii was dried over Na2SO4was filtered and concentrated, resulting in 72,1 mg of a white solid. Yield = 87%.1H and13C NMR and MS showed the presence specified in the header of the product, having a melting point 201-203oC. []D= +25,6, []578= +26,9, []546= +30,7, []436= +53,8 (c = 1,0, CHCl3: CH3OH = 1 : 1).
Receive (4-TRANS)-4,5 dihydro-2,4 diphenyl-5-oxazolidinone acid
A 10 ml flask was added (4S-TRANS)-4,5-dihydro-2,2-diphenyl-5-oxazolidinone acid methyl ester (0,509 g, is 1.81 mmol) was dissolved in tetrahydrofuran (4,7 ml). Was added dropwise lithium hydroxide (1 in N. H2O, 2.0 ml, 1,99 mmol). A two-phase mixture was intensively stirred. Within two minutes after the addition of lithium hydroxide was obtained light solution. After 15 minutes, TLC showed that the reaction was completed (ethyl acetate : hexane = 1:1, PMK/ethanol).
Then the reaction mixture was diluted with 10 ml THF, and the resulting cloudy solution was cooled to 0oC. the Reaction abruptly stopped by adding dropwise 2.0 ml, 1 N. water CHl. Then, the solution was diluted with 20 ml ethyl acetate and 15 ml of water was which. Shared layers, and the aqueous fraction extrage is racchi was dried over Na2SO4, filtered and concentrated. The obtained concentrate was soluble in a mixture of benzene and methanol and less soluble in methanol, CHCl3, ethyl acetate or mixtures thereof. The concentrate was dried under high vacuum overnight and resulted 0,448 g is specified in the header of the product as a white solid. (Yield = 93%). So pl. = 201 - 203oC. []D= +25,6, []578= +26,9, []546= +30,7, []436= +53,8 (c = 1,0, CHCl3: CH3OH = 1:1)
Receive (4-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid
Ethanol (0.1 ml) was mixed with tetrahydrofuran (1.0 ml) and the mixture was cooled to -78oC. was Added dropwise n-utility (n-BuLi) (2,12 M, 0,050 ml) and the mixture was heated to 0oC. was Added solid ethyl ester (4S-CIS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid, having the structure
(20 mg, 0,0678 mmol) and the reaction mixture was stirred 1 hour in the presence of a small amount of water). A mixture of the original CIS-oxazolidinone ether and the corresponding TRANS-oxazolidinone ether (position 5) was detected by thin-layer chromatography (very slight hydrolysis was observed at this point). Reglamentary). After 18 hours, TLC showed the presence of mainly specified in the header of the product - TRANS-acid and traces of the original substance - CIS-ether (solvent system: hexane EtOAc = 2:1 (traces of CIS-ether) and EtOAc : acetone : H2O : MeOH = 7:1:1:1 (specified in the header of the product).
The reaction abruptly stopped phosphate (pH 4,3) buffer, and the reaction mixture was extracted with ethyl acetate (5 x 10 ml). Dry the organic layer, the solvent was removed, resulting in approximately 17 mg (93%) specified in the header of the product. (NMR shown in the header of the product - TRANS-acid). So pl. = 135oC []D= -92,5(c = 1,0, CHCl3).
Receipt of (4S-TRANS)- and (4S-CIS)-4,5, -dihydro-2,4,diphenyl-5-oxazolidinone acids
Ethyl ester (202 mg, 0,6890 mmol) (4S-CIS)-4,5,dihydro-2,4-diphenyl-5-oxazolidinone acid was dissolved in tetrahydrofuran (1.5 ml) and the resulting solution was added dropwise lithium hydroxide (1 N. waters., 0,718 ml). Received a heterogeneous solution. The reaction mixture was stirred overnight at room temperature, after which the solution became transparent. (Thin-layer chromatography /ethyl acetate : hexane = 1 : 1/ showed a small amount of starting material. Thin-layer chromatographie products).
Added 1 N. HCl (0,718 ml) followed by the addition of saturated NaCl (approximately 10 ml) and ethyl acetate (about 10 ml). The aqueous layer was washed with ethyl acetate 5 times (approximately 10 ml), after which the aqueous layer had a pH of approximately 5.5, acidified to a pH of 3.4 and was extracted with approximately 10 ml of ethyl acetate. The combined organic layers were dried over MgSO4and filtered. The ethyl acetate evaporated under reduced pressure, resulting in 183 mg (100%) of the mixture specified in the header of CIS - and TRANS-products (in accordance with1H NMR the ratio of CIS:TRANS = 3:1).
Getting 7-triethylsilyl-13-[[(4S-TRANS)-4,5,-dihydro-2,4 - diphenyl-5-oxazolyl]-carbonyl]baccatin III
(a) 7-Triethylcitrate III
(I) 12b of the atomic charges-2a, 3,4,4 a,5,6,9,10,11,12,12 a,12b - dodecahydro-6,9,11-trihydroxy-4a-8,13,13-tetramethyl - 5-oxo-4-[(triethylsilyl)oxy]-7,11-methane-1H-cyclo-[3,4]Benz[1,2-b]oxet-12-silt ether 2aR(2a,-4,4 a,6,9,11,12,12 a,12)] benzoic acid
In dried over a flame and purged with argon 3-necked flask with a capacity of 1 l equipped with a mechanical stirrer and a digital thermometer) was added 10-deacetylbaccatin III (27.4 g, 50.3 mmol, containing H2O - 1,57%, CH3OH - 1.6%, and ethyl acetate - 0,09% and hexane - 0.03%) and 4-dimethylaminopyridine (2,62 (K. F.) = < 0,01). Added methylene chloride (256 ml, wt.% H2O (K. F.) = < 0,01) (the temperature of the reaction solution grew during the addition of the methylene chloride from the 23oC to 25oC), and the resulting homogeneous solution was cooled to -50oC.
Was added dropwise over 3 minutes, triethylamine (16 ml, 120 mmol, wt.% H2O (K. F.) = 0,08) and the resulting solution was stirred at -50oC for 5 minutes, then was added dropwise neat (pure) triethylsilane (18.6 ml, III mmol). Adding triethylsilane spent 10 minutes during which the temperature of the reaction mixture did not rise above -50oC. while adding triethylsilane the reaction solution became very muddy.
The resulting mixture was stirred at about -50oC for 1 hour and then allowed her to stand (without stirring) in the refrigerator at -48oC for 22 hours. (A separate experiment showed that stirring the reaction mixture at -45oC for 8 hours and provides about 60% conversion). The mixture is then removed from the refrigerator and heated to about -10oC. TLC analysis of the mixture (solvent: ethyl acetate developer: phosphomolybdenum acid/ethanol) showed no what cetecom (1 l) and washed with water (890 ml).
The resulting aqueous layer was separated and was extracted with ethyl acetate (250 ml). The combined organic layers were washed 5,7% aqueous solution of NaH2PO4(2 x 250 ml, the measured pH of 5.7-aqueous solution of NaH2PO4was equal 4,300,05 measured pH of the combined wash water NaH2PO4was equal 5,750,05), polysystem aqueous NaCl (250 ml), saturated aqueous NaCl (250 ml), dried over Na2SO4, filtered and concentrated on a rotary evaporator. (All operations concentration on a rotary evaporator in this example was carried out at the temperature of the water bath 35oC).
The obtained semi-solid substance was further dried under high vacuum (about 1 mm RT. Art. within 20 minutes) and received in the result of 41.5 g of a white solid. The crude product was then dissolved in CH2Cl2(400 ml) (for dissolved solids used heated in a water bath at 35oC), and the volume of the resulting solution was reduced to about 150 ml on a rotary evaporator. Immediately began crystallization, after which the mixture was allowed to stand at room temperature for 1 hour. Added hexane (100 ml) and subjected the mixture to a smooth twist the owls. The solid was filtered, washed (3 x 250 ml) with a mixture of CH2Cl2: hexane = 1:9 on a vacuum filter and dried under high vacuum (approximately 0.2 mm RT. Art. within 42 hours), with the result of 26.1 g (79%) indicated in the title product as a white powder. The mother liquor was concentrated on a rotary evaporator and the residue was led out of CH2Cl2, receiving 4.5 g (14%) specified in the header of the product as white crystals. The recrystallization was performed in the same way as when receiving the first portion of the product: the solid was dissolved in CH2Cl2(100 ml) without heating, and the resulting solution was reduced by rotary evaporator to approximately 7 ml of Crystallization was started within 5 minutes. The mixture was allowed to stand at room temperature for 1 hour, and then in a cold room at 4oC for 42 hours. The crystals were filtered off, washed with a mixture of CH2Cl2: hexane = 1:9 (3 x 50 ml) on a vacuum filter and dried under high vacuum (approximately 0.2 mm RT. Art. for 18 hours). 1H NMR spectrum of this portion was identical1H NMR spectrum of the first portion of the product. The total yield of the two portions was 93% (without amendments) (see table who/SUB>)
TCX: Rf= 0,60 (silica gel, E. SLA). Developer - phosphomolybdenum acid/ethanol.
(II) [2R - (2a,4,4 a,6,9,11,12,12 a,12b)] - 6,12 b-o-Bis(atomic charges)-12-(benzoyloxy-2a, - 3,4,4 a, 5,6,9,10,11,12,12 a,12b - dodecahydro-9,11-dihydro-4a, 8,13,13-tetramethyl-4-[(triethylsilyl)oxy]-7,11-methane-1H-cyclodina[3,4]Benz[1,2-b]oxet-5-he
(7-triethylcitrate III)
Obtained in the above stage (I) specified in the header of the product (21,4 g, 32,4 mmol) was added in dried over a flame and purged with argon 3-necked flask with a capacity of 1 l equipped with a mechanical stirrer and a digital thermometer) and was dissolved in THF (360 ml, freshly distilled from sodium/benzophenone). The resulting solution was cooled to -70oC. was Added dropwise over 23 minutes a solution of n-utility (n-BuLi) (14,6 ml 2,56 M-th solution in hexano, of 37.3 mmol, titrated three times with diphenyloxazole acid in THF at 0oC). During the addition the temperature of the reaction mixture did not rise above -68oC. by adding n-utillity formed solid particles that are not dissolved at -70oC. the resulting mixture was stirred at -70oC for 20 minutes and then was heated to -48oC. When heated to -48oC was obtained a transparent homogeneous solution.
oC, 1 ATM) in argon before use). The temperature of the reaction mixture during the addition was not increased above -45oC. the resulting solution was stirred at -48oC for 20 minutes and then at 0oC for 1 hour. The solution was diluted with ethyl acetate (350 ml), washed with saturated aqueous NH4Cl (250 ml) and layers were separated. The aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. (All operations were concentrated on a rotary evaporator in this example was carried out at the temperature of the water bath 35oC). The impact on semi-solid substance high vacuum (approximately 1.5 mm RT. Art. within 1/2 hour) gave to 24.7 g of a white solid.
The crude product was dissolved in CH2Cl2(300 ml) and the resulting solution was reduced by rotary evaporator to about 70 ml within one minute began crystallization. The mixture was left to stand at room temperature for 45 minutes and then in a cold room at 4oC for 18 hours. The crystals were filtered off, proliveno 0.2 mm RT. Art. for 19 hours), with the result of 20.9 g (92.0%) specified in the header of the product as fine white needle-shaped crystals. The mother liquor was concentrated on a rotary evaporator and the residue was led from a mixture of CH2Cl2and hexanol, resulting in 0,82 g (3,6%) specified in the header of the product in the form of small white crystals.
The crystallization mother liquor was carried out as follows. The residue was dissolved in CH2Cl2(10 ml) and the resulting solution was reduced by rotary evaporator to about 5 ml of the Extract at room temperature for 1/2 hour and did not lead to the formation of crystals. Added hexane (5 ml) in portions of 1 ml and the solution was which. When this fell slightly crystals. The mixture was left to stand at room temperature for 1/2 hour (formed larger crystals), and then in a cool place at 4oC for 18 hours. The crystals were filtered off, washed with a mixture of CH2Cl2and hexanol with a ratio of 1:9 on a vacuum filter and dried under high vacuum (approximately 0.15 mm RT. century 21 hours). The total output of the two received portions was 95.5%. So pl. = 218-219oC (decomposition); []2D2= - 78,4oC (C = 1,0, Snta/ethanol).
(b) 7-Triethylsilyl-13-[[(4S-TRANS)-4,5-dihydro-2,4-diphenyl-5 - oxazolyl] carbonyl]baccatin III
7-Triethylcitrate III obtained in the above stage (a), (0,209 g, 0,298 mmol), oxazoline obtained as listed in title product of example 6 (an 80.2 mg, 0,300 mmol), dicyclohexylcarbodiimide (84 mg, 0,407 mmol) and 4-dimethylaminopyridine (25 mg, 0,205 mmol) was added to the flask for 1 drachma (3,888 g), kiln dried and purged with argon, and suspended in toluene (1.0 ml). After stirring for 1 hour at room temperature some solid substance was dissolved, the mixture had a yellowish color. The heterogeneous mixture was heated to 85oC. TLC after 2 1/2 hours showed the presence of starting material (ethyl acetate:hexane = 1: 1, PMK/ethanol, UV). Continued heating at 85oC. After 5 hours, TLC showed essentially the same. The reaction mixture gave the opportunity to mix at room temperature overnight. After 14 hours of exposure at room temperature, TLC results were the same. The heterogeneous mixture was diluted with 1 ml of ethyl acetate was noticed some sludge) and filtered through a layer of celite. Celite was washed h ml of ethyl acetate and the filtrate was concentrated, resulting in 0,34 is Athyn III were represented in the ratio of approximately 8:1, respectively; there were also a number of 1,3-dicyclohexylmethane and traces of either the original oxazoline or impurities.
The mixture was partially separated on silica gel (column: diameter 20 mm, length 90 mm) at the ratio of ethyl acetate to hexane from 1:2 to 1:1. TLC analysis showed the presence of small spots with a slightly lower Rfthan those specified in the header of the product. Mixed fraction of this mixture and the product were combined. First spot: listed in title product (0,267 g white solid, yield = 94%). (1H NMR showed the ratio of the target product and the above-mentioned impurities of approximately 18:1); the first spot and the aforementioned mixed fractions: 11,5 mg oil 1H NMR showed the ratio of the target product and different impurities, different approximately 2:1). So pl. = 139 - 142oC []D= -49,5, []578= -52,6, []546= -63,5, []436= -157,0(to 1.0, CHCl3).
Getting 7-triethylsilyl-13-[[(4S-TRANS)-4,5, -dihydro-2,4 - diphenyl-5-oxazoline]-carbonyl]baccatin III
In the flask for 1 drachma (3,888 g), dried over a flame and purged with argon, was added (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone sour Aravali in toluene (1.2 ml). Immediately added diisopropylcarbodiimide (63 g, 0,503 mmol) and slightly yellow heterogeneous mixture was stirred at room temperature. After some time it was received very turbid yellow solution. At this point the flask was hermetically closed and immersed in an oil bath at a temperature of 80oC. After 3 hours of storage at approximately 80oC got more of a dark orange solution. The reaction mixture was directly concentrated. 1H NMR showed the ratio of the desired product combinations to 7-triethylenemelamine III of approximately 6:1. The product was partially purified by chromatography on silica gel with ethyl acetate : hexane = 1:3, and the result was 0,300 g white solid. TLC showed the selected product and by-product of Diisopropylamine.
1H NMR showed only the desired product combination and mixture in the ratio of about 25: 1 and a byproduct of Diisopropylamine. The ratio of the target product combinations by-product of Diisopropylamine was approximately 12:1.
In accordance with these results, the yield of the target product was about 85%. So pl. = 139 - 142oC. []D= -49,5, []578= -52,6
Getting 7-triethylsilyl-13-[[(4S-TRANS)-4,5, -dihydro-2,5 - diphenyl-5-oxazolyl]-carbonyl]baccatin III
7-Triethylcitrate III (indicated in this example as "A" and (4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid (denoted in this example as "B") were put in contact with each other under the conditions specified in the following table 2, and has been specified in the header of the connection.
So pl. = 139-142oC. []D= -49,5, []578= -52,6, []546= -63,5, []436= -157,0, (C = 1,0, CHCl3).
The key to table 2
R2POCl =
= bis(2-oxo-3-oxazolidinyl)fatfingered
DCC = dicyclohexylcarbodiimide
DMAP = 4-dimethylaminopyridine
DIC = diisopropylcarbodiimide
ArCOCl = 2,4,6-trichlorobenzoyl =
CDI = carbonyldiimidazole
t - BuCOCl = pualeilani
1,2 - DCE = 1,2-dichloroethane
NEt3= triethylamine
THF = tetrahydrofuran
PhCH3= toluene
Example 12a
All reagents were mixed together before adding the solvent. By chromatography was allocated to 108% (90 g) is specified in the header of the product (containing about 10% impurities). NMR showed no evidence of starting compound A. Koh(2 equiv.) DMAP (3 EQ.), DMAPHCl (2 EQ. in CHCl3and 1 EQ. compound B showed that the molar concentration of B, equal to 0.07 M, was not allowed to continue the reaction is fast enough to observe the formation specified in the header of the product by NMR for 27 hours).
Example 12b
All reagents were mixed together before adding the solvent. Specified in title product was obtained in relation to the original compound A, equal to about 9: 1 (NMR). By chromatography was allocated 87% (0,63 g) is specified in the header of the product.
Example 12c
All reagents were mixed together before adding the solvent. Specified in title product was obtained in relation to the original compound A, is approximately 1:1 (NMR). After 1 hour, the further progress of the reaction was not observed/
Example 12d
Within 1 hour was allowed for the formation of activated oxazoline B (by adding R2POCl to the original compound B) before adding the parent compound A. Specified in title product was obtained in relation to the original compound A, is equal to about 1:6 (NMR). After 5 hours the further course of the reaction was negligible.
Example 12e
Within 1 hour was carried out by contacting the CDI and ihtnologov connection in relation to the original compound A and impurities, approximately 1:1:1 (NMR). It was noted that prior to the addition of DMAP was no reaction and the excess heat causing some decomposition.
Example 12f
Last added ArCOCl. Has been specified in the header of the product to the original compound A, is approximately 1:1 (NMR). After 1.5 hours the further progress of the reaction was not observed.
Example 12g
Last added ArCOCl. Has been specified in the header of the product to the original compound A, is approximately 1:1 (NMR). After 1 hour, the further progress of the reaction was not observed.
Example 12h
Last added ArCOCl. Has been specified in the header of the product to the original compound A, is approximately 1:1 (NMR). There has been no further progress of the reaction was not observed after 3.5 hours.
Example 12i
Before adding the parent compound A provided pre-formation of a mixed anhydride for 1 hour (by adding t - BuCOCl to the original compound B). Received (NMR) specified in the header of the product to the original compound A, is equal to about 1:2. There has been no further progress of the reaction was observed after 2 hours.
Example 12j
Before adding the source soedinenijam the compound B). Received (NMR) specified in the header of the product to the original compound A, equal to about 3:1. No further progress was not observed after 1 hour.
Example 12k
Before adding the parent compound provided A preliminary formation of a mixed anhydride for 1 hour (by adding t - BuCOCl to the original compound B). Later, 1 hour after addition of the starting compound A was added DMAP. Received (NMR) specified in the header of the product to the original compound A, is equal to about 1:4. No reaction without DMAP was not observed; 2 hours after the addition of DMAP further progress of the reaction was not observed.
Example 12l
Before adding the parent compound provided A preliminary formation of a mixed anhydride for 1 hour (by adding t - BuCOCl to the original compound B). After 16 hours was added DMAP at 55oC. Received (NMR) specified in the header of the product to the original compound A, is equal to about 1:6. Before adding DMAP was not observed at all or there was very little reaction.
Getting 7-triethylsilyl-13-[[(4S-TRANS-4,5-dihydro-2,4 - diphenyl-5-oxazolyl]-carbonyl]baccatin III
In dried is about acid (65,0 mg, 0,243 mmol), 7-triethylcitrate III (0,142 g, 0,203 mmol), DCC (75 mg, 256 mmol) and pyrrolidinedione (38 mg, 256 mmol) and partially dissolved in toluene (1.0 ml). The obtained yellow heterogeneous mixture was stirred at room temperature. TLC after 3 hours showed the presence specified in the header of the product (EtOAc:hexane = 1:1, PMK/EtOH, UV). (TLC through 7 and 23 hours after mixing at room temperature showed no change).
The reaction mixture was diluted with ethyl acetate (1 ml), filtered through a layer of celite and concentrated, resulting in 0,275 g of an oily yellow solid. 1H NMR showed the desired specified in the header of the product and 7-triethylcitrate III ratio of about 8:1. Also attended containing N-allocatio by-product of combining agent in approximately the same amount as 7-triethylcitrate III.
The solid was chromatographically on silica gel with EtOAc:hexane = 1:2, resulting in 0,176 non-white solids. The output is approximately 92%.1H NMR showed only the target product combinations and N-allocatio in respect of approximately 11:1.
Getting 7-triethylsilyl-13-[[(4S-TRANS)-4,5-dihydr the coin was added (4S-TRANS)-4,5, -dihydro-2,4-diphenyl-5-oxazolidinone acid (66,7 mg of 0.250 mmol), 7-triethylcitrate III (0,146 g, 0,208 mmol), dicyclohexylcarbodiimide (79 mg, 0,383 mmol) and 4-morpholinopropan (41 mg, of 0.250 mmol) and partially dissolved in toluene (1 ml). The yellow heterogeneous mixture was stirred at room temperature. TLC after 3 hours showed the presence specified in the header of the product (ethyl acetate:hexane = 1: 1, PMK/EtOH, UV). (TLC through 7 and 23 hours after mixing at room temperature showed that no further changes have occurred).
The reaction mixture was diluted with ethyl acetate (1 ml), filtered through a layer of celite and concentrated, resulting in 0,280 g of yellowish solid.1H NMR showed the presence of the target specified in the header of product combinations and the lack of 7-creativemedia III (although the traces detected by TLC). Containing N-allocatio a byproduct of combining agent was present in relation to the headline product, equal to about 1:9.
The solid was subjected to chromatography on silica gel with EtOAc:hexane = 1:2 and received 0,196 g of a white solid.1H NMR showed only specified in the header of the combined product []578= -52,6, []546= -63,5, []436= -157,0 (C = 1,0, CHCl3).
Getting 7-triethylsilyl-13-[[(4S-TRANS)-4,5-dihydro-2,4 - diphenyl-5-oxazolyl] -carbonyl] baccatin III and 7-triethylsilyl - 13-[[(4S-CIS)-4,5-dihydro-2,4-diphenyl-5-oxazolyl]-carbonyl]- baccatin III
Prepare a mixture of CIS - and TRANS-oxazolinone products specified in the header of example 9, the ratio of CIS:TRANS = 3:1 (100 mg), 7-trisilicate III (219 mg, 0,3121 mmol), DCC (97 mg) and DMAP (23 mg) and toluene (0.9 ml). After 1 hour of heating at 80oC a significant amount of 7-triethylenemelamine III was unreacted. Added another sample DMAP (97 mg) and DCC (23 mg) and the mixture was heated at 80oC all night. Thin layer chromatography (TLC) (hexane:ethyl acetate = 2:1) showed the presence of minor quantities of source material.
The reaction mixture was diluted with methylene chloride (20 ml) was added a saturated solution of sodium bicarbonate (10 ml, aq.) and the water layer was extracted with methylene chloride /2 x 10 ml/, and the combined organic layers were dried over anhydrous MgSO4. After concentration in vacuo the product was purified by HPLC (hexane:ethyl acetate = 4:1) and received smese and remove some part of dicyclohexylamine by filtering the product weighed 260 mg. Another purification by HPLC gave 117 mg of pure specified in the header of the TRANS-product (45%) and 45 mg (15%) of the mixture specified in the header of the products (TRANS:CIS = 2:1). The mixture was purified by preparative TLC (hexane:ethyl acetate = 1:1) and obtained 11 g of CIS-product, specified in the header.
Receiving Taxol
Obtained in example 10 is specified in the header of product combinations (is 0.102 g, 0,107 mmol) were loaded into a flask with a capacity of 10 ml and was dissolved in tetrahydrofuran (1.2 ml). Then added methanol (1.2 ml), and the homogeneous solution was cooled to 0oC. was Added dropwise HCl in water., 1 N., of 0.59 ml, 0.59 mmol) and light the homogeneous solution was stirred at 0oC. After 3 hours finding at 0oC TLC (ethyl acetate:hexane = 1:1, PMK/ethanol, UV) showed that starting material remained, and bright, and the homogeneous solution was transferred to a cold place at 4oC. After 18 hours exposure at 4oC TLC analysis showed that the reaction is essentially completed (ethyl acetate : hexane = 1:1, PMK/ethanol, UV). Received the following connection:
Light the homogeneous solution was heated to room temperature. Added 3.5 ml of a saturated aqueous solution of NaHCO3(observed bubbling), resulting received erogenous the mixture is vigorously stirred at room temperature. After stirring at room temperature for 1 hour the mixture was still heterogeneous. Next, the mixture was diluted with 7 ml of water and 4 ml of tetrahydrofuran. The obtained light the homogeneous solution was stirred at room temperature.
TLC after 2 1/2 hours after adding NaHCO3showed only the presence of Taxol (ethyl acetate:hexane = 2:1, PMK/ethanol, UV). The reaction mixture was diluted with 25 ml ethyl acetate and 25 ml of water and shake. Shared layers, and the aqueous portion was extracted with ethyl acetate (3 x 25 ml). The combined organic fractions were dried over Na2SO4was filtered and concentrated, resulting in 104 mg not quite white glassy solid.1H NMR showed that the Taxol. The obtained solid was purified by chromatography on silica gel (column: diameter 20 mm and length 70 mm) at the ratio of ethyl acetate to hexane 2:1 to 4:1 and got 79,0 mg specified in the title compounds as white solids. Output 86.4 per cent.
Getting 7,13-bis TES baccatin
Baccatin III (3,102 g 5,290 mmol) was dissolved in dry dimethylformamide (DMF) (21 ml). To this solution at 0oC was added imidazole (1.80 g, of 26.5 mmol), and then chlorotrityl what Etat (350 ml) and washed with water (4x20 ml) and brine. The organic layer was dried and concentrated in vacuum and the residue was chromatographically (20% ethyl acetate in hexano) that gave 4,00 g (89,1%) of the target product.
Getting 1-DMS-7,13-TES baccatin
7,13-TES baccatin (2,877 g 3,534 mmol) was dissolved in dry DMF (17,7 ml). To this solution at 0oC was added imidazole (720,9 mg, or 10.60 mmol), and then dimethylchlorosilane (91,18 ml, or 10.60 mmol). The reaction mixture was stirred at the same temperature for 45 minutes and then was diluted with ethyl acetate (300 ml) and washed with water (4 x 20 ml). The organic phase was dried and concentrated in vacuum. The residue was chromatographically (10% ethyl acetate in hexano) and got 2,632 g (85,4%) of the target product.
Example 19.
Getting 4-hydroxy-7,13-bis TES-1-DMS baccatin
Siciliano derived baccatin from example 18 (815 mg, 0,935 mmol) was dissolved in THF (15.6 ml). To this solution at 0oC was added Red-Al (0,910 ml, 60 wt.%, 4,675 mmol). After 40 minutes the reaction abruptly stopped with saturated solution of sodium tartrate (7 ml). After 5 minutes the reaction mixture was diluted with ethyl acetate (250 ml). The organic phase is washed with water and brine, and dried. Then the organic layer was concentrated in vacuum and ostatniego baccatin.
Getting C-4-cyclopropylamino ether 7,13-bis TES-1-DMS baccatin
C-4 hydroxyl derivative baccatin from example 19 (196 mg, 0,236 mmol) was dissolved in dry THF (4,7 ml). This solution at 0oC was treated with LHMDS (0,283 ml, IM, 0,283 mmol) and after 30 minutes exposure at this temperature was added cyclopropanecarbonyl (to 0.032 ml, 0,354 mmol). The reaction mixture was stirred at 0oC for 1 hour and then abruptly cooled saturated solution of NH4Cl (3 ml). The reaction mixture was extracted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum. The obtained residue was chromatographically (10% ethyl acetate in hexano) and the result was 137 mg (65%) of the target product.
Getting C4-cyclopropylacetic
7,13-TES-1-DMS-4-cyclopropylacetic from example 20 (673 mg, 0,749 mmol) was dissolved in dry acetonitrile (6 ml) and THF (2 ml). To this solution at 0oC was added pyridine (2.25 ml), and then 48% HF solution (6,74 ml). After 30 minutes exposure at 0oC was added tetrabutylammonium (TBAF) (2.25 ml, 1 M, 2.25 mmol). Until was not consumed starting material (TLC analysis), added additional do ml) and washed with 1 N. HCl, a saturated solution of NaHCO3brine and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano), resulting in 366 mg (80%) of the target product.
Getting 7-TES-4-cyclopropylacetic
4-cyclopropylacetic from example 21 (46.6 mg, 0,076 mmol) was dissolved in dry dimethylformamide (1 ml). To this solution at 0oC was added imidazole (20.7 mg, 0,305 mmol). The reaction mixture was washed with water and brine, dried, and then concentrated in vacuum. The residue was chromatographically (30-50% ethyl acetate in hexano) and the result was 36 mg (65,1%) of the target product.
Getting 2',7-bis TES-4-cyclopropaneacetic
A solution of the compound from example 22 (30.0 mg, 0,0413 mmol) in THF (1 ml) was cooled to -40oC and was treated with LHMDS (0,062 ml, holding 0.062 mmol). After 5 minutes was added a solution of lactam (Ways of getting this - lactam described in U.S. patent N 5175315) (23,6 mg, holding 0.062 mmol) in THF (0.5 ml). The reaction mixture was stirred at 0oC for 1 hour and then abruptly cooled saturated solution of NH4Cl (1 ml). Next, the reaction mixture was extracted with ethyl acetate (40 ml) and washed with water and brine. The organic phase was dried and conc (53,6%) of the desired product together with 5.1 mg (17%) of the starting material.
Getting 4-cyclopropanol ester of paclitaxel
Solution in acetonitrile (0.5 ml) of the product from example 23 (22,0 mg, at 0.020 mmol) was treated at 0oC pyridine (0,60 ml), and then 48% HF solution (0,180 ml), the reaction mixture was kept at 5oC overnight, then was diluted with ethyl acetate (30 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano), resulting in 10 mg (57,2%) of the target product.
1H NMR (300 MHz, CDCl3): 8,10-of 8.06 (m, 2H), 7,76-7,26 (m, 13H),? 7.04 baby mortality (d, J = 9.1 Hz, 1H), 6,14 (m, 1H), of 5.82 (d, J = 9.1 Hz, 1H), 5,65 (d, J = 6,9 Hz, 1H), 4,85 (m, 2H), 4,39 (m, 1H), 4,19 (AB sq, J = 8,4 Hz, 2H), 3,80 (q, j = 6,9 Hz, 1H)and 3.59 (d, J = 4,8 Hz, 1H), 2,60-of 1.13 (m, 24H, incl. the singlets at 2,23, 1,77, 1,66, 1,23, 1,14, 3H each).
MCBP: calculated for C49H54NO14(MH+- 880,3544 found - 880,3523.
Getting 4-cyclobutyl ether 7,13-TES-1-DMS-baccatin
A solution of the product from example 19 (113,6 mg, 0,137 mmol) in THF (2.6 ml) was treated at 0oC LHMDS (0,178 ml, 1 M, 0,178 mmol). After 30 minutes exposure at 0oC was added cyclobutanecarbonitrile (24,4 mg, 0,206 mmol). The reaction mixture was stirred at 0oC for 1 hour and sharply romivani water and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (10% ethyl acetate in hexano) and received 80 mg (64,1% of the target product).
Getting 4-cyclobutylamine
To a solution of the compound from example 25 in acetonitrile (3 ml) at 0oC was added dry pyridine (0,61 ml), and then 48% HF (1,83 ml). After 1 hour exposure at 0oC was added tetrabutylammonium (and 0.61 ml, 1 M, 0.61 mmol). Until was not spent all the source material was added tetrabutylammonium. Then partially solvent was removed and the residue was diluted with ethyl acetate (150 ml) and washed with 1 N. hydrochloric acid and a saturated solution of NaHCO3. The organic layer then was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and received in the 95,6 mg (75%) of the target product.
Getting 4-cyclobutyl ester of 7-TES-baccatin
4-cyclobutylmethyl from example 26 (85 mg, 0,136 mmol) was dissolved in dry dimethylformamide (1.4 ml). To the solution at 0oC was added imidazole (36,9 mg, 0,543 mmol) and TESCl (91,2 μl, 0,543 mmol). The reaction mixture was diluted with ethyl acetate (75 ml) and washed with water and brine. Organic is the result received 74 mg (73.6 per cent) of the target product.
Getting 2',7-TES-4-cyclobutylmethyl
7-TES-4-cyclobutylmethyl from example 27 (41 mg, by 0.055 mmol) was dissolved in THF (1 ml). This solution was cooled to -40oC and was treated with LHMDS (0,083 ml, 1 M, 0,083 mmol), and then a solution of the lactam of example 23 (31.7 mg, 0,083 mmol) in THF (0.5 ml). The reaction mixture was kept at 0oC for 1 hour, and then abruptly cooled NH4Cl (2 ml). Next, the reaction mixture was extracted with ethyl acetate (50 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum and the residue was chromatographically (20-30% ethyl acetate in hexano), resulting in 56 mg (90.2 per cent) of the target product.
Getting 4-cyclobutylmethyl
2', 7-TES-4-cyclobutylmethyl from example 28 (47 mg, 0,042 mmol) was dissolved in acetonitrile (1 ml), to this solution at 0oC was added pyridine (0,125 ml), and then 48% HF (0,375 ml). The reaction mixture was kept at 5oC all night. Then the reaction mixture was diluted with ethyl acetate (50 ml) and washed with 1 N. HCl, a saturated solution of NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and received as a result of 31.8 mg (84,9%) a, H) 5,80 (d, J = 9.0 Hz, 1H), 5,66 ( doctor J = 7,1 Hz, 1H), a 4.83 (m, 2H), to 4.41 (m, 1H), 4.26 deaths (AB kV, J = 8,4 Hz, 2H), 3,78 (d, J = 7,0 Hz, 1H), 3,57 (d, J = 5,2 Hz, 1H), 3,42 (m, 1H) 2,61-1,14 (m, 25H, incl. the singlets at 2,23, 1,76, 1,68, 1,23, 1,14, 3H each).
MCBP: calculated for C50H56NO14(MH+) - 894,3701 found - 894,3669.
Getting 4-cyclopentenone ether 7,13-TES-1-DMS-baccatin
A solution of the compound from example 19 (147 mg, 0,177 mmol) in THF (3.5 ml) was treated at 0oC LHMDS (0,230 ml, 1 M, 0,230 mmol). After 30 minutes, was added cyclopentanecarbonitrile (32,3 μl, 0,266 mmol). The reaction mixture at the same temperature was stirred for 1 hour, and then abruptly cooled saturated solution of NH4Cl. Next, the reaction mixture was extracted, washed, dried and concentrated in vacuum. The residue was chromatographically (10% ethyl acetate in hexano) and got in the 90 mg (55%) of the target product.
Getting 4-cyclopentylacetic
A solution of the product from example 30 (75 mg, of 0.081 mmol) in acetonitrile (1.6 ml) was treated at 0oC pyridine (0,24 ml), and then 48% HF (0,72 ml). The reaction mixture was stirred at 0oC for 1 h, then was added tetrabutylammonium (0,405 ml, 1 M, 0,405 mmol). After 1 hour debasement solution of NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (50% ethyl acetate in hexano) and received 44 mg (85%) of the target product.
Getting 4-cyclopentenone ester of 7-TES-baccatin
Cyclopentylacetyl (35 mg, by 0.055 mmol) was dissolved in dry dimethylformamide (1 ml). To this solution at 0oC was added imidazole (14,9 mg, 0,219 mmol), and then TESCl (36 μl, 0,219 mmol). The reaction mixture was stirred at 0oC for 30 minutes and was diluted with ethyl acetate (50 ml). The organic layer was washed and dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano), resulting in 31 mg (75%) of the target product.
Getting 4-cyclopentenone ester of 2',7-TES-baccatin
A solution of the product from example 32 (24.5 mg, 0,0324 mmol) in THF (0.6 ml) was treated at -40oC LHMDS (0,049 ml, 1 M, 0,049 mmol) and then a solution of the lactam of example 23 (18.6 mg, 0,049 mmol) in THF (0.3 ml). The reaction mixture was stirred at 0oC for 1 hour and then abruptly cooled saturated solution of NH4Cl. Next, the reaction mixture was extracted with ethyl acetate (35 ml) and washed, and then dried and concentrated what about the product together with 7.8 mg (31,8%) of unreacted starting material.
Getting 4-cyclopentenone ester of paclitaxel
A solution of the product in example 33 (13 mg, 0,0115 mmol) in acetonitrile 0.3 ml) was treated at 0oC pyridine (or 0.035 ml), and then 48% HF (0,103 ml). The reaction mixture was kept at 5oC all night. Then the reaction mixture was diluted with ethyl acetate (30 ml) and washed with 1 N. HCl, NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (50% ethyl acetate in hexano) and received as a result of 7.3 mg (70.3 per cent) of the target product.
1H NMR (300 MHz, CDCl3): 8,17-to 8.14 (m, 2H), 7,74-7,26 (m, 13H), of 6.90 (d, J = 8,9 Hz, 1H), 6,27 (s, 1H), 6,20 (m, 1H), of 5.75 (d, J = 8,9 Hz, 1H), 5,69 (d, J = 7,0 Hz, 1H), 4,79 (m, 2H), of 4.44 (m, 1H), 4,24 (AB kV, J = 8,4 Hz, 2H), 3,81 (d, J = 7,0 Hz, 1H), 3.46 in (d, J = 4,7 Hz, 1H), 3,06 (m, 1H) 2,56-1,15 (m, 27H, incl. the singlets at 2,24, 1,82, 1,68, 1,33, 1,15, 3H each).
MCBP: calculated for C51H57NO14Na(MNa+) - 930,3677 found 930,3714.
Getting 2',7-similarvideo-4-cyclopropylamino with fullaway side chain
A solution of the product from example 22 (or 75.8 mg, 0.104 g mmol) in THF (2 ml) was treated at -40oC LHMDS (0,136 ml, 1 M, 0,136 mmol) and the lactam (methods of obtaining beta-lactam described in U.S. patent N 5227400) systems (57.3 mg, 1,156 mmol). Rea is a thief NH4Cl (1 ml). The reaction mixture was then extracted with ethyl acetate, washed and dried and concentrated in vacuum. The residue was chromatographically (20% ethyl acetate in hexano) and received in the result of 113 mg (100%) of the target product.
A = Benzyloxycarbonyl
B = 2-Furyl
D = Silyl protective group
Getting 4-cyclopropylamino ether taxane with fullaway side chain
A solution of the product in example 35 (2 ml) in acetonitrile was treated at 0oC pyridine (0,27 ml), and then 48% HF (0,81 ml). The reaction mixture was kept at 5oC for 3 hours, diluted with ethyl acetate (75 ml) and washed with 1 N. HCl, a saturated solution of NaHCO3, brine and dried and concentrated in vacuum. The residue was chromatographically (50-60% ethyl acetate in hexano) and received 68 mg (88,2%) of the target product.
1H NMR (300 MHz, CDCl3): 8,09-of 8.06 (m, 2H), 7,62-7,37 (m, 3H), 7,26 (s, 1H), 6,37-6,30 (m, 3H), to 6.19 (m, 1H), 5,65 (d, J = 7,0 Hz, 1H), lower than the 5.37 (d, J = 9.9 Hz, 1H), 5,23 (d, J = 9.9 Hz, 1H), 4,82 (d, J = 8,3 Hz, 1H), amounts to 4.76 (d, J = 4,1 Hz, 1H), 4,42 (m, 1H), 4,18 (AB kV, J = 8,4 Hz, 2H), 3,85 (d, J = 6,9 Hz, 1H), 3,37 (d, J = 5.4 Hz, 1H), 2,55-a 1.01 (m, 33H, incl. the singlets at 2,23, 1,90, 1,66, 1,26, 1,14, 3H each, 1,33 9H).
MCBP: calculated for C45H56NO16(MH+) - 866,3599 found - hand side chain
A solution of the product from example 22 in THF (0.8 ml) was treated at -40oC LHMDS (0,050 ml, 1 M, 0,050 mmol). After 2 minutes added-lactam of example 35 (18.2 mg, 0,050 mmol). The reaction mixture was stirred at 0oC for 1 hour and cooled by mixing with a saturated solution of NH4Cl. The reaction mixture then was extracted and washed, and then dried and concentrated in vacuum. The residue was chromatographically (20% ethyl acetate in hexano) and the result was of 33.0 mg (89.4 per cent) of the target product.
Getting 4-cyclobutyl ether taxane with fullaway side chain
A solution of the product from example 37 (30 mg, or 0.027 mmol) in acetonitrile (1 ml) was treated at 0oC pyridine (of 0.081 ml), and then 48% HF (0,243 ml). The reaction mixture was kept at 5oC overnight and was diluted with ethyl acetate (50 ml), washed with 1 N. HCl, a saturated solution of NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and 22 mg (92.4 per cent) of the target product.
1H NMR (300 MHz, CDCl3): 8,13-8,10 (m, 2H), 7,62 was 7.45 (m, 3H), 6.42 per-6,38 (m, 3H), 6.30-in (s, 1H), to 6.19 (m, 1H), 5,65 (d, J = 7,1 Hz, 1H), of 5.34 (d, J = 9.6 Hz, 1H), 5,18 (d, J = 9.8 Hz, 1H), 4,90 (d, J = 7.7 Hz, 1H), 4,73 (DD, J = 2.0 Hz, J = 5,7, ,26, of 1.15, 3H each, 1,33 9H).
Getting 7,13-TES-1-DMS-4-butylamphetamine
C4-hydroxyl derivative baccatin from example 19 (181 mg, 0,218 mmol) was dissolved in dry THF (4.4 ml). This solution at 0oC was treated with LHMDS (0,262 ml, 1 M, 0,262 mmol) and after 30 minutes at this temperature was added butyrylcholine (0,34 ml, 0.33 mmol). The reaction mixture was stirred at 0oC for 1 hour, and then abruptly cooled by mixing with saturated NH4Cl (3 ml). Next, the reaction mixture was extracted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum. The obtained residue was chromatographically (10% ethyl acetate in hexano) and the result was 138 mg (70.3 per cent) of the target product.
Getting C4-Butrimova ether baccatin
7,13-TES-I-DMS-4-Butylacrylate from example 39 (527 mg, 0,586 mmol) was dissolved in dry acetonitrile (19,5 ml). To this solution at 0oC was added pyridine (1,95 ml), and then 48% HF solution (5,86 ml). After 30 minutes exposure at 0oC the reaction mixture was kept at 5oC all night. Then was diluted with ethyl acetate (400 ml) and washed with 1 N. HCl, a saturated solution of NaHCO3brine and ptx2">
Getting 7-TES-4-butylamphetamine
4-Butyrylacetate from example 40 (286 mg, 0,466 mmol) was dissolved in dry dimethylformamide (2.3 ml). To this solution at 0oC was added imidazole (127 mg, of 1.86 mmol), and then TESCl (0,313 ml of 1.86 mmol). The reaction mixture was stirred at 0oC for 30 minutes and then was diluted with ethyl acetate (100 ml). Next, the reaction mixture was washed with water and brine and dried, and then concentrated in vacuum. The residue was chromatographically (30-50% ethyl acetate in hexano) and got the result is 283.3 mg (83.5 per cent) of the target product.
Getting 2',7-bis TES-C-4-butyraldoxime
A solution of the product from example 41 (300,6 mg, 0,413 mmol) in THF (8,3 ml) was cooled to - 40oC and was treated with LHMDS (0,619 ml, 0,619 mmol). After 5 minutes was added a solution of the lactam of example 23 (236 mg, 0,619 mmol) in THF (4,1 ml). The reaction mixture was stirred at 0oC for 1 minute and then cooled mixture with a saturated solution of NH4Cl (3 ml). Next, the reaction mixture was extracted with ethyl acetate (150 ml) and washed with water and brine. The organic phase was dried and concentrated in vacuum. The residue was chromatographically (20-30-60% ethyl acetate in hexano) and received 377 mg (82.3 per cent) of Calimera 42 (366 mg, 0,334 mmol) in acetonitrile (15.3 ml) was treated at 0oC pyridine (0,926 ml), and then 48% HF solution (2,78 ml). The reaction mixture was kept at 5oC overnight and was diluted with ethyl acetate (200 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and received in the 274 mg (94,5%) of the target product.
1H NMR (300 MHz, CDCl3): 8,12-of 8.09 (m, 2H), 7,71-7,32 (m, 13H), 7,00 (d, J = 8,9 Hz, 1H), and 6.25 (s, 1H), 6,16 (m, 1H), 5,73 (d, J = 8,8 Hz, 1H), 5,64 (d, J = 7,0 Hz, 1H), around 4.85 (d, J = 9.4 Hz, 1H), amounts to 4.76 (m, 1H), to 4.38 (m, 1H), 4,20 (AB kV, J = 8,4 Hz, 2H), of 3.77 (d, J = 6,9 Hz, 1H), 3,70 (d, J = 4.3 Hz, 1H), 2,66-0,85 (m, 26H, incl. the singlets at 2,20, 1,76, 1,65, 1,21, 1,11, 3H each, a triplet at 0,88 3H).
Getting 7,13-TES-1-DMS-ethylcarbodiimide
A solution of the product from example 19 (205 mg, 0,247 mmol) in THF (5 ml) was treated at 0oC LHMDS (0,296 ml, 1 M, 0,296 mmol). After 30 minutes exposure at 0oC was added ethylchloride (0,0354 ml, 0,370 mmol). The reaction mixture was stirred at 0oC for 1 hour and cooled by mixing with a saturated solution of NH4Cl (3 ml). Next, the reaction mixture was extracted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried and concentrated in x2">
Getting C4-acylcarnitine
To a solution of the product from example 44 (152 mg, 0,169 mmol) in acetonitrile (5.6 ml) at 0oC was added dry pyridine (of 0.56 ml), and then 48% HF solution (1,69 ml). After 30 minutes exposure at 0oC the reaction mixture was stirred all night at the 5oC. Then the residue was diluted with ethyl acetate (150 ml) and washed with 1 N. hydrochloric acid and a saturated solution of NaHCO3. The organic layer was dried and concentrated in vacuum. The obtained residue was chromatographically (60% ethyl acetate in hexano) and received in the result of 99 mg (95.4% of the target product).
Getting 7-TES-C4-acylcarnitine
4-Ethylcarbonate from example 45 (95 mg, 0,154 mmol) was dissolved in dry dimethylformamide (0,771 ml). To this solution at 0oC was added imidazole (42 mg, 0,617 mmol) and TESCl (104 μl, 0,617 mmol). The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano) and received in the result of 95 mg (84.4 per cent) of the target product.
Getting 2',7-TES-C4-ethylcarbonate
7-TES-C4-ethylcarbonate from the use of the LHMDS (0,192 ml, 1M, 0,192 mmol), and then a solution of the lactam of example 23 (73,1 mg, 0,192 mmol) in tetrahydrofuran (1.3 ml). The reaction was carried out at 0oC for 1 hour and stopped by mixing with NH4Cl (3 ml). The reaction mixture was extracted with ethyl acetate (10 ml) and washed with water and brine. The organic layer was dried and concentrated in vacuum and the residue was chromatographically (20-30% ethyl acetate in hexano), resulting in 118 mg (83.0 per cent) of the target product.
Getting C4-ethylcarbonate
2', 7-TES-4-ethylcarbonate from example 47 (114 mg, 0,103 mmol) was dissolved in acetonitrile (5,1 ml) and to this solution at 0oC was added pyridine (0,285 ml), and then 48% HF (0,855 ml). The reaction was carried out at the 5oC all night. Then the reaction mixture was diluted with ethyl acetate (100 ml), washed with 1 N. HCl, a saturated solution of NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and received 75 mg (82,8%) of the target product.
1H NMR (300 MHz, CDCl3): 8,09-of 8.06 (m, 2H), 7,75-7,24 (m, 13H), 7,14 (d, J = 9.0 Hz, 1H), 6,24 (s, 1H), 6,10 (m, 1H), 5,79 (d, J = 7,1 Hz, 1H), to 5.66 (d, J = 6,9 Hz, 1H), 4.95 points (d, J = 8,2 Hz, 1H), and 4.75 (m, 1H), to 4.41-4,16 (m, 5H), the 3.89 (d, J = 4.3 Hz, 1H), 3,81 (d, J = 6,9 Hz, 1H), 2,56-1,11 (m, 23H, incl. the CSO-C4-butyrolactone with fullaway side chain
A solution of 7-silyl-4-butylamphetamine from example 41 (266 mg, 0,365 mmol) in THF (7.3 ml) was treated at -40oC LHMDS )0,548 ml, 1 M, 0,548 mmol). After 2 minutes the solution was added to the lactam of example 35 (201 mg, 0,548 mmol) in tetrahydrofuran (3.6 ml). The reaction mixture was stirred at 0oC for 1 hour and cooled by mixing with a saturated solution of NH4Cl. Next, the reaction mixture was extracted and washed, dried and concentrated in vacuum. The residue was chromatographically (20% ethyl acetate in hexano), resulting in 399,0 mg (99%) of the target product.
Getting C4-butyrolactone with fullaway side chain
A solution of the product from example 49 (399 mg, 0,364 mmol) in acetonitrile (18.2 ml) was treated at 0oC pyridine (1,01 ml), and then 48% HF (3,03 ml). The reaction mixture was kept at 5oC overnight, then was diluted with ethyl acetate (200 ml), washed with 1 N. HCl, a saturated solution of NaHCO3and brine. Then the organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and got 305 mg (96,5%) of the target product.
1H NMR (300 MHz, CDCl3): 8,05-8,02 (m, 2H), 7,56-7,35 (m, 4H), 6,33-of 6.26 (m, 3H), x 6.15 (m, 1H), 5,59 (d, J = 7,0 Hz, 1H), of 5.40 (d, J = 9,7 MCP, incl. the singlets at 2,18, 1,82, 1,62, 1,21, 1,09, 3H each, 1,28, 9H, triplet when 0,94 3H).
Getting 7,13-bis TES-1-DMS-C4-methylcarbonate
The compound from example 19 (118 mg, 0,150 mmol) was dissolved in THF (3 ml). To this solution at 0oC was added LHMDS (0,180 ml, 1 M, 0,180 mmol). After 30 minutes, was added methylchloroform (0,174 ml, 0,225 mmol). After another 30 minutes the reaction was stopped by mixing with NH4Cl. The reaction mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with water (10 ml x 2) and brine (10 ml). Then the organic phase was dried and concentrated in vacuum. The residue was chromatographically (5-10% ethyl acetate in hexano) and resulted from 104 mg (82.1% of the target product.
Getting C4-methylcarbonate
The compound from example 51 (89,0 mg, 0,105 mmol) was dissolved in CH3CN (3.5 ml). To this solution at 0oC was added pyridine (0,30 ml), and then 48% HF (1,05 ml). The reaction mixture was stirred at 0oC for 6 hours and then was diluted with ethyl acetate (100 ml). Next, the reaction mixture was washed with 1 N. HCl (10 ml) and a saturated solution (NaHCO3(10 x 3). The organic phase was dried and concentrated in vacuum. The residue was chromatographically (50% EtOAc/hexane) - Rev. < / BR>
The compound from example 52 (115.5 mg, 0,192 mmol) was dissolved in dimethylformamide (0,960 ml). To this solution at 0oC was added imidazole (52,2 mg, 0,767 mmol), and then TESCl (0,128 Il 0,767 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate (100 ml). The organic layer was washed with water (10 ml x 2) and brine (10 ml). Then the organic phase was dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano) and received in the 133 mg (96.8 per cent) of the target product.
Getting 2',7-similarvideo-C4-methylcarbamates with fullaway side chain
A solution of 7-silyl-4-methylcarbonate from example 53 (227,8 mg, 0,318 mmol) in THF (6.4 ml) was treated at -40oC LHMDS (0,350 ml, 1 M, 0,350 mmol). After 2 minutes was added a solution of the lactam of example 35 (140 mg, 0,382 mmol) in THF (3.6 ml). The reaction mixture was stirred at 0oC for 1 hour and cooled by mixing with a saturated solution of NH4Cl. Next, the reaction mixture was extracted and washed, and then dried and concentrated in vacuum. The residue was chromatographically (20% ethyl acetate in hexano) and received in the 332,0 mg (96,3%) of the target product.
Getting C4-methylcarbamates with f is atively at 0oC pyridine E. (1.7 ml), and then 48% HF (5,1 ml). The reaction mixture was kept at 5oC overnight, then was diluted with ethyl acetate (200 ml) and washed with 1 N. HCl, a saturated solution of NaHCO3and brine. Then the organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano) and received 260 mg (99,0%) of the target product.
1H NMR (300 MHz, CDCl3): 8,05-8,02 (m, 2H), 7,53-7,37 (m, 4H), 6,29-x 6.15 (m, 4H), 5,62 (d, J = 6,9 Hz, 1H), of 5.40 (d, J = 9.6 Hz, 1H), and 5.30 (d, J = 9.6 Hz, 1H), 4,91 (d, J = 9,3 Hz, 1H), and 4.68 (m, 1H), 4,34 (m, 1H), 4.16 the (AB kV, J = 8.5 Hz, 2H), 3,88 (c, 3H), 3,80 (d, J = 8,9 Hz, 1H), 3,69 (d, J = 5.5 Hz, 1H), 2,63-1,08 (m, 28H, incl. the singlets at 2,18, 1,85, 1,60, 1,20, 1,08, 3H each, 1,26, 9H).
Getting 2',7-similarvideo-C4-methylcarbonate
The compound of example 53 (113,3 mg, 0,158 mmol) was dissolved in THF (3,16 ml). To this solution at -40oC was added 1 HM (0,237 ml, 1 M, 0,237 mmol), and then-lactam of example 23 (90,43 mg, 0,237 mmol). Following the same procedure as described above, received 159 mg (of 91.6%) of the target product.
The compound of example 56 (149 mg, 0,136 mmol) was dissolved in CH3CN (6.8 ml). To this solution at 0oC was added pyridine (0,377 ml), and then 48%-Mer 58
Getting C4-cyclopropylamino ester of 7-TES-13-ocsillating
To a suspension of the product from example 22 (72 mg, 0,099 mmol) and the product from example 6 (of 29.4 mg, 0,110 mmol) in toluene (2 ml) at room temperature was added 4-dimethylaminopyridine (DMAP) (13,4 mg, 0,110 mmol). After 10 minutes, was added dicyclohexylcarbodiimide (DCC) (22,6 mg, 0,110 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then the reaction mixture was filtered through celite and washed with ethyl acetate. The organic layer was concentrated in vacuum. The residue was chromatographically (30% ethyl acetate in hexano) and got the desired product (99 mg) with a yield of 100%.
1H NMR (CDCl3): 8,27-8,24 (m, 2H), 8,03-7,26 (m, 13H), 6.42 per (s, 1H), between 6.08 (m, 1H), 5,67 (d, J = 7,0 Hz, 1H), ceiling of 5.60 (d, J = 6.0 Hz, 1H), 4.92 in (d, J = 6,1 Hz, 1H), 4,87 (d, J = 8,3 Hz, 1H), 4,50 (DD, J = 6,6 Hz, J = 10.3 Hz, 1H), 4,16 (AB kV, J = 8,3 Hz, 2H), 3,85 (d, J = 6,9 Hz, 1H), 2,56-0,52 (m, 39H, incl. the singlets at 2,15, 2,02, 1,68, 1,20, 1,18, 3H each triplet in 0,92, 9H).
MCBP: calculated for C55H66NO13Si (MH+) - 976,4303 found - 976,4271.
Getting C-4 cyclopropylamino ester of paclitaxel
To a solution of the product from example 58 (of 83.4 mg, 0,084 mmol) in THF (0.8 ml) and methanol (0.8 ml) at 0oC was added 1 N. HCl (0,42 ml). The reaction mixture holds the target NaHCO3(2.1 ml). Next, the reaction mixture was stirred at room temperature for 3 hours, then was poured into H2O and was extracted with ethyl acetate (4 x 20 ml). The combined organic layer was dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano), resulting in the desired product (45 mg) with a yield of 60%.
In kiln dried and purged with argon, the flask with a capacity of 25 ml was dissolved BMS-189892-01 (485 mg, 3.0 mmol) (note 1) in dry methanol (5 mg). To this flask was added dropwise via syringe trimethylsilanol (326 mg, 3.0 mmol) at 0oC. the Reaction mixture was stirred at 0oC for 5 minutes, and then deleted the vodoledyanym bath. Next, the reaction mixture was stirred 14 hours at room temperature. Then the reaction mixture was concentrated in vacuo and dried under high vacuum, resulting in compound 1 (691 mg), 100%) as a white foam.
1. Chem Abs.: 34408-064-33.
In the flask with a capacity of 25 ml was dissolved in a saturated solution of NaHCO3(10 ml) obtained in example 60 compound 1 (691 mg, 3.0 mol). To this solution was added benzoylchloride (512 mg, 3.0 mmol) at room temperature. The reaction mixture Preselectable and washed with water (2 x 5 ml) and hexane (2 x 5 ml). The solid was dried under high vacuum, giving the product 2 as a white solid (745 mg, 86%).
In kiln dried and purged with argon, the flask with a capacity of 25 ml, equipped with a trap Dean-stark was dissolved compound 2 (745 mg, 2.58 mmol) in toluene (12 ml) and dimethylformamide (2.5 ml). To this solution was added pyridinium paratoluenesulfonyl (502 mg, 2.0 mmol). The reaction mixture was heated under reflux with stirring for 28 hours. Next, the mixture was diluted with ethyl acetate (50 ml) and washed with water (20 ml). The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo, resulting in the crude product 3 (630 mg, 77%) as a dark oil. The crude product 3 was purified by column chromatography (silica gel, column 2 x 12 cm, 10% ethyl acetate in hexane as eluent), resulting in the product 3 as a thick colorless oil (540 mg, 66%).
In the flask with a capacity of 25 ml was dissolved product 3 (540 mg, 2.1 mmol) in THF (6 ml) and H2O (3 ml). To this solution was added in one portion at room temperature solid 1 OH (82 mg, 2,0 mmol ml of 1 N. solution) dropwise at room temperature. Then the mixture was poured into H2O (10 ml), was extracted with CH2Cl2(4 x 15 ml), dried over MgSO4, filtered and concentrated in vacuo, resulting in the crude product 4 (420 mg, 82%) as a yellow oil which was used directly in the next stage without further purification.
In kiln dried and purged with argon, the flask with a capacity of 25 ml suspended in toluene (10 ml) at room temperature product 4 (140 mg, 0.54 mmol), VM-184260-01 (346 mg, 0,495 mmol) and dimethylaminopyridine (66 mg, 0.54 mmol). After stirring the suspension for 20 minutes was added in one portion 1,3-dicyclohexylcarbodiimide (CC) (111 mg, 0.54 mmol) and the mixture was stirred at room temperature for 2 hours. Then to the reaction mixture was added dimethylaminopyridine (66 mg, 0.54 mmol) and 1,3-dicyclohexylcarbodiimide (CC) (111 mg, 0.54 mmol). The reaction mixture was stirred for 14 hours. Next, the mixture was poured into a saturated solution of H4Cl (20 ml) and was extracted with ethyl acetate (100 ml). The organic extract was filtered through celite, after which the layer of celite washed with ethyl acetate (4 x 50 ml). The combined organic layers were dried over MgSO4was filtered and the end column chromatography (silica gel, 2 x 12 cm, 5% ethyl acetate in hexane as eluent) and received the product 5 (413 mg, 89% in the form of a colorless oil.
In kiln dried and purged with argon, the flask with a capacity of 25 ml was dissolved in THF (2.0 ml) and methanol (2.0 ml) 5 product (92 mg, 0,094 mmol). To this flask was added aqueous HCl (0.5 ml of a 2.0 n solution) at 0oC. Then the solution was placed in cold (6oC) bath for 14 hours. The reaction mixture was heated to room temperature and the flask was added a saturated solution of NaHCO3(5.0 ml). The reaction mixture was stirred 3 hours at room temperature. Next was poured into H2O (10 ml) and was extracted with CH2Cl2(4 x 20 ml). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo, resulting in the crude product (70 mg) as a white solid. To a hot solution of the crude product, dissolved in CH3OH (3.0 ml) was added H2O (about 1.0 ml) until the solution became turbid. The solution was cooled in the refrigerator overnight. Was filtered white solid, using the average filter with a porous glass plate, and dried under high vacuum, resulting in a horse is about ether 7-TES baccatin C-13 occaionally side chain
To a suspension in toluene (2.5 ml) of the product from example 22 (92,3 mg, to 0.127 mmol) and the product from example 63 (36,0 mg, 0,140 mmol) at room temperature was added 4-dimethyl aminopyridine (17,1 mg, 0,140 mmol). After 10 minutes, was added DCC (28.8 mg, 0,140 mmol). After 2 hours exposure at room temperature was added a second portion of the reactants. The reaction mixture was stirred overnight at room temperature. Then the reaction mixture was filtered and washed with ethyl acetate. The organic layer was concentrated in vacuum. The residue was chromatographically (30% ethyl acetate in hexano) and received in the target product (125 mg) with a yield of 100%.
1H NMR (CDCl3): 8,20-7,80 (m, 4H), 7,62-7,39 (m, 7H), 6,38 (m, 3H), between 6.08 (m, 1H), 5,67 (m, 2H), 5,20 (d, J = 5,9 Hz, 1H), 5,20 (d, J = 5,9 Hz, 1H), 4,88 (d, J = 9,2 Hz, 1H), 4,49 (DD, J = 6,6 Hz, J = 10,2 Hz, 1H), 4.16 the (AB kV, J = 8,4 Hz, 2H), 3,86 (d, J = 6,8 Hz, 1H), 2,54-0,52 (m, 39H, incl. the singlets at 2,14, 2,03, 1,67, 1,21, 1,15, 3H each triplet in 0,91, 9H).
Getting C-4 cyclopropylamino ether taxane with fullaway side chain
The compound of example 66 (69 mg, 0,0715 mmol) was dissolved in THF (1.4 ml) and MeOH (1.4 ml). Then this solution was treated at 0oC 1 N. s and was treated with a saturated solution of NaHCO3(6.5 ml). After 6 hours exposure at room temperature, the reaction mixture was extracted with ethyl acetate (4 x 20 ml). The combined organic layer was concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano), which gave the target product (or 37.4 mg) with a yield of 60%.
1H NMR (CDCl3): 8,12-of 8.09 (m, 2H), 7,74-7,26 (m, 7H), 6,85 (d, J = 9,3 Hz, 1H), 6,39 (s, 2H), 6.30-in (s, 1H), 6,20 (m, 1H), to 5.93 (d, J = 9,3 Hz, 1H), 5,67 (d, J = 7,0 Hz, 1H), 4,88 (s, 1H), 4,82 (d, J = 7.7 Hz, 1H), 4,42 (m, 1H), 4,20 (AB kV, J = 8.5 Hz, 2H), 3,85 (d, J = 6,8 Hz, 1H), 2,54-0,88 (m, 24H, incl. the singlets at 2,23, 1,88, 1,67, 1,24, 1,14, 3H each).
Getting C-4 cyclopropylamine ether-2'-ethylcarbonate
To a solution of the product from example 24 (1,333 g of 1.52 mmol) in dichloromethane (22,8 ml) at 0oC was added EtPr2N (1,586 ml, 9,10 mmol), and then EtOCOCl (of 0.87 ml, 9,10 mmol). The reaction mixture was stirred at 0oC for 6 hours. Then the reaction mixture was diluted with ethyl acetate (200 ml), washed with water (20 ml x 3) and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (50% ethyl acetate in hexano) and received in the target product (1,281 g) opening and 88.8% with 86 mg ex is, = 2.1 Hz, J' = 9,3 Hz, 1H), of 5.68 (d, J = 7,0 Hz, 1H), 5,55 (d, J = 2.4 Hz, 1H), a 4.83 (d, J = 8,2 Hz, 1H), of 4.44 (m, 1H), 4,23 (m, 1H), 3,83 (d, J = 7,0 Hz, 1H), 2,53-0.87 (m, 27H, incl. the singlets at 2,22, 0,95, 1,87, 1,67, 1,26, 3H each triplet when 1,32, 3H).
Getting C-4 cyclopropane-2'-ethylcarbonate-7-substituted precursor
2'-Ethylcarbonate from example 68 (53 mg, 0,056 mmol) was dissolved in dimethyl sulfoxide (0.5 ml), then added Ac2O (0.5 ml). The reaction mixture was stirred at room temperature for 14 hours. Then the mixture was diluted with ethyl acetate (50 ml), washed with water (5 ml × 3), saturated solution of NaHCO3and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano) and as a result got 56,3 mg of the desired product with a yield of 100%.
1H NMR (CDCl3): 8,10-8,07 (m, 2H), 7,76-7,26 (m, 13H), of 6.90 (d, J = 9.4 Hz, 1H), 6,56 (s, 1H), 6,23 (m, 1H) 6,03 (d, J = 9.5 Hz, 1H), 5,70 (d, J = 6,9 Hz, 1H), 5,58 (d, J = 2.1 Hz, 1H), 4,84 (d, J = 8,9 Hz, 1H), 4,66 (c, 2H), is 4.21 (m, 5H), 3,91 (d, J = 6,8 Hz, 1H), 2,80-0.87 (m, 30H, incl. the singlets at 2,17, 2,12, 2,11, 1,75, 1,22, 1,20, 3H each triplet when 1,32, 3H).
Getting C-4 cyclopropane-2'-ethylcarbonate-7-phosphate predecessor
(1.30 grams), and then a solution of NIS (434 mg, 1,929 mmol) in THF (25.7 mm) and diversificat (537 mg, 1,929 mmol). The reaction mixture was stirred at room temperature for 5 hours. Then the reaction mixture was filtered through celite, washed with ethyl acetate. Solvent was removed and the residue was dissolved in ethyl acetate (200 ml), washed with 1% solution of NaHSO3and brine and dried over MgSO4. The organic phase was concentrated in vacuum. The residue was chromatographically (50% ethyl acetate in hexano) and got 1,278 mg of product with a yield of 80.1%.
1H NMR (CDCl3): 8,10-8,07 (m, 2H), 7,76-7,26 (m, 23H), of 6.90 (d, J = 9.4 Hz, 1H), 6.35mm (s, 1H), 6,23 (m, 1H) 6,02 (d, J = 9.5 Hz, 1H), of 5.68 (d, J = 6,8 Hz, 1H), 5.56mm (s, 1H), 5.40 to (m, 1H), 5,04 (m, 4H), and 4.75 (d, J = 9.0 Hz, 1H), 4,20 (m, 5H), to 3.89 (d, J = 6,8 Hz, 1H), 2,78 is 0.86 (m, 27H, incl. the singlets at 2,18, 1,99, 1,67, 1,18, 1,05, 3H each triplet when 1,31, 3H).
Getting C-4 cyclopropane-2'-ethylcarbonate-7-phosphate
The compound of example 70 (1,278 g of 1.03 mmol) was dissolved in dry acetonitrile (41,2 ml). To this solution was added Pd/C catalyst (438 mg, 10%, 0,412 mmol). The reaction mixture was first made at 50 psig (3.5 kg/cm2within 12 hours. Then the reaction mixture was filtered and concentrated in vacuo, resulting in a 1.08 g of the crude product with vyhoda the
Getting triethylamine salt C-4-cyclopropane-2'-ethylcarbonate-7-phosphate
To a solution of the product from example 71 (1.08 g, of 1.02 mmol) in ethyl acetate (6.8 ml) was added 0,100 m solution of triethanolamine (6.8 ml, 0.15 M) in ethyl acetate. The resulting mixture was kept at -20oC all night. Then the mixture was filtered, the solid washed with cold mixture of 10% ethyl acetate and hexane, and dried under vacuum for 12 hours, resulting in targeted drug precursor (1,00 g) with a yield of 81.2 per cent. The purity of the final product was determined by HPLC, which gave approximately 97% purity.
1H NMR (CD3OD): 8,10-8,07 (m, 2H), 7,80-7,26 (m, 14H), 6,38 (s, 1H), 6,07 (m, 1H), of 5.89 (d, J = 5,2 Hz, 1H), 5,63 (d, J = 7,0 Hz, 1H), 5,55 (d, J = 5,2 Hz, 1H), 5,22 (m, 1H), 4,87 (m,2H), 4,23 (m, 5H), 3,88 (d, J = 7,0 Hz, 1H), 3,80 (m, 6H), 3,30 (m, 1H), 3,18 (m, 6H), 2,97 is 0.86 (m, 26H, incl. the singlets at 2,15, 1,94, 1,69, 1,57, 1,13, 3H each triplet at 1,30, 3H).
MCBP: calculated for C53H61NO20P (MH+), M=acid) - 1062, 3525, found - 1062, 3550.
Getting 7-TES-13-TMS baccatin
7-TES baccatin from example 10 (1,895 g 2,707 mmol) was dissolved in dry dimethylformamide (10,8 ml). To this solution at 0oC was added imidazole (736,4 mg, 10,83 mmol), and then trimethylchlorosilane (TMSCI) (1, is, and ethyl acetate (400 ml) and washed with water (20 ml x 3) and brine (15 ml). The organic layer was dried and concentrated in vacuum. The residue was chromatographically (20% ethyl acetate in hexano) and got the result 1,881 g (90%) of the target product.
Getting 7-TES-13-TMS-1-DMS baccatin
7-TES-13-TMS baccatin from example 73 (305 mg, 0,430 mmol) was dissolved in dry dimethylformamide (2 ml). To this solution at 0oC was added imidazole (87,6 mg, 1,289 mmol), and then dimethylchlorosilane (122 mg, 1,289 mmol). After 1 hour the reaction mixture was diluted with ethyl acetate (150 ml). Washed with water (10 ml x 3) and brine (10 ml). The obtained organic layer was dried and concentrated in vacuum. The residue was chromatographically (10% ethyl acetate in hexano), resulting in 305 mg (92.4 per cent) of the target product.
Getting 7-TES-13-TMS-1-DMS-C4-hydroxyacetone
1-DMS-7-TES-13-TMS baccatin of example 74 was dissolved in dry THF (8 ml). To this solution at 0oC was added Red-Al (0,314 ml, 60%, of 1.61 mmol). The mixture was stirred at 0oC for 40 minutes, after which the reaction was stopped by adding a saturated solution of sodium tartrate (1 ml) for 2 minutes. The reaction mixture was extracted with ethyl acetate (150 ml) and washed with water (15 ml x 2) and brine (15 ml). The organic layer was dried and Kong (45,3%) of the target product.
1H NMR (300 MHz, CDCl3): 8,10-of 8.06 (m, 2H), 7,55-7,39 (m, 3H), to 6.39 (s, 1H), 5,59 (d, J = 5.5 Hz, 1H), and 4.68 (DD, J1= 3,9 Hz, J2= 9.6 Hz, 1H), br4.61 (m, 1H), 4.53-in (m, 1H), 4,21 (AB kV, J = 7.8 Hz, 2H), a 4.03 (DD, J1= 6,1 Hz, J2= to 11.6 Hz, 1H), 3,74 (s, 1H), 3,48 (d, J = 5.7 Hz, 1H), 2,74-of 0.48 (m, 34H, incl. the singlets at 2,15, 2,06, 1,54, 1,16, 0,92, 3H each), and 0.28 (s, 9H), -0,015 and -0,32 (doublets, 3H each).
Getting 7-TES-13-TMS-1-DMS-C4-[OC(O)CH=CH2]baccatin
The compound of example 75 (99 mg, 0.125 mmol) was dissolved in dry THF (2.5 ml). To this solution at 0oC was added LHMDS (0,150 ml, 1 M, 0,150 mmol). After 30 minutes, was added akriloilkhlorida (0,153 ml, 0,188 mmol). After another 30 minutes the reaction was stopped by adding a saturated solution of NH4Cl. The reaction mixture was extracted with ethyl acetate (100 ml) and washed with water (10 ml x 2) and brine (10 ml). The organic phase was dried and concentrated in vacuum. The residue was chromatographically (5-10% ethyl acetate in hexano) and received as a result of 57.5 mg (54,6%) of the target product.
Getting C4-[OC(O)CH=CH2] baccatin
The compound of example 76 (105 mg, 0.125 mmol) was dissolved in CH2CN (2.5 ml). To this solution at 0oC was added pyridine (0,374 ml), and then 48% HF (1,12 ml). The reaction mixture was kept at 4o3(5 ml x 3) and brine. The organic phase is then dried and concentrated in vacuum. The residue was chromatographically (60% ethyl acetate in hexano), resulting in to 60.6 mg (81,3%) of the target product.
Receiving TES-C4-[OC)O)CH=CH2]baccatin
Triol of example 77 (60,0 mg, 0,100 mmol) was dissolved in dry dimethylformamide (0,66 ml). To this solution at 0oC was added imidazole (to 27.2 mg, 0.400 mmol), and then TESCI (0,0672 ml, 0.400 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate (75 ml) and washed with water (5 ml x 3) and brine. The organic layer was dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano), resulting in 56,0 mg (78.4 per cent) of the target product.
Getting 2',7-bis TES-4-[OC(O)CH=CH2]paclitaxel
Baccatin from example 78 (50 mg, 0,0702 mmol) was dissolved in dry THF (1.4 ml). To this solution at -40oC was added LHMDS (0,0843 ml, 1 M, 0,0843 mmol), and then immediately the solution of the lactam of example 23 (40,1 mg, 0,105 mmol) in THF (0.7 ml). After 2 minutes exposure at -40oC the reaction mixture was stirred at 0oC for 1 hour. Then the reaction was stopped by adding to the reaction mixture, a saturated solution of NH4Cl who was interaval in vacuum. The residue was chromatographically (20-30% ethyl acetate in hexano), resulting in 66 mg (86%) of the target product.
Getting C4-[OC(O)CH=CH2]paclitaxel
The compound of example 79 (46 mg, 0,0421 mol) was dissolved in CH2CN (0,85 ml). To this solution at 0oC was added pyridine (0,125 ml), and then 48% HF (0,375 ml). The reaction was carried out at 4oC all night. Then the reaction mixture was diluted with ethyl acetate (40 ml) and washed with 1 N. HCl (3 ml) and a saturated solution of NaHCO3(3 ml x 3). The organic layer was dried and concentrated in vacuum. The residue was chromatographically (70% ethyl acetate in hexano) and received in the 28 mg (76,9%) of the target product.
Getting 7, 13-bis TES-1-DMS-C4-[C(O)C6H5] baccatin
The compound from example 19 (279 ml, 0,336 mmol) was dissolved in dry THF (7 ml). To this solution at 0oC was added LHMDS (0,403 ml, 1 M, 0,403 mmol). After 30 minutes, was added benzoyl chloride (0,0585 ml, 0,504 mmol). After another 30 minutes the reaction was stopped by adding to the reaction mixture, a saturated solution of NH4Cl. The reaction mixture was extracted with ethyl acetate (150 ml). The organic layer was washed with water and brine and dried and concentrated in vacuum. The mod is 2">
Getting C4-benzoylacetone
The compound of example 81 (161 mg, 0,172 mmol) was dissolved in CH3CN. To this solution at 0oC was added pyridine (0,57 ml), and then 48% HF (1.80m). After 5 hours of exposure at 4oC was added another portion of the reagent. The reaction was carried out at 4oC all night. Then the reaction mixture was diluted with ethyl acetate (100 ml) and washed with 1 N. HCl (5 ml) and a solution of NaHCO3(5 ml x 3). The organic phase was dried and concentrated in vacuum. The residue was chromatographically (30-50% ethyl acetate in hexano) and received in the 48 mg (43,0%) target final product.
Getting 7-TES-C4-benzoylacetone
Triol of example 82 (48,0 mg, 0,074 mmol) was dissolved in dimethylformamide (0,40 ml). To this solution at 0oC was added imidazole (20,1 mg, 0,296 mmol), and then TESC1 (0,0496 ml, 0,296 mmol). After 30 minutes the reaction mixture was diluted with ethyl acetate (45 ml) and washed with water (1 ml x 3) and brine. The organic phase was dried and concentrated in vacuum. The residue was chromatographically (40% ethyl acetate in hexano) and received in the 48 mg (85,0%) target final product.
Getting C4-benzoylacetate
Soedinenie mmol), and then lactam of example 23 (273,5 mg, 0,718 mmol). Following the same procedure as described in the previous examples, received 415 mg (75,9%) compounds. After that, there can be obtained the analogue of paclitaxel removed from protection by dissolving the above compound in CH3CN (16.5 ml) and added at 0oC pyridine (0,36 ml), and then 48% HF (3.0 ml). Following the stages described in example 80, the received analog of paclitaxel with the release of 315 mg (94,8%).
Getting 4-cyclobutylamine with fullaway side chain
7-TES-4-cyclobutylmethyl from example 27 (154 mg, 0,208 mmol) was dissolved in dry toluene (4 ml). To this solution at room temperature was added the free acid from example 63 (64,2 mg of 0.250 mmol) and 4-dimethylaminopyridine (30,5 mg of 0.250 mmol). After 10 minutes was added dicyclohexylcarbodiimide (51,4 mg of 0.250 mmol). The reaction mixture was stirred for 2 hours, and at the same time added to another portion dicyclohexylcarbodiimide and 4-dimethylaminopyridine. The reaction mixture was again stirred for 12 hours. Then the reaction mixture was filtered through celite and the filtered solid residue was washed with ethyl acetate. The combined organic layer was concentrated in vacuum and the obtained OST is 2">
A solution of the compound (A) (182 mg, 0,186 mmol) in THF (2 ml) and MeOH (2 ml) was treated at 0oC 1 N. HCl (1,86 ml). After 1 hour of exposure 0oC the reaction mixture was kept overnight at 4oC. Then the reaction mixture was treated with saturated solution of NaHCO3(9.6 ml). After 5 hours exposure at room temperature, the reaction mixture was diluted with ethyl acetate (120 ml) and washed with water (4 x 10 ml). Then the organic layer was dried MgSO4and concentrated in vacuum. The residue was chromatographically (40-60% ethyl acetate in hexano) and got 77 mg (47% of the target product).
1H NMR (CDCl3): 8,15-to 8.12 (m, 2H), 7,73-7,35 (m, 9H), 6,87 (d, J = 9,2 Hz, 1H), 6,44 (m, 2H), 6,28 (s, 1H), 6,20 (m, 1H), of 5.89 (d, J = 9,2 Hz, 1H), 5,66 (l, H = 7,1 Hz, 1H), 4,90 (d,J = 8,1 Hz, 1H), around 4.85 (s, 1H), of 4.44 (m, 1H), 4,27 (AB kV, J 8,4 Hz, 2H), 3,80 (d, J = 7,0 Hz, 1H), of 3.56 (m, 1H), 2,61 to 0.92 (m, 25H, incl. the singlets at 2,22, 1,83, 1,69, 1,23, 1,13, 3H each), 13C NMR (CDCl3): 203,6 174,4 172,4 171,2 166,9 166,8 150,9 142,5 142,0 133,5 133,3 132,9 131,9 130,1 130,0 129,7 129,0 128,5 127,0 110,8 108,0 84,6 80,8 78,9 76,4 75,4 75,0 72,0 71,3 58,5 50,1 45,6 43,1 38,8 35,6 35,5 26,7 25,3 25,1 21,9 20,7, 18,2 14,6 9,5. MCBP: calculated for C48H54NO15(MH+) - 884,3493 found - 884,3472.
Receiving paclitaxel
In a flask with a capacity of 5 ml was added the compound of example 10 (b) and dissolving it in THF. Dabany the solution was stirred at 0oC for 1/2 hour and then transferred into a cold room with a temperature of 4oC. 19 1/2 hours after adding HCl thin layer chromatography (TLC) showed the absence of starting material. The reaction solution was poured into a flask containing ml Polynesians of NaCl. The obtained heterogeneous mixture was stirred at room temperature for minutes. The mixture was filtered and the solid is washed with 15 ml of water and subjected to air drying in the funnel with a porous glass plate. Then white substance, dissolved in THF, poured through the Frit into another flask and concentrated, resulting in 0,169 g of a glassy solid. The material was transferred into a test tube and dissolved in 1.0 ml THF. Was added triethylamine (NEt3) (4 EQ., 0.3 mol, 88 ml), resulting in the formed precipitate. The heterogeneous mixture was stirred at room temperature. TLC showed that the reaction was essentially complete after 4.25 hours after the addition of triethylamine. The mixture was diluted with 5 ml ethyl acetate and 5 ml of water and were shaken, separated layers. The aqueous portion was extracted twice with 5 ml of ethyl acetate. The combined organic fractions were washed in 5 ml of HCl (nerist.), 5 ml saturated aqueous NaCl, dried over N is xela) with the release of 93.9 per cent.
Results on the study of activity in the disease model M in mice in vivo (data after claims)
Method. Mice-hybrids of Balb/c x DBA/2 F1 intraperitoneally implanted with 0.5 ml of 2% extract of lung carcinoma M, as described in the article "Assessment of lung carcinoma as a model for screening antitumor drugs" (Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Abtitumor Drugs), Cancer Treatment Report, 65, 3-4 (1981).
Next, the mice are also injected intraperitoneally injection of the studied compounds at different doses of 5 and 8 days after implantation. Mice track on the survival of approximately 75 days after implantation. One group of mice for each experiment leave the control.
The average survival time of the treated mice (T) is compared with the average survival time for the control group (C). The ratio of these two values for each group of mice treated with the investigational compound, expressed as % (as % T/C) in table 3.
1. The method of obtaining taxane with oxazolinone side chain of the formula III or its salt
where R1= R5or or7where R5-phenyl, C1- C10-alkyl, C2- C20alkenyl and R7- C1- C10oxygraph or R14O - group;
R10, R11is independently hydrogen, C1- C10-alkyl, C2- C10alkenyl, C3- C7-cycloalkyl, phenyl;
R14- hidroxizina group,
wherein the oxazoline of formula II or its salt
where R1, R3and R4have the above values,
subjected to interaction with taxonom, formula XI having a hydroxyl group directly attached to its C - 13, or its salt
where R8, R9, R10and R11have the above values,
in the presence of the agents of the combination.
2. The method according to p. 1, characterized in that the agent combination comprises a compound selected from the group consisting of dicyclohexylcarbodiimide, 1,3-diisopropylcarbodiimide, 1-/3-dimethylamino-propyl/-3-ethylcarbodiimide, bis/2-oxo-3-oxazolidinyl/phosphorochloridate, carbonyldiimidazole, pivaloyloxy and 2,4,6-trichlorobenzaldehyde, together with a compound selected from the group consisting of 1-hydroxybenzotriazole, N-hydroxysuccinimide, triethylamine, pyridine or pyridine, substituted at the 4-position with-N(R16)(R17), where R16and R17is independently selected from C1- C10-Alki the>cycloalkenyl or heterocycle, or R16and R17together with the nitrogen atom to which they are attached, form heterologous.
3. The method according to p. 1, wherein R1- phenyl, or C1- C10-alkoxy, R3is phenyl, benzyl, or furyl, R4is hydrogen, lower alkylcarboxylic, R9is hydroxyl or a protected hydroxyl group, R10- C1- C10-alkyl and R11is phenyl.
4. The method according to p. 3, wherein R1is phenyl or tert-Butylochka, R3is phenyl or furyl, R8is hydroxyl or acetyloxy, R9is hydroxyl or trialkylsilanes, R10is methyl and R11is phenyl.
5. The method according to p. 4, wherein the oxazoline of formula II represents /4S-TRANS/-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid or /4S-CIS/-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid or their mixture, as mentioned Texan formula IX represents a 7-triethylcitrate III or 7-trimethylsilylcyanation III.
6. Texan with oxazolinone side chain of the formula III or its salt
where R1, R3, R4, R8, R9, R10and R11are specified in paragraph 1.
7.UP> is hydrogen, R8is hydroxyl, lower alkylcarboxylic, R9is hydroxyl or a protected hydroxyl group, R10- C1- C10-alkyl and R11is phenyl.
8. Connection on p. 7, where R1is phenyl or furyl, R8is hydroxyl, R9is hydroxyl or trialkylsilanes, R10is methyl and R11is phenyl.
8. Connection on p. 7, where R1is phenyl or tert-butylacrylate, R3is phenyl or furyl, R8is hydroxyl, R9is hydroxyl or trialkylsilanes, R10is methyl and R11is phenyl.
9. Connection on p. 8, which is a 7-triethylsilyl-13-[[(4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolyl]-carbonyl] baccatin III or 7-trimethylsilyl-13-[[(4S-TRANS)-4,5-dihydro-2,4-diphenyl-5-oxazolyl] -carbonyl]-baccatin III.
10. Oxazolinone compound or its salt of the formula I
where R1, R3and R4are specified in paragraph 1 values;
R2-R7O - group, where R7- C1- C10-alkyl.
11. Connection on p. 10, where R1- phenyl, or C1- C10-alkoxy, R2- C1- C10-alkoxy, R3is phenyl, benzyl, or furyl, R4- hydrogen.
12. Connection on p. 11, where R1
14. The method of obtaining oxazolinone the compounds of formula I or its salt
where R1, R2, R3and R4are specified in the PP.1 and 12 values,
characterized in that it includes a stage of contacting the compounds of formula V or its salt
acid capable of dehydration of compounds of formula V or its salts for the formation of compounds of formula I or its salts.
15. The method according to p. 14, wherein the acid is chosen from the group consisting of sulfonic acids, carboxylic acids and mineral acids.
16. The method according to p. 14, characterized in that the compounds of formula V used as a compound Va or its salt
to obtain as with/SUP> and R4are specified in the PP.1 and 10 values,
or as the compounds of formula V or its salt using the following connection Vc or its salt
to obtain as compound I or its salts of the following compounds Ic or its salt:
where R1, R2, R3and R4are specified in the PP.1 and 10 values.
17. The method according to p. 16, wherein R1is phenyl or tert-butylacrylate, R2- methoxy - or ethoxypropan, R3is phenyl and R4- hydrogen.
18. The method of obtaining oxazolinone the compounds of formula I
characterized in that it includes a stage of contacting compounds of the following formula V or its salt:
in the presence of a base with an activating agent capable of activating the hydroxyl group of compounds of formula V or its salt, in order to carry out the intramolecular substitution and formation of the compound of formula I or its salts, provided that when R1the l
19. The method according to p. 18, characterized in that the activating agent selected from the group consisting of alkylsulfonates, arylsulfonamides, phosphorus oxychloride, pentachloride phosphorus and thionyl chloride, and a base selected from the group consisting of pyridine, triethylamine, diisopropylethylamine, lutidine, 1,8-diazabicyclo-5,4,0-undec-7-ene, hexamethyldisilazide lithium and carbonates of alkali metals.
20. The method according to p. 18, characterized in that the compounds of formula V used as a compound or its salt of the formula Vc
to obtain as the compounds of formula I or its salts following compound Ia or its salt:
or the fact that as the compounds of formula V used as a compound or its salt of the formula Va
to obtain as the compounds of formula I or its salt of the compound or its salt of the formula Ic
21. The method according to the SUP> is phenyl and R4- hydrogen.
where R1- C1- C10- alkyl or phenyl; R2, R3and R4are specified in the PP.1 and 10 values,
characterized in that it includes a stage of contacting the compounds of formula VII or its salt
where R2, R3and R4are specified in the PP.1 and 10 values
with a compound of formula VIII or its salt
where R1- have the above meanings;
E - C1- C10alkyl,
provided that when E is ethyl, R4is hydrogen and R1- phenyl, R2not ethoxypropan.
24. The method according to p. 23, wherein the process is carried out in the presence of amine base.
25. The method according to p. 23, characterized in that the compounds of formula VII or its salt is used as a compound VIIa or its salt
to obtain as the compounds of formula I or its salt of the compound Ia or its salt:
or the fact that as soedineniya the above values, to obtain as the compounds of formula I or its salt compound IC or its salt
where R1, R2, R3and R4have the above values.
26. The method according to p. 25, wherein R1- phenyl, R2- methoxy - or ethoxypropan, R3is phenyl and R4- hydrogen.
27. The method of obtaining oxazolinone the compounds of formula II or its salt
where R1, R3and R4are specified in paragraph 1 values
characterized in that conduct hydrolysis of oxazoline formula I or its salt
28. The method according to p. 27, characterized in that the oxazoline of formula I the substituents in positions 4 and 5 give zespolona and at least part of the resulting hydrolysis product of formula II formed in accordance with the aforementioned method, the carboxyl group in position 5 invert so that the above-mentioned substituents were in the TRANS-position.
29. The method according to p. 27, wherein R is phenyl or tert-butylacrylate, R2- methoxy - or ethoxypropan, R3- phenyl, R4- hydrogen.
30. Oxazoline.
31. Connection on p. 30, where R1- phenyl, or C1- C10- alkoxygroup, R3is phenyl or furyl, R4- hydrogen.
32. Connection on p. 31, where R1is phenyl or tert-butylacrylate and R3is phenyl or furyl.
33. Connection on p. 32, which is a /4-TRANS/-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid or /4-CIS/-4,5-dihydro-2,4-diphenyl-5-oxazolidinone acid.
34. The method of obtaining taxane carrying a side chain, of the formula X or salt
where R1, R3, R4, R8, R9, R10and R11are specified in paragraph 1 values
characterized in that it includes a stage of contacting taxane with oxazolinone side chain of the formula III or its salt
with aqueous acid, is able to reveal oxazolinone ring of compounds of formula III or its salts, for education taxane with the side chain of the formula X or salt and an acidic salt with the amino group in the compound of formula X is obtained by contact with revealing the ring acid.
35. The method according to p. 34, characterized in that the acid - phenyl, or C1- C10- alkoxygroup, R3- phenyl, R4is hydrogen, R8the hydroxy - group or lower alkylcarboxylic, R9the hydroxy - group or a protected hydroxyl group, R10- C1- C10-alkyl and R11is phenyl.
37. The method according to p. 34, wherein R1is phenyl or tert-butylacrylate, R3- phenyl, R8the hydroxy - group or acetyloxy, R9the hydroxy - group or trialkylsilanes, R10is methyl and R11is phenyl.
38. The method according to p. 34, characterized in that taxonomy fragment in position 7 or 10 contains at least one hydroxyl group, which removes the protection.
39. The method according to p. 38, characterized in that the ring opening protect and unprotect a protected hydroxyl group (C-7 taxane performed simultaneously using aqueous acid.
40. The method of obtaining weight-bearing side chain taxane formula IV or its salt
characterized in that it includes a stage of contacting taxane with the side chain of the formula X or salt
where R1, R the education taxane, bearing a side chain of formula IV or its salt.
41. The method according to p. 40, characterized in that as a reason to use bicarbonate of an alkali metal.
42. The method according to p. 40, characterized in that the compounds of formula IV have the Taxol or Taxotere.
43. The method according to p. 40, characterized in that taxon bearing a side chain of formula X or salt, receive a process comprising a stage of contacting taxane with oxazolinone side chain, the following formula III or its salt
where R1, R3, R4, R8, R9, R10and R11are specified in the PP.1 and 10 values,
with aqueous acid, is able to reveal the ring oxazoline group taxane formula III or its salt, with the formation of compound X or its salts.
44. The method according to p. 43, characterized in that taxon with oxazolinone side chain of the formula III or its salt obtained by the method comprising a stage of contacting oxazoline formula II or its salt
with taxonom having a hydroxyl group attached directly to C-13, or its salt of the formula IX, where R8, R9, R10and R11have a mn is III or its salts.
45. The method according to p. 44, characterized in that oxazolinone compound of formula II or its salt obtained by the method comprising a stage of transformation groups-C(O)-R2oxazoline the following formula I or its salts at the carboxyl group
46. The method according to p. 45, characterized in that the said oxazolinone compound of formula I or its salt obtained by the method comprising a stage of contacting compounds of the following formula V or its salt
with an activating agent capable of activating the hydroxyl group of compounds of formula V or its salt to allow intramolecular substitution and formation of the compounds of formula I or its salt, in the presence of a base.
47. The method according to p. 45, characterized in that oxazolinone compound of formula I or its salt obtained by the method comprising a stage of contacting compounds of the following formula V or its salt
acid capable of dehydration, soedinyayuschihsya fact, what oxazolinone compound of formula I or its salt, where R1- R1and R11- C1- C10- alkyl or phenyl, receiving method, comprising the stage of contacting the compounds of formula VII or its salt
where R2, R3and R4are specified in the PP.1 and 10 values,
with a compound of formula VIII or its salts
where R1have the above meanings;
E - C1- C10- alkyl.
49. The method according to p. 40, characterized in that taxon with the side chain of the formula X or its salt obtained by the method comprising the following stages:
(a) obtaining oxazoline compounds of the following formula I or its salt
where R1, R2, R3and R4have the values specified in paras.1 and 10;
(b) turning oxazoline formula I or its salts in the oxazoline of formula II or its salt
(c) a combination of oxazoline formula II or its salt with taxonom having a hydroxyl group attached directly to C-13, or its salt in the presence of the agent combinations for education taxane carrying oxazolinone side chain of the following formula III or its salt:
50. The compound of formula X or salt
51. The method according to p. 27, characterized in that the oxazoline of formula I the substituents in positions 4 and 5 introduce in CIS-position to form the corresponding TRANS compound of the formula I, in which the inverted group-C/O/-R2in the 5-position.
52. Connection on p. 50, where R1- phenyl, or C1- C10-alkoxygroup, R3is phenyl or furyl, R4- hydrogen.
53. Connection on p. 52, where R1is phenyl or tert-butyl-oxygraph, R3is phenyl or furyl, R8- hydroxy - or acetyloxy, R9- hydroxy - or trialkylsilanes, R10- C3- C7- cycloalkyl and R11- phenyl, provided that R10is not methyl.
54. Connection on p. 53, where R10- C3- C7- cycloalkyl.
55. Connection on p. 54, where R10- cyclopropyl or cyclobutyl.
56. The compound of formula IV
where R1- R5or R7, 2- C10alkenyl or phenyl;
R7- C1- C10- alkyl;
where R8is hydrogen, the hydroxy-group, R14- O - group;
R9is hydrogen, the hydroxy-group, R14- O - group;
R10and R11is independently hydrogen, C1- C10- alkyl, C2- C10alkenyl, C3- C7- cycloalkyl or phenyl;
provided that R10is not methyl.
57. Connection on p. 56, where R1- phenyl, or C1- C10- alkoxygroup, R3is phenyl or furyl, R4is hydrogen, R8the hydroxy - group, the lowest alkylcarboxylic, R9the hydroxy - group or a protected hydroxyl group, R10- C3- C7- cycloalkyl, R11is phenyl.
58. Connection on p. 57, where R1is phenyl or tert-Butylochka group, R3- phenyl, 2 - or 3-furanyl, R8- hydroxy - or trialkylsilanes, R10- C3- C7- cycloalkyl selected from cyclopropyl, cyclobutyl or cyclopentyl, R11is phenyl.
where R10you the>0- cyclopropyl.
where R10selected from the group consisting of cyclopropyl, cyclobutyl and cyclopentyl.
63. The compound of formula IV'< / BR>
where R1, R3and R4is mentioned in paragraph (1 value;
T is a piece
where R8is hydrogen, the hydroxy-group, or R14- O-group, where R14- hidroxizina group;
R20- hydrogen, -OC/O/OR21group, where R21- C1- C6- alkyl,
R30- or hydroxy-group-OCH2(OCH2)mOP(O)(OH)2group, where m = 0 to 6, provided that when R30group-OCH2(OCH2)mOP(O)(OH)2, R10is not methyl,
and basic salts of phosphoroscope.
64. Connection on p. 63, where R10- C3- C7- cycloalkyl, R2- phenyl, or C1- C10-alkoxygroup, R3is phenyl, furyl or benzyl, R4is hydrogen, R8is hydroxy, lower alkylcarboxylic, R11- phenyl, R20- OC/O/OR21group, where R21- ethyl, RSUB>3- C7- cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl and cyclopentyl, R1is phenyl or tert.butylacrylate, R3- phenyl, 2 - or 3-furanyl, R4is hydrogen and R11is phenyl.
66. Connection on p. 65, where the basic salt is selected from the group consisting of sodium, lysine arginine, N-metilglyukaminovoy, triethylamine and triethanolamine salts.
67. Connection on p. 65, where R20- OC/O/OR21where R21- ethyl.
70. The method of obtaining the compounds of formula XIV
where R20- hidroxizina group or hydrogen;
R - C/O/R10group, where R10is hydrogen, C1- C10- alkyl, C2- C10alkenyl, C3- C7cycloalkyl;
Ac is acetyl;
Bz is benzyl,
characterized in that it includes
A interaction baccatin III formula A
with a suitable agent in excess for the protection of hydroxy groups at C-7 and C-13 in an inert organic solvent at a temperature of from -30oC to room;
(B) interaction of the product of stage (A) with trimethylsilanol or dimethylsilanol in the presence of a tertiary amine base is imagedata lithium at a temperature of from -30 to 0oC;
(D) interaction of the product of stage (C) with acylchlorides, acid anhydride or mixed anhydride in the presence of the anion of the alkali metal secondary amine base at a temperature from -30oC to room;
(E) removing the protection from the product of stage (D) reaction with pyridine-fluoride in acetonitrile, and then tetrabutylammonium or cesium fluoride in tetrahydrofuran (THF), and if necessary (C-7 - hidroxizina group).
(F) interaction of the product of stage (E) with a suitable agent for the implementation of the protection of the hydroxy-group at C-7.
where R1- R5or or7where R5- phenyl, C1- C10- alkyl, C2- C10alkenyl, R7- C3- C7- alkyl;
R4is hydrogen;
R3is phenyl, benzyl, or furyl,
where R8and R9is hydrogen or a hydroxy-group, or R14O - group, where R14- hidroxizina group;
R10and R11- independently - hydrogen, C1- C10alkyl, C2- C10alkenyl, C3- C7cycloalkyl, phenyl,
or its salts or hydrates, characterized in that it includes:, where R is the same as listed above with the appropriate-lactam of the formula B:
where A is benzyloxycarbonyl;
B is phenyl, benzyl, or furyl;
D - strong protective group for the implementation of substitution in the side chain;
(B) then removing the protection from the product of stage (A) at positions C-2' and C-7 molecules.
72. The compound of formula XII
where X is selected from trimethylsilane or dimethylsilane;
Bz is benzoyl.
73. The compound of formula XIII
R is selected from hydrogen or-C/O/R10where R10selected from H, C1- C10- alkyl, C2- C10- alkenyl, C3- C7- cycloalkyl.
74. The compound of formula XIV
where R20is hydrogen or hidroxizina group;
R is selected from hydrogen or-C/O/R10where R10selected from a hydrogen atom, a C1- C10-alkyl, C2- C10-alkenyl, C3- C7-cycloalkyl or phenyl;
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