Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3‐benzazepone moiety of WMS‐1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5‐(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4‐(2‐hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N‐sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel–Crafts acylation of acid 12a containing the N‐tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron‐withdrawing triflyl group resulted in the desired 3‐benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K2CO3‐induced elimination of trifluoromethanesulfinate. In a one‐pot three‐step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.

is investigated in clinical trials [10][11][12] and, furthermore, its positive effects in animal models of Alzheimer's disease and neuropathic pain have been reported. [13][14][15] However, poor receptor selectivity and low bioavailability represent two major problems associated with ifenprodil. In addition to its interactions with the ifenprodil binding site of the NMDA receptor, ifenprodil interacts depending on its relative and absolute configuration with related σ 1 , σ 2 , α 1 , 5-HT 1A , and 5-HT 2 receptors. [16][17][18][19] In in vitro and in vivo experiments, fast biotransformation, in particular, fast conjugation, of the phenol of ifenprodil (1) with glucuronic acid was detected. [20] In Figure 1, negative allosteric modulators of GluN2B subunitcontaining NMDA receptors derived from ifenprodil are displayed. In besonprodil (2, IC 50 = 30 nM), [21] the phenol of ifenprodil is replaced by the benzoxazolone system, which cannot be conjugated with glucuronic acid anymore. In WMS-1410 (3) the flexible β-aminoalcohol moiety of ifenprodil is integrated into a 3-benzazepine ring, [22] which resulted in increased receptor selectivity and metabolic stability. [23,24] Thus, the metabolically more stable benzoxazolone system of besonprodil (2) and the conformationally restricted 3-benzazepine system of WMS-1410 (3), leading to higher receptor selectivity, should be combined in one compound 4. In this study, we focus on the synthesis of novel oxazolo-annulated 3-benzazepines 4 designed as more selective and metabolically more stable analogs of ifenprodil. sulfate. [25] Unfortunately, all variations of this experiment led to several compounds. A clear reaction product could not be identified, although the halogen-lithium exchange appeared to be successful.
Even the reaction with the test electrophile benzaldehyde did not result in an isolable product (Scheme 1). Therefore, the alternative synthesis of 7 involved the establishment of the oxazolone ring starting with the phenol 8 already containing the hydroxyethyl moiety. The oxazolone moiety of 10 was prepared in three steps comprising regioselective nitration of phenol 8, reduction of the nitro compound 9a with H 2 and Pd/C, and finally, treatment of the aminophenol 9b with 1,1′-caronyldiimidazole. As for the further transformations, the rather acidic benzoxazolone system 10 has to be protected, the PMB group was introduced in 3-position at the benzoxazolone system to afford the (benzoxazolyl)ethanol 7 (Scheme 1).
The oxazolobenzazepinone 15 was envisaged as the second key intermediate in the total synthesis of 4. For the synthesis of ketone 15, the primary alcohol 7 was reacted with N-tosylglycine methyl ester in a Mitsunobu reaction. [26] The NH-acidity of the p-toluenesulfonamide is high enough to react as an acid under Mitsunobu conditions and the tertiary sulfonamide 11a was obtained in 80% yield. After saponification of the methyl ester 11a with LiOH, the acid 12a was isolated in 64% yield. Several reaction conditions were investigated to achieve the intramolecular Friedel-Crafts acylation with the acid 12a ((F 3 CCO) 2 O/ SnCl 4 , 0°C [23,27] ; Ac 2 O/TiCl 4 , −70°C; (F 3 CCO) 2 O/TiCl 4 , −30°C, P 4 O 10 , 0°C [28] ) or the corresponding acid chloride (TiCl 4 , −70°C; AlCl 3 , 20°C) to end up with a seven-membered ketone. As a result, either no transformation occurred and the acid 12a was still detected or the tetrahydroisoquinoline 14 was formed. A yield of 77% of the tetrahydroisoquinoline 14 was obtained, when using the reaction conditions previously optimized to cyclize analogous alkoxyphenyl derivatives to afford 7-alkoxy substituted tetrahydro-3-benzazepines [22,26] (Scheme 2).
The formation of the tetrahydroisoquinoline 14 was explained by activation of the acid or the acid chloride with the Lewis acid to give an acylium ion. Due to the electron-donating properties of the adjacent N-atom incorporated in the sulfonamide, the release of C═O is F I G U R E 1 Evolution of oxazolo-annulated 3-benzazepines 4 starting with the lead compound ifenprodil (1) via benzoxazolone besonprodil (2) and 3-benzazepine WMS-1410 (3). *Only one enantiomer of the racemic mixture is depicted for clarity faster than the cyclization of the acylium ion. Thus, the stabilized iminium ion 13 is formed, which reacts intramolecularly in an electrophilic aromatic substitution to provide the tetrahydroisoquinoline 14 (Scheme 2).
To avoid the undesired decarbonylation, the intermediate iminium ion of type 13 was destabilized by the introduction of a stronger electron-withdrawing group at the N-atom. For this purpose, the trifluoromethylsulfonyl (triflyl, SO 2 CF 3 , Tf) moiety was selected as a protective group. [29,30] Thus, the Mitsunobu reaction of the primary alcohol 7 with N-triflylglycine methyl ester provided the methyl ester 11b, which was saponified with LiOH to obtain the acid 12b. The reaction of the triflyl-protected acid 12b with P 4 O 10 in CH 2 Cl 2 at reflux temperature led to the seven-membered ketone 15 in 60% yield. The corresponding tetrahydroisoquinoline could not be detected. Obviously, the electron-withdrawing triflyl group inhibited completely the release of CO. It has to be noted that the yield of 60% is the result of several optimization rounds (Scheme 2).
The first oxazolobenzazepin-9-ol 18a was prepared by NaBH 4 reduction of the ketone 15 (Scheme 3). However, the pharmacological activity, that is, the interaction of the compounds with the ifenprodil binding site, requires the basicity of the amino moiety within the tricyclic system. Therefore, the CF 3 SO 2 moiety has to be removed. The or reductively (TiCl 4 /Li 0 ) failed to give the secondary amine. However, it has been reported that the triflyl protective group can be cleaved off by the elimination of sulfinate (CF 3 SO 2 − ) using strong bases. As an example, n-BuLi was able to remove the triflyl group from N,Ndibenzyl-1,1,1-trifluoromethanesulfonamide, leading to CF 3 SO 2 − and an imine, which was trapped by n-BuLi. [31] In the case of ketone 15, strong bases such as LDA or KO t Bu led to decomposition. However, the weak base K 2 CO 3 in refluxing acetone resulted in the elimination of trifluoromethanesulfinate. The intermediate iminoketone 16 was not isolated but directly treated with NaBH(OAc) 3 . [32] The reducing agent NaBH(OAc) 3 was able to reduce the cyclic imine, but not the ketone. Moreover, the solvent acetone formed an iminium ion with the new secondary amine, which was also reduced by NaBH(OAc) 3  Therefore, ligands were envisaged containing both, the benzoxazolone as well as the 3-benzazepine system.
Herein, we present the synthesis of the envisaged ox- observed. Finally, the triflyl protective group could be cleaved off by the base-induced elimination of trifluoromethanesulfinate. In a onepot three-step procedure, various N-substituted oxazolobenzazeoin-9ols 18a-c were available.
As the substitution pattern of the final products 18a-c differs considerably from the lead compounds, the affinity toward GluN2B subunit-containing NMDA receptors was not yet evaluated. However, the synthetic route to get access to this novel type of negative