Carabersat, SB-204269
N-[(3R,4S)-6-乙酰基-3,4-二氢-3-羟基-2,2-二甲基-2H-1-苯并吡喃-4-基]-4-氟-苯甲酰胺Chemical Name: (+)-(3R,4S)-N-(6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4-fluorobenzamide
CAS No. 184653-84-7, 179075-80-0 (14C-labeled)
项目整合开发状态: Phase II
项目研究机构: GlaxoSmithKline (Originator)
合成路线:The reaction of 4-iodofluorobenzene (I) with 14C-labeled potassium cyanide and CuI in DMF at 160 C gives the labeled 4-fluorobenzonitrile (II),which is hydrolyzed with KOH in ethanol/water at 115 C to yield labeled 4-fluorobenzoic acid (III).Finally,this compound is condensed with (3R,4S)-6-acetyl-3-hydroxy-3,4-dihydro-2H-1-benzopyran-4-amine (IV) by means of EDC and HOBT in dichloromethane to afford the target labeled compound.
合成路线:Compound is synthesized by hydrogenolytic debromination of (3R,4S)-N-(6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-2,5-dibromo-4-fluorobenzamide (I) by means of tritium gas over Pd/C in DMF.
📌 参考资料/链接：
参考文献标题:Novel receptor
文献作者:Herdon,H.J.; Jerman,J.C.; Chan,W.N.(GlaxoSmithKline plc)
参考来源:JP 1998511083; US 5985334; WO 9618650
📄 详细内容
合成路线:The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 6-acetyl-2,2-dimethyl-2H-1-benzopyran (III),which is enantioselectively epoxidized by means of Mn+3 salen catalysts,yielding the chiral epoxide (IV).The cleavage of the epoxide ring of (IV) with ammonia in ethanol affords the (3R,4S)-trans-aminoalcohol (V).The acylation of (V) with 3-chloro-4-fluorobenzoyl chloride (VI) and triethylamine yields the (3R,4S)-trans-amide (VII).The cyclization of (VII) by means of diethylaminosulfur trifluoride (DAST) in dichloromethane affords the (3aS-cis)-oxazoline (VIII),which is finally treated with 5N H2SO4.
合成路线:The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 5-acetyl-2,2-dimethyl-2H-1-benzopyran (III),which is enantioselectively epoxidized catalyzed by chiral salen Mn(III) catalysts to yield the (3R,4R)-epoxide (IV).The reaction of (IV) with ammonia in ethanol affords the (3R,4S)-aminoalcohol (V),which is finally acylated with 4-fluorobenzoyl chloride (VI) and TEA in dichloromethane to provide the target amide.Alternatively,the target amide can also be obtained by direct cleavage of the epoxide ring of (IV) with 4-fluorobenzamide (VII) by means of tBu-OK in tert-butanol.
参考文献标题:Synthesis of novel trans-4-(substituted-benzamido)-3,4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile
文献作者:Chan,W.N.; Evans,J.M.; Hadley,M.S.; Herdon,H.J.; Jerman,J.C.; Morgan,H.K.; Stean,T.O.; Thompson,M.; Upton,N.; Vong,A.K.
参考来源:J Med Chem 1996,39(23),4537
产品链接: CAS No. 184653-84-7››