Carabersat, SB-204269, -Drug Synthesis Database

【结构式】

【药物名称】Carabersat, SB-204269

【化学名称】(+)-(3R,4S)-N-(6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-4-fluorobenzamide

【CA登记号】184653-84-7, 179075-80-0 (14C-labeled)

【分子式】C₂₀H₂₀FNO₄

【分子量】357.3851

【开发单位】GlaxoSmithKline (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antiepileptic Drugs, Antimigraine Drugs, NEUROLOGIC DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【1】 Chan, W.N.; et al.; 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. J Med Chem 1996, 39, 23, 4537.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	18123	1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone	99-93-4	C₈H₈O₂	详情	详情
(II)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(III)	28706	1-(2,2-dimethyl-2H-chromen-6-yl)-1-ethanone		C₁₃H₁₄O₂	详情	详情
(IV)	28707	1-[(1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-1-ethanone		C₁₃H₁₄O₃	详情	详情
(V)	28708	1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone		C₁₃H₁₇NO₃	详情	详情
(VI)	17263	4-fluorobenzoyl chloride	403-43-0	C₇H₄ClFO	详情	详情
(VII)	37090	4-fluorobenzamide	824-75-9	C₇H₆FNO	详情	详情

合成路线2

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.

参考文献中间体

【1】 Herdon, H.J.; Jerman, J.C.; Chan, W.N. (GlaxoSmithKline plc); Novel receptor. JP 1998511083; US 5985334; WO 9618650 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54686	1-Fluoro-4-iodobenzene; 4-Fluoroiodobenzene; 4-Iodofluorobenzene; p-Fluoroiodobenzene	352-34-1	C₆H₄FI	详情	详情
(II)	14144	4-Fluorobenzonitrile	1194-02-1	C₇H₄FN	详情	详情
(II)	54688	4-fluorobenzonitrile		C₇H₄FN	详情	详情
(III)	54687	4-Fluorobenzoic acid	456-22-4	C₇H₅FO₂	详情	详情
(III)	54689	4-fluorobenzoic acid		C₇H₅FO₂	详情	详情
(IV)	28708	1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone		C₁₃H₁₇NO₃	详情	详情

合成路线3

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.

参考文献中间体

【1】 Herdon, H.J.; Jerman, J.C.; Chan, W.N. (GlaxoSmithKline plc); Novel receptor. JP 1998511083; US 5985334; WO 9618650 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	54690	N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-2,5-dibromo-4-fluorobenzamide		C₂₀H₁₈Br₂FNO₄	详情	详情

Extended Information