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【结 构 式】

【分子编号】48146

【品名】3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine

【CA登记号】

【 分 子 式 】C9H12N2S

【 分 子 量 】180.27376

【元素组成】C 59.96% H 6.71% N 15.54% S 17.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

Condensation of substituted aniline (I) with acrylic acid (II) in toluene affords bicyclic derivative (III), whose carbonyl is reduced by means of Red-Al in toluene to yield compound (IV). Conversion of (IV) into bicyclic hydrazine (V) is then performed by treatment with NaNO2 and HOAc followed by reduction of the resulting diazo derivative with LiAlH4 in THF. Derivative (V) is then subjected to a Fisher indole cyclization process by reaction with ketone (VI) and HCl in iPrOH to provide compound (VII), which is then regioselectively reduced with NaCNBH3 in TFA to give tetracyclic indoline (VIII). N-Protection of (VIII) with Boc2O and NaOH affords Boc protected derivative (IX), which is then selectively brominated by means of NBS in DMF to yield bromo derivative (X). Finally, the desired compound is obtained by a Suzuki cross-coupling reaction between (X) and boronic acid (XI) catalyzed by Pd(PPh3)4, followed by Boc removal with TFA in CH2Cl2.

1 Robichaud, A.J.; Chen, W.; McClung, C.; et al.; Synthesis and biological evaluation of novel, selective 5-HT2C receptor agonists for the treatment of obesity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 105.
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) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(II) 19139 acrylic acid 79-10-7 C3H4O2 详情 详情
(III) 48910 2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one C9H9NOS 详情 详情
(IV) 22617 2,3,4,5-tetrahydro-1,5-benzothiazepine C9H11NS 详情 详情
(V) 48146 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine C9H12N2S 详情 详情
(VI) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(VII) 48147 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole C14H16N2S 详情 详情
(VIII) 48150 (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole C14H18N2S 详情 详情
(IX) 48149 tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate C19H26N2O2S 详情 详情
(X) 48911 tert-butyl (8aS,12aR)-2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate C19H25BrN2O2S 详情 详情
(XI) 48912 2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid 68716-47-2 C6H5BCl2O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

Nitrosation of tetrahydrobenzothiazepine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.

1 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98.
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) 22617 2,3,4,5-tetrahydro-1,5-benzothiazepine C9H11NS 详情 详情
(II) 48145 5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine C9H10N2OS 详情 详情
(III) 48146 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine C9H12N2S 详情 详情
(IV) 18178 4,4-piperidinediol 73390-11-1 C5H11NO2 详情 详情
(V) 48147 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole C14H16N2S 详情 详情
(VI) 48148 6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole C14H18N2S 详情 详情
(VII) 48149 tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate C19H26N2O2S 详情 详情
(VIII) 48150 (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole C14H18N2S 详情 详情
(IX) 48151 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone C10H11ClFNO 详情 详情
Extended Information