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【结 构 式】 
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【分子编号】25876 【品名】2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol 【CA登记号】6274-29-9 |
【 分 子 式 】C7H9NOS 【 分 子 量 】155.2206 【元素组成】C 54.17% H 5.84% N 9.02% O 10.31% S 20.66% |
合成路线1
该中间体在本合成路线中的序号：(VI)The monosilylation of 2-butyl-2-ethylpropane-1,3-diol (I) with TBDMS-Cl and NaH in THF gives silyl ether (II), which is oxidized with NaIO4 and RuCl3 in CCl4/acetonitrile/water yielding silylated hexanoic acid (III).Elimination of the silyl group of (III) with tetrabutylammonium fluoride (TBAF) affords the hydroxyacid (IV), which is treated with refluxing 48% HBr to give the 2-(bromomethyl)-2-ethylhexanoic acid (V). The condensation of (V) with 2-amino-methoxythiophenol (VI) by means of triethylamine or pyrrolidine in DMF provides intermediate (VII), which is cyclized by means of p-toluenesulfonic acid in refluxing tetradecane to give the 1,5-benzothiazepinone (VIII). The reaction of (VIII) with N-bromosuccinimide (NBS) in dichloromethane yields the 7-bromo derivative (IX), which is treated with bromobenzene (X), K2CO3 and CuBr to afford the 5-phenylbenzothiazepinone (XI). The reduction of the carbonyl group of (XI) with LiAlH4 in ethyl ether gives the benzothiazepine (XII), which is then oxidized with OsO4 in THF/ tert-butanol yielding the S,S-dioxide (XIII). Finally, this compound is demethylated with AlBr3 and ethanethiol in dichloromethane.
| 【1】 Brieaddy, L.E.; Handlon, A.L.; Hodgson, G.L. Jr. (Glaxo Wellcome plc); Hypolipidemic benzothiazepines. EP 0792268; JP 1999500102; US 5998400; WO 9616051 . |
| 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) | 25871 | 2-butyl-2-ethyl-1,3-propanediol | 115-84-4 | C9H20O2 | 详情 | 详情 |
| (II) | 25872 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethyl-1-hexanol | C15H34O2Si | 详情 | 详情 | |
| (III) | 25873 | 2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethylhexanoic acid | C15H32O3Si | 详情 | 详情 | |
| (IV) | 25874 | 2-ethyl-2-(hydroxymethyl)hexanoic acid | C9H18O3 | 详情 | 详情 | |
| (V) | 25875 | 2-(bromomethyl)-2-ethylhexanoic acid | C9H17BrO2 | 详情 | 详情 | |
| (VI) | 25876 | 2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol | 6274-29-9 | C7H9NOS | 详情 | 详情 |
| (VII) | 25877 | 2-[[(2-amino-5-methoxyphenyl)sulfanyl]methyl]-2-ethylhexanoic acid | C16H25NO3S | 详情 | 详情 | |
| (VIII) | 25878 | 3-butyl-3-ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H23NO2S | 详情 | 详情 | |
| (IX) | 25879 | 7-bromo-3-butyl-3-ethyl-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H22BrNO2S | 详情 | 详情 | |
| (X) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (XI) | 25880 | 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C22H26BrNO2S | 详情 | 详情 | |
| (XII) | 25881 | 7-bromo-3-butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl methyl ether; 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine | C22H28BrNOS | 详情 | 详情 | |
| (XIII) | 25882 | 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1H-1lambda(6),5-benzothiazepine-1,1-dione | C22H28BrNO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Condensation of 2-amino-5-methoxythiophenol (I) with 4-(methylamino)benzoic acid (II) in hot polyphosphoric acid produces the benzothiazole derivative (III), which is finally submitted to methyl ether cleavage by means of BBr3 to give the target hydroxy compound.
| 【1】 Mathis, C.A.; Wang, Y.; Holt, D.P.; Huang, G.-F.; Debnath, M.L.; Klunk, W.E.; Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem 2003, 46, 13, 2740. |
| 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) | 25876 | 2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol | 6274-29-9 | C7H9NOS | 详情 | 详情 |
| (II) | 64844 | 4-(methylamino)benzoic acid | C8H9NO2 | 详情 | 详情 | |
| (III) | 64845 | 4-(6-methoxy-1,3-benzothiazol-2-yl)-N-methylaniline; N-[4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-N-methylamine | C15H14N2OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号： (XIV)Selective mono-protection of 2,2-dibutyl-1,3-propanediol (X) using one equivalent of TBDMSCl and NaH in THF yields the TBDMS ether (XI), which is then oxidized by means of NaIO4 in the presence of a catalytic amount of RuCl3 in CCl4/acetonitrile/H2O, followed by desilylation with TBAF in THF to give the hydroxy acid (XII). Bromination of alcohol (XII) with concentrated HBr at reflux provides the bromo acid (XIII), which by condensation with 2-amino-5-methoxythiophenol (XIV) [prepared by hydrolysis of 2-amino-6-methoxybenzothiazole (XV) with KOH at reflux] by means of Et3N in DMF and subsequent cyclization using p-TsOH in refluxing tetradecane produces the 1,5-benzothiazepin-4-one derivative (XVI). Bromination of compound (XVI) with NBS in CH2Cl2 results in the 7-bromobenzothiazepinone (XVII), which is arylated with bromobenzene (XVIII) in the presence of CuBr and K2CO3 at reflux to afford the 5-phenylbenzothiazepinone derivative (XIX). Reduction of lactam (XIX) using AlH3 (generated in situ from LiAlH4 and H2SO4) in Et2O/THF followed by oxidation of the thioether moiety with NMMO and catalytic OsO4 in THF yields the sulfone (XX) , which is finally submitted to simultaneous bromide substitution and O-demethylation using MeSNa in the presence of NaBH4 in DMF at 120 °C .
| 【1】 Starke, I., Blomberg, D., Dahlstrom, M. (AstraZeneca AB; AstraZeneca plc). Chemical compounds. EP 1345918, JP 2004196815, JP 2004516285, US 2004067933, US 7192945, WO 2002050051. |
| 【2】 Brieaddy, L.E., Handlon, A.L., Hodgson, G.L. Jr. (GlaxoSmithKline plc). Hypolipidemic benzothiazepines., EP 0792268, JP 1999500102, US 5998400, WO 1996016051. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 25876 | 2-amino-5-methoxyphenylhydrosulfide; 5-Methoxy-2-aminothiophenol;2-Mercapto-4-methoxyaniline;2-amino-5-methoxybenzenethiol；2-Amino-5-methoxy-1-benzenethiol | 6274-29-9 | C7H9NOS | 详情 | 详情 |
| (I) | 68515 | 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide | C24H33NO3S2 | 详情 | 详情 | |
| (X) | 59709 | 2,2-dibutyl-1,3-propanediol;2,2-DIBUTYLPROPANE-1,3-DIOL;2-N-BUTYL-2-(HYDROXYMETHYL)-1-HEXANOL | 24765-57-9 | C11H24O2 | 详情 | 详情 |
| (XI) | 68522 | 2-butyl-2-(((tert-butyldimethylsilyl)oxy)methyl)hexan-1-ol | C17H38O2Si | 详情 | 详情 | |
| (XII) | 68523 | 2-butyl-2-(hydroxymethyl)hexanoic acid | C11H22O3 | 详情 | 详情 | |
| (XIII) | 59712 | 2-(bromomethyl)-2-butylhexanoic acid | C11H21BrO2 | 详情 | 详情 | |
| (XV) | 68524 | 2-amino-6-methoxybenzothiazole;6-Methoxy-2-aminobenzothiazole;6-Methoxy-2-benzothiazolamine | 1747-60-0 | C8H8N2OS | 详情 | 详情 |
| (XVI) | 68525 | 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C18H27NO2S | 详情 | 详情 | |
| (XVII) | 68526 | 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C18H26BrNO2S | 详情 | 详情 | |
| (XVIII) | 13365 | Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene | 108-86-1 | C6H5Br | 详情 | 详情 |
| (XIX) | 68527 | 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one | C24H30BrNO2S | 详情 | 详情 | |
| (XX) | 68528 | 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one 1,1-dioxide | C24H30BrNO4S | 详情 | 详情 |