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【结 构 式】

【分子编号】68515

【品名】3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1,1-dioxide

【CA登记号】 

【 分 子 式 】C24H33NO3S2

【 分 子 量 】447.663

【元素组成】C 64.39% H 7.43% N 3.13% O 10.72% S 14.33%

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:(I)

Condensation of the 1,5-benzothiazepin-8-ol derivative (I) with ethyl bromoacetate (II) in the presence of Bu4NBr and Na2CO3 in refluxing acetonitrile yields ethyl ester (III), which is then hydrolyzed with NaOH in EtOH to give the corresponding acid (IV). Subsequent coupling of carboxylic acid (IV) with (R)-2-phenylglycine methyl ester hydrochloride (V) using TBTU and DIEA in CH2Cl2 followed by hydrolysis of the resultant methyl ester (VI) with NaOH in MeOH produces the N-acyl amino acid (VII). After coupling of acid (VII) with tert-butyl glycinate (VIII), using the same procedure as above, the resulting tert-butyl ester (IX) is finally cleaved using TFA in CH2Cl2 .

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.
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) 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
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 68516 ethyl 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetate   C28H39NO5S2 详情 详情
(IV) 68517 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetic acid   C26H35NO5S2 详情 详情
(V) 68518 (R)-2-phenylglycine methyl ester hydrochloride   C9H11NO2.HCl 详情 详情
(VI) 68519 (R)-methyl 2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetate   C35H44N2O6S2 详情 详情
(VII) 68520 (R)-2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetic acid   C34H42N2O6S2 详情 详情
(VIII) 27841 tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester 6456-74-2 C6H13NO2 详情 详情
(IX) 68521 (R)-tert-butyl 2-(2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetamido)acetate   C40H53N3O7S2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

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
Extended Information