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【结 构 式】 
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【药物名称】Elobixibat;A-3309 【化学名称】N-[2(R)-[2-[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yloxy]acetamido]-2-phenylacetyl]glycine 【CA登记号】439087-18-0 【 分 子 式 】C36H45N3O7S2 【 分 子 量 】695.888 |
【开发单位】Albireo AB (SE); licensed to Ferring Pharmaceuticals (CH) worldwide, 【药理作用】Ileal Sodium-Dependent Bile Acid Transporter (IBAT) Inhibitor；Agent for Constipation |
合成路线1
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
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 |