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【结 构 式】 
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【分子编号】59709 【品名】2,2-dibutyl-1,3-propanediol;2,2-DIBUTYLPROPANE-1,3-DIOL;2-N-BUTYL-2-(HYDROXYMETHYL)-1-HEXANOL 【CA登记号】24765-57-9 |
【 分 子 式 】C11H24O2 【 分 子 量 】188.31036 【元素组成】C 70.16% H 12.85% O 16.99% |
合成路线1
该中间体在本合成路线中的序号：(VI)Reduction of malonate (V) with LiAlH4 affords diol (VI). Reaction of diol (VI) with an acetic acid solution of hydrobromic acid, followed by acidic hydrolysis of the generated acetate ester, furnishes bromo alcohol (VII). This is oxidized to the bromo aldehyde (VIII) employing either DMSO and SO3-pyridine complex or NaOCl in the presence of TEMPO and KBr. Treatment of aryl chloride (IV) with sodium sulfide, followed by addition of bromo aldehyde (VIII) leads to the sulfide adduct (IX). After protection of the aldehyde group of (IX) as the dimethyl acetal (X) by means of trimethyl orthoformate and p-toluenesulfonic acid, the sulfide function of (X) is oxidized to sulfone (XI) with peracetic acid. Acetal hydrolysis in (XI) under acidic conditions then gives aldehyde (XII). Reductive alkylation of the nitro compound (XII) by catalytic hydrogenation in the presence of Pd/C and formaldehyde yields the dimethylamino derivative (XIII)
| 【1】 Manning, R.E.; Tremont, S.J.; Glenn, K.C.; Keller, B.T. (Pharmacia Corp.); Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders. WO 0168096 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 59707 | 4-(2-chloro-5-nitrobenzyl)phenyl methyl ether; 1-chloro-2-(4-methoxybenzyl)-4-nitrobenzene | C14H12ClNO3 | 详情 | 详情 | |
| (V) | 59708 | ethyl 2-butyl-2-(2-methoxyacetyl)hexanoate | C15H28O4 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 59710 | 2-(bromomethyl)-2-butyl-1-hexanol | C11H23BrO | 详情 | 详情 | |
| (VIII) | 59712 | 2-(bromomethyl)-2-butylhexanoic acid | C11H21BrO2 | 详情 | 详情 | |
| (IX) | 59711 | 2-butyl-2-({[2-(4-methoxybenzyl)-4-nitrophenyl]sulfanyl}methyl)hexanal | C25H33NO4S | 详情 | 详情 | |
| (X) | 59713 | 4-(2-{[2-butyl-2-(dimethoxymethyl)hexyl]sulfanyl}-5-nitrobenzyl)phenyl methyl ether; 1-{[2-butyl-2-(dimethoxymethyl)hexyl]sulfanyl}-2-(4-methoxybenzyl)-4-nitrobenzene | C27H39NO5S | 详情 | 详情 | |
| (XI) | 59714 | [2-butyl-2-(dimethoxymethyl)hexyl][2-(4-methoxybenzyl)-4-nitrophenyl]dioxo-lambda~6~-sulfane; 2-butyl-2-(dimethoxymethyl)hexyl 2-(4-methoxybenzyl)-4-nitrophenyl sulfone | C27H39NO7S | 详情 | 详情 | |
| (XII) | 59716 | 2-butyl-2-({[2-(4-methoxy-2-methylbenzyl)-4-nitrophenyl]sulfonyl}methyl)hexanal | C26H35NO6S | 详情 | 详情 | |
| (XIII) | 59715 | 2-butyl-2-({[4-(dimethylamino)-2-(4-methoxybenzyl)phenyl]sulfonyl}methyl)hexanal | C27H39NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |