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【结 构 式】 
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【分子编号】59715 【品名】2-butyl-2-({[4-(dimethylamino)-2-(4-methoxybenzyl)phenyl]sulfonyl}methyl)hexanal 【CA登记号】 |
【 分 子 式 】C27H39NO4S 【 分 子 量 】473.677 【元素组成】C 68.46% H 8.3% N 2.96% O 13.51% S 6.77% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(XIII)Intramolecular cyclization of (XIII) in the presence of potassium tert-butoxide affords a racemic mixture of syn adducts, which can be resolved by chiral chromatography to provide the target (R,R)-isomer (XIV). Methyl ether cleavage in (XIV) employing methanesulfonic acid affords phenol (XV). This is then alkylated with 4-chlorobutanol (XVI) yielding ether (XVII). After conversion of the primary hydroxyl group of (XVII) into mesylate (XVIII), condensation with diazabicyclo[2.2.2]octane produces the title ammonium salt
| 【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 |
|---|---|---|---|---|---|---|
| (XIII) | 59715 | 2-butyl-2-({[4-(dimethylamino)-2-(4-methoxybenzyl)phenyl]sulfonyl}methyl)hexanal | C27H39NO4S | 详情 | 详情 | |
| (XIV) | 59717 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C27H39NO4S | 详情 | 详情 | |
| (XV) | 59718 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C26H37NO4S | 详情 | 详情 | |
| (XVI) | 22336 | 4-chloro-1-butanol | 928-51-8 | C4H9ClO | 详情 | 详情 |
| (XVII) | 59719 | (4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-[4-(4-hydroxybutoxy)phenyl]-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione | C30H45NO5S | 详情 | 详情 | |
| (XVIII) | 59720 | 4-{4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepin-5-yl]phenoxy}butyl methanesulfonate | C31H47NO7S2 | 详情 | 详情 | |
| (XIX) | 28358 | 1,4-diazabicyclo[2.2.2]octane | 280-57-9 | C6H12N2 | 详情 | 详情 |