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【结 构 式】 
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【分子编号】16189 【品名】(2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid 【CA登记号】 |
【 分 子 式 】C10H8O3S 【 分 子 量 】208.23772 【元素组成】C 57.68% H 3.87% O 23.05% S 15.4% |
合成路线1
该中间体在本合成路线中的序号：(XII)2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (±)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI), which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII). The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII), which, by treatment with methanol and H2SO4, is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV). The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr·TsOH) affords the corresponding tetrahydropyranyl ether (XV), which is reduced with NaBH4 in ethanol, giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI). Finally, this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water, followed by acidification with HCl. 3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before, giving the racemic dioxolane (XVIII). This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained. This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.
| 【1】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386. |
| 【2】 Nakano, J.; Taya, N.; Chaki, H.; Yamafuji, T.; Momonoi, K. (Toyama Chemical Co., Ltd.); Benzo b thiophen-5-yl deriv. and process for producing the same. EP 0565965 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 | |
| (IV) | 16181 | 1-benzothiophene-5-carbaldehyde | C9H6OS | 详情 | 详情 | |
| (XI) | 16188 | 2-(1-benzothiophen-5-yl)-2-hydroxyacetic acid | C10H8O3S | 详情 | 详情 | |
| (XII) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (XIII) | 16190 | (5R)-5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 | |
| (XIV) | 16191 | methyl (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoate | C11H10O3S | 详情 | 详情 | |
| (XV) | 16192 | methyl (2S)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propanoate | C17H20O4S | 详情 | 详情 | |
| (XVI) | 16193 | (2R)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | C16H20O3S | 详情 | 详情 | |
| (XVII) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XVIII) | 16195 | 5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-(tert-butoxy)-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine (IV), which is treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).
| 【1】 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 . |
| 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) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (II) | 16820 | 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether | C9H9ClF3NO | 详情 | 详情 | |
| (III) | 16821 | 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether | C9H10F3NO | 详情 | 详情 | |
| (IV) | 16822 | tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine | C10H12F3NO | 详情 | 详情 | |
| (V) | 16823 | tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine | C10H13F2NO | 详情 | 详情 | |
| (VI) | 31629 | 2-bromo-2-cyclopropylacetonitrile | C5H6BrN | 详情 | 详情 | |
| (VII) | 16825 | 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile | C15H19FN2O | 详情 | 详情 | |
| (VIII) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
| (IX) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
| (X) | 31627 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol | C11H13ClFNO | 详情 | 详情 | |
| (XI) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
| (XII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 | |
| (XVI) | 16951 | (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C40H54O4 | 详情 | 详情 | |
| (XVII) | 31628 | 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid | C26H32FN3O5 | 详情 | 详情 |