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【结 构 式】 
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【分子编号】30223 【品名】1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol 【CA登记号】 |
【 分 子 式 】C10H10N2S 【 分 子 量 】190.26888 【元素组成】C 63.13% H 5.3% N 14.72% S 16.85% |
合成路线1
该中间体在本合成路线中的序号：(I)Alkylation of 2-mercapto-1-o-tolylimidazole (I) with the bromopropoxy tetrahydroquinolinone (II) in the presence of DBU gave sulfide (III). Then, asymmetric oxidation of (III) with cumene hydroperoxide and titanium tetraisopropoxide, using D-diethyl tartrate as the chiral auxiliary produced the target (S)-sulfoxide with low enantiomeric excess. Several recrystallizations from EtOH-EtOAc yielded the enantiomerically rich compound.
| 【1】 Nishi, T.; Chu, G.-N.; Okada, M.; Tamura, K.; Unemi, F.; Koga, Y.; Kido, M.; Igawa, T.; Ozeki, Y.; Uno, T.; Synthesis of 2(1H)-quinolinone derivatives and their inhibitory activity on the release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) from platelets. Chem Pharm Bull 1995, 43, 10, 1724. |
| 【2】 Nishi, T.; Uno, T.; Shu, Y.; Tamura, K.; Okada, M. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs.. EP 0651747; JP 1995033765; US 5541198; WO 9426732 . |
| 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) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
| (II) | 30224 | 6-(3-bromopropoxy)-3,4-dihydro-2(1H)-quinolinone | C12H14BrNO2 | 详情 | 详情 | |
| (III) | 30225 | 6-(3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]propoxy)-3,4-dihydro-2(1H)-quinolinone | C22H23N3O2S | 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 enantiomerically pure sulfoxide was prepared by a different route, starting from the alkylation of hydroxyquinolinone (A) with (S)-glycidyl tosylate (IV) to give the chiral epoxide (V). Ring opening with mercaptoimidazole (I) afforded the enantiomerically rich (R)-mercapto alcohol (VI), which after recrystallization from EtOH provided the pure (R)-isomer. Oxidation with m-chloroperbenzoic acid yielded a diastereomeric mixture of hydroxy sulfoxides (VII). After separation by column chromatography, the required (S)-sulfoxide was converted to mesylate (VIII), and finally reduced with lithium triethylborohydride to afford the target (S)-compound.
| 【1】 Nishi, T.; Chu, G.-N.; Okada, M.; Tamura, K.; Unemi, F.; Koga, Y.; Kido, M.; Igawa, T.; Ozeki, Y.; Uno, T.; Synthesis of 2(1H)-quinolinone derivatives and their inhibitory activity on the release of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) from platelets. Chem Pharm Bull 1995, 43, 10, 1724. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 30226 | 6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril | C9H9NO2 | 详情 | 详情 | |
| (I) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
| (IV) | 16740 | (2S)-(+)-Glycidyl tosylate; (2S)oxiranylmethyl 4-methylbenzenesulfonate | 70987-78-9 | C10H12O4S | 详情 | 详情 |
| (V) | 30227 | 6-[(2S)oxiranylmethoxy]-3,4-dihydro-2(1H)-quinolinone | C12H13NO3 | 详情 | 详情 | |
| (VI) | 30228 | 6-[((2R)-2-hydroxy-3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]propyl)oxy]-3,4-dihydro-2(1H)-quinolinone | C22H23N3O3S | 详情 | 详情 | |
| (VII) | 30229 | 6-[((2R)-2-hydroxy-3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl)oxy]-3,4-dihydro-2(1H)-quinolinone | C22H23N3O4S | 详情 | 详情 | |
| (VIII) | 30230 | (1R)-2-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-[[(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)oxy]methyl]ethyl methanesulfonate | C23H25N3O6S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alternatively, the intermediate chiral hydroxy sulfoxide (XIX) was prepared by the following procedures. Alkylation of mercaptoimidazole (I) with 3-chloropropanol (XVII) gave thioether (XVIII). This was oxidized with cumene hydroperoxide and titanium tetraisopropoxide in the presence of either D-diethyl tartrate or (R)-mandelic acid as the chiral auxiliaries to provide, after recrystallization from methyl ethyl ketone, the optically pure sulfoxide (XIX). Subsequent treatment with methanesulfonyl chloride and triethylamine gave mesylate (XX), which was finally condensed with the sodium salt of 6-hydroxytetrahydroquinolinone (XXI) in DMSO at 60 C.
| 【1】 Matsugi, M.; et al.; Practical asymmetric oxidation of 3-[1-(2-methylphenyl)imidazol-2-ylthio]propan-1-ol based on a titanium-mandelic acid complex. Tetrahedron Lett 1998, 39, 31, 5591. |
| 【2】 Nishi, T.; Uno, T.; Shu, Y.; Tamura, K.; Okada, M. (Otsuka Pharmaceutical Co., Ltd.); Carbostyril derivs.. EP 0651747; JP 1995033765; US 5541198; WO 9426732 . |
| 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) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
| (XVII) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (XVIII) | 30239 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]-1-propanol | C13H16N2OS | 详情 | 详情 | |
| (XIX) | 30240 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XX) | 30241 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl methanesulfonate | C14H18N2O4S2 | 详情 | 详情 | |
| (XXI) | 30242 | sodium 2-oxo-1,2,3,4-tetrahydro-6-quinolinolate | C9H8NNaO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The cyclization of 2-methylphenyl isothiocyanate (I) with 2-aminoacetaldehyde dimethylacetal (II) in methanol gives the 1-(2-methylphenyl)imidazole-2-thiol (III), which is condensed with 3-bromopropanol (IV) by means of NaOH in refluxing water to yield the sulfide (V). The asymmetric oxidation of sulfide (V) with Ti(O-iPr)4, cumene hydroperoxide (CHP) and (R)-(-)-mandelic acid as chiral catalyst in dichloromethane affords the (S)-sulfinyl derivative (VI), which is treated with Ms-Cl to provide the expected mesylate (VII). Finally, this compound is condensed with the sodium salt of 6-hydroxy-1,2,3,4-tetrahydroquinolin-2one (VIII) to give the target compound.
| 【1】 Matsugi, M.; et al.; Catalytic asymmetric oxidation of sulfide with titanium-mandelic acid complex: Practical synthesis of (S)-3-[1-(2-methylphenyl)imidazol-2-ylsulfinyl]propan-1-ol, the key intermediate of OPC-29030. Tetrahedron 2001, 57, 14, 2739. |
| 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) | 50207 | 6-isothiocyanato-1-methyl-1,3-cyclohexadiene; 2-methyl-2,4-cyclohexadien-1-yl isothiocyanate | C8H9NS | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 30223 | 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol | C10H10N2S | 详情 | 详情 | |
| (IV) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (V) | 30239 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]-1-propanol | C13H16N2OS | 详情 | 详情 | |
| (VI) | 50208 | (3-hydroxypropyl)[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfoniumolate | C13H16N2O2S | 详情 | 详情 | |
| (VII) | 50209 | [1-(2-methylphenyl)-1H-imidazol-2-yl][3-[(methylsulfonyl)oxy]propyl]sulfoniumolate | C14H18N2O4S2 | 详情 | 详情 | |
| (VIII) | 50210 | C9H8NNaO2 | 详情 | 详情 |