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【结 构 式】 
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【药物名称】OPC-29030 【化学名称】(S)-(+)-6-[3-[1-(2-Methylphenyl)imidazol-2-ylsulfinyl]propoxy]-1,2,3,4-tetrahydroquinolin-2-one 【CA登记号】161190-38-1 【 分 子 式 】C22H23N3O3S 【 分 子 量 】409.51091 |
【开发单位】Otsuka (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis |
合成路线1
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
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
In a further procedure, the bromophenyl imidazole (XIII) was prepared by treatment of 4-bromo-2-methylaniline (IX) with carbon disulfide and DCC to produce isothiocyanate (X). Condensation with 2,2-diethoxyethylamine (XI) gave thiourea (XII), which was cyclized in refluxing 8 N HCl to the 1-aryl-2-mercaptoimidazole (XIII). This was alkylated with the chloropropoxy quinolinone (XIV) to give sulfide (XV). Sharpless oxidation in the presence of D-diethyl tartrate produced the (S)-sulfoxide (XVI). Finally, hydrogenolysis of the halogen atom over Pd/C furnished the title compound.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (IX) | 30231 | 4-bromo-2-methylphenylamine; 4-bromo-2-methylaniline | 583-75-5 | C7H8BrN | 详情 | 详情 |
| (X) | 30232 | 4-bromo-2-methylphenyl isothiocyanate; 4-bromo-1-isothiocyanato-2-methylbenzene | 19241-38-4 | C8H6BrNS | 详情 | 详情 |
| (XI) | 30233 | 3,3-diethoxypropylamine; 3,3-diethoxy-1-propanamine | 41365-75-7 | C7H17NO2 | 详情 | 详情 |
| (XII) | 30234 | N-(4-bromo-2-methylphenyl)-N'-(3,3-diethoxypropyl)thiourea | C15H23BrN2O2S | 详情 | 详情 | |
| (XIII) | 30235 | 1-(4-bromo-2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(4-bromo-2-methylphenyl)-1H-imidazole-2-thiol | C10H9BrN2S | 详情 | 详情 | |
| (XIV) | 30236 | 6-(3-chloropropoxy)-3,4-dihydro-2(1H)-quinolinone | C12H14ClNO2 | 详情 | 详情 | |
| (XV) | 30237 | 6-(3-[[1-(4-bromo-2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]propoxy)-3,4-dihydro-2(1H)-quinolinone | C22H22BrN3O2S | 详情 | 详情 | |
| (XVI) | 30238 | 6-(3-[[1-(4-bromo-2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propoxy)-3,4-dihydro-2(1H)-quinolinone | C22H22BrN3O3S | 详情 | 详情 |
合成路线4
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5
An alternative procedure for the chiral hydroxy sulfoxide (XIX) involved a lipase-catalyzed kinetic resolution. Transesterification of racemic hydroxy sulfoxide (XXII) with isopropenyl acetate (XXIII) catalyzed by lipase AL yielded the acetate ester of the required (S)-isomer (XXIV), along with the unreacted (R)-alcohol (XXV). Separation was achieved upon treatment with phthalic anhydride (XXVI) in the presence of DMAP and pyridine to produce the phthalic acid derivative (XXVII) of the unreacted alcohol, which could be separated from the desired acetate ester (XXIV) by means of selective extraction. The target enantiomerically pure (S)-hydroxy sulfoxide intermediate (XIX) was then obtained by methanolysis of the acetate ester (XXIV) with K2CO3, followed by two recrystallizations from EtOAc. The corresponding (R)-alcohol was recovered by NaOH hydrolysis of the phthalate ester (XXVII), and was completely racemized by treatment with aqueous HCl.
| 【1】 Morita, S.; et al.; Synthesis of a key intermediate, (S)-2-[(3-hydroxypropyl)sulfinyl]-1-(o-tolyl)imidazole, for the antiplatelet aggregation inhibitor, OPC-29030 via lipase-catalyzed enantioselective transesterification. Tetrahedron Asymmetry 1997, 8, 22, 3707. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 30240 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXII) | 30245 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXIII) | 21178 | isopropenyl acetate | 108-22-5 | C5H8O2 | 详情 | 详情 |
| (XXIV) | 30243 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propyl acetate | C15H18N2O3S | 详情 | 详情 | |
| (XXV) | 30246 | 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]-1-propanol | C13H16N2O2S | 详情 | 详情 | |
| (XXVI) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (XXVII) | 30244 | 2-[(3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfinyl]propoxy)carbonyl]benzoic acid | C21H20N2O5S | 详情 | 详情 |
合成路线6
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 |