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【结 构 式】 
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【药物名称】J-114871 【化学名称】(1R,5S,6S)-2-[5(R)-[4-[1(R),3-Diamino-3-oxopropyl]phenyl]pyrrolidin-3(S)-ylsulfanyl]-6-[1(R)-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid hydrochloride 【CA登记号】 【 分 子 式 】C23H31ClN4O5S 【 分 子 量 】511.04432 |
【开发单位】Banyu (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems |
合成路线1
(R)-4-hydroxy-2-pyrrolidinone (I) was protected as the tert-butyldimethylsilyl ether, and then converted to tert-butyl carbamate (II) by means of Boc2O. Subsequent condensation of (II) with Grignard reagent (III), followed by reduction with NaBH4, and acetal hydrolysis yielded the pyrrolidinyl benzaldehyde (IV). Horner-Emmons reaction of (IV) with phosphonate (V) produced the cinnamic acid derivative (VI), and further Michael addition to (VI) of the chiral lithium amide (VII) furnished aminoester (VIII). After hydrogenolysis of both N-benzyl groups of (VIII), the resulting primary amine (IX) was protected with Boc2O, and the silyl ether was then cleaved by means of tetrabutylammonium fluoride to give the hydroxypyrrolidine derivative (X). This was converted to the required thiol (XI), which was then coupled with the carbapenem phosphate (XII). Finally, hydrogenolysis of the 4-nitrobenzyl ester of (XII) provided the title compound.
| 【1】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969. |
| 【2】 Imamura, H.; Sato, H.; Shimizu, A.; et al.; J-114,870 and J-114,871, novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenems: Synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-56. |
| 【3】 Sato, H.; Shimizu, A.; Imamura, H.; et al.; J-111,225, a novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenem; synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-61. |
| 【4】 Imamura, H.; Ohtake, N.; Shimizu, A.; et al.; Structure-activity relationships of trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Part 2: J-111,225, J-114,870, J-114,871 and related compounds. Bioorg Med Chem Lett 2000, 10, 2, 115. |
| 【5】 Ushijima, R.; Sugimoto, Y.; Shimizu, A.; Kiyonaga, H.; Nagano, R.; Nakagawa, S.; Sakuraba, S.; Sato, H.; Hashizume, T.; Nakano, M.; Imamura, H.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Carbapenem derivs.. EP 1048669; JP 2000143512; WO 9931106 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 | |
| (I) | 30864 | N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt | C15H16LiN | 详情 | 详情 | |
| (II) | 30850 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (III) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (IV) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (VI) | 30853 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-1-pyrrolidinecarboxylate | C26H41NO5Si | 详情 | 详情 | |
| (VII) | 30854 | N-Benzyl-N-(1(S)-phenylethyl)amide lithium salt | C15H16LiN | 详情 | 详情 | |
| (VIII) | 30855 | tert-butyl (2R,4R)-2-[4-((1R)-1-[benzyl[(1S)-1-phenylethyl]amino]-3-ethoxy-3-oxopropyl)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C41H58N2O5Si | 详情 | 详情 | |
| (IX) | 30856 | tert-butyl (2R,4R)-2-[4-[(1R)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C26H44N2O5Si | 详情 | 详情 | |
| (X) | 30857 | tert-butyl (2R,4R)-2-(4-[(1R)-1-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C25H38N2O7 | 详情 | 详情 | |
| (XI) | 30858 | (3R)-3-amino-3-[4-[(2R,4S)-4-sulfanylpyrrolidinyl]phenyl]propanamide | C13H19N3OS | 详情 | 详情 | |
| (XII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
合成路线2
In an alternative procedure, aldehyde (IV) was condensed with ethyl acetate in the presence of lithium hexamethyldisilazide to give hydroxyester (XIII). This was esterified with chloroacetyl chloride to provide (XIV) as a diastereomeric mixture. Kinetic resolution of (XIV) employing lipase selectively hydrolyzed the undesired isomer to furnish hydroxyester (XV), which was separated from the required chloroacetate (XVI). After hydrolysis of the chloracetyl ester (XVI) by means of ammonium hydroxide, the resulting alcohol was converted to mesylate (XVII). Subsequent displacement in (XVII) by NaN3 afforded the corresponding azide, which was reduced to amine (IX) by hydrogenation over Pd/C. This was converted to the title compound by the same sequence as above.
| 【1】 Imamura, H.; Sato, H.; Shimizu, A.; et al.; J-114,870 and J-114,871, novel trans-3,5-disubstituted pyrrolidinylthio 1beta-methylcarbapenems: Synthesis and physicochemical properties. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-56. |
| 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) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (IX) | 30856 | tert-butyl (2R,4R)-2-[4-[(1R)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C26H44N2O5Si | 详情 | 详情 | |
| (XIII) | 30859 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(3-ethoxy-1-hydroxy-3-oxopropyl)phenyl]-1-pyrrolidinecarboxylate | C26H43NO6Si | 详情 | 详情 | |
| (XIV) | 30860 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-[1-[(2-chloroacetyl)oxy]-3-ethoxy-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C28H44ClNO7Si | 详情 | 详情 | |
| (XV) | 30861 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(1R)-3-ethoxy-1-hydroxy-3-oxopropyl]phenyl]-1-pyrrolidinecarboxylate | C26H43NO6Si | 详情 | 详情 | |
| (XVI) | 30862 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-[(1S)-1-[(2-chloroacetyl)oxy]-3-ethoxy-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C28H44ClNO7Si | 详情 | 详情 | |
| (XVII) | 30863 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-[(1S)-3-ethoxy-1-[(methylsulfonyl)oxy]-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C27H45NO8SSi | 详情 | 详情 |