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【结 构 式】 
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【药物名称】J-114870 【化学名称】(1R,5S,6S)-2-[5(R)-[4-[1(S),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 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】 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. |
| 【3】 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. |
| 【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 |
|---|---|---|---|---|---|---|
| (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) | 30864 | N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt | C15H16LiN | 详情 | 详情 | |
| (VIII) | 30865 | tert-butyl (2R,4R)-2-[4-((1S)-1-[benzyl[(1R)-1-phenylethyl]amino]-3-ethoxy-3-oxopropyl)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C41H58N2O5Si | 详情 | 详情 | |
| (IX) | 30866 | tert-butyl (2R,4R)-2-[4-[(1S)-1-amino-3-ethoxy-3-oxopropyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C26H44N2O5Si | 详情 | 详情 | |
| (X) | 30867 | tert-butyl (2R,4R)-2-(4-[(1S)-1-[(tert-butoxycarbonyl)amino]-3-ethoxy-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C25H38N2O7 | 详情 | 详情 | |
| (XI) | 30868 | (3S)-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 required isomer to furnish hydroxyester (XVI), which was separated from the undesired chloroacetate (XV). Alcohol (XVI) 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 finallyconverted 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) | 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 | |
| (XVI) | 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 | |
| (XVII) | 30869 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-[(1R)-3-ethoxy-1-[(methylsulfonyl)oxy]-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C27H45NO8SSi | 详情 | 详情 |
合成路线3
Silylation of 4(R)-hydroxy-2-pyrrolidone (I) with TBDMS-Cl and imidazole in DMF gives the silyl ether (II), which is protected at the NH group with Boc2O, TEA and DMAP in acetonitrile to yield the protected pyrrolidone derivative (III). Reaction of pyrrolidone (III) with the Grignard reagent (IV) in THF affords the 2-hydroxypyrrolidine adduct (V) in equilibrium with an open-chain form (VI). Reduction of the ketonic group of (VI) with NaBH4 in methanol in the same vessel provides the alcohol (VII), which is cyclized by means of MsCl and TEA in dichloromethane and then treated with TsOH in THF/H2O to furnish the pyrrolidine-benzaldehyde (VIII). The Wittig condensation of the aldehyde group of (VIII) with the phosphonate (IX) by means of NaH in THF gives the cinnamic ester derivative (X), which is desilylated with TBAF in THF to yield the hydroxy pyrrolidine (XI). Stereo-controlled condensation of (XI) with the chiral amine (XII) by means of BuLi in THF affords the N-alkylated b-amino ester (XIII), which is debenzylated with H2 over Pd(OH)2/C in HOAc/methanol to provide the free amino ester (XIV). The protection of the NH2 group of (XIV) with Boc2O and TEA in dioxane/water gives the N-protected amino ester (XV), which is hydrolyzed with NaOH in hot ethanol to afford the carboxylic acid (XVI).
| 【1】 Yamada, K.; Miura, K.; Nishimura, I.; Shimizu, A.; Morishima, H.; Abe, S.; Nakajima, S.; Sakuraba, S.; Imamura, H.; Sato, H.; Sugimoto, Y.; Stereoselective synthesis of a broad spectrum 1 beta-methylcarbapenem, J-114,870. Tetrahedron 2000, 56, 39, 7705. |
| 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) | 48236 | (R)-4-hydroxy-2-pyrrolidinone | 22677-21-0 | C4H7NO2 | 详情 | 详情 |
| (II) | 48237 | (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 30850 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (IV) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (V) | 48228 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-2-hydroxy-1-pyrrolidinecarboxylate | C24H41NO6Si | 详情 | 详情 | |
| (VI) | 48229 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-oxobutylcarbamate | C24H41NO6Si | 详情 | 详情 | |
| (VII) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (VIII) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (IX) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (X) | 48230 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C28H45NO5Si | 详情 | 详情 | |
| (XI) | 48231 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H31NO5 | 详情 | 详情 | |
| (XII) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (XIII) | 48232 | tert-butyl (2R,4R)-2-[4-[(1S)-1-[benzyl[(1R)-1-phenylethyl]amino]-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C37H48N2O5 | 详情 | 详情 | |
| (XIV) | 48233 | tert-butyl (2R,4R)-2-[4-[(1S)-1-amino-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H34N2O5 | 详情 | 详情 | |
| (XV) | 48234 | tert-butyl (2R,4R)-2-(4-[(1S)-3-(tert-butoxy)-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C27H42N2O7 | 详情 | 详情 | |
| (XVI) | 48235 | (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-[(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]phenyl]propionic acid | C23H34N2O7 | 详情 | 详情 |
合成路线4
Reaction of the carboxylic acid (XVI) with MsCl and TEA in THF yields the fully protected mixed anhydride (XVII). The chemo-selective ammonolysis of anhydride (XVII) gives amide (XVIII), which by displacement of the mesyloxy group with potassium thioacetate in hot DMF yields the thioacetate (XIX). Removal of the Boc protecting groups of (XIX) with HCl in ethyl acetate affords compound (XX), which is reprotected with allyl chloroformate (XXI) and TEA in dichloromethane to provide the bis(allyloxycarbonyl) compound (XXII). Hydrolysis of the thioacetate group of (XXII) with NaOH in methanol gives the thiol compound (XXIII), which is condensed with the carbape- nem diphenyl phosphate (XXIV) by means of DIEA in acetonitrile to provide the expected adduct (XXV). Finally, this compound is deprotected by a treatment with Bu3SnH and PdCl2(PPh3)2 in dichloromethane/water.
| 【1】 Yamada, K.; Miura, K.; Nishimura, I.; Shimizu, A.; Morishima, H.; Abe, S.; Nakajima, S.; Sakuraba, S.; Imamura, H.; Sato, H.; Sugimoto, Y.; Stereoselective synthesis of a broad spectrum 1 beta-methylcarbapenem, J-114,870. Tetrahedron 2000, 56, 39, 7705. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XVI) | 48235 | (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-[(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]phenyl]propionic acid | C23H34N2O7 | 详情 | 详情 | |
| (XVII) | 48238 | tert-butyl (2R,4R)-2-(4-[(1S)-1-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]-3-oxopropyl]phenyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C25H38N2O11S2 | 详情 | 详情 | |
| (XVIII) | 48239 | tert-butyl (2R,4R)-2-(4-[(1S)-3-amino-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C24H37N3O8S | 详情 | 详情 | |
| (XIX) | 48240 | tert-butyl (2R,4S)-4-(acetylsulfanyl)-2-(4-[(1S)-3-amino-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-1-pyrrolidinecarboxylate | C25H37N3O6S | 详情 | 详情 | |
| (XX) | 48241 | S-((3S,5R)-5-[4-[(1S)-1,3-diamino-3-oxopropyl]phenyl]pyrrolidinyl) ethanethioate | C15H21N3O2S | 详情 | 详情 | |
| (XXI) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (XXII) | 48242 | allyl (2R,4S)-4-(acetylsulfanyl)-2-[4-((1S)-1-[[(allyloxy)carbonyl]amino]-3-amino-3-oxopropyl)phenyl]-1-pyrrolidinecarboxylate | C23H29N3O6S | 详情 | 详情 | |
| (XXIII) | 48243 | C21H27N3O5S | 详情 | 详情 | ||
| (XXV) | 48244 | allyl (4R,5S,6S)-3-([(3S,5R)-1-[(allyloxy)carbonyl]-5-[4-((1S)-1-[[(allyloxy)carbonyl]amino]-3-amino-3-oxopropyl)phenyl]pyrrolidinyl]sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H42N4O9S | 详情 | 详情 |