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【结 构 式】 
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【分子编号】30852 【品名】tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C22H35NO4Si 【 分 子 量 】405.60974 【元素组成】C 65.15% H 8.7% N 3.45% O 15.78% Si 6.92% |
合成路线1
该中间体在本合成路线中的序号：(IV)The protection of 4(R)-hydroxypyrrolidin-2-one (I) first with TBDMS-Cl and then with Boc2O gives the fully protected compound (II), which is condensed with the Grignard reagent of the 4-bromobenzaldehyde dimethyl acetal (III) yielding after working up the substituted benzaldehyde (IV). The reduction of (IV) with NaBH4 affords the benzyl alcohol (V), which is treated with methanesulfonyl chloride to give the corresponding mesylate (VI). The reaction of (VI) with methylamine, followed by protection with Boc2O yields the protected secondary amine (VII), which is desilylated with tetrabutylammonium fluoride to afford the pyrrolidinol (VIII). The reaction of (VIII) with MsCl gives the mesylate (IX), which is treated with potassium thioacetate to provide the acetylsulfanyl derivative (X). The hydrolysis and deprotection of (X) with HCl yields the pyrrolidinethiol (XI), which is condensed with the carbapenem phosphoric ester (XII) to afford the final 4-nitrobenzyl ester intermediate (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.
| 【1】 Sato, H.; Morishima, H.; Sakuraba, S.; Yamada, K.; Imamura, H.; Shimizu, A.; Sugimoto, Y.; Practical synthesis of a 1beta-methylcarbapenem, J-111,225, using 4-mercapto-2-[4-(N-methylaminomethyl)phenyl]pyrrolidine as a precursor. Chem Pharm Bull 2001, 49, 4, 476. |
| 【2】 Imamura, H.; et al.; Discovery of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems. Bioorg Med Chem 2000, 8, 8, 1969. |
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (V) | 30870 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(hydroxymethyl)phenyl]-1-pyrrolidinecarboxylate | C22H37NO4Si | 详情 | 详情 | |
| (VI) | 30871 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)phenyl]-1-pyrrolidinecarboxylate | C25H43NO4SSi | 详情 | 详情 | |
| (VII) | 30872 | tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C28H48N2O5Si | 详情 | 详情 | |
| (VIII) | 30873 | tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C22H34N2O5 | 详情 | 详情 | |
| (IX) | 30874 | tert-butyl (2R,4R)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-pyrrolidinecarboxylate | C25H40N2O5S | 详情 | 详情 | |
| (X) | 30875 | tert-butyl (2R,4R)-4-(acetylsulfanyl)-2-(4-[[(tert-butoxycarbonyl)(methyl)amino]methyl]phenyl)-1-pyrrolidinecarboxylate | C24H36N2O5S | 详情 | 详情 | |
| (XI) | 30876 | (3S,5R)-5-[4-[(methylamino)methyl]phenyl]pyrrolidinylhydrosulfide; (3S,5R)-5-[4-[(methylamino)methyl]phenyl]-3-pyrrolidinethiol | C12H18N2S | 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 |
| (XIII) | 30877 | 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[((3S,5R)-5-[4-[(methylamino)methyl]phenyl]pyrrolidinyl)sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C29H34N4O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The Grignard condensation of the chiral pyrrolidinone (I) with 4-(dimethoxymethyl)phenylmagnesium bromide (II) in THF, followed by reduction with NaBH4, gives the aminoalcohol (III), which is cyclized to the pyrrolidine (IV) by means of MsCl and TEA in dichloromethane. Hydrolysis of the dimethyl acetal of (IV), followed by separation of the resulting diastereomeric mixture of aldehydes, yields the desired diastereomer (V). The reduction of (V) with NaBH4, followed by reaction with Ms-Cl in dichloromethane, affords the mesylate (VI), which by reaction with methylamine provides the secondary amine (VII). The protection of (VII) with allyl chloroformate and TEA, cleavage of the silyl-protecting group gives the hydroxy pyrrolidine (VIII), which is treated with MsCl and TEA to yield the mesylate (IX). The reaction of (IX) with potassium thioacetate in hot DMF affords the sulfanyl pyrrolidine (X), which is condensed with the penem diphenyl phosphate (XI) by means of DIEA in acetonitrile to provide the protected intermediate (XII). Finally, (XII) is converted into the target compound by reaction with PdCl2(PPh3)2 and Bu3SnH in dichloromethane/water.
| 【1】 Imamura, H.; et al.; A novel 1beta-methylcarbapenem, J-111,225: Effects of the C-3 and C-5 stereochemistry of the pyrrolidinylthio side chain on antibacterial activities. J Antibiot 2000, 53, 3, 314. |
| 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) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (II) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (III) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (IV) | 43978 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-1-pyrrolidinecarboxylate | C24H41NO5Si | 详情 | 详情 | |
| (V) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (VI) | 30871 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)phenyl]-1-pyrrolidinecarboxylate | C25H43NO4SSi | 详情 | 详情 | |
| (VII) | 43979 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(methylamino)methyl]phenyl]-1-pyrrolidinecarboxylate | C23H40N2O3Si | 详情 | 详情 | |
| (VIII) | 43980 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C20H26N2O5 | 详情 | 详情 | |
| (IX) | 43981 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-pyrrolidinecarboxylate | C23H32N2O5S | 详情 | 详情 | |
| (X) | 43982 | allyl (2R,4S)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C20H26N2O4S | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 43983 | allyl (4R,5S,6S)-3-[[(3S,5R)-1-[(allyloxy)carbonyl]-5-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C33H41N3O8S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The Grignard condensation of the chiral pyrrolidinone (I) with 4-(dimethoxymethyl)phenylmagnesium bromide (II) in THF, followed by reduction with NaBH4, gives the aminoalcohol (III), which is cyclized to the pyrrolidine (IV) by means of MsCl and TEA in dichloromethane. Hydrolysis of the dimethyl acetal of (IV), followed by separation of the resulting diastereomeric mixture of aldehydes, yields the desired diastereomer (V). The reduction of (V) with NaBH4, followed by reaction with Ms-Cl in dichloromethane, affords the mesylate (VI), which by reaction with methylamine provides the secondary amine (VII). The protection of (VII) with allyl chloroformate and TEA, cleavage of the silyl-protecting group gives the hydroxy pyrrolidine (VIII), which is treated with MsCl and TEA to yield the mesylate (IX). The reaction of (IX) with potassium thioacetate in hot DMF affords the sulfanyl pyrrolidine (X), which is condensed with the penem diphenyl phosphate (XI) by means of DIEA in acetonitrile to provide the protected intermediate (XII). Finally, (XII) is converted into the target compound by reaction with PdCl2(PPh3)2 and Bu3SnH in dichloromethane/water.
| 【1】 Imamura, H.; et al.; A novel 1beta-methylcarbapenem, J-111,225: Effects of the C-3 and C-5 stereochemistry of the pyrrolidinylthio side chain on antibacterial activities. J Antibiot 2000, 53, 3, 314. |
| 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) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (II) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (III) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (IV) | 43978 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-1-pyrrolidinecarboxylate | C24H41NO5Si | 详情 | 详情 | |
| (V) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (VI) | 30871 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)phenyl]-1-pyrrolidinecarboxylate | C25H43NO4SSi | 详情 | 详情 | |
| (VII) | 43979 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-[(methylamino)methyl]phenyl]-1-pyrrolidinecarboxylate | C23H40N2O3Si | 详情 | 详情 | |
| (VIII) | 43980 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C20H26N2O5 | 详情 | 详情 | |
| (IX) | 43981 | allyl (2R,4R)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-pyrrolidinecarboxylate | C23H32N2O5S | 详情 | 详情 | |
| (X) | 43982 | allyl (2R,4S)-2-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C20H26N2O4S | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 43983 | allyl (4R,5S,6S)-3-[[(3S,5R)-1-[(allyloxy)carbonyl]-5-(4-[[[(allyloxy)carbonyl](methyl)amino]methyl]phenyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C33H41N3O8S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)(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5
该中间体在本合成路线中的序号：(IV)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6
该中间体在本合成路线中的序号：(VIII)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7
该中间体在本合成路线中的序号：(IV)(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8
该中间体在本合成路线中的序号：(IV)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 |