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【结 构 式】

【分子编号】30851

【品名】bromo[4-(dimethoxymethyl)phenyl]magnesium

【CA登记号】

【 分 子 式 】C9H11BrMgO2

【 分 子 量 】255.39414

【元素组成】C 42.33% H 4.34% Br 31.29% Mg 9.52% O 12.53%

与该中间体有关的原料药合成路线共 6 条

合成路线1

该中间体在本合成路线中的序号:(III)

After protection of 4-bromobenzaldehyde (I) with triethyl orthoformate in MeOH, the resultant bromo ketal (II) was converted to the corresponding Grignard reagent (III) with magnesium in THF. Conjugate addition of (III) to the steroid epoxide (IV) in the presence of CuCl gave rise to the 11-beta-aryl steroid (V). Introduction of a 17-spiro oxirane moiety into ketone (V) to yield (VI) was accomplished by reaction with the sulfur ylide generated from trimethylsulfonium iodide and potassium tert-butoxide. Subsequent epoxide opening in (VI) with NaOMe gave rise to the methoxy alcohol (VII), which was further alkylated with iodomethane under Williamson's ether synthesis conditions to provide the dimethoxy derivative (VIII). Acid hydrolysis of both ketal groups of (VIII) with concomitant alcohol dehydration led to the dienone (IX). The aldehyde function of (IX) was finally converted to the target oxime by treatment with hydroxylamine hydrochloride in pyridine.

1 Schubert, G.; Kaufmann, G.; Sobeck, L.; Oettel, M.; Elger, W.; Kurischko, A. (Jenapharm GmbH); 11-Benzaldoximeestradiene-derivates, a process for their preparation and pharmaceutical compsns. containing them. CA 2130516; DE 4322283; EP 0648778 .
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) 22231 4-Bromobenzaldehyde 1122-91-4 C7H5BrO 详情 详情
(II) 23438 (4-bromophenyl)(methoxy)methyl methyl ether; 1-bromo-4-(dimethoxymethyl)benzene C9H11BrO2 详情 详情
(III) 30851 bromo[4-(dimethoxymethyl)phenyl]magnesium C9H11BrMgO2 详情 详情
(IV) 56197   C20H28O4 详情 详情
(V) 56198 (5R,8S,11R,13S,14S)-11-[4-(dimethoxymethyl)phenyl]-5-hydroxy-3,3-dimethoxy-13-methyl-1,2,3,4,5,6,7,8,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C29H40O6 详情 详情
(VI) 56199   C30H42O6 详情 详情
(VII) 56200 (8S,11R,13S,14S,17S)-11-[4-(dimethoxymethyl)phenyl]-3,3-dimethoxy-17-(methoxymethyl)-13-methyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-5H-cyclopenta[a]phenanthrene-5,17-diol C31H46O7 详情 详情
(VIII) 56201 (8S,11R,13S,14S,17S)-11-[4-(dimethoxymethyl)phenyl]-3,3,17-trimethoxy-17-(methoxymethyl)-13-methyl-1,2,3,4,6,7,8,11,12,13,14,15,16,17-tetradecahydro-5H-cyclopenta[a]phenanthren-5-ol C32H48O7 详情 详情
(IX) 56202 4-[(8S,11R,13S,14S,17S)-17-methoxy-17-(methoxymethyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl]benzaldehyde C28H34O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

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3

该中间体在本合成路线中的序号:(II)

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:(III)

(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)

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6

该中间体在本合成路线中的序号:(III)

(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
Extended Information