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【结 构 式】 
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【分子编号】27493 【品名】2-methylenesuccinic acid 【CA登记号】97-65-4 |
【 分 子 式 】C5H6O4 【 分 子 量 】130.10024 【元素组成】C 46.16% H 4.65% O 49.19% |
合成路线1
该中间体在本合成路线中的序号：(II)Michael addition of itaconic acid (II) to 4-tert-butylaniline (I), and further lactamization afforded pyrrolidone carboxylic acid (III). This was esterified with H2SO4 in MeOH, and the resulting methyl ester (IV) was reduced to alcohol (V) with NaBH4 in boiling tetrahydrofuran. Optical resolution of (V) was achieved by condensation with phthalic anhydride (VI) to give amide (VII), followed by coupling of the remaining carboxylic acid group of (VII) with chiral alpha-methylbenzyl amine (VIII) yielding (IX). After separation of the diastereomeric mixture (IX), hydrolysis of the phthalate ester furnished the required (S)-alcohol (X) (2). Mesylate (XI), prepared from alcohol (X) and MsCl in the presence of Et3N, was condensed with methyl 4-hydroxybenzoate (XII) to afford ether (XIII). Then, basic hydrolysis of the methyl ester of (XIII) provided the title compound.
| 【1】 Yano, S.; Ogawa, K.; Shirasaka, T.; Ohno, T. (Taiho Pharmaceutical Co., Ltd.); Optically active 1-phenylpyrrolidine derivative, intermediate for producing the same, and process for producing both. WO 9406767 . |
| 【2】 Watanabe, S.; et al.; Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses. Eur J Med Chem 1994, 29, 675. |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (III) | 27494 | 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (IV) | 27495 | methyl 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylate | C16H21NO3 | 详情 | 详情 | |
| (V) | 27496 | 1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 27497 | 2-[([1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methoxy)carbonyl]benzoic acid | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 15148 | 1-phenylethylamine; DL-a-methylbenzylamine; 1-phenyl-1-ethanamine | 618-36-0 | C8H11N | 详情 | 详情 |
| (IX) | 27498 | [1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinyl]methyl 2-[[(1-phenylethyl)amino]carbonyl]benzoate | C31H34N2O4 | 详情 | 详情 | |
| (X) | 27499 | (4S)-1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (XI) | 27500 | [(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methyl methanesulfonate | C16H23NO4S | 详情 | 详情 | |
| (XII) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XIII) | 27501 | methyl 4-([(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methoxy)benzoate | C23H27NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The Michael addition of 4-tert-butylaniline (I) with 2-methylenesuccinic acid (II) followed by cyclization gives racemic 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3-carboxylic acid (III) (1), which is treated with SOCl2 and condensed with (S)(-)-1-(4-methylphenyl)ethylamine (IV) to yield a diastereomeric mixture of amides (V). The resolution of (V) by silicagel chromatography affords the (S,S)-diastereomer (VI), which is treated with N2O4 and NaOAc in CCl4 to provide 1-(4-tert-butylphenyl)-5-oxopyrrolidine-3(S)-carboxylic acid (VII). The reduction of (VII) with BH3/THF in dichloromethane gives the corresponding carbinol (VIII), which is treated with MsCl and TEA in dichloromethane to yield the mesylate (IX). The condensation of (IX) with 4-hydroxybenzoic acid methyl ester (X) by means of K2CO3 in DMF affords the corresponding phenyl ether (XI), which is finally hydrolyzed with HCl/AcOH to furnish the target compound.
| 【1】 Ohno, T.; Ogawa, K.; Yano, S.; Kobayashi, K.; Shirasaka, T.; Yamada, H.; Yamamoto, A.; Synthesis of the optical isomers of 4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-yl]methyloxybenzoic acid (S-2) and their biological evaluation as antilipidemic agent. Chem Pharm Bull 1999, 47, 11, 1549. |
| 【2】 Watanabe, S.; et al.; Synthesis of 4-[1-(substituted phenyl)-2-oxo-pyrrolidin-4-yl]methyloxybenzoic acids and related compounds, and their inhibitory capacities toward fatty-acid and sterol biosyntheses. Eur J Med Chem 1994, 29, 675. |
| 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) | 27492 | 4-(tert-butyl)aniline | 769-92-6 | C10H15N | 详情 | 详情 |
| (II) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (III) | 27494 | 1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (IV) | 37195 | (2S)-2-(4-methylphenyl)-1-propanamine; (2S)-2-(4-methylphenyl)propylamine | C10H15N | 详情 | 详情 | |
| (V) | 37196 | 1-[4-(tert-butyl)phenyl]-N-[(2S)-2-(4-methylphenyl)propyl]-5-oxo-3-pyrrolidinecarboxamide | C25H32N2O2 | 详情 | 详情 | |
| (VI) | 37197 | (3S)-1-[4-(tert-butyl)phenyl]-N-[(2S)-2-(4-methylphenyl)propyl]-5-oxo-3-pyrrolidinecarboxamide | C25H32N2O2 | 详情 | 详情 | |
| (VII) | 37198 | (3S)-1-[4-(tert-butyl)phenyl]-5-oxo-3-pyrrolidinecarboxylic acid | C15H19NO3 | 详情 | 详情 | |
| (VIII) | 27499 | (4S)-1-[4-(tert-butyl)phenyl]-4-(hydroxymethyl)-2-pyrrolidinone | C15H21NO2 | 详情 | 详情 | |
| (IX) | 37199 | (4S)-1-[4-(tert-butyl)phenyl]-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-pyrrolidinone | C18H27NO2S | 详情 | 详情 | |
| (X) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (XI) | 27501 | methyl 4-([(3S)-1-[4-(tert-butyl)phenyl]-5-oxopyrrolidinyl]methoxy)benzoate | C23H27NO4 | 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 condensation of itaconic acid (I) with (R)-1-phenylethylamine (II) produced a mixture of diastereomeric pyrrolidinones (III). The desired isomer (IV) was then isolated after conversion to the corresponding methyl ester. Introduction of the fluorine atom to give (VI) was achieved by either treatment with diethylaminosulfur trifluoride (DAST) or via conversion to the corresponding mesylate and further displacement by tetrabutylammonium fluoride. Hydroxylation of the lithium enolate of (VI) by means of O2 and (EtO)3P afforded the trans-3-hydroxy-4-(fluoromethyl)pyrrolidinone (VII). This was converted to mesylate (VIII) and subsequently displaced by NaN3 to provide the cis azide (IX). Hydrogenation of the azido group of (IX) over Pd/C in the presence of di-tert-butyl dicarbonate produced the Boc-protected amine (X). The pyrrolidinone ring was then reduced to pyrrolidine (XI) with borane in THF, and further hydrogenation over Pd/C at 50 C removed the alpha-methylbenzyl group, yielding (XII). Optionally, acid deprotection of the Boc group of (XII) provided intermediate (XIII).
| 【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73. |
| 【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 36288 | (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 36289 | (3S)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (I) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IV) | 36290 | methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (V) | 36291 | (4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H17NO2 | 详情 | 详情 | |
| (VI) | 36292 | (4R)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO | 详情 | 详情 | |
| (VII) | 36293 | (3R,4S)-4-(fluoromethyl)-3-hydroxy-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO2 | 详情 | 详情 | |
| (VIII) | 36294 | (3R,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinyl methanesulfonate | C14H18FNO4S | 详情 | 详情 | |
| (IX) | 36295 | (3S,4S)-3-azido-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H15FN4O | 详情 | 详情 | |
| (X) | 36296 | tert-butyl (3S,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H25FN2O3 | 详情 | 详情 | |
| (XI) | 36297 | tert-butyl (3S,4S)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H27FN2O2 | 详情 | 详情 | |
| (XII) | 36298 | tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate | C10H19FN2O2 | 详情 | 详情 | |
| (XIII) | 36299 | (3S,4S)-4-(fluoromethyl)-3-pyrrolidinamine; (3S,4S)-4-(fluoromethyl)pyrrolidinylamine | C5H11FN2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Itaconic acid mono-tert-butyl ester (IV) was prepared via esterification of itaconic acid (I) with methanol in the presence of an acidic ion exchange resin to form the mono-methyl ester (II), which was further converted to methyl tert-butyl ester (III) upon treatment with isobutylene and sulfuric acid. Subsequent hydrolysis of the methyl ester function of (III) using LiOH furnished mono-ester (IV). Reduction of acid (IV) to the primary alcohol (V) was accomplished using the NaBH4-I2 reagent. Michael addition of p-bromothiophenol (VI) to the unsaturated ester (V) provided the thioether adduct (VII). Mitsunobu coupling of alcohol (VII) with benzo[1,2,3]triazin-4-one (VIII) yielded the 3-substituted triazinone (IX). The biphenyl system (XI) was then obtained by Suzuki coupling of the aryl bromide (IX) with (4-chlorophenyl)tributyltin (X) in the presence of palladium tetrakis(triphenylphosphine) and lithium chloride. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI) gave acid (XII), which was subsequently coupled to O-allyl hydroxylamine (XIII) to afford the allyl hydroxamate (XIV). The O-allyl group was finally removed by treatment with tributyltin hydride and a palladium catalyst.
| 【1】 Le Diguarher, T.; Kucharvzyk, N.; Chollet, A.-M.; et al.; Solid-phase synthesis of alpha-substituted 3-bisarylthio N-hydroxy propionamides as specific MMP inhibitors. Bioorg Med Chem 2002, 10, 3, 531. |
| 【2】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 . |
| 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) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 34820 | 2-(2-methoxy-2-oxoethyl)acrylic acid | 7338-27-4 | C6H8O4 | 详情 | 详情 |
| (III) | 59619 | 1-(tert-butyl) 4-methyl 2-methylenesuccinate | C10H16O4 | 详情 | 详情 | |
| (IV) | 59620 | 3-(tert-butoxycarbonyl)-3-butenoic acid | C9H14O4 | 详情 | 详情 | |
| (V) | 59621 | tert-butyl 2-(2-hydroxyethyl)acrylate | C9H16O3 | 详情 | 详情 | |
| (VI) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
| (VII) | 59622 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-hydroxybutanoate | C15H21BrO3S | 详情 | 详情 | |
| (VIII) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
| (IX) | 59623 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C22H24BrN3O3S | 详情 | 详情 | |
| (X) | 59624 | tributyl(4-chlorophenyl)stannane | C18H31ClSn | 详情 | 详情 | |
| (XI) | 59625 | tert-butyl 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C28H28ClN3O3S | 详情 | 详情 | |
| (XII) | 59626 | 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoic acid | C24H20ClN3O3S | 详情 | 详情 | |
| (XIII) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 | |
| (XIV) | 59627 | N-(allyloxy)-2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanamide | C27H25ClN4O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Cyclization of itaconic acid (I) with 3-nitroaniline (II) at 100 C gives rise to 1-(3-nitrophenyl)-5-oxopyrrolidine-3-carboxylic acid (III). Subsequent condensation of acid (III) with methyl 3-amino-3-(3,5-dichlorophenyl)propanoate (IV) in the presence of EDC and HOAt yields amide (V). Reduction of the nitro group of (V) to the corresponding amine (VI) is effected by means of Zn and HOAc. Amine (VI) is then condensed with the cyclic thiourea (VII) employing HgCl2 to furnish the di-Boc-protected guanidine (VIII). Saponification of the methyl ester function of (VIII) then gives acid (IX). The N-Boc groups of (IX) are finally removed by treatment with trifluoroacetic acid to furnish the title compound.
| 【1】 Dominguez, C.; Chen, G.; Liu, L.; Liu, Q.; Han, N.; Xi, N.; Xu, S.; Huang, Q.; Siegmund, A.; Handley, M.; Kiselyov, A.S. (Amgen Inc.); 1-(Aminophenyl)-2-pyrrolidones as integrin inhibitors. EP 1240158; US 2002019402; WO 0144230 . |
| 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) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 57781 | 1-Amino-3-Nitrobenzene; 3-Nitroaniline; m-Nitroaniline | 99-09-2 | C6H6N2O2 | 详情 | 详情 |
| (III) | 57782 | 1-(3-nitrophenyl)-5-oxo-3-pyrrolidinecarboxylic acid | C11H10N2O5 | 详情 | 详情 | |
| (IV) | 57783 | methyl 3-amino-3-(3,5-dichlorophenyl)propanoate | C10H11Cl2NO2 | 详情 | 详情 | |
| (V) | 57784 | methyl 3-(3,5-dichlorophenyl)-3-({[1-(3-nitrophenyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)propanoate | C21H19Cl2N3O6 | 详情 | 详情 | |
| (VI) | 57785 | methyl 3-({[1-(3-aminophenyl)-5-oxo-3-pyrrolidinyl]carbonyl}amino)-3-(3,5-dichlorophenyl)propanoate | C21H21Cl2N3O4 | 详情 | 详情 | |
| (VII) | 57786 | di(tert-butyl) 2-thioxodihydro-1,3(2H,4H)-pyrimidinedicarboxylate | C14H24N2O4S | 详情 | 详情 | |
| (VIII) | 57787 | di(tert-butyl) 2-({3-[4-({[1-(3,5-dichlorophenyl)-3-methoxy-3-oxopropyl]amino}carbonyl)-2-oxo-1-pyrrolidinyl]phenyl}imino)dihydro-1,3(2H,4H)-pyrimidinedicarboxylate | C35H43Cl2N5O8 | 详情 | 详情 | |
| (IX) | 57788 | N-{[1-(3-{[1,3-bis(tert-butoxycarbonyl)tetrahydro-2(1H)-pyrimidinylidene]amino}phenyl)-5-oxo-3-pyrrolidinyl]carbonyl}-3-(3,5-dichlorophenyl)-beta-alanine | C34H41Cl2N5O8 | 详情 | 详情 |