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【结 构 式】 
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【分子编号】16695 【品名】(2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid 【CA登记号】147-71-7 |
【 分 子 式 】C4H6O6 【 分 子 量 】150.08804 【元素组成】C 32.01% H 4.03% O 63.96% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of D-tartaric acid (I) with EtOH in the presence of an acid catalyst gives diethyl D-tartrate (II), which is treated with isobutyraldehyde and anhydrous CuSO4 in the presence of methanesulfonic acid yielding diethyl 2,3-O-isobutylidene-D-tartrate (III). The 1,3-dioxolane diester (III) was then reduced with LAH to afford (4R,5R)-4,5-bis(hydroxymethyl)-2-isopropyl-1,3-dioxolane (IV), which is treated with methanesulfonyl chloride in pyridine yielding (4R,5R)-4,5-bis(methylsulfonyloxymethyl)-2-isopropyl-1,3-dioxolane (V). The bis(methanesulfonate) (V) is reacted with NaN3 in DMF to give (4R,5R)-4,5-bis(azidomethyl)-2-isopropyl-1,3-dioxolane (VI), which is reduced with hydrogen in the presence of 10% Pd/C in EtOH to afford (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane (VII). The diamine (VII) is reacted with an equimolar amount of in situ generated K2PtI4 to afford cis-diiodo[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II) (VIII), which is finally treated with malonic acid disilver salt in H2O to obtain (IX).
| 【1】 Kim, Y.; Rim, J.; Yoo, K.; Kim, G.; Gam, J.; Kim, K.H.; Kim, D.-K.; Song, S.; Synthesis of carbon-14 labelled cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI 2053R). J Label Compd Radiopharm 1994, 34, 2, 157-64. |
| 【2】 Kim, D.-K.; Kim, K.H.; SKI-2053R. Drugs Fut 1995, 20, 11, 1128. |
| 【3】 Kim, D.-K.; Cho, Y.-B.; Park, J.-G.; Tai, J.-H.; Kim, K.H.; Hong, W.-S.; Kim, H.-T.; Kim, G.; Gam, J.; Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes. J Med Chem 1994, 37, 10, 1471-85. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (III) | 16697 | diethyl (4S,5S)-2-isopropyl-1,3-dioxolane-4,5-dicarboxylate | C12H20O6 | 详情 | 详情 | |
| (IV) | 16698 | [(4R,5R)-5-(hydroxymethyl)-2-isopropyl-1,3-dioxolan-4-yl]methanol | C8H16O4 | 详情 | 详情 | |
| (V) | 16699 | (4R,5R)-2-isopropyl-4,5-bis([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolane | C14H28O4S2 | 详情 | 详情 | |
| (VI) | 16700 | 1-[[(4R,5R)-2-isopropyl-5-(triazanylmethyl)-1,3-dioxolan-4-yl]methyl]triazane | C8H22N6O2 | 详情 | 详情 | |
| (VII) | 16701 | [(4R,5R)-5-(aminomethyl)-2-isopropyl-1,3-dioxolan-4-yl]methylamine; [(4R,5R)-5-(aminomethyl)-2-isopropyl-1,3-dioxolan-4-yl]methanamine | C8H18N2O2 | 详情 | 详情 | |
| (VIII) | 16702 | cis-diiodo[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum; cis-[(4R,5R)-2-isopropyl-1,3-dioxolane-4,5-dimethanamine-N,N']diiodoplatinum | C8H16I2N2O2Pt | 详情 | 详情 | |
| (IX) | 16703 | malonic acid disilver salt | C3H2Ag2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of D-tartaric acid (I) with 2,2-dimethoxypropane (II) and Ts-OH gives the acetonide (III), which is reduced with NaBH4 in ethanol to yield the diol (IV). The reaction of (IV) with Ts-OH and TEA affords the ditosylate (V), whose acetonide is cleaved with HCl to provide the diol (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the cyclic sulfite (VII), which is oxidized with NaIO4 and RuCl3 to yield the cyclic sulfate (VIII). The reaction of (VIII) with sodium azide in acetone/water affords the azide (IX), which is treated with sulfuric acid in THF/water to provide the azido alcohol (X). The reduction of the azido group of (X) with H2 over Pd/C affords the amino alcohol (XI), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XII) by means of TEA in THF, providing the intermediate amide (XIII). Spontaneous cyclization of the amide (XIII) under the reaction conditions gives the oxazoline (XIV), which is condensed with the perhydroisoquinoline (XV) by means of K2CO3 in isopropanol to yield the oxazoline intermediate (XVI). Finally, the cleavage of the oxazoline ring of (XVI) by means of thiophenol (XVII) affords the target compound.
| 【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 55018 | (4S,5S)-1,3-dioxolane-4,5-dicarboxylic acid | C5H6O6 | 详情 | 详情 | |
| (IV) | 55019 | [(4R,5R)-5-(hydroxymethyl)-1,3-dioxolan-4-yl]methanol | C5H10O4 | 详情 | 详情 | |
| (V) | 55020 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | C19H22O8S2 | 详情 | 详情 | |
| (VI) | 55021 | (2R,3R)-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H22O8S2 | 详情 | 详情 | |
| (VII) | 55022 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxo-1,3,2lambda~4~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O9S3 | 详情 | 详情 | |
| (VIII) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
| (IX) | 55024 | C18H20N3NaO10S3 | 详情 | 详情 | ||
| (X) | 55025 | (2S,3S)-3-azido-2-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H21N3O7S2 | 详情 | 详情 | |
| (XI) | 55026 | (2S,3S)-2-amino-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H23NO7S2 | 详情 | 详情 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XIII) | 55027 | 3-({[(1S,2S)-2-hydroxy-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}carbonyl)-2-methylphenyl acetate | C28H31NO10S2 | 详情 | 详情 | |
| (XIV) | 55028 | 3-[(4S)-4-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-methylphenyl acetate | C21H23NO7S | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVI) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The methylation of 3-cyanopyridine (I) with methyl iodide in acetone gives 3-cyano-1-methylpyridinium iodide (II), which is reduced with NaBH4 in methanol/water yielding 1-methyl-1,2,5,6-tetrahydropyridine-3-carbonitrile (III). The reaction of (III) with ethyl chloroformate and K2CO3 in 1,1,1-trichloroethane affords 3-cyano-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (IV), which is cyclized with sodium azide by means of AlCl3 in refluxing THF giving tetrazole (V). Alkylation of (V) with ethyl iodide and NaOH in refluxing acetone, followed by column chromatography, yields 3-(2-ethyltetrazol-5-yl)-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (VI). The decarboxylation of (VI) with HBr in acetic acid affords 2-ethyl-5-(1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VII), which is methylated with formaldehyde/formic acid or with methyl iodide to give 2-ethyl-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VIII). Finally, this compound is treated with L-(+)-tartaric acid.
| 【1】 Pedersen, H.; Bogeso, K.P.; Moltzen, E.K.; et al.; Bioisosteres of arecoline: 1,2,3,6-Tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity. J Med Chem 1994, 37, 24, 4085-99. |
| 【2】 Castañer, J.; Mucke, H.A.M.; LU-25-109T. Drugs Fut 1998, 23, 8, 843-846. |
| 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) | 14062 | Nicotinonitrile; 3-Cyanopyridine | 100-54-9 | C6H4N2 | 详情 | 详情 |
| (II) | 17511 | 3-Cyano-1-methylpyridinium iodide | 1004-16-6 | C7H7IN2 | 详情 | 详情 |
| (III) | 17512 | 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarbonitrile | C7H10N2 | 详情 | 详情 | |
| (IV) | 17513 | ethyl 5-cyano-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H12N2O2 | 详情 | 详情 | |
| (V) | 17514 | ethyl 5-(2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H13N5O2 | 详情 | 详情 | |
| (VI) | 17515 | ethyl 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H17N5O2 | 详情 | 详情 | |
| (VII) | 17516 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1,2,3,6-tetrahydropyridine | C8H13N5 | 详情 | 详情 | |
| (VIII) | 17517 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C9H15N5 | 详情 | 详情 | |
| (IX) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)1) The esterification of 4-fluoro-3-hydroxybenzoic acid (I) with trimethyl orthoformate and sulfuric acid gives the methyl ester (II), which is condensed with propargyl bromide (III) by means of K2CO3 in acetone, yielding the corresponding ether (IV). The cyclization of (IV) by heating at 220 C in N,N-diethylaniline affords 8-fluoro-2H-1-benzopyran-5-carboxylic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing ethanol to the corresponding free acid (VI). The reaction of (VI) with thionyl chloride and then with ammonia affords the carboxamide (VII), which is nitrated with NaNO2 and iodine, giving the 8-fluoro-3-nitro-2H-1-benzopyran-5-carboxamide (VIII). The hydrogenation of the double bond of (VIII) with NaBH4 in isopropanol yields the 3,4-dihydro compound (IX), which is then further reduced at the nitro group with H2 and RaNi in ethanol/THF, providing racemic 3-amino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (X). Optical resolution of (X) with L-(+)-tartaric acid gives the 3(R)-amino derivative (XI), which is alkylated with cyclobutanone (XII) and sodium cyanoborohydride in methanol/acetic acid to afford robalzotan (XIII). Finally, this compound is treated with L-(+)-tartaric acid (XIV) in THF/ethyl ether.
| 【1】 Leeson, P.; Castañer, J.; Sorbera, L.A.; Robalzotan Tartrate Hydrate. Drugs Fut 1999, 24, 7, 740. |
| 【2】 Muroi, M.; Tobita, T.; Nozaki, Y. (Takeda Chemical Industries, Ltd.); Physiologically active substances TAN-1323, their preparation method and use. JP 1991290193 . |
| 【3】 Sohn, D.D.; Johansson, L.; Hanson, S. (AstraZeneca plc); A new process. WO 9846586 . |
| 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) | 26364 | 4-fluoro-3-hydroxybenzoic acid | 51446-31-2 | C7H5FO3 | 详情 | 详情 |
| (II) | 26365 | methyl 4-fluoro-3-hydroxybenzoate | C8H7FO3 | 详情 | 详情 | |
| (III) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (IV) | 26366 | methyl 4-fluoro-3-(2-propynyloxy)benzoate | C11H9FO3 | 详情 | 详情 | |
| (V) | 26367 | methyl 8-fluoro-2H-chromene-5-carboxylate | C11H9FO3 | 详情 | 详情 | |
| (VI) | 26368 | 8-fluoro-2H-chromene-5-carboxylic acid | C10H7FO3 | 详情 | 详情 | |
| (VII) | 26369 | 8-fluoro-2H-chromene-5-carboxamide | C10H8FNO2 | 详情 | 详情 | |
| (VIII) | 26370 | 8-fluoro-3-nitro-2H-chromene-5-carboxamide | C10H7FN2O4 | 详情 | 详情 | |
| (IX) | 26371 | 8-fluoro-3-nitro-5-chromanecarboxamide | C10H9FN2O4 | 详情 | 详情 | |
| (X) | 26372 | 3-amino-8-fluoro-5-chromanecarboxamide | C10H11FN2O2 | 详情 | 详情 | |
| (XI) | 26373 | (3R)-3-amino-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide | C10H11FN2O2 | 详情 | 详情 | |
| (XII) | 26374 | cyclobutanone | 1191-95-3 | C4H6O | 详情 | 详情 |
| (XIII) | 26375 | (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-chromene-5-carboxamide | C18H23FN2O2 | 详情 | 详情 | |
| (XIV) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)L-Tartaric acid (I) was converted to succinimimide (II) upon treatment with benzylamine in refluxing xylene with azeotropic removal of water. Subsequent reduction of (II) with borane, generated from NaBH4 and BF3, afforded pyrrolidine (III). Removal of the N-benzyl group of (III) was effected by hydrogenolysis over Pd/C, and the resulting secondary amine (IV) was coupled with the N-protected 3-thioacetylproline (V) to furnish amide (VI). Deacetylation of (VI) under basic conditions provided thiol (VII). Condensation of thiol (VII) with carbapenem enolphosphate (VIII) afforded thioether (IX). The 4-nitrobenzyl protecting groups of (IX) were finally removed by hydrogenolysis over Pd/C.
| 【1】 Park, S.W.; Park, S.Y.; Kim, D.J.; Shin, K.J.; Kang, Y.K.; Yoo, K.H.; Jae Seo, K.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems having a new moiety at C-2. Bioorg Med Chem Lett 1999, 9, 16, 2385. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 33017 | (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione | 75172-31-5 | C11H11NO4 | 详情 | 详情 |
| (III) | 33018 | (3S,4S)-1-benzyl-3,4-pyrrolidinediol | C11H15NO2 | 详情 | 详情 | |
| (IV) | 33019 | (3S,4S)-3,4-pyrrolidinediol | C4H9NO2 | 详情 | 详情 | |
| (V) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (VI) | 33020 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate | C19H23N3O8S | 详情 | 详情 | |
| (VII) | 33021 | 4-nitrobenzyl (2S,4S)-2-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C17H21N3O7S | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 33022 | 4-nitrobenzyl (4R,5S,6S)-3-[((3S,5S)-5-[[(3S,4S)-3,4-dihydroxypyrrolidinyl]carbonyl]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C34H37N5O13S | 详情 | 详情 |