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【结 构 式】 
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【分子编号】24066 【品名】2-oxopropionic acid 【CA登记号】127-17-3 |
【 分 子 式 】C3H4O3 【 分 子 量 】88.06296 【元素组成】C 40.92% H 4.58% O 54.5% |
合成路线1
该中间体在本合成路线中的序号：(D)The reduction of ethylene ketal (XXI) with LiAlH4 produces the hydroxymethyl compound (XXII), which by selective tosylation with tosyl chloride yields the tosyloxymethyl compound (XXIII). The cyclization of (XXIII) with NaH in DMF affords the epoxy methane derivative (XXIV), which is deprotected by treatment with piruvic acid (D) in THF to give 2-(3-hydroxy-1-octen-1-yl)-3,5-epoxymethanocyclopentane-1-carboxaldehyde (XXV). The selective protection of the hydroxyl group of (XXV) with ethyl vinyl ether (E) affords the 1-ethoxyethoxy compound (XXVI), which is submitted to homologation in the aldehyde group by treatment with methoxymethylene-triphenylphosphorane (F) and butyllithium in THF, followed by hydrolysis of the non-isolated enol ether with mercuric acetate - water to give the acetaldehyde homolog (XXVII). The Wittig reaction of (XXVII) with 4-carboxybutyltriphenylphosphonium chloride (G) and NaH in DMSO yields 9,11-dideoxy-11alpha,9alpha-epoxymethano-15-(1-ethoxyethoxy)-PGE2 (XXVIII), which is finally deprotected by treatment with acetic acid in THF-water.
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (D) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (F) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (G) | 39165 | (3-carboxypropyl)(triphenyl)phosphonium chloride | C22H22ClO2P | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (XXII) | 39158 | (1R,2R,3S,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(hydroxymethyl)cyclopentanol | C21H38O6 | 详情 | 详情 | |
| (XXIII) | 39159 | [(1S,2S,3R,4R)-2-(1,3-dioxolan-2-yl)-3-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-hydroxycyclopentyl]methyl 4-methylbenzenesulfonate | C28H44O8S | 详情 | 详情 | |
| (XXIV) | 39160 | (1S,2E)-3-[(1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-2-oxabicyclo[2.2.1]hept-6-yl]-1-pentyl-2-propenyl 1-ethoxyethyl ether; (1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane | C21H36O5 | 详情 | 详情 | |
| (XXV) | 39161 | (1S,4R,5S,6R)-6-[(E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C15H24O3 | 详情 | 详情 | |
| (XXVI) | 39162 | (1S,4R,5S,6R)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C19H32O4 | 详情 | 详情 | |
| (XXVII) | 39164 | 2-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]acetaldehyde | C20H34O4 | 详情 | 详情 | |
| (XXVIII) | 39166 | (Z)-7-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid | C25H42O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)By condensation of N-(2-methyl-3-phenylallyl) hydrazine (I) with pyruvic acid (II) acetate-buffered aqueous medium.
| 【1】 Kuhnle, H.F.; Wolff, H.P.; Synthesis and hypoglycemic activity of N-alkylated hydrazonopropionic acids. J Med Chem 1985, 28, 10, 1436. |
| 【2】 Castaner, J.; Prous, J.; BM-42304. Drugs Fut 1986, 11, 3, 173. |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 4-amino-2-(trifluoromethyl)benzonitrile (I) with 2-oxopropionic acid (II) by means of SOCl2 gives the corresponding amide (III), which is finally condensed with the methyl sulfone (IV) by means of BuLi in THF.
| 【1】 Ekwuribe, N.N.; James, K.D.; A two-step synthesis of the anti-cancer drug (R,S)-bicalutamide. Synthesis (Stuttgart) 2002, 7, 850. |
| 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) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 58597 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-oxopropanamide | C11H7F3N2O2 | 详情 | 详情 | |
| (IV) | 46256 | 4-fluorophenyl methyl sulfone; (4-fluorophenyl)(methyl)dioxo-lambda(6)-sulfane | C7H7FO2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXX)Keto amide (XXXI) was obtained by acylation of L-proline benzyl ester (XII) with pyruvic acid (XXX). Subsequent hydrogenolysis of the benzyl ester group provided pyruvyl proline (XXXII). The target dehydrodidemnin B was then prepared by coupling of didemnin A (XXIX), from either natural or synthetic sources, with pyruvyl proline (XXXII)
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 【2】 Rinehart, K.L.; Lithgow-Bertelloni, A.M. (PharmaMar, SA); Dehydrodidemnin B. WO 9104985 . |
| 【3】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (XXIX) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 | |
| (XXX) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (XXXI) | 62541 | benzyl (2S)-1-pyruvoyl-2-pyrrolidinecarboxylate | C15H17NO4 | 详情 | 详情 | |
| (XXXII) | 62542 | (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid | C8H11NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)The condensation of 2,3-dimethoxybenzaldehyde (VI) with pyruvic acid (VII) by means of KOH in ethanol/water gives 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII), which is reductocondensed with methylamine (IV) by means of H2 over Pd/C in ethanol/ acetic acid to yield 4-(2,3-dimethoxyphenyl)-2-methylamino)butyric acid (IX). Reaction of acid (IX) with benzyl chloroformate (X) and NaOH in water affords the carbamate (XI), which is treated with refluxing SOCl2 to provide 4-[2-(2,3-dimethoxyphenyl)ethyl]-3-methyloxazolidine-2,5-dione (XII). Reaction of oxazolidinone (XII) with AlCl3 in dichloromethane provides 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII), which is reduced with H2 over Pd/C in ethanol containing some methanolic HCl in an autoclave at 80 C to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V). Finally, this compound is demethylated by treatment with AlCl3 in hot toluene. Alternatively, 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII) can first be demethylated with 48% HBr to give 5,6-dihydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIV), which is then reduced by means of H2 over Pd/C in an autoclave at 80 C.
| 【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046. |
| 【2】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 . |
| 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) | 49435 | 6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol | C11H15NO2 | 详情 | 详情 | |
| (IV) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (V) | 37381 | N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C13H19NO2 | 详情 | 详情 | |
| (VI) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
| (VII) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (VIII) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 详情 | 详情 | |
| (IX) | 37377 | 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid | C13H19NO4 | 详情 | 详情 | |
| (X) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XI) | 37378 | 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid | C21H25NO6 | 详情 | 详情 | |
| (XII) | 37379 | 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione | C14H17NO5 | 详情 | 详情 | |
| (XIII) | 37380 | 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C13H17NO3 | 详情 | 详情 | |
| (XIV) | 37387 | 5,6-dihydroxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C11H13NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Quinoline (IV) was prepared by condensation of 3,5-dimethoxyaniline (I), pyruvic acid (II) and o-tolualdehyde (III) in refluxing EtOH. After activation of (IV) as the acid chloride (V) by means of SOCl2 in benzene, its condensation with guanidine (VI) in DMF yielded the corresponding acyl guanidine.
| 【1】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 . |
| 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) | 25780 | 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine | 10272-07-8 | C8H11NO2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 27085 | 2-methylbenzaldehyde | 529-20-4 | C8H8O | 详情 | 详情 |
| (IV) | 27086 | 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarboxylic acid | C19H17NO4 | 详情 | 详情 | |
| (V) | 27087 | 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarbonyl chloride | C19H16ClNO3 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Quinoline (IV) was prepared by condensation of 2-(2-methoxyethyl)aniline (I), pyruvic acid (II) and benzaldehyde (III) in refluxing EtOH. After activation of (IV) as the imidazolide (V) by means of 1,1'-carbonyldiimidazole in DMF, its condensation with guanidine (VI) in the same solvent yielded the corresponding acyl guanidine.
| 【1】 Doebner, O.; Ueber alpha-alkylcinchoninsauren. Ber 1887, 20, 277-80. |
| 【2】 Pfitzinger, W.; Chinolinederivate aus isatinsaure. J Prakt Chem 1886, 33, 100. |
| 【3】 Kitamori, T.; Hosoya, J.; Mori, H.; Banno, H.; Kibayashi, K.; Yamashita, H.; Fujiwara, J.; MS-31-038. Drugs Fut 1999, 24, 12, 1306. |
| 【4】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 . |
| 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) | 27088 | 2-(2-methoxyethoxy)aniline | C9H13NO2 | 详情 | 详情 | |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 27089 | 8-(2-methoxyethoxy)-2-phenyl-4-quinolinecarboxylic acid | C19H17NO4 | 详情 | 详情 | |
| (V) | 27090 | 1H-imidazol-1-yl[8-(2-methoxyethoxy)-2-phenyl-4-quinolinyl]methanone | C22H19N3O3 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The condensation between pyruvic acid (I) and thiocarbohydrazide (II) provided 4-amino-3-mercapto-6-methyl-1,2,4-triazin-5(4H)-one (III). Further ring closure of (III) with (4-methylphenoxy)acetic acid (IV) by means of POCl3 yielded the required thiadiazolo triazinone.
| 【1】 Shridhara, K.; Sarojini, B.K.; Holla, B.S.; Antony, G.; Synthesis of some new biologically active thiadiazolotriazinones - Part II. Farmaco 1999, 54, 3, 149. |
合成路线9
该中间体在本合成路线中的序号：(II)Condensation of 2,3-dimethoxybenzaldehyde (I) with pyruvic acid (II) in the presence of KOH produced oxobutenoic acid (III), which was hydrogenated in the presence of methylamine to give amino acid (IV). Reaction of (IV) with benzyl chloroformate afforded carbamate (V), which was subsequently cyclized to the N-carboxyanhydride (VI) upon treatment with SOCl2. Friedel-Crafts intramolecular acylation using AlCl3 yielded amino tetralone (VII). Reduction of the keto group of (VII) to give amino tetralin (VIII) was effected by catalytic hydrogenation over Pd/C. Finally, dealkylation of the methyl ether groups of (VIII) with AlCl3 in hot toluene afforded the title dihydroxy compound.
| 【1】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 37376 | (E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid | C12H12O5 | 详情 | 详情 | |
| (IV) | 37377 | 4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid | C13H19NO4 | 详情 | 详情 | |
| (V) | 37378 | 2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid | C21H25NO6 | 详情 | 详情 | |
| (VI) | 37379 | 4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione | C14H17NO5 | 详情 | 详情 | |
| (VII) | 37380 | 5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 37381 | N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine | C13H19NO2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)3-Methylquinoxalin-2-one (III) was prepared by condensation of 1,2-phenylenediamine (I) with pyruvic acid (II). Alkylation of (III) with benzyl chloride furnished a mixture of the desired N-benzyl quinoxalinone (IV) and the O-benzyl isomer (V). These compounds were separated by means of radial chromatography. Bromination of (IV) with N-bromosuccinimide in the presence of benzoyl peroxide furnished the bromomethyl derivative (VI). Finally, condensation of bromide (VI) with salicylanilide (VII) under phase-transfer conditions provided the title compound.
| 【1】 Copper, J.E.; Smith, C.D.; Lawrence, D.S.; Structure-activity studies of substituted quinoxalinones as multiple-drug-resistance antagonists. J Med Chem 2001, 44, 4, 594. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 48019 | 3-methyl-2(1H)-quinoxalinone | 14003-34-0 | C9H8N2O | 详情 | 详情 |
| (IV) | 48020 | 1-benzyl-3-methyl-2(1H)-quinoxalinone | C16H14N2O | 详情 | 详情 | |
| (V) | 48021 | benzyl 3-methyl-2-quinoxalinyl ether; 2-(benzyloxy)-3-methylquinoxaline | C16H14N2O | 详情 | 详情 | |
| (VI) | 48022 | 1-benzyl-3-(bromomethyl)-2(1H)-quinoxalinone | C16H13BrN2O | 详情 | 详情 | |
| (VII) | 48023 | 2-hydroxy-N-phenylbenzamide | 87-17-2 | C13H11NO2 | 详情 | 详情 |