【结 构 式】 |
【分子编号】24305 【品名】4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride 【CA登记号】59703-00-3 |
【 分 子 式 】C7H9ClN2O3 【 分 子 量 】204.61284 【元素组成】C 41.09% H 4.43% Cl 17.33% N 13.69% O 23.46% |
合成路线1
该中间体在本合成路线中的序号:(II)The acylation of 3,4-dihydroxyphenylglycine (I) with 4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl chloride (II) by means of N,N-diethyl-1,1,1-trimethylsilylamine (DTSA) gives the corresponding N-acyl derivative (III), which is acetylated with acetic anhydride and pyridine in THF yielding the corresponding diacetoxy compound (IV). The condensation of (IV) with benzyl 6B-amino-6a-formamidopenicillanate (V) [obtained from the trichloroethoxycarbonyl derivative (VI)] by means of dicyclohexyl carbodiimide (DCC) in dichloroethane affords the fully protected compound (VII), which is debenzylated by hydrogenolysis with H2 over Pd/C in THF - water giving the free acid (VIII). Finally, this compound is desacetylated with Subtilisin Calsberg.
【1】 Milner, P.H. (SmithKline Beecham plc); beta -Lactam antibacterial agents. EP 0071395; GB 2107307; US 4539149; US 4609652; US 4877783 . |
【2】 Prous, J.; Castaner, J.; Formidacillin sodium. Drugs Fut 1986, 11, 9, 739. |
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) | 24304 | 2-amino-2-(3,4-dihydroxyphenyl)acetic acid | 56144-53-7 | C8H9NO4 | 详情 | 详情 |
(II) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
(III) | 24306 | 2-(3,4-dihydroxyphenyl)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]acetic acid | C15H17N3O7 | 详情 | 详情 | |
(IV) | 24307 | 2-[Bis(methoxycarbonyl)phenyl]-2-(4-ethyl-2,3-dioxopiperazin-1-ylcarboxamido)acetic acid | C17H19N3O8 | 详情 | 详情 | |
(V) | 24308 | phenethyl (2S,6S)-6-amino-6-(formylamino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C17H21N3O4S | 详情 | 详情 | |
(VI) | 24309 | phenethyl (2S,6R)-6-(formylamino)-3,3-dimethyl-7-oxo-6-[[(3,3,3-trichloropropanoyl)oxy]amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C20H22Cl3N3O6S | 详情 | 详情 | |
(VII) | 24310 | 6(S)-[2-[3,4-Bis(methoxycarbonyl)phenyl]-2-(4-ethyl-2,3-ddioxopiperazin-1-ylcarboxamido)acetamido]-6-(formamido)-2,2-dimethylpenam-3(S)-carboxylic acid benzyl ester; 6(S)-[2-[3,4-Bis(methoxycarbonyl)phenyl]-2-(4-ethyl-2,3-ddioxopiperazin-1-ylcarboxamido)acetamido]-6-(formamido)-2,2-dimethylpenam-3(S)-carboxylic acid benzyl ester | C34H38N6O11S | 详情 | 详情 | |
(VIII) | 24311 | 6(S)-[2-[3,4-Bis(methoxycarbonyl)phenyl]-2-(4-ethyl-2,3-ddioxopiperazin-1-ylcarboxamido)acetamido]-6-(formamido)-2,2-dimethylpenam-3(S)-carboxylic acid; 6(S)-[2-[3,4-Bis(methoxycarbonyl)phenyl]-2-(4-ethyl-2,3-ddioxopiperazin-1-ylcarboxamido)acetamido]-6-(formamido)-2,2-dimethylpenam-3(S)-carboxylic acid | C26H30N6O11S | 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 condensation of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride (I) with threonine (II) in methylene chloride gives alpha-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-beta-hydroxybutyric acid (III), which is then condensed with diphenylmethyl 7-beta-amino-3-[(1-methyltetrazol-5-yl)thiometnyl)-Delta3-cephem-4-carboxylate (IV) by means of ethyl chloroformate and N-methyl morpholine yielding diphenylmethyl 7-beta-[alpha-(4-ethyl-2,3-dioxo-1-piperazi-necarboxamido)-beta-hydroxybutyramido]-3-(11-methyltetrazol-5-yl)thiomethyl]-Delta3-cephem-4-carboxylate (V). The methoxylation of (V) with lithium methoxide-methylene chloride THF affords diphenyl methyl 7-beta-[alpha-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-beta-hydroxybutyramido]-7-alpha-methoxy-3-[(1-methyltetrazol-5-yl)thiamethyl-Delta3-cephem-4-carboxylate (VI), which is finally hydrolyzed with trifluoroacetic acid, and treated with NaHCO3 to obtain the sodium salt.
【1】 Saikawa, I.; et al. (Toyama Chemical Co., Ltd.); Novel 7alpha-methoxycephalosporins and process for producing the same. FR 2455051; GB 2048241; JP 80141.491; JP 8125188; US 4263292 . |
【2】 Burnie, J.; Serradell, M.N.; Castaner, J.; Cefbuperazone Sodium. Drugs Fut 1985, 10, 1, 14. |
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) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
(II) | 28908 | L-Threonine; (2R,3S)-2-amino-3-hydroxybutyric acid | 632-20-2 | C4H9NO3 | 详情 | 详情 |
(III) | 28909 | (2R,3S)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutyric acid | C11H17N3O6 | 详情 | 详情 | |
(IV) | 28910 | benzhydryl (6R,7R)-7-amino-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N6O3S2 | 详情 | 详情 | |
(V) | 28911 | benzhydryl (6R,7R)-7-[((2R,3S)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C34H37N9O8S2 | 详情 | 详情 | |
(VI) | 28912 | benzhydryl (6R,7S)-7-[((2R,3S)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxybutanoyl)amino]-7-methoxy-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C35H39N9O9S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(V)The condensation of N-(1-methoxycarbonyl-1-propen-2-yl)-alpha-amino-p-hydroxyphenylacetic sodium salt (III) with 7-amino-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid (II) by means of ethyl chlorocarbonate and N,O-bis(trimethylsilyl)acetamide (A) in acetonitrile gives 7-(alpha-amino-p-hydroxy-phenylacetamido)-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (IV), which is then condensed with 4-ethyl-2,3-dioxopiperazino-1-carbonyl chloride (V) by means of K2CO3 in ethyl acetate water.
【1】 Saikawa, I.; et al.; Nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. BE 0837682 . |
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; T-1551. Drugs Fut 1979, 4, 9, 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 |
---|---|---|---|---|---|---|
(A) | 33433 | trimethyl-N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]silanamine; N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]-N-(trimethylsilyl)amine | C9H23NSi2 | 详情 | 详情 | |
(II) | 32663 | (6R,7R)-7-amino-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 24209-38-9 | C10H12N6O3S2 | 详情 | 详情 |
(III) | 33434 | sodium (2R)-2-(4-hydroxyphenyl)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]ethanoate | C13H14NNaO5 | 详情 | 详情 | |
(IV) | 33435 | (6R,7R)-7-[[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-3-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H19N7O5S2 | 详情 | 详情 | |
(V) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(V)The condensation of acetoxymethyl derivative (VI) with N-(1-methoxycarbonyl-1-propen-2-yl)-alpha-amino-p-hydroxyphenylacetic sodium salt (III) by means of ethyl chlorocarbonate and N,O-bis(trimethylsilyl)acetamide (A) gives 7-(alpha-amino-p-hydroxyphenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (IX), which is then condensed with acyl chloride (V) by means of K2CO3 in ethyl acetate water to afford (VII), which is then condensed with 1-methyl-5-mercapto-1H-tetrazole (VIII) by means of NaHCO3 in a phosphate buffer.
【1】 Saikawa, I.; et al.; Nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. BE 0837682 . |
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; T-1551. Drugs Fut 1979, 4, 9, 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 |
---|---|---|---|---|---|---|
(A) | 33433 | trimethyl-N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]silanamine; N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]-N-(trimethylsilyl)amine | C9H23NSi2 | 详情 | 详情 | |
(III) | 33434 | sodium (2R)-2-(4-hydroxyphenyl)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]ethanoate | C13H14NNaO5 | 详情 | 详情 | |
(V) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
(VI) | 33436 | [(6R,7R)-7-amino-2-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl acetate | C10H14N2O4S | 详情 | 详情 | |
(VII) | 33437 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C25H27N5O10S | 详情 | 详情 | |
(VIII) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
(IX) | 32643 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H19N3O7S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(IV)The cyclization of diethyl oxalate (I) with N-ethylethylenediamine (II) in ethanol gives ethyl-2,3-dioxopiperazine (III), which by reaction first with trimethylsilyl chloride and triethytamine and then with phosgene in THF is converted into 4-ethyl-2,3-dioxopiperazine-1-carboxylic acid chloride (IV). Finally, this compound is condensed with 6-D-(-)-alpha-aminophenylacetamidopenicillanic acid (V) by means of triethylamine in THF - water.
【1】 Saikawa, I.; et al.; Penicillins and cephalosporins and process for producing the same. DE 2519400; FR 2269937; FR 2320295; GB 1508062 . |
【2】 Loren, J.G.; Castañer, J.; Piperacillin. Drugs Fut 1978, 3, 11, 829. |
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) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
(II) | 39928 | N(1)-ethyl-1,2-ethanediamine; N-(2-aminoethyl)-N-ethylamine | 110-72-5 | C4H12N2 | 详情 | 详情 |
(III) | 39929 | 1-ethyl-2,3-piperazinedione | 59702-31-7 | C6H10N2O2 | 详情 | 详情 |
(IV) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
(V) | 31107 | (2S,5R,6R)-6-[[(2R)-2-amino-2-phenylethanoyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid | 69-53-4 | C16H19N3O4S | 详情 | 详情 |