• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【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%

与该中间体有关的原料药合成路线共 5 条

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
Extended Information