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【结 构 式】

【分子编号】22689

【品名】(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid

【CA登记号】

【 分 子 式 】C23H20N2O6S

【 分 子 量 】452.48768

【元素组成】C 61.05% H 4.46% N 6.19% O 21.22% S 7.09%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of 2-[2-(benzoyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoic acid (I) with 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (II) by means of mesyl chloride, phosphorus oxychloride or thionyl chloride in basic medium and dichloromethane as solvent gives the protected derivative of the desired product (III), which is then treated with AlCl3 and anisole and acidified with diluted HCl.

参考文献 中间体
合成目标
【1】 Hamashima, Y. (Shionogi & Co. Ltd.); 7-Carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. EP 0136721; ES 8604602; ES 8605278; ES 8700222; GB 2154580; GB 2198727; JP 1985078987; JP 1985163884; JP 1985246388; US 4634697; US 4748170 .
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) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(II) 22690 benzyl (7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H14N2O3S 详情 详情
(III) 22691 benzyl (7R)-7-[[(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C37H32N4O8S2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(I)

Synthesis of intermediate (I): 1a) Dimethyl acetonedicarboxylate (IV) is treated with MgCl2 and triethylamine, giving the corresponding magnesium complex (V), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (VI). The reduction of (VI) with NaBH4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (VII), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the OH group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (VIII). The hydrolysis of (VIII) with aqueous NaOH in toluene gives the corresponding diacid (IX), which is selectively esterified with benzyl alcohol in acidic medium yielding (I). 1b) The reaction of methyl 2-(2-aminothiazol-4-yl)acetate (X) with beozyloxycarbonyl chloride and NaHCO3 gives the protected compound (XI), which is condensed with methyl 3-methoxyacrylate (XII) by means of sodium methoxide in DMF to yield dimethyl ester (VIII), already obtained.

参考文献 中间体
合成目标
【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(IV) 22692 dimethyl 3-oxopentanedioate 1830-54-2 C7H10O5 详情 详情
(V) 22693 Bis(3-Hydroxy-2-pentenoic acid dimethyl ester) magnesium salt C14H18MgO10 详情 详情
(VI) 22694 dimethyl (E)-2-(2-amino-1,3-thiazol-4-yl)-3-hydroxy-2-pentenedioate C10H12N2O5S 详情 详情
(VII) 22695 dimethyl 2-(2-amino-1,3-thiazol-4-yl)-3-hydroxypentanedioate C10H14N2O5S 详情 详情
(VIII) 22696 dimethyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C18H18N2O6S 详情 详情
(IX) 22697 (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioic acid C16H14N2O6S 详情 详情
(X) 22698 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate 64987-16-2 C6H8N2O2S 详情 详情
(XI) 22699 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate C14H14N2O4S 详情 详情
(XII) 22700 methyl (E)-3-methoxy-2-propenoate 34846-90-7 C5H8O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

Synthesis of intermediate (I): 1c) The bromination of diketene (XIII) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (XIV), which by cyclization with thiourea by means of K2CO3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (XV). The reaction of (XV) with benzyloxycarbonyl chloride and pyridine affords the protected compound (XVI), which is formylated with diphenyl methyl formiate (XVII) and NaH to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (XVIII) The Wittig condensation of (XVIII) with benzyl triphenylphosphoranylidene acetate (XIX) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (XX), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.

参考文献 中间体
合成目标
【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
(I) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(XIII) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(XIV) 22715 benzhydryl 4-bromo-3-oxobutanoate C17H15BrO3 详情 详情
(XV) 22716 benzhydryl 2-amino-1,3-thiazole-4-carboxylate C17H14N2O2S 详情 详情
(XVI) 22717 benzhydryl 2-[[(benzyloxy)carbonyl]amino]-1,3-thiazole-4-carboxylate C25H20N2O4S 详情 详情
(XVII) 22718 benzhydryl formate C14H12O2 详情 详情
(XVIII) 22719 benzhydryl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-hydroxy-2-propenoate C27H22N2O5S 详情 详情
(XIX) 22668 benzyl 2-(triphenylphosphoranylidene)acetate C27H23O2P 详情 详情
(XX) 22721 1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C36H30N2O6S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IV)

The Wittig condensation of diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4 yl-2-formyl acetate with benzyloxycarbonylmethylene triphenylphosphorane (II) in toluene or dioxane gives 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4 (benzyloxycarbonyl)-2-butenoic acid diphenylmethyl ester (III), which is hydrolyzed partiaily wth trifluoroacetic acid and anisole to the 2-butenoic acid (IV). The condensation of (IV) with 7-beta-amino-3-cephem-4-carboxylic acid benzyl ester (V) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane affords the protected final product (VI), which is finally debenzylated by means of AlCl3 and anisole in methylene chloride.

参考文献 中间体
合成目标
【1】 Yoshida, T.; Synthesis and biological properties of 7Beta-[(Z)-2-(2-amino-4-thiazoyl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxilic acid (7432-S), a new oral cephem antibiotic. J Antibiot 1987, 40, 10, 1468.
【2】 Hamashima, Y. (Shionogi & Co. Ltd.); 7-Carboxyalkenoylamido-3-cephem-4-carboxylic acid derivs.. EP 0136721; ES 8604602; ES 8605278; ES 8700222; GB 2154580; GB 2198727; JP 1985078987; JP 1985163884; JP 1985246388; US 4634697; US 4748170 .
【3】 Castaner, J.; Prous, J.; 7432-S. Drugs Fut 1987, 12, 12, 1117.
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) 24153 benzhydryl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-3-oxopropanoate C27H22N2O5S 详情 详情
(II) 22668 benzyl 2-(triphenylphosphoranylidene)acetate C27H23O2P 详情 详情
(III) 22721 1-benzhydryl 5-benzyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C36H30N2O6S 详情 详情
(IV) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(V) 24157 benzyl (6R,7R)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C14H14N2O3S 详情 详情
(VI) 24158 benzyl (6R,7R)-7-[[(Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C37H32N4O8S2 详情 详情
Extended Information