Cefclidin, E-1040, -Drug Synthesis Database

【结构式】

【药物名称】Cefclidin, E-1040

【化学名称】(6R,7R)-3-[(4-Carbamoyl-1-quinuclidinio)methyl]-7--[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy-iminoacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
　　　　　　(+)-1-[[(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-4-carbamoylquinuclidinium hydroxide inner salt 7(2)-(Z)-(O-methyloxime)

【CA登记号】105239-91-6

【分子式】C₂₁H₂₆N₈O₆S₂

【分子量】550.61937

【开发单位】Eisai (Originator)

【药理作用】Cephalosporins

合成路线1 合成路线2 合成路线3

合成路线1

A new synthesis for [14C]-E-1040 has been described: The cyclization of [14C]-labeled potassium thiocyanate (I) with 2-(N-chlorocarboxamidino)-2-(methoxyimino)acetic acid (II) in methanol by means of triethylamine gives 2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid (III), which is treated with PCl5 in dichloromethane, yielding the corresponding acyl chloride (IV). Finally, this compound is condensed with 7-amino-3-(4-carbamoylquinuclidinio-1-ylmethyl)-3-cephem-4-carboxylate (V) by means of sodium acetate in dichloromethane.

参考文献中间体

【1】 Sugiyama, I.; Nomoto, S.; Mizuo, H.; Yamauchi, H.; Synthesis of (6R,7R)-7-[2-(5-amino-1,2,4-[5-C-14]thiadiazol-3-yl)-(Z)-2-methoxyiminoacetamido]-3-[(4-carbomoyl-1-quinuclidinio)methyl]ceph-3-em-4-carboxylate([C-14]E1040). J Label Compd Radiopharm 1991, 29, 12, 1309.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(II)	11756	3-Amino-3-(chloroimino)-2-(methoxyimino)propionic acid	C₄H₆ClN₃O₃	详情	详情
(III)	11757	2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid	C₅H₆N₄O₃S	详情	详情
(III)	45072	2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid	C₅H₆N₄O₃S	详情	详情
(IV)	11758	2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride	C₅H₅ClN₄O₂S	详情	详情
(IV)	45073	2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl chloride	C₅H₅ClN₄O₂S	详情	详情
(V)	11759	(6R,7R)-7-amino-3-[[4-(aminocarbonyl)-1-azoniabicyclo[2.2.2]oct-1-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₆H₂₂N₄O₄S	详情	详情

合成路线2

A new synthesis of [14C]-labeled E-1040 with the label in the quinuclidine ring has been reported: The reduction of [14C]-labeled bromoacetic acid (I) with borane-dimethyl sulfide complex in ethyl ether gives 2-bromoethanol (II), which is condensed with piperidine-4-carboxamide (III) by means of K2CO3 and KI in refluxing isopropanol, yielding the [14C]-labeled 1-(2-hydroxyethyl)piperidine-4-carboxamide (IV). The reaction of (IV) with SOCl2 in refluxing acetonitrile affords the 1-(2-chloroethyl)piperidine-4-carbonitrile (V), which is cyclized by means of lithium diisopropylamide in THF, giving the quinuclidine (VI). The hydrolysis of (VI) with sulfuric acid gives [14C]-labeled quinuclidine-4-carboxamide (VII), which is finally condensed with the 3-chloromethylcephalosporin (VIII) by means of Na in acetone and a treatment with trifluoroacetic acid.

参考文献中间体

【1】 Woolley, G.T.; Sugiyama, I.; Yamauchi, H.; Mizuo, H.; Synthesis of 14C-labelled cefclidin (E1040). J Label Compd Radiopharm 1992, 31, 9, 663.

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)	23660	2-Bromoacetic acid	79-08-3	C₂H₃BrO₂	详情	详情
(I)	45074	2-bromoacetic acid		C₂H₃BrO₂	详情	详情
(II)	10059	Ethylene bromohydrin; 2-Bromo-1-ethanol	540-51-2	C₂H₅BrO	详情	详情
(II)	45075	2-bromo-1-ethanol		C₂H₅BrO	详情	详情
(III)	11762	4-Piperidinecarboxamide; Isonipecotamide	39546-32-2	C₆H₁₂N₂O	详情	详情
(IV)	11763	1-(2-Hydroxyethyl)-4-piperidinecarboxamide		C₈H₁₆N₂O₂	详情	详情
(IV)	45076	1-(2-hydroxyethyl)-4-piperidinecarboxamide		C₈H₁₆N₂O₂	详情	详情
(V)	11764	1-(2-Chloroethyl)-4-piperidinecarbonitrile		C₈H₁₃ClN₂	详情	详情
(V)	45077	1-(2-chloroethyl)-4-piperidinecarbonitrile		C₈H₁₃ClN₂	详情	详情
(VI)	11765	4-Quinuclidinecarbonitrile		C₈H₁₂N₂	详情	详情
(VI)	45078	4-quinuclidinecarbonitrile		C₈H₁₂N₂	详情	详情
(VII)	11766	4-Quinuclidinecarboxamide		C₈H₁₄N₂O	详情	详情
(VII)	45079	4-quinuclidinecarboxamide		C₈H₁₄N₂O	详情	详情
(VIII)	11767	4-methoxybenzyl (6R,7R)-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₁H₂₁ClN₆O₆S₂	详情	详情

合成路线3

The reaction of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(methoxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (I) with N-methyl-N-(trimethylsilyl)trifluoroacetamide and then with iodotrimethylsilane in dichloromethane gives the corresponding silylated 3-iodomethyl derivative (II), which is then treated with 4-carbamoylquinuclidine (III) in acetonitrile.

参考文献中间体

【1】 Kamiya, T.; Machida, Y.; Negi, S.; Nomoto, S.; Saito, I.; Sugiyama, I.; Yamauchi, H. (Eisai Co., Ltd.); Cephem cpds. having at the 3-position a (1,4-methylene-1-piperidinio)methyl group or a (1-quinuclidinio)methyl group. AU 8652240; EP 0188255; ES 8703885; JP 1987030786; JP 1987123189; US 4748171; US 5010188 .
【2】 Prous, J.; Castaner, J.; E-1040. Drugs Fut 1988, 13, 2, 117.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide	C₆H₁₂F₃NOSi	详情	详情
(I)	21858	(7R)-3-[(acetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	C₁₅H₁₆N₆O₇S₂	详情	详情
(II)	21860	trimethylsilyl (7R)-3-(iodomethyl)-7-[(2-(methoxyimino)-2-[5-[(trimethylsilyl)amino]-1,2,4-thiadiazol-3-yl]acetyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₉H₂₉IN₆O₅S₂Si₂	详情	详情
(III)	11766	4-Quinuclidinecarboxamide	C₈H₁₄N₂O	详情	详情

Extended Information