(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】15075

【品名】(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

【CA登记号】

【分子式】C₁₉H₂₂N₈O₆S₂

【分子量】522.566

【元素组成】C 43.67% H 4.24% N 21.44% O 18.37% S 12.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

FK-037 can be obtained by related ways: 1) The formylation of 5-amino-1-(2-hydroxyethyl)pyrazole (I) with formic acid - acetic anhydride gives 5-formamido-1-(2-hydroxyethyl)pyrazole (II), which is condensed with 7beta-(tert-butoxycarbonylamino)-3-(chloromethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (III) by means of NaI in DMF, yielding 7beta-(tert-butoxycarbonylamino)-3-[3-formamido-2-(2-formyloxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester iodide (IV). The treatment of (IV), first with trifluoroacetic acid and anisole and then with HCl, affords 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylic acid chloride (V). The condensation of (V) with 2-(2-formamidothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid (VI) by means of POCl3 in ethyl acetate gives 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-formamido-thiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (VII), which is deformylated with HCl affording 3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-7beta-[2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-cephem-4-carboxylate (VIII). Finally, this compound is treated with H2SO4 to give FK-037. 2) Compound (VIII) can also be obtained by condensation of (V) with 1-[2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetyl]benzo- triazole-3-oxide (IX) in THF.

参考文献中间体

合成目标

【1】 Sakane, K.; Kawabata, K.; Miyai, K.; Inamoto, Y. (Fujisawa Pharmaceutical Co., Ltd.); New cephem cpd. and process for preparation thereof. AU 8822271; EP 0307804; JP 1989151589; US 4952578 .
【2】 Sakane, K.; Kawabata, K.; Ohki, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of cephalosporin cpd. JP 1992173792 .
【3】 Ohki, H.; Kawabata, K.; Okuda, S.; Kamimura, T.; Sakane, K.; FK037, a new parenteral cephalosporin with a broad antibacterial spectrum: Synthesis and antibacterial activity. J Antibiot 1993, 46, 2, 359.
【4】 Prous, J.; Graul, A.; Castaner, J.; FK-037. Drugs Fut 1994, 19, 4, 325.

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)	15068	2-(5-amino-1H-pyrazol-1-yl)-1-ethanol		C₅H₉N₃O	详情	详情
(II)	15069	2-[5-(formylamino)-1H-pyrazol-1-yl]ethyl formate		C₇H₉N₃O₃	详情	详情
(III)	15070	benzhydryl (6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₆H₂₇ClN₂O₅S	详情	详情
(IV)	15071	benzhydryl (6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-([5-(formylamino)-1-[2-(formyloxy)ethyl]-2-iodo-1H-2lambda(5)-pyrazol-2-yl]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₃₃H₃₆IN₅O₈S	详情	详情
(V)	15072	(6R,7R)-7-amino-3-[[5-amino-2-chloro-1-(2-hydroxyethyl)-1H-2lambda(5)-pyrazol-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₃₃H₃₆IN₅O₈S	详情	详情
(VI)	15073	2-(2-Formamidothiazole-4-yl)-2-methoxyimino acetic acid; 2-[2-(formylamino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid	83594-38-1	C₇H₇N₃O₄S	详情	详情
(VII)	15074	(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-[2-(formylamino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₂₀H₂₂N₈O₇S₂	详情	详情
(VIII)	15075	(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₉H₂₂N₈O₆S₂	详情	详情
(IX)	15076	3-[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]-3H-1,2,3-benzotriazol-1-ium-1-olate		C₁₂H₁₀N₆O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

3) The condensation of 4-chloro-2(Z)-(methoxyimino)-3-oxobutyric acid (IX) with 7beta-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazoliomethyl]-3-cephem-4-carboxylate (X) by means of POCl3 in DMF gives the corresponding acetamide (XI), which is then cyclized with thiourea by means of sodium acetate in water to obtain compound (VII). Finally, this compound is treated with H2SO4 to give FK-037.

参考文献中间体

合成目标

【1】 Sakane, K.; Kawabata, K.; Ohki, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of cephalosporin cpd. JP 1992173792 .
【2】 Prous, J.; Graul, A.; Castaner, J.; FK-037. Drugs Fut 1994, 19, 4, 325.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	15075	(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₉H₂₂N₈O₆S₂	详情	详情
(IX)	15077	4-chloro-2-(methoxyimino)-3-oxobutyric acid		C₅H₆ClNO₄	详情	详情
(X)	15078	(6R,7R)-7-amino-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₃H₁₇N₅O₄S	详情	详情
(XI)	15079	(6R,7R)-3-[[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-2-ium-2-yl]methyl]-7-[[4-chloro-2-(methoxyimino)-3-oxobutanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₈H₂₁ClN₆O₇S	详情	详情
(XII)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情

Extended Information