benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】31135

【品名】benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

【CA登记号】

【分子式】C₂₁H₁₉ClN₂O₃S

【分子量】414.91224

【元素组成】C 60.79% H 4.62% Cl 8.54% N 6.75% O 11.57% S 7.73%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XII)

The reaction of 7-(5-amino-5-carboxypentanamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (I), first with benzoyl chloride in acetone-water, and then with diphenyldiazomethane, gives benzhydryl 7-[5-benzamido-5-(benzhydryloxycarbonyl)pentanamido]-3-hydroxymethyl-3-cephem-4-carboxylate (II), which by reaction with PCl5 under stronger conditions than before gives benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate (XII), which is condensed with (VII) by means of POCl3 in DMF as before, yielding the chloromethyl compound (XIII). The reaction of (XIII) with triphenyiphosphine and NaI affords the phosphonium salt (XIV), which is finally submitted to a Wittig condensation with formaldehyde giving (X). The hydrolysis of (X) with HCl in methanol affords the 2-amino derivative (XI), which is finally fully deprotected by treatment with trifluoroacetic acid in anisole.

参考文献中间体

合成目标

【1】 Takaya, T.; Tagasuki, H.; Masugi, T.; Yamanaka, H.; Kawabata, K. (Fujisawa Pharmaceutical Co., Ltd.); Starting compounds for 7-acylamino-3-vinylcephalosporanic acid derivatives and processes for their preparation. EP 0030630; EP 0123024; EP 0244637; JP 6279452; US 4409214; US 4423213 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; FR-17,027. Drugs Fut 1983, 8, 8, 682.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	31127	sodium (6R,7R)-7-[(5-amino-5-carboxypentanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₄H₁₈N₃NaO₇S	详情	详情
(II)	31128	benzhydryl (6R,7R)-7-[[6-(benzhydryloxy)-5-(benzoylamino)-6-oxohexanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₄₇H₄₃N₃O₈S	详情	详情
(VII)	24084	2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid	C₁₂H₁₅N₃O₆S	详情	详情
(X)	31133	benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₄H₃₃N₅O₈S₂	详情	详情
(XI)	31134	benzhydryl (6R,7R)-7-[(2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₃H₃₃N₅O₇S₂	详情	详情
(XII)	31135	benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₂₁H₁₉ClN₂O₃S	详情	详情
(XIII)	31136	benzhydryl (6R,7R)-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₃H₃₂ClN₅O₈S₂	详情	详情
(XIV)	31137	[[(6R,7R)-2-[(benzhydryloxy)carbonyl]-7-([2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl](triphenyl)phosphonium	C₅₁H₄₇N₅O₈PS₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The partial hydrolysis of 7-(phenylacetamido) cephalosporanic acid (I) followed by esterification with diphenyldyazomethane (II) gives benzhydryl 3-(hydroxymethyl)-7-(phenylacetamido)-3-cephem-4-carboxylate (III), which by reaction with PCl5 affords benzhydryl 7-amino-3-(chloromethyl)-3- cephem-4-carboxylate (IV). The condensation of (IV) with N-(tert-butoxycarbonyl)-2(R)-(4-hydroxyphenyl) glycine (V) by means of dicyclohexylcarbodiimide (DCC) yields benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxypheny) acetamido]-3-(chloro-methyl)-3-cephem-4-carboxylate (VI), which by reaction with NaI in acetone is converted to the corresponding iodomethyl derivative (VII).The reaction of (VII) with triphenylphosphine in ethyl acetate affords the phosphonium salt (VIII), which is submitted to a Wittig condensation with acetaldehyde to yield benzhydryl 7-[(R)-2-(tert-butoxycarbonylamino)-2-(4-hydroxyphenyl)acetamido]-3-(propenyl)-3-cephem-4-carboxylate (IX). Finally this compound is deprotected by a treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Winocour, P.; Vezina, M.; Kornbrust, D.; Sullivan, T.; Durkin, J.; Synthesis and structure-activity relationsships of a new oral cephalosporin, BMY-28100 and related compounds. J Antibiot 1987, 40, 7, 991.
【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; CEFPROZIL. Drugs Fut 1989, 14, 6, 507.
【3】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	59721	(6R,7R)-3-[(acetyloxy)methyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₁₈H₁₇N₂O₆S	详情	详情
(II)	40585	1-[diazo(phenyl)methyl]benzene	C₁₃H₁₀N₂	详情	详情
(III)	59722	benzhydryl (6R,7R)-3-(hydroxymethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₂₉H₂₆N₂O₅S	详情	详情
(IV)	31135	benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₂₁H₁₉ClN₂O₃S	详情	详情
(V)	59723	(2R)-2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)ethanoic acid	C₁₃H₁₇NO₅	详情	详情
(VI)	59724	diphenylmethyl 3-(chloromethyl)-7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₄H₃₄ClN₃O₇S	详情	详情
(VII)	59725	diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₄H₃₄IN₃O₇S	详情	详情
(VIII)	59726	[(7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-2-{[(diphenylmethyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl](triphenyl)phosphonium	C₅₂H₄₉N₃O₇PS	详情	详情
(IX)	59727	diphenylmethyl 7-{[2-{[(2,2-dimethylpropanoyl)oxy]amino}-2-(4-hydroxyphenyl)acetyl]amino}-8-oxo-3-(1-propenyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₆H₃₇N₃O₇S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XX)

Acylation of the cephem nucleus (XX) with the intermediate acid (XVI) via activation with either DCC or the Vilsmeier reagent provided amide (XXI). The ester groups of (XXI) were then cleaved with trifluoroacetic acid to give acid (XXII). Finally, condensation of (XXII) with pyridine thione (VII) furnished the title compound.

参考文献中间体

合成目标

【1】 Singh, J.; et al.; A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243. Org Process Res Dev 2000, 4, 6, 488.
【3】 Springer, D.M.; Luh, B.Y.; D'Andrea, S.V.; Hudyma, T.W.; Kim, O.K. (Bristol-Myers Squibb Co.); Cephalosporin derivs.. EP 0966472; WO 9823621 .
【2】 Kim, O.; et al.; Discovery, synthesis and SAR of BMS-247243, a novel cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA) and susceptible Staphylococcus aureus (MSSA). 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1062.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	46012	4-[3-[2,6-dimethyl-4-thioxo-1(4H)-pyridinyl]propyl]-4-methylmorpholin-4-ium iodide	C₁₅H₂₅IN₂OS	详情	详情
(XVI)	46020	2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid	C₁₇H₁₉Cl₂NO₅S	详情	详情
(XX)	31135	benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₂₁H₁₉ClN₂O₃S	详情	详情
(XXI)	46023	benzhydryl (6R,7R)-7-[(2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetyl)amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate	C₃₈H₃₆Cl₃N₃O₇S₂	详情	详情
(XXII)	46024	(6R,7R)-7-([2-[(4-[(E)-3-[(carboxymethyl)amino]-3-oxo-1-propenyl]-2,5-dichlorophenyl)sulfanyl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	C₂₁H₁₈Cl₃N₃O₇S₂	详情	详情

Extended Information