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【结 构 式】

【药物名称】Cefditoren pivoxil, ME-1207, Spectracef, Meiact

【化学名称】(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-[2(Z)-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester
　　　　　　(6R,7R)-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-3-[(Z)-2-(4-methyl-5-thiazolyl)vinyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester 7(2)-(Z)-(O-methyloxime)

【CA登记号】117467-28-4

【 分 子 式 】C25H28N6O7S3

【 分 子 量 】620.72991

【开发单位】Meiji Seika (Originator), Abbott (Licensee), Purdue Pharma (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9

合成路线1

参考文献 中间体
【1】 撒应福，任秉钧．2006．头孢类抗生素的制备方法，发明专利申请公开说明书．CN 1763046
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) 66165 sodium (6S,7S)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C14H14NaN5O6S2 详情 详情
(II) 11159 iodomethyl pivalate C6H11IO2 详情 详情
(III) 66166 (6R,7R)-tert-butoxymethyl 7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C19H25N5O7S2 详情 详情
(IV) 66167 (6S,7S)-tert-butoxymethyl 7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C19H24ClN5O6S2 详情 详情
(V) 66168 (6R,7R)-tert-butoxymethyl 7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C19H24IN5O6S2 详情 详情
(VI) 66169 (((6S,7S)-7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-2-((tert-butoxymethoxy)carbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)triphenylphosphonium iodide 　 C37H39IN5O6S2P 详情 详情
(VII) 66170 (6R,7R)-tert-butoxymethyl 7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-3-((triphenylphosphoranylidene)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, iodide salt 　 C37H38N5O6S2P 详情 详情
(VIII) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情

合成路线2

参考文献 中间体
【1】 Kumar Y.Prasad M, SinghK.et aL 2005. Preparation of intermediates for the synthesis of 3-[2-(4-methylthiazole-5-yD vinyl] cephalosporins W0 2005100330
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) 66171 Ethanone,1-(4-methyl-5-thiazolyl)-;Ketone,methyl 4-methyl-5-thiazolyl ;5-Acetyl-4-methylthiazole 38205-55-9 C6H7NOS 详情 详情
(II) 66172 5-Thiazolemethanol,4-methyl-;(4-Methylthiazol-5-yl)methanol;4-Methyl-5-(hydroxymethyl)thiazole;4-Methyl-5-thiazolemethanol 1977-06-6 C5H7NOS 详情 详情
(III) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情
(IV) 66173 (6R)-benzhydryl 8-oxo-7-(2-phenylacetamido)-3-((triphenylphosphoranylidene)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C47H39N2O4SP 详情 详情
(V) 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情
(VI) 66175 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 94088-75-2 C13H10N4O2S3 详情 详情

合成路线3

参考文献 中间体
【1】 Kumar Y.Prasad M Singh K, et al. 2005 .Intermediates useful in the synthesis d 3-(2-substituted-vinyl)cephalosporins W0 2005100367
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) 66176 (6R)-benzhydryl 3-(chloromethyl)-8-oxo-7-(2-phenylacetamido)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C30H27ClN2O4 详情 详情
(II) 66173 (6R)-benzhydryl 8-oxo-7-(2-phenylacetamido)-3-((triphenylphosphoranylidene)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 　 C47H39N2O4SP 详情 详情
(III) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情
(IV) 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情
(V) 66175 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 94088-75-2 C13H10N4O2S3 详情 详情

合成路线4

参考文献 中间体
【1】 Kumar Y, Prasad M, Singh K, et&L 2005.DepletionofE-isomers in preWntion ofZ-enriched 3-(2-substitutecl rrinyl) crephalosporins W0 2005100369
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) 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情
(II) 66175 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 94088-75-2 C13H10N4O2S3 详情 详情

合成路线5

参考文献 中间体
【1】 Prabhat KS.Vempali A.Sundaravadivelan S.et aL2005.An imprared Wooessfortlk preparation of cefditoren and its intermediates W0 2005003141
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) 11151 4-methoxybenzyl (7R)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 104146-10-3 C24H23ClN2O5S 详情 详情
(II) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情
(III) 11154 4-methoxybenzyl (7R)-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C29H27N3O5S2 详情 详情
(IV) 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情
(V) 66175 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 94088-75-2 C13H10N4O2S3 详情 详情

合成路线6

参考文献 中间体
【1】 Prasad M, Kumar Y, Singh K, et aL 2005. Process for selective preparation of Z-isomer of cefditoren and pharmaceutically acceptable salts and esters thenof. W0 2005016936
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II） 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情
(I) 11151 4-methoxybenzyl (7R)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 104146-10-3 C24H23ClN2O5S 详情 详情
(III) 66175 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 94088-75-2 C13H10N4O2S3 详情 详情

合成路线7

参考文献 中间体
【1】 Deshpande PB, Luthra PK. 2003. Process for the preparatiou of ceftlitoren using the thioesterofthiazolylacetic acid US Pat Appl PubL US 2003225265
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) 66177 (Z)-2-(2-aminothiazol-4-yl)-3-methoxyacrylic acid 　 C7H8N2O3S 详情 详情
(II) 66178 (Z)-S-(5-phenylfuran-2-yl) 2-(2-aminothiazol-4-yl)-2-(methoxyimino)ethanethioate 　 C16H13N3O3S2 详情 详情
(III) 66174 (6R,7R)-7-amino-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-1-azabicyclo[4.2.0]octane-2-carboxylic acid 　 C14H17N3O3S 详情 详情

合成路线8

参考文献 中间体
【1】 Sakagsmi K, Atsumi K, Yamamoto Y，et aL 1991. Synthesis and activity of pivaloyloxymethyl一[( Z-(2-anunothiazol-4-yD-2-methoxyiminoaceuunido]一3(Z)-(4-methylthiazol-5-yl) vinyl-3-cepllern-4-carbox)rlate (ME1207) and its related compound. Chem Pharm Bull, 39 (9): 2433^-2436
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) 11151 4-methoxybenzyl (7R)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 104146-10-3 C24H23ClN2O5S 详情 详情
(II) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情
(III) 11154 4-methoxybenzyl (7R)-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C29H27N3O5S2 详情 详情
(IV) 11155 4-methoxybenzyl (7R)-7-amino-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H21N3O4S2 详情 详情
(V) 66179 (Z)-3-methoxy-2-(2-(tritylamino)thiazol-4-yl)acrylic acid 　 C26H22N2O3S 详情 详情

合成路线9

The reaction of 3-(chloromethyl)-7-(phenylacetamido)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (I) with triphenylphosphine and NaI in acetone gives the corresponding phosphonium salt (II), which is condensed with 4-methylthiazole-5-carboxaldehyde (III) by means of NaHCO3 in dichloromethane affording 3-[2(Z)-(4-methylthiazol-5-yl)vinyl]-7-(phenylacetamido)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (IV). The cleavage of the amido group of (IV) with PCl5 and pyridine yields the 7-amino compound (V), which is condensed with 2-(methoxyimino)-2-[2-(tritylamino)thiazol-4-yl]acetic acid (VI) by means of POCl3 in dichloromethane giving 3-[2(Z)-(4-methylthiazol-5-yl)vinyl]-7-[2(Z)-methoxyimino)-2-(2-tritylamino)thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (VII). The deprotection of (VII) with trifluoroacetic acid and anisole yields the free amino acid (VIII), which is finally esterified with iodomethyl pivalate (IX) in DMF.

参考文献 中间体
【1】 Yamamoto, Y.; Yoshida, T.; Tamura, A.; Atsumi, K.; Fukatsu, S.; Sakagami, K.; Nishihata, K.; Synthesis and oral activity of pivaloyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3(Z)--(4-methylthiazol-5-yl)vinyl-3-cephem-4-carboxylate (ME1207) and its related compound. Chem Pharm Bull 1992, 39, 9, 2433.
【2】 Atsumi, K.; Sakagami, K.; Yamamoto, Y.; Yoshida, T.; Nishihata, K.; Kondo, S.; Fukatsu, S. (Meiji Seika Kaisha, Ltd.); New cephalosporin cpds. and the production thereof. EP 0175610; ES 8704955; JP 1986178991; JP 1987019593 .
【3】 Castaner, J.; Prous, J.; Cefditoren Pivoxil. Drugs Fut 1992, 17, 8, 665.
【4】 Sakagami, K.; Tamura, A.; Yoshida, T.; Nishihata, K.; Fukatsu, S.; Atsumi, K.; Synthesis and oral activity of ME1207, a new orally active cephalosporin. J Antibiot 1990, 43, 8, 1047.
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) 11151 4-methoxybenzyl (7R)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 104146-10-3 C24H23ClN2O5S 详情 详情
(II) 11152 4-methoxybenzyl (7R)-8-oxo-7-[(2-phenylacetyl)amino]-3-[(triphenylphosphoranyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C42H39N2O5PS 详情 详情
(III) 11153 4-Methyl-1,3-thiazole-5-carbaldehyde 82294-70-0 C5H5NOS 详情 详情
(IV) 11154 4-methoxybenzyl (7R)-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C29H27N3O5S2 详情 详情
(V) 11155 4-methoxybenzyl (7R)-7-amino-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H21N3O4S2 详情 详情
(VI) 11156 2-(Methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetamide C25H22N4O2S 详情 详情
(VII) 11157 4-methoxybenzyl (7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C27H26N6O6S3 详情 详情
(VIII) 11158 (7R)-7-[[2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C19H18N6O5S3 详情 详情
(IX) 11159 iodomethyl pivalate C6H11IO2 详情 详情
Extended Information