【结 构 式】 |
【药物名称】Cefdinir, PD-134393, CI-983, FR-80482, FK-482, Omnicef, Cefzon 【化学名称】(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid 【CA登记号】91832-40-5 【 分 子 式 】C14H13N5O5S2 【 分 子 量 】395.41821 |
【开发单位】Fujisawa (Originator), Abbott (Licensee) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
【1】 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982. |
【2】 胡艾希,徐娟娟,伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229 |
【3】 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480 |
【4】 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007. |
【5】 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743. |
【6】 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738. |
【7】 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995. |
【8】 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001. |
【9】 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989. |
【10】 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997. |
【11】 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998. |
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) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
(II) | 69618 | (6R,7R)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C8H10N2O4S | 详情 | 详情 | |
(III) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
(VIII) | 64882 | (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 79349-82-9 | C9H10N2O3S | 详情 | 详情 |
(IX) | 69619 | (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate | C31H22N4O2S3 | 详情 | 详情 |
合成路线2
【1】 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982. |
【2】 胡艾希,徐娟娟,伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229 |
【3】 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480 |
【4】 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007. |
【5】 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743. |
【6】 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738. |
【7】 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995. |
【8】 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001. |
【9】 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989. |
【10】 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997. |
【11】 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998. |
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) | 23541 | ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
(II) | 39961 | ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate | C6H8ClNO4 | 详情 | 详情 | |
(III) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
(IV) | 48461 | (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate;ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate | C26H23N3O3S | 详情 | 详情 | |
(V) | 48462 | 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid;(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid | 128438-01-7 | C24H19N3O3S | 详情 | 详情 |
(VI) | 69620 | 1-(2,5-dimethoxyphenyl)propan-2-amine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate | C24H19N3O3S.C11H17NO2 | 详情 | 详情 | |
(VII) | 69619 | (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate | C31H22N4O2S3 | 详情 | 详情 | |
(VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
合成路线3
【1】 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480 |
【2】 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007. |
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) | 23541 | ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
(II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(III) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
合成路线4
【1】 Gonzalez M,Rodriguez Z,Tolon B,et al.An alternative procedure for preparation of cedinir.Farmaco,2003,58:409. |
【2】 朱阳,刘国庆,陆建中,等.(Z)-2-(2-氨基噻唑-4-基)-2-三苯甲氧基亚氨基乙酸合成的改进.中国医药工业杂志,1997,28:27. |
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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(II) | 20853 | ethyl 2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate | C6H9NO4 | 详情 | 详情 | |
(III) | 39961 | ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate | C6H8ClNO4 | 详情 | 详情 | |
(IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(V) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
合成路线5
【1】 任红阳,厉昆,陈亮.制备(Z)-2-(2-氨基-4-噻唑)-2-羟基亚胺乙酸酯及其衍生物的方法:CN,Patent 1,709,879,2005. |
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) | 69621 | (Z)-ethyl 2-(hydroxymethylene)-3-oxobutanoate | C7H10O4 | 详情 | 详情 | |
(II) | 69622 | (Z)-ethyl 4-chloro-2-(hydroxymethylene)-3-oxobutanoate | C7H9ClO4 | 详情 | 详情 | |
(III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
合成路线6
【1】 宫平,宫凤仙,王钝.2-(2-氨基-噻唑)-(Z)-羟基亚胺基乙酸乙酯的合成.沈阳药科大学学报,1998,15:235. |
【2】 Arita H,Ikeda K,Akamatsu H.Production of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid ester:JP,Patent 09,194,470 1997. |
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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(II) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
(III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
(IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
合成路线7
【1】 Cabri W,Alpegiani M,Pozzi G,et al.A process for the preparation of cephalosporins side chain:WO,Patent 2.003,040,116,2003. |
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) | 10183 | (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetic acid;2-(2-Amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid | 66338-96-3 | C5H5N3O3S | 详情 | 详情 |
(II) | 69623 | triethylamine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate | C24H19N3O3S.C6H15N | 详情 | 详情 | |
(III) | 69619 | (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate | C31H22N4O2S3 | 详情 | 详情 |
合成路线8
合成路线9
【1】 Singh GP,Sen H,Srivastava D,et al.Stable bioavailable crystalline form or cefdinir and a process for the preparation thereof:US,Patent 2,005,245,738,2005. |
合成路线10
【1】 Dandala R,Prasada Rao KVV,Sivakumaran MS.Process for preparaing cefinir:US,Patent 2,004,242,557,2004. |
【2】 Prasada Rao KVV,Dandala R,Sivakumaran M,et al.Improved synthesis of Cefdinir and its polymorphic form,an antibacterial active pharmaceutical ingredient.Synthetic Commun,2007,37:2275. |
合成路线11
【1】 Deshpande PB,Khadangale BP,Ramasubbu C.Novel amorphous hydrate of a cephalosporin antibiotic:WO,Patent 2,004,046,154,2004. |
合成路线12
【1】 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997. |
合成路线13
【1】 Kremminger P,Silberberger H.Tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid:WO,Patent 2,006,008,160,2006. |
【2】 Kremminger P,Silberberger H.Alkanoyl amide solvates of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid:WO,Patent 2,006,008,161,2006. |
合成路线14
合成路线15
【1】 Datta D,Dantu M,Mishra B,et al.Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates:WO,Patent 2,004,058,695,2004. |
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) | 58114 | 4-bromo-2-(methoxyimino)-3-oxobutanoic acid;(Z)-4-bromo-2-(methoxyimino)-3-oxobutanoic acid | C5H6BrNO4 | 详情 | 详情 | |
(II) | 69629 | C3H7Cl2NO3S | 详情 | 详情 | ||
(III) | 69630 | C8H12BrClN2O6S | 详情 | 详情 | ||
(IV) | 64882 | (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 79349-82-9 | C9H10N2O3S | 详情 | 详情 |
(V) | 69631 | (6R,7R)-7-((Z)-4-bromo-2-(methoxyimino)-3-oxobutanamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H14BrN3O6S | 详情 | 详情 | |
(VI) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
合成路线16
【1】 Sakane K,Goto J.Production of 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)-3-cephem compound:JP,Patent 02,000,790,1990. |
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) | 69632 | (Z)-2-(acetoxyimino)-2-(2-aminothiazol-4-yl)acetyl chloride | C7H6ClN3O3S | 详情 | 详情 | |
(II) | 69633 | (E)-trimethylsilyl N-(trimethylsilyl)acetimidate;N,O-Bis(trimethylsilyl)acetamide;Trimethylsilyl N-trimethylsilylacetamidate; | 10416-59-8 | C8H21NOSi2 | 详情 | 详情 |
(III) | 64882 | (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 79349-82-9 | C9H10N2O3S | 详情 | 详情 |
(IV) | 69634 | (6R,7R)-7-((Z)-2-(acetoxyimino)-2-(2-aminothiazol-4-yl)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic aci | C16H15N5O6S2 | 详情 | 详情 |
合成路线17
The condensation of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (I) with 4-bromoacetoacetyl bromide (II) by means of trimethylsilylacetamide in ethyl acetate gives benzhydryl 7-(4-bromoaceto-acetamido)-3-vinyl-3-cephem-4-carboxylate (III), which by reaction with NaNO2 - acetic acid in dichloromethane and then with urea is converted to benzhydryl 7-[4-bromo-2-(hydroxyimino)acetoacetamido]-3-vinyl-3-cephem-4 carboxylate (IV). The cyclization of (IV) with thiourea in dimethylacetamide affords benzhydryl 7-[2-(2-aminothiazol-4-yl) (hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (V), which is finally hydrolyzed with trifluoroacetic acid - anisole as usual.
【1】 Kawabata, K.; Masugi, T.; Takaya, T.; Taksugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Syn-isomer of 7-substd.-3-vinyl-3-cephem cpds., pr. EP 0105459; ES 8600309; ES 8800235; US 4559334 . |
【2】 Castaner, J.; Prous, J.; FK-482. Drugs Fut 1988, 13, 3, 224. |
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) | 22001 | benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H20N2O3S | 详情 | 详情 | |
(II) | 15619 | 5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid | C6H8O5S | 详情 | 详情 | |
(III) | 22003 | benzhydryl (6R,7R)-7-[(4-bromo-3-oxobutanoyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H23BrN2O5S | 详情 | 详情 | |
(IV) | 22004 | benzhydryl (6R,7R)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H22BrN3O6S | 详情 | 详情 | |
(V) | 22005 | benzhydryl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H23N5O5S2 | 详情 | 详情 | |
(VI) | 63021 | N-(trimethylsilyl)acetamide | 13435-12-6 | C5H13NOSi | 详情 | 详情 |
(VII) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
(VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
合成路线18
The condensation of 2-(2-aminothiazol-4-yl)-2(Z)-(trityoloxyimino)thioacetic acid 2-benzothiazolyl ester (I) with 7-amino-3-vinyl-3-cephem-4-carboxylic acid (II) by means of tributylamine in DMA gives the corresponding amide (III), which is deprotected by means of HCl and formic acid to provide cefdinir.
【1】 Singh, S.K.; Kumar, Y.; Prasad, M.; Prasad, A.; Kumar, N.P. (Ranbaxy Laboratories Ltd.); Process for the preparation of cefdinir. WO 0391261 . |
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) | 64881 | S-(1,3-benzothiazol-2-yl) 2-(2-amino-1,3-thiazol-4-yl)-2-{[(triphenylmethyl)oxy]imino}ethanethioate | C31H22N4O2S3 | 详情 | 详情 | |
(II) | 64882 | (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 79349-82-9 | C9H10N2O3S | 详情 | 详情 |
(III) | 64883 | 7-[(2-(2-amino-1,3-thiazol-4-yl)-2-{[(triphenylmethyl)oxy]imino}acetyl)amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C33H27N5O5S2 | 详情 | 详情 |