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【结 构 式】 
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【分子编号】39961 【品名】ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate 【CA登记号】 |
【 分 子 式 】C6H8ClNO4 【 分 子 量 】193.58656 【元素组成】C 37.23% H 4.17% Cl 18.31% N 7.24% O 33.06% |
与该中间体有关的原料药合成路线共 3 条
合成路线1
该中间体在本合成路线中的序号：(VI)The protection of the amino group of ethyl 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetate (I) with trityl chloride (B) by means of triethylamine in CH2Cl2 gives ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetate (II), which is hydrolyzed to the corresponding acid (III) with NaOH in refluxing dioxane-water. The condensation of (III) with 7-aminocephalosporanic acid (IV) by means of dicyclohexylcarbodiimide in CH2Cl2 containing triethylamine affords 7-(2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetamido]cephalosporanic acid (V). The elimination of the trityl group is performed with hot 55% formic acid yielding the corresponding free acid, which is finally treated with NaHCO3 in water.
| 【1】 Neuman, M.; Castaner, J.; HR-756. Drugs Fut 1978, 3, 10, 749. |
| 【2】 Heymes, R.; Lutz, A. (Aventis Pharma SA); Oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acid processes for preparing them and pharmaceutical compositions incorporating them. BE 0850662; ES 455089; ES 466539; GB 1580621; GB 1580623; JP 52102293; JP 5247013 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (B) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (I) | 10182 | Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester | 64485-88-7 | C8H11N3O3S | 详情 | 详情 |
| (II) | 39963 | ethyl 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate | C27H25N3O3S | 详情 | 详情 | |
| (III) | 25058 | 2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | 64485-90-1 | C25H21N3O3S | 详情 | 详情 |
| (IV) | 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 | |
| (V) | 39964 | (6R,7R)-3-[(acetoxy)methyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C35H31N5O7S2 | 详情 | 详情 | |
| (VI) | 39961 | ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate | C6H8ClNO4 | 详情 | 详情 | |
| (VII) | 39962 | ethyl 4-chloro-2-(methoxyimino)-3-oxobutanoate | C7H10ClNO4 | 详情 | 详情 | |
| (VIII) | 20853 | ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate | C6H9NO4 | 详情 | 详情 | |
| (IX) | 20854 | ethyl 2-(methoxyimino)-3-oxobutanoate | C7H11NO4 | 详情 | 详情 | |
| (X) | 10181 | ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate | 60845-87-6 | C7H10BrNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)
| 【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
该中间体在本合成路线中的序号：(III)
| 【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 |
Extended Information