ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate -Drug Synthesis Database

【结构式】

【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 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：(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.

参考文献中间体

合成目标

【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)

参考文献中间体

合成目标

【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)

参考文献中间体

合成目标

【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