【结 构 式】 |
【药物名称】Cefcanel daloxate hydrochloride, KY-109 【化学名称】(6R,7R)-7beta-[2(R)-(S-Alanyloxy)-2-phenylacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester 【CA登记号】92602-21-6, 97275-40-6 (free base) 【 分 子 式 】C27H28ClN5O9S3 【 分 子 量 】698.19731 |
【开发单位】Kyoto Pharmaceutical (Originator), AstraZeneca (Licensee) 【药理作用】Cephalosporins |
合成路线1
1) The esterification of 7-[(R)-mandelamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (KY-087; I) with 4-bromomethyl-5-methyl-1,3-dioxol-2-one (II) by means of potassium acetate in DMF gives the corresponding ester (KY-106; III), which is condensed with tert-butoxycarbonyl-L-alanine (IV) by means of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMP) in dichloromethane affording the protected final product (V). Finally, this compound is deprotected with HCl in methanol-acetone.
【1】 Kaneya, N.; Nishizawa, S.; Tamaki, S.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); Antibiotic amino acid derivatives of cephalosporins.. JP 59116292; US 4605651; WO 8401949 . |
【2】 Kakeya, N.; Nishizawa, S.; Nishimura, K.; Yoshimi, A.; Tamaki, S.; Mori, T.; Kitao, K.; KY-109, A new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties. J Antibiot 1985, 38, 3, 380-9. |
【3】 Prous, J.; Castaner, J.; CEFCANEL DALOXATE HYDROCHLORIDE < Prop INNM >. Drugs Fut 1989, 14, 1, 13. |
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) | 20334 | (7R)-7-[[2-(2-hydroxyphenyl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C19H18N4O5S3 | 详情 | 详情 | |
(II) | 13462 | 4-(Bromomethyl)-5-methyl-1,3-dioxol-2-one | 80715-22-6 | C5H5BrO3 | 详情 | 详情 |
(III) | 20336 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-[[(2R)-2-hydroxy-2-phenylethanoyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H22N4O8S3 | 详情 | 详情 | |
(IV) | 20337 | N-(tert-butoxycarbonyl)alanine | C8H15NO4 | 详情 | 详情 | |
(V) | 20338 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]propanoyl]oxy)-2-phenylethanoyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C32H35N5O11S3 | 详情 | 详情 |
合成路线2
2) The reaction of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (VI) with 2-O-(tert-butoxycarbonyl-L-alanyl)mandelic acid (VII) by means of triethylamine in THF gives the corresponding amide (VIII), which is then esterified with dioxolone (II) as before to afford the protected product (V), already obtained.
【1】 Prous, J.; Castaner, J.; CEFCANEL DALOXATE HYDROCHLORIDE < Prop INNM >. Drugs Fut 1989, 14, 1, 13. |
【2】 Kakeya, N.; Nishizawa, S.; Nishimura, K.; Yoshimi, A.; Tamaki, S.; Mori, T.; Kitao, K.; KY-109, A new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties. J Antibiot 1985, 38, 3, 380-9. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 20338 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]propanoyl]oxy)-2-phenylethanoyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C32H35N5O11S3 | 详情 | 详情 | |
(VI) | 20339 | (7R)-7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 30246-33-4 | C11H12N4O3S3 | 详情 | 详情 |
(VII) | 20340 | (11R)-2,2,8-trimethyl-4,6,9-trioxo-11-phenyl-3,5,10-trioxa-7-azadodecan-12-oic acid | C17H21NO8 | 详情 | 详情 | |
(VIII) | 20341 | (7R)-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-7-[[(2R)-5,11,11-trimethyl-4,7,9-trioxo-2-phenyl-3,8,10-trioxa-6-azadodec-1-anoyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C28H31N5O10S3 | 详情 | 详情 |
合成路线3
3) The reaction of the 7-aminocephem derivative (VI) with ethyl acetoacetate (IX) at room temperature gives the 3-aminocrotonate derivative (X), which is esterified with dioxolone (II) as before yielding the ester derivative (XI). The acidic (HCl) hydrolysis of (XI) in methanol-dichloromethane affords the 7-aminocephem derivative (XII) , which is finally condensed with 2-O-(tert-butoxycarbonyl-L-alanyl)mandelic acid (VII) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane to yield the protected product (V), already obtained.
【1】 Nishizawa, S.; et al. (Kyoto Pharmaceutical Industries, Ltd.); Production of cephalosporin compounds.. JP 85034975 . |
【2】 Nishizawa, S.; Tamaki, S.; Kakeya, N.; Kitao, K. (Kyoto Pharmaceutical Industries, Ltd.); Cephalosporin cpds.. WO 8505360 . |
【3】 Prous, J.; Castaner, J.; CEFCANEL DALOXATE HYDROCHLORIDE < Prop INNM >. Drugs Fut 1989, 14, 1, 13. |
【4】 Kakeya, N.; Nishizawa, S.; Nishimura, K.; Yoshimi, A.; Tamaki, S.; Mori, T.; Kitao, K.; KY-109, A new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties. J Antibiot 1985, 38, 3, 380-9. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(V) | 20338 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-[[(2R)-2-([2-[(tert-butoxycarbonyl)amino]propanoyl]oxy)-2-phenylethanoyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C32H35N5O11S3 | 详情 | 详情 | |
(VI) | 20340 | (11R)-2,2,8-trimethyl-4,6,9-trioxo-11-phenyl-3,5,10-trioxa-7-azadodecan-12-oic acid | C17H21NO8 | 详情 | 详情 | |
(VII) | 20339 | (7R)-7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 30246-33-4 | C11H12N4O3S3 | 详情 | 详情 |
(IX) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
(X) | 20343 | (7R)-7-[[(Z)-4-ethoxy-1-methyl-3,4-dioxo-1-butenyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H20N4O6S3 | 详情 | 详情 | |
(XI) | 20344 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-[[(Z)-4-ethoxy-1-methyl-3,4-dioxo-1-butenyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H24N4O9S3 | 详情 | 详情 | |
(XII) | 20345 | (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (7R)-7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H16N4O6S3 | 详情 | 详情 |