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【结 构 式】 
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【分子编号】32660 【品名】tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C14H20N2O5S 【 分 子 量 】328.38928 【元素组成】C 51.21% H 6.14% N 8.53% O 24.36% S 9.76% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The methylation of ethyl 3-oxo-2-hydroxyiminobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 3-oxo-2-methoxyiminobutyrate (II), which is brominated with Br2 in CHCl3 to afford ethyl 4-bromo-3-oxo-2-methoxyiminobutyrate (III). The cyclization of (III) with thiourea (A) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (IV), which is acylated with chloroacetyl chloride in dimethylacetamide to yield ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate (V). The hydrolysis of (V) with KOH in ethanol-water gives the corresponding free acid (VI), which is treated with PCl5 in methylene chloride to obtain the acyl chloride (VII). The condensation of tert-butyl 7-aminocephalosporanate (VIII) with (VII) by means of pyridine in methylene chloride gives tert-butyl 7-[alpha-methoxyimino-(2-chloroacetamidothiazol-4-yl)acetamido]cephalosporanate (IX), which is desacylated with thiourea and triethylbenzylammonium bromide in THF-ethanol yielding tert-butyl 7-[alpha-methoxyimino-alpha-(2-aminothiazol-4-yl)acetamido]cephalosporanate (X), which is hydrolyzed with trifluoroacetic acid to afford the free cephalosporanic acid (Xl). Finally, this compound is condensed with 1-methyl-5-mercaptotetrazol (XII) by means of NaHCO3 and triethylbenzylammoniurn bromide in water.
| 【1】 Ochiai, M.; et al.; New cephalosporin derivatives with high antibacterial activities. Chem Pharm Bull 1977, 25, 11, 3115-17. |
| 【2】 Ochiai, M.; et al.; Cephalosporin derivatives and their preparation. BE 0853545; JP 52125188; ZA 7702030 . |
| 【3】 Ochiai, M.; et al. (Takeda Chemical Industries, Ltd.); Thiazolylacetamido cephasloporin type compounds. DE 2556736; ES 464772; FR 2294690; GB 1536283; NL 7514811; US 4098888 . |
| 【4】 Serradell, M.N.; Castaner, J.; Blancafort, P.; SCE-1365. Drugs Fut 1980, 5, 3, 146. |
| 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 |
| (I) | 20853 | ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate | C6H9NO4 | 详情 | 详情 | |
| (II) | 20854 | ethyl 2-(methoxyimino)-3-oxobutanoate | C7H11NO4 | 详情 | 详情 | |
| (III) | 10181 | ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate | 60845-87-6 | C7H10BrNO4 | 详情 | 详情 |
| (IV) | 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 |
| (V) | 20859 | ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate | C10H12ClN3O4S | 详情 | 详情 | |
| (VI) | 20860 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid | 64486-18-6 | C8H8ClN3O4S | 详情 | 详情 |
| (VII) | 32659 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride | 75532-64-8 | C8H7Cl2N3O3S | 详情 | 详情 |
| (VIII) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (IX) | 32661 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H26ClN5O8S2 | 详情 | 详情 | |
| (X) | 32662 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C20H25N5O7S2 | 详情 | 详情 | |
| (XI) | 29686 | (6R,7R)-3-[(acetoxy)methyl]-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H17N5O7S2 | 详情 | 详情 | |
| (XII) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)7-Aminocephalosporanic acid (I) was converted to tert-butyl ester (II) by treatment with isobutylene and sulfuric acid. Subsequent diazotization, followed by reaction with methanol and rhodium catalyst, provided the 7-methoxy derivative (IIIa-b) as a diastereomeric mixture. The desired 7S-isomer was then deprotected with trifluoroacetic acid in anisole, yielding carboxylic acid (IV). Coupling of acid (IV) with 3-iodobenzylamine (VI) via activation as the mixed anhydride (V) with ethyl chloroformate gave rise to amide (VII). The sulfide group of (VII) was finally converted into the title sulfone by oxidation with oxone.
| 【1】 Levy, M.A.; Gleason, J.G. (SmithKline Beecham plc); Interleukin converting enzyme and apoptosis. EP 0851760; JP 1999514345; WO 9707805 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 43145 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C15H21NO6S | 详情 | 详情 | |
| (IIIb) | 43146 | tert-butyl (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C15H21NO6S | 详情 | 详情 | |
| (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) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (IV) | 43147 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C11H13NO6S | 详情 | 详情 | |
| (V) | 43148 | C14H17NO8S | 详情 | 详情 | ||
| (VI) | 20865 | 3-iodobenzylamine; (3-iodophenyl)methanamine | C7H8IN | 详情 | 详情 | |
| (VII) | 43149 | ((6R,7S)-2-[[(3-iodobenzyl)amino]carbonyl]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl acetate | C18H19IN2O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.
| 【1】 DE 2921316 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castañer, J.; Ceftazidime. Drugs Fut 1981, 6, 10, 612. |
| 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) | 29669 | Pyridine | 110-86-1 | C5H5N | 详情 | 详情 |
| (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) | 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 |
| (V) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (VI) | 37478 | ethyl 2-(hydroxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate | C26H23N3O3S | 详情 | 详情 | |
| (VII) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
| (VIII) | 37479 | tert-butyl 2-[([(Z)-2-ethoxy-2-oxo-1-[2-(tritylamino)-1,3-thiazol-4-yl]ethylidene]amino)oxy]-2-methylpropanoate | C34H37N3O5S | 详情 | 详情 | |
| (IX) | 29047 | 2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C32H33N3O5S | 详情 | 详情 | |
| (X) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (XI) | 37480 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H51N5O9S2 | 详情 | 详情 | |
| (XII) | 37481 | (6R,7R)-3-[(acetoxy)methyl]-7-([2-(2-amino-1,3-thiazol-4-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C19H21N5O9S2 | 详情 | 详情 |