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【结 构 式】 
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【分子编号】29047 【品名】2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid 【CA登记号】 |
【 分 子 式 】C32H33N3O5S 【 分 子 量 】571.69724 【元素组成】C 67.23% H 5.82% N 7.35% O 13.99% S 5.61% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 7-amino-3-bromomethyl-3-cephem-4-carboxylic acid tert-butyl ester 1-oxide (I) with 2-(2-tritylamino-4-thiazolyl)-2-[2-(tert-butoxycarbonyl)-2-propyloxyimino]acetic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives the corresponding amide (III), which is treated with N-allyl-pyridine-2-thione (IV) in dimethylacetamide yielding the pyridinium salt (V). Finally, this compound is deprotected by a treatment with HCl in formic acid. The thione (IV) is prepared as follows: The reaction of 2-bromopyridine (VI) with allyl bromide (VII) in acetone gives N-allyl-2-bromopyridinium bromide (VIII), which is then treated with potassium hydrosulfide in water.
| 【1】 Labeeuw, B.; Salhi, A. (Sanofi-Synthelabo); Derivatives of pyridinium thiomethyl cephalosporins. EP 0088853; FR 2516515; JP 58090590; US 4593022 . |
| 【2】 Serradell, M.N.; Matthews, R.; Castaner, J.; Burnie, J.; CM-40874. Drugs Fut 1985, 10, 3, 193. |
| 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) | 29048 | tert-butyl 7-amino-3-(bromomethyl)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H17BrN2O4S | 详情 | 详情 | |
| (II) | 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 | |
| (III) | 29049 | tert-butyl 3-(bromomethyl)-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C44H48BrN5O8S2 | 详情 | 详情 | |
| (IV) | 29050 | 1-allyl-2(1H)-pyridinethione | C8H9NS | 详情 | 详情 | |
| (V) | 29051 | 1-allyl-2-([[2-(tert-butoxycarbonyl)-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]sulfanyl)pyridinium bromide | C52H57BrN6O8S3 | 详情 | 详情 | |
| (VI) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (VII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VIII) | 29053 | 1-allyl-2-bromopyridinium bromide | C8H9Br2N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |