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【结 构 式】 
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【分子编号】15673 【品名】2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride 【CA登记号】39098-97-0 |
【 分 子 式 】C6H5ClOS 【 分 子 量 】160.6238 【元素组成】C 44.87% H 3.14% Cl 22.07% O 9.96% S 19.96% |
合成路线1
该中间体在本合成路线中的序号：(E)The reaction of the Schift base (XV) phenyllithium and CH3SCl (D) in DMF gives the corresponding methylthio derivative (XVI), which is debenzylated with 2,4-DNPH p-toluenesulfonate in ethanol yielding p-methoxybenzyl-7beta-amino-7alpha-thiomethyl-3-acetoxymethyl-3-cephem-4-carboxylate (XVII). The acylation of (XVII) with 2-thienylacetyl chloride (E) / pyridine in CH2Cl2 provided the corresponding 2-thienylacetamido derivative (XVIII), which by methanolysis in the presence of thallium trinitrate gives the 7alpha-methoxy derivative (XIX). The p-methoxybenzyl ester of (XIX) is cleaved with TFA-anisole affording 7alpha-methoxycephalothin-(7alpha-methoxy-7-(2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid) (XX), which is deacetylated with citrus acetyl enzyme yielding the corresponding hydroxymethyl compound (XXI). Finally, this compound is treated with chlorosulfonyl isocyanate in THF or acetonitrile.
| 【1】 Ratcliffe, R.W.; Christensen, B.G.; Total synthesis of beta-lactam antibiotics. III. (rac)-Cefoxitin. Tetrahedron Lett 1973, 46, 4653-56. |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【3】 Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488 . |
| 【4】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Antibiotics and processes for their production. DE 2203653; FR 2161866; GB 1350772 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (D) | 39830 | methanesulfenyl chloride | 5813-48-9 | CH3ClS | 详情 | 详情 |
| (XV) | 39829 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H23N3O8S | 详情 | 详情 | |
| (XVI) | 39831 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-(methylsulfanyl)-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H25N3O8S2 | 详情 | 详情 | |
| (XVII) | 39832 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-amino-7-(methylsulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H22N2O6S2 | 详情 | 详情 | |
| (XVIII) | 39833 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-(methylsulfanyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H26N2O7S3 | 详情 | 详情 | |
| (XIX) | 39834 | 4-methoxybenzyl (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C25H26N2O8S2 | 详情 | 详情 | |
| (XX) | 39835 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N2O7S2 | 详情 | 详情 | |
| (XXI) | 39836 | (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H16N2O6S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(E)The hydrolysis of p-methoxybenzyl-7-aminocephalosporanate (XIV) with trifluoroacetic acid gives the corresponding tree acid (XXII), which is treated with tert-butoxycarbonylazide (F) yielding the tert-butoxycarbonylamidocephalosporanic acid (XXIII). This compound is deacetylated by treatment with citrus acetyl sterase in an aqueous phosphate buffer affording the 3-hydroxymethyl derivative (XXIV), which by reaction with chlorosulfonyl isocyanate gives the 3-carbamoyloxymethyl compound (XXV). The hydrolysis of (XXV) with TFA yields 3-carbamoyloxymethyl-7beta-amino-3-cephem-4-carboxylic acid (XXVI), which is esterified with diphenyldiazomethane in dioxane affording the benzhydryl ester (XXVII). The acylation of (XXVII) with 2-thienylcarbonyl chloride (E) in CH2Cl2 gives the acylated ester (XXVIII), which by methoxylation of (XXVIII) can also be performed through hydroxylation with phenyllithium and tert-butyl hypochlorite (G) in tert-butanol to the 7-hydroxy compound (XXXII), which is then methylated with diazomethane to (XXX). Finally, this compound is hydrolyzed with trifluoroacetic acid.
| 【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【2】 Hazen, G.C. (Merck & Co., Inc.); Process for preparin cephalosporin compounds. DD 100957; ES 408969; US 3780033 . |
| 【3】 Christensen, B.G.; Firestone, R.A.; Process for preparing cephalosporin compounds. DD 100956; ES 408970; US 3775410 . |
| 【4】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Process for preparing penicillin and cephalosporin compounds. FR 2163144; GB 1401060; US 3843641 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (F) | 39837 | 2,2-dimethylpropanoyl azide | C5H9N3O | 详情 | 详情 | |
| (XIV) | 39828 | 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C18H20N2O6S | 详情 | 详情 | |
| (XXII) | 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 | |
| (XXIII) | 39838 | (6R,7R)-3-[(acetoxy)methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C15H20N2O6S | 详情 | 详情 | |
| (XXIV) | 39839 | (6R,7R)-7-[(2,2-dimethylpropanoyl)amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C13H18N2O5S | 详情 | 详情 | |
| (XXV) | 39840 | (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-7-[(2,2-dimethylpropanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H19N3O6S | 详情 | 详情 | |
| (XXVI) | 39805 | (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C9H11N3O5S | 详情 | 详情 | |
| (XXVII) | 39804 | benzhydryl (6R,7R)-7-amino-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H21N3O5S | 详情 | 详情 | |
| (XXVIII) | 39841 | benzhydryl (6R,7R)-3-[[(aminocarbonyl)oxy]methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C28H25N3O6S2 | 详情 | 详情 | |
| (XXX) | 39843 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 | |
| (XXXII) | 39842 | benzhydryl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-hydroxy-7-[[(Z)-1-methoxy-2-(2-thienyl)ethylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H27N3O7S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(E)Fermentation of Streptomyces lactamdurans NRRL-3802 produces sodium 7beta-(D-5-amino-S-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylate (XXXIII), which is tosylated as usual to the N-tosyl derivative (XXXIV). The esterification of (XXXIV) with methyl chloromethyl ether (H) in CH2Cl2 yields the methoxymethyl ester (XXXV), which is finally treated first with 2-thienylcarbonyl chloride (E) on a 4-angstrom molecular sieve in dichloroethane, and then with HCl methanol.
| 【1】 Weinstock, L.M.; Preparation of 7-acylaminocephalosporin derivatives. DE 2456528; FR 2253022; GB 1480757; JP 50105687 . |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (H) | 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 |
| (XXXIII) | 39846 | (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-[(5-amino-5-carboxypentanoyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C16H22N4O9S | 详情 | 详情 | |
| (XXXIV) | 39847 | (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-[(5-carboxy-5-[[(4-methylphenyl)sulfonyl]amino]pentanoyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C23H28N4O11S2 | 详情 | 详情 | |
| (XXXV) | 39848 | methoxymethyl (6R,7S)-3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-7-[(6-(methoxymethoxy)-5-[[(4-methylphenyl)sulfonyl]amino]-6-oxohexanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H36N4O13S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(E)The acylation and methoxylation of 7-aminocephalosporanic acid (XXII) to (XX) can also be performed as follows: The acid (XXII) is esterified with diphenyldiazomethane in dioxane giving the ester (XXXVI), which is treated with NaNO2 and p-toluenesulfonic acid in CH2Cl2 yielding benzhydryl 7-diazocephalosporanate (XXXVII). The reaction of this compound with BrN3 in CH2Cl2-acetonitrile affords benzhydryl 7alpha-bromo-7beta-azidocephalosporanate (XXXVIII), which by hydrolysis with MeOH and AgBF4 is converted into the corresponding 7beta-methoxy compound (XXXIX). Hydrogenation of the azido group of (XXXIX) with H2 over PtO2 in dioxane gives 7alpha-methoxy-7beta-aminocephalosporanate (XL), which is acylated with 2-thienylcarbonyl chloride (E) in CH2Cl2 affording benzhydryl-7alpha-methoxy-7beta-(2-thienylacetamido)cephalosporanate (XLI). Finally, this compound is hydrolyzed to (XX) with trifluoroacetic acid.
| 【1】 Christensen, B.G.; et al.; In 7-Stellung substituierte Cephalosphoransaureester und Verfahren zu ihrer Herstellung. DE 2143331 . |
| 【2】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434. |
| 【3】 Christensen, B.G.; Cama, L.D. (Merck & Co., Inc.); Antibiotics and processes for their production. DE 2203653; FR 2161866; GB 1350772 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (XX) | 39835 | (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H18N2O7S2 | 详情 | 详情 | |
| (XXII) | 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 | |
| (XXXVI) | 39849 | benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N2O5S | 详情 | 详情 | |
| (XXXVII) | 39850 | C23H21N3O5S | 详情 | 详情 | ||
| (XXXVIII) | 39851 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-azido-7-bromo-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H19BrN4O5S | 详情 | 详情 | |
| (XXXIX) | 39852 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-azido-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H22N4O6S | 详情 | 详情 | |
| (XL) | 39853 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H24N2O6S | 详情 | 详情 | |
| (XLI) | 39854 | benzhydryl (6R,7S)-3-[(acetoxy)methyl]-7-methoxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H28N2O7S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)The ozonolysis of p-nitrobenzyl ester of 7-amino-3-methylenecephem-4-carboxylic acid (I) in CH2Cl2 gives the p-nitrobenzyl ester of 7-amino-3-hydroxy-3-cephem-4-carboxylic acid (II), which is then condensed with thiophene-2-acetyl chloride (A) in aqueous THF to afford p-nitrobenzyl ester of 7-(thiophene-2-acetamido)-3-hydroxy-3-cephem-4-carboxylic acid (III). The chlorination of (III) with SOCl2, PCl3, POCl3, (COCl)2 or COCl2 in DMF yields p-nitrobenzyl ester of 7-(thiophene-2-acetamido)-3-chloro-3-cephem-4-carboxylic acid (IV), which is then partially hydrolyzed with dry pyridine and PCl5 giving p-nitrobenzyl ester of 7-amino-3-chloro-3-cephem-4-carboxylic acid (V). This compound can be acylated easily to p-nitrobenzyl ester of 7-(D-alpha-phenylglycylamido)-3-chloro-3-cephem-4-carboxylic acid (VI), which is finally hydrogenolyzed with Zn and conc. HCl. An alternative way starting also from (V) is its hydrogenolysis with H2 over Pd/C in THF-MeOH giving the 7-amino-3-chloro-3-cephem-4-carboxylic acid (VII), which is then acylated as usual.
| 【1】 Bogan, J.A.; Castaner, J.; Cefaclor. Drugs Fut 1977, 2, 6, 369. |
| 【2】 Chauvette, R.R. (Eli Lilly and Company); Alpha-aminoacyl-3-halo-cephalosporins. DE 2408698; ES 423531; FR 2218877; GB 1461323; JP 49110689; JP 56138190 . |
| 【3】 Chauvette, R.R.; Pennington, P.A.; Chemistry of cephalosporin antibiotics. 30. 3-Methoxy- and 3-halo-3-cephems. J Med Chem 1975, 18, 4, 403-8. |
| 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) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (I) | 40050 | 4-nitrobenzyl (6R,7R)-7-amino-3-methylene-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C15H15N3O5S | 详情 | 详情 | |
| (II) | 40051 | 4-nitrobenzyl (6R,7R)-7-amino-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H13N3O6S | 详情 | 详情 | |
| (III) | 40052 | 4-nitrobenzyl (6R,7R)-3-hydroxy-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C20H17N3O7S2 | 详情 | 详情 | |
| (IV) | 40053 | 4-nitrobenzyl (6R,7R)-3-chloro-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C20H16ClN3O6S2 | 详情 | 详情 | |
| (V) | 40054 | 4-nitrobenzyl (6R,7R)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H12ClN3O5S | 详情 | 详情 | |
| (VI) | 40056 | 4-nitrobenzyl (6R,7R)-7-[[(2R)-2-amino-2-phenylethanoyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C22H19ClN4O6S | 详情 | 详情 | |
| (VII) | 40057 | (6R,7R)-7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C7H7ClN2O3S | 详情 | 详情 | |
| (VIII) | 40058 | 4-(chloromethyl)-2,3,5-trimethylphenyl methyl ether; 2-(chloromethyl)-5-methoxy-1,3,4-trimethylbenzene | C11H15ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)1) The acylation of 7-aminocephalosporanic acid (I) with 2-thienylacetyl chloride (II) gives the acylated compound (III), which is treated with wheat bran enzyme to obtain 3-(hydroxymethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (IV). The esterification of (IV) with diphenyldiazomethane affords the corresponding diphenylmethyl ester (V), which is treated with carbonyldiimidazole (CDI) in THF to yield the imidazolecarbonyl ester (VI). The reaction of (VI) with dimethylamine in ethyl acetate/water gives the dimethylcarbamoyl derivative (VII) as a mixture of the 3- and 2-cephem derivatives, which is oxidized with m-chloroperbenzoic acid to the corresponding S-oxides and separated by column chromatography to give pure 3-cephem derivative (VIII). Elimination of the oxide group of (VIII) with PCl3 in DMF affords 3-(dimethylcarbamoyloxymethyl)-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid diphenyl ester (IX), which is treated with PCl5 and pyridine to obtain compound (X) with a free amino group. The acylation of (X) with 2-[2-(tritylamino)thiazol-4-yl]-2(Z)-(trityloxyimino)acetic acid (XI) by means of dicyclohexylcarbodiimide (DCC) gives the fully protected cephem derivative (XII), which is deprotected with trifluoroacetic acid and anisole to yield 7-[2-(2-aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-(N,N-dimethylcarbamoyloxymethyl)-3-cephem-4-carboxylic acid sodium salt (XIII). Finally, this compound is esterified with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF.
| 【1】 Fromtling, R.A.; Castaner, J.; E-1101. Drugs Fut 1995, 20, 8, 766. |
| 【2】 Negi, S.; et al.; Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins. J Antibiot 1994, 47, 12, 1507-25. |
| 【3】 Negi, S.; Yamanaka, M.; Katsu, K.; Sugiyama, I.; Komatu, Y.; Kamata, A.; Tsuruoka, A.; Machida, Y. (Eisai Co., Ltd.); 7-Acyl-3-(substd. carbamoyloxy)cephem cpds., use thereof and process for their preparation. EP 0484966; EP 0761671; JP 1992178392; JP 1992282388; JP 1993311173; JP 1993311174; JP 1994092969; JP 1998067784; US 5559225; US 5587473; US 5604217 . |
| 【4】 Negi, S.; Yamanaka, M.; Sugiyama, I.; et al.; E1101, a new oral cephalosporin: I. Synthesis and structure-activity relations of 3-substituted carbamoyloxymethyl cephems. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 894. |
| 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) | 15672 | 7-Aminocephalosporanic acid; 3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ACA | C10H12N2O5S | 详情 | 详情 | |
| (II) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (III) | 15674 | 3-[(acetoxy)methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | 51098-29-4 | C16H16N2O6S2 | 详情 | 详情 |
| (IV) | 15675 | 3-(hydroxymethyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H14N2O5S2 | 详情 | 详情 | |
| (V) | 15676 | benzhydryl 3-(hydroxymethyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H24N2O5S2 | 详情 | 详情 | |
| (VI) | 15677 | benzhydryl 3-[[(1H-imidazol-1-ylcarbonyl)oxy]methyl]-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H26N4O6S2 | 详情 | 详情 | |
| (VII) | 15678 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O6S2 | 详情 | 详情 | |
| (VIII) | 15679 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-5,8-dioxo-7-[[2-(2-thienyl)acetyl]amino]-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O7S2 | 详情 | 详情 | |
| (IX) | 15678 | benzhydryl 3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H29N3O6S2 | 详情 | 详情 | |
| (X) | 15681 | benzhydryl 7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C24H25N3O5S | 详情 | 详情 | |
| (XI) | 15682 | 2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-[(benzhydryloxy)imino]acetic acid | C31H25N3O3S | 详情 | 详情 | |
| (XII) | 15683 | benzhydryl 7-([2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-[(benzhydryloxy)imino]acetyl]amino)-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C55H48N6O7S2 | 详情 | 详情 | |
| (XIII) | 15684 | 7-[2-(2-Aminothiazol-4-yl)-3(Z)-(hydroxyimino)acetamido]-2-(N,N-dimethylcarbamoyloxy)-3-cephem-4-carboxylic acid sodium salt | C16H17N6NaO7S2 | 详情 | 详情 | |
| (XIV) | 15685 | 1-iodoethyl isopropyl carbonate | C6H11IO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Acylation of 7-aminocephalosporanic acid (I) with 2-thienyleacetyl chloride (II) in the presence of NaOH led to amide (III). The carboxylate group of (III) was then protected as the corresponding benzhydryl ester (IV) upon treatment with diphenyldiazomethane. Mitsunobu coupling of the hydroxymethyl cephem (IV) with triclosan (V), with partial double-bond isomerization, gave rise to a mixture of the desired delta-3 ether (VI) and its delta-2 isomer (VII), which were separated by repeated column chromatography. Isomerization was minimized by conducting the reaction at -20 C. Finally, removal of the benzhydryl ester group of (VI) was accomplished by treatment with trifluoroacetic acid in the presence of anisole.
| 【1】 Li, Q.; et al.; NB2001, a novel antibacterial agent with broad-specrum activity and enhanced potency against beta-lactamase-producing strains. Antimicrob Agents Chemother 2002, 46, 5, 1262. |
| 【2】 Lobl, T.J.; Chan, M.F.; Li, Q.; Doppalapudi, V.R.; Hixon, M.S.; Castillo, R. (NewBiotics, Inc.); Improved beta-lactam antibiotics. WO 0183492 . |
| 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) | 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) | 15673 | 2-(2-thienyl)acetyl chloride; 2-Thiopheneacetyl chloride | 39098-97-0 | C6H5ClOS | 详情 | 详情 |
| (III) | 55051 | (6R,7R)-3-(hydroxymethyl)-8-oxo-7-{[2-(2-thienyl)acetyl]amino}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C14H14N2O5S2 | 详情 | 详情 | |
| (IV) | 39801 | benzhydryl (6R,7R)-3-(hydroxymethyl)-8-oxo-7-[[2-(2-thienyl)acetyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C27H24N2O5S2 | 详情 | 详情 | |
| (V) | 55052 | 2,4,4'-Trichloro-2'-hydroxydiphenyl ether; Triclosan | 3380-34-5 | C12H7Cl3O2 | 详情 | 详情 |
| (VI) | 55053 | benzhydryl (6R,7R)-3-{[5-chloro-2-(2,4-dichlorophenoxy)phenoxy]methyl}-8-oxo-7-{[2-(2-thienyl)acetyl]amino}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C39H29Cl3N2O6S2 | 详情 | 详情 | |
| (VII) | 55054 | benzhydryl (6R,7R)-3-{[5-chloro-2-(2,4-dichlorophenoxy)phenoxy]methyl}-8-oxo-7-{[2-(2-thienyl)acetyl]amino}-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C39H29Cl3N2O6S2 | 详情 | 详情 |