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【结 构 式】 
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【药物名称】Cefonicid sodium, SK&F-D-75073-Z2, Monocid 【化学名称】[6R-[6alpha,7beta(R*)]]-7-[(Hydroxyphenylacetyl)amino]-8-oxo-3-[[[1-(sulfomethyl)-1H-tetrazol-5-yl]thio]methyl]-5-thia]-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt 【CA登记号】61270-78-8, 61270-58-4 (free acid) 【 分 子 式 】C18H16N6Na2O8S3 【 分 子 量 】586.53522 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins |
合成路线1
The reaction of aminomethansulfonic acid (I) with phthalic anhydride (II) by means of potassium acetate in refluxing acetic acid gives phthalimidomethansulfonic acid (III), which by reaction with PCl5 in refluxing benzene is converted into its acyl chloride (IV). The condensation of (IV) with tert-butylamine (A) in CHCl3 affords N-tert-butylphthalimidomethansulfonamide (V), which by reaction with hydrazine hydrate in refluxing ethanol yields 2-aminomethan-N-tert-butylsulfonamide (VI). The reaction of (VI) with CS2 and MeI by means of triethylamine in ethanol gives N-tert-butylsulfamoylmethyldithiocarbamic acid methyl ester (VII), which is cyclized with NaN3 in hot water to afford 1-(N-tert-butylsulfamoylmethyl)tetrazol-5-thiol (VIII). The hydrolysis of (VIII) with trifluoroacetic acid yields compound 1-sulfamoylmethyltetrazol-5-thiol (IX).
| 【1】 Berges, D.A.; 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. DE 2611270; FR 2304343; US 4048311 . |
| 【2】 Castaner, J.; Serradell, M.N.; Thorpe, P.; Blancafort, P.; Cefonicid sodium. Drugs Fut 1979, 4, 9, 634. |
| 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) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (I) | 33363 | aminomethanesulfonic acid | 13881-91-9 | CH5NO3S | 详情 | 详情 |
| (II) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 33364 | (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methanesulfonic acid | C9H7NO5S | 详情 | 详情 | |
| (IV) | 33365 | (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methanesulfonyl chloride | C9H6ClNO4S | 详情 | 详情 | |
| (V) | 33366 | N-(tert-butyl)(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methanesulfonamide | C13H16N2O4S | 详情 | 详情 | |
| (VI) | 33367 | amino-N-(tert-butyl)methanesulfonamide | C5H14N2O2S | 详情 | 详情 | |
| (VII) | 33368 | methyl [(tert-butylamino)sulfonyl]methylcarbamodithioate | C7H16N2O2S3 | 详情 | 详情 | |
| (VIII) | 33369 | N-(tert-butyl)(5-sulfanyl-1H-1,2,3,4-tetraazol-1-yl)methanesulfonamide | C6H13N5O2S2 | 详情 | 详情 | |
| (IX) | 33370 | (5-sulfanyl-1H-1,2,3,4-tetraazol-1-yl)methanesulfonic acid | C2H4N4O3S2 | 详情 | 详情 |
合成路线2
Compound 1-sulfamoylmethyltetrazol-5-thiol (IX) can also be obtained by reaction of (I) with CS2 and MeI by means of KOH in refluxing ethanol to give sulfomethyldithiocarbamic acid methyl ester (XIII), which is then cyclized with NaN3 in hot water.
| 【1】 Berges, D.A.; 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. DE 2611270; FR 2304343; US 4048311 . |
| 【2】 Castaner, J.; Serradell, M.N.; Thorpe, P.; Blancafort, P.; Cefonicid sodium. Drugs Fut 1979, 4, 9, 634. |
合成路线3
a) By reaction of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-mandelamidocephalosporanic acid (XII) by means of NaHCO3. b) ByCondensation of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-aminocephalosporanic acid (X) by means of NaHCO3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (XI). Finally, this compound is acylated with D-O-dichloroacetylmandeloyl chloride (A) by means of NaHCO3 in acetone-water to afford the target compound. b) ByCondensation of 1-sulfamoylmethyltetrazol-5-thiol (IX) with 7-aminocephalosporanic acid (X) by means of NaHCO3 in acetone - water to give 7-amino-3-(1-sulfamoyl-methyltetrazol-5-ylthio-methyl)-3-cephem-4-carboxylic acid (XI). Finally, this compound is acylated with D-O-dichloroacetylmandeloyl chloride (A) by means of NaHCO3 in acetone-water to afford the target compound.
| 【1】 Berges, D.A.; 7-Acyl-3-(sulfonic acid and sulfamoyl substituted tetrazolyl thiomethyl)cephalosporins.. DE 2611270; FR 2304343; US 4048311 . |
| 【2】 Castaner, J.; Serradell, M.N.; Thorpe, P.; Blancafort, P.; Cefonicid sodium. Drugs Fut 1979, 4, 9, 634. |
| 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) | 33373 | (1R)-2-chloro-2-oxo-1-phenylethyl 2,2-dichloroacetate | C10H7Cl3O3 | 详情 | 详情 | |
| (IX) | 33370 | (5-sulfanyl-1H-1,2,3,4-tetraazol-1-yl)methanesulfonic acid | C2H4N4O3S2 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 33372 | (6R,7R)-7-amino-8-oxo-3-([[1-(sulfomethyl)-1H-1,2,3,4-tetraazol-5-yl]sulfanyl]methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N6O6S3 | 详情 | 详情 | |
| (XII) | 33371 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-hydroxy-2-phenylethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H18N2O7S | 详情 | 详情 |