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【结 构 式】 
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【分子编号】28420 【品名】5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide 【CA登记号】13183-79-4 |
【 分 子 式 】C2H4N4S 【 分 子 量 】116.14672 【元素组成】C 20.68% H 3.47% N 48.24% S 27.61% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 7-beta-bromoacetamido-7-alphamethoxycephalosporanic acid (I) with D-cysteine (II) in water at pH 7 gives 7-(2-aminocarboxyethylthio)acetamido-7-alpha-methoxycephalosporanic acid (III), which is then condensed with 5-mercapto-1-methyl-1H-tetrazole (IV) in water at pH 6.5-7 and at 60 C.
| 【1】 Iwamatsu, K.; Inoue, S.; Miyauchi, K.; Kondo, S.; Seki, S.; Yamada, Y. (Meiji Seika Kaisha, Ltd.); 7alpha-Methoxycephalosporin derivatives. JP 55083791 . |
| 【2】 Blancafort, P.; Castaner, J.; Loren, J.G.; Serradell, M.N.; MT-141. Drugs Fut 1982, 7, 6, 395. |
| 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) | 31959 | (6R,7S)-3-[(acetoxy)methyl]-7-[(2-bromoacetyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-beta-bromoacetamido-7-alphamethoxycephalosporanic acid | C13H15BrN2O7S | 详情 | 详情 | |
| (II) | 25404 | D-cysteine; (S)-2-Amino-3-mercaptopropionic acid | 921-01-7 | C3H7NO2S | 详情 | 详情 |
| (III) | 31960 | (6R,7S)-3-[(acetoxy)methyl]-7-[(2-[[(2S)-2-amino-2-carboxyethyl]sulfanyl]acetyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-(2-aminocarboxyethyIthio)acetamido-7-alpha-methoxycephalosporanic acid | C16H21N3O9S2 | 详情 | 详情 | |
| (IV) | 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：(V)The condensation of 4-carboxy-3-hydroxy-5-mercaptoisothiazol (I) with 7beta-bromoacetamido-7alpha-methoxycephalosporanic acid (II) gives 7beta-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamido-7alpha-methoxycephalosporanic acid (III), which by treatment with NaHCO3 in hot water is converted into 7beta-[4-(carbamoyl)(carboxy)methylene-1,3-dithietan-2-yl]carboxamido-7alpha-methoxycephalosporanic acid (IV). Finally, this compound is condensed with 5-mercapto-1-methyltetrazol (V) by means of Na2CO3 in water.
| 【1】 Iwanami, M.; Maeda, T.; Nagano, Y.; Fujimoto, M.; Nagano, N.; Yamazaki, A.; 7alpha-Methoxy-7beta-(1,3-dithietane-2-carboxamido)cephalosporanic acid derivatives. BE 0867994; DE 2824559; FR 2405952; NL 7806208; US 4263432; US 4404373 . |
| 【2】 Blancafort, P.; Castaner, J.; Sweetman, A.J.; Serradell, M.N.; Cefotetan. Drugs Fut 1981, 6, 10, 609. |
| 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) | 32288 | 3-hydroxy-5-sulfanyl-4-isothiazolecarboxylic acid | C4H3NO3S2 | 详情 | 详情 | |
| (II) | 31959 | (6R,7S)-3-[(acetoxy)methyl]-7-[(2-bromoacetyl)amino]-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-beta-bromoacetamido-7-alphamethoxycephalosporanic acid | C13H15BrN2O7S | 详情 | 详情 | |
| (III) | 32289 | (6R,7S)-3-[(acetoxy)methyl]-7-([2-[(4-carboxy-3-hydroxy-5-isothiazolyl)sulfanyl]acetyl]amino)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H17N3O10S3 | 详情 | 详情 | |
| (IV) | 32290 | (6R,7S)-3-[(acetoxy)methyl]-7-([[4-(2-amino-1-carboxy-2-oxoethylidene)-1,3-dithietan-2-yl]carbonyl]amino)-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C17H17N3O10S3 | 详情 | 详情 | |
| (V) | 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3
该中间体在本合成路线中的序号：(XII)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4
该中间体在本合成路线中的序号：(IV)The condensation of 7-[alpha-amino-alpha-(4-hydroxyphenyl)acetamido]cephalosporanic acid (I) with 4-hydroxy-6-methylpyridine-3-carboxylic acid N-hydroxysuccinimide ester (II) by means of triethylamine and sodium 2-ethylhexanoate in DMF chloromethaneethyl ether gives 7-[alpha-(4-hydroxy-6-methylpyridin-3-carboxamido)-alpha-(4-hydroxyphenyl)acetamido]cephalosporanic acid (III), which is then treated with 1-methyl-5-mercaptotetrazol (IV) and NaHCO3 in a phosphate buffer.
| 【1】 Yamada, H.; et al. (Sumitomo Chemical Co., Ltd.); N-acylamino-alpha-arylacetamido cephalosporins and antibacterial compositions and methods containing them. DE 2539664; ES 456652; FR 2283688; GB 1510730; US 4156724 . |
| 【2】 Leeson, P.A.; Serradell, M.N.; Castaner, J.; Mealy, N.E.; Blancafort, P.; SM-1652. Drugs Fut 1980, 5, 5, 254. |
| 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) | 32643 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H19N3O7S | 详情 | 详情 | |
| (II) | 32642 | 1-[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]oxy]-2,5-pyrrolidinedione | C11H10N2O5 | 详情 | 详情 | |
| (III) | 32644 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C25H24N4O9S | 详情 | 详情 | |
| (IV) | 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5
该中间体在本合成路线中的序号：(VIII)The condensation of alpha-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetic acid (I) with 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (VI) by means of ethyl chlorocarbonate and N,O-bis(trimethylsilyl)acetamide (A) gives the 3-acetoxymethyl derivate (VII), which is then condensed with 1-methyl-5-mercapto-1H-tetrazole (VIII) by means of NaHCO3 in a phosphate buffer.
| 【1】 Saikawa, I.; et al.; Nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. BE 0837682 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; T-1551. Drugs Fut 1979, 4, 9, 675. |
| 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) | 33433 | trimethyl-N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]silanamine; N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]-N-(trimethylsilyl)amine | C9H23NSi2 | 详情 | 详情 | |
| (I) | 33432 | (2R)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoic acid | C15H17N3O6 | 详情 | 详情 | |
| (VI) | 33436 | [(6R,7R)-7-amino-2-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl acetate | C10H14N2O4S | 详情 | 详情 | |
| (VII) | 33437 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C25H27N5O10S | 详情 | 详情 | |
| (VIII) | 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6
该中间体在本合成路线中的序号：(VIII)The condensation of acetoxymethyl derivative (VI) with N-(1-methoxycarbonyl-1-propen-2-yl)-alpha-amino-p-hydroxyphenylacetic sodium salt (III) by means of ethyl chlorocarbonate and N,O-bis(trimethylsilyl)acetamide (A) gives 7-(alpha-amino-p-hydroxyphenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (IX), which is then condensed with acyl chloride (V) by means of K2CO3 in ethyl acetate water to afford (VII), which is then condensed with 1-methyl-5-mercapto-1H-tetrazole (VIII) by means of NaHCO3 in a phosphate buffer.
| 【1】 Saikawa, I.; et al.; Nouvelles céphaslosporines, leur procédé de préparation et leur application en thérapeutique. BE 0837682 . |
| 【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; T-1551. Drugs Fut 1979, 4, 9, 675. |
| 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) | 33433 | trimethyl-N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]silanamine; N-[(E)-1-methyl-2-(trimethylsilyl)ethylidene]-N-(trimethylsilyl)amine | C9H23NSi2 | 详情 | 详情 | |
| (III) | 33434 | sodium (2R)-2-(4-hydroxyphenyl)-2-[[(Z)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino]ethanoate | C13H14NNaO5 | 详情 | 详情 | |
| (V) | 24305 | 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride | 59703-00-3 | C7H9ClN2O3 | 详情 | 详情 |
| (VI) | 33436 | [(6R,7R)-7-amino-2-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl acetate | C10H14N2O4S | 详情 | 详情 | |
| (VII) | 33437 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C25H27N5O10S | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 32643 | (6R,7R)-3-[(acetoxy)methyl]-7-[[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H19N3O7S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(III)Silylated 4-oxoazetidine-2-carboxylic acid (I) was converted to the mixed anhydride with isobutyl chloroformate, and then reduced to alcohol (II) with NaBH4. Subsequent Mitsunobu coupling of (II) with mercaptotetrazole (III) provided thioether (IV). Desilylation of (IV) was then achieved by treatment with CsF in MeOH to give (V). Reaction of 4-(trifluoromethyl)benzyl chloride (VI) with methylamine afforded secondary amine (VII). This was reacted with phosgene and diisopropyl ethylamine to produce the carbamoyl chloride (VIII). Finally, condensation of this chloride with azetidinone (V) in the presence of lithium bis(trimethylsilyl)amide furnished the target urea.
| 【1】 Yoakim, C.; Ogilvie, W.W.; Cameron, D.R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Hache, B.; Kawai, S.; Naud, J.; O'Meara, J.A.; Plante, R.; Deziel, R.; Potent beta-lactam inhibitors of human cytomegalovirus protease. Antivir Chem Chemother 1998, 9, 5, 379. |
| 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) | 28418 | (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 28419 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 28421 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C12H23N5OSSi | 详情 | 详情 | |
| (V) | 28422 | (4R)-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C6H9N5OS | 详情 | 详情 | |
| (VI) | 28423 | 1-(chloromethyl)-4-(trifluoromethyl)benzene | 939-99-1 | C8H6ClF3 | 详情 | 详情 |
| (VII) | 28424 | N-methyl-N-[4-(trifluoromethyl)benzyl]amine | C9H10F3N | 详情 | 详情 | |
| (VIII) | 28425 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene | C10H9ClF3NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Silylated 4-oxoazetidine-2-carboxylic acid (I) was converted to the mixed anhydride with isobutyl chloroformate, and then reduced to alcohol (II) with NaBH4. Subsequent Mitsunobu coupling of (II) with mercaptotetrazole (III) provided thioether (IV). Desilylation of (IV) was then achieved by treatment with CsF in MeOH to give (V). Reaction of 4-nitrobenzyl chloride (VI) with methylamine afforded secondary amine (VII). This was reacted with phosgene and diisopropyl ethylamine to produce the carbamoyl chloride (VIII). Finally, condensation of this chloride with azetidinone (V) in the presence of lithium bis(trimethylsilyl)amide furnished the target urea.
| 【1】 Yoakim, C.; Ogilvie, W.W.; Cameron, D.R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Hache, B.; Kawai, S.; Naud, J.; O'Meara, J.A.; Plante, R.; Deziel, R.; Potent beta-lactam inhibitors of human cytomegalovirus protease. Antivir Chem Chemother 1998, 9, 5, 379. |
| 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) | 28418 | (2R)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 28419 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-2-azetidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 28421 | (4R)-1-[tert-butyl(dimethyl)silyl]-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C12H23N5OSSi | 详情 | 详情 | |
| (V) | 28422 | (4R)-4-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-2-azetidinone | C6H9N5OS | 详情 | 详情 | |
| (VI) | 22580 | 1-(chloromethyl)-4-nitrobenzene | 100-14-1 | C7H6ClNO2 | 详情 | 详情 |
| (VII) | 28426 | N-methyl(4-nitrophenyl)methanamine | C8H10N2O2 | 详情 | 详情 | |
| (VIII) | 28427 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-nitrobenzene | C9H9ClN2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IX)trans-4-Hydroxy-L-proline (I) was esterified with methanolic HCl, generated from acetyl chloride in MeOH, and the resulting 4-hydroxyproline methyl ester (II) was protected with allyl chloroformate to afford the allyl carbamate (III). Mesylation of the hydroxyl group of (III) with methanesulfonyl chloride, followed by reduction of the methyl ester with LiBH4, provided the alcohol (V). The mesylate group of (V) was then displaced by potassium thioacetate yielding thioacetate ester (VI). Iodo compound (VII) was obtained by mesylation of alcohol (VI) followed by substitution with NaI in acetone. 1-Methyl-5-mercaptotetrazole (IX), prepared by reaction of methyl isothiocyanate (VIII) with NaN3, was then condensed with iodide (VII) to give adduct (X). After deacetylation of thioacetate (X) with methanolic NaOH, the resulting pyrrolidinethiol (XI) was coupled with enol phosphate (XII) to give the protected carbapenem (XIII). The allyl ester and carbamate protecting groups of (XIII) were finally removed by treatment with Bu3SnH in the presence of palladium catalyst.
| 【1】 Kim, D.J.; Koo, K.D.; Shin, K.J.; Kim, C.; Park, S.W.; Yoo, K.H.; Synthesis and biological properties of new 1beta-methylcarbapenems having tetrazolothioether moiety. Bioorg Med Chem Lett 2000, 10, 13, 1421. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (V) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VI) | 42203 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C11H17NO4S | 详情 | 详情 | |
| (VII) | 42204 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(iodomethyl)-1-pyrrolidinecarboxylate | C11H16INO3S | 详情 | 详情 | |
| (VIII) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (IX) | 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 |
| (X) | 42205 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-1-pyrrolidinecarboxylate | C13H19N5O3S2 | 详情 | 详情 | |
| (XI) | 42206 | allyl (2S,4S)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C11H17N5O2S2 | 详情 | 详情 | |
| (XII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XIII) | 42207 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H32N6O6S2 | 详情 | 详情 |