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【结 构 式】 
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【分子编号】10184 【品名】1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol 【CA登记号】2592-95-2 |
【 分 子 式 】C6H5N3O 【 分 子 量 】135.12532 【元素组成】C 53.33% H 3.73% N 31.1% O 11.84% |
合成路线1
该中间体在本合成路线中的序号：(V)The synthesis of [14C]-labeled cefepime has been reported: The cyclization of [14C]-thiourea (I) with 4-bromo-2-(methoxyimino)-3-oxobutyric acid ethyl ester (II) in ethanol gives 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid ethyl ester (III), which is hydrolyzed with NaOH in methanol to the corresponding free acid (IV). The esterification of (IV) with 1-hydroxybenzotriazole (V) by means of dicyclohexylcarbodiimide in THF affords the corresponding active ester (VI), which is condensed with 7-amino-3-(1-methylpyrrolidiniomethyl)-3-cephem-4-carboxylate (VII) by means of NaOH in THF-water and isolated as the sulfate salt (VIII). Finally, this compound is treated with triethylamine in N-methyl-2-pyrrolidone.
| 【1】 Swigor, J.E.; Standridge, R.T.; Synthesis of 7-[alpha-(2-amino-[2-14C]thiazol-4-yl)-alpha-(Z)-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate hydrochloride ([14C]cefepime hydrochloride). J Label Compd Radiopharm 1993, 33, 8, 759. |
| 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) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (I) | 44602 | thiourea | CH4N2S | 详情 | 详情 | |
| (II) | 10181 | ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate | 60845-87-6 | C7H10BrNO4 | 详情 | 详情 |
| (III) | 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 |
| (III) | 44603 | ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate | C8H11N3O3S | 详情 | 详情 | |
| (IV) | 10183 | (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetic acid；2-(2-Amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid | 66338-96-3 | C5H5N3O3S | 详情 | 详情 |
| (IV) | 44604 | 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid | C5H5N3O3S | 详情 | 详情 | |
| (V) | 10184 | 1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol | 2592-95-2 | C6H5N3O | 详情 | 详情 |
| (VI) | 10185 | 1-(2-Amino-1,3-thiazol-4-yl)-2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime | C11H8N6O3S | 详情 | 详情 | |
| (VI) | 44605 | 1-(2-amino-1,3-thiazol-4-yl)-2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime | C11H8N6O3S | 详情 | 详情 | |
| (VII) | 10186 | (6R,7R)-7-amino-3-[(1-methyltetrahydro-1H-pyrrolium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H19N3O3S | 详情 | 详情 | |
| (VIII) | 10187 | 1-[((6R,7R)-7-[[2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methyltetrahydro-1H-pyrrolium | C19H25N6O5S2 | 详情 | 详情 | |
| (VIII) | 44606 | 1-[((6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium | C19H25N6O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIb)Treatment of 6-methoxy-1,4-dimethylcarbazole (I) with pivaloyl chloride and NaI in refluxing acetonitrile cleaved the methyl ether and afforded pivalate (II). The condensation of this with the Vilsmeier reagent from N-methylformanilide and phosphoryl chloride gave the formyl compound (III). Condensation of (III) with aminoacetaldehyde diethyl acetal in the presence of a catalytic amount of p-toluenesulfonic acid in refluxing toluene with azeotropic distillation of water, followed by hydrogenation of the intermediate imine in the presence of PtO2, afforded the corresponding amine, which was subsequently converted to the N-tosyl derivative (IV) on treatment with tosyl chloride and triethylamine. Refluxing (IV) with hydrogen chloride in aqueous dioxane effected cyclization, with simultaneous elimination of the tosyl and pivaloyl groups yielding the 9-hydroxyellipticine (V) (1). Glutaric acid monobenzyl ester (VIa) was converted to the active ester (VII) on treatment with 1-hydroxybenzotriazole (VIb) and dicyclohexyl carbodiimide, and this was condensed with (V) to afford diester (VIII). Finally, the benzyl ester was deprotected by hydrogenolysis in the presence of palladium-carbon and hydrogen.
| 【1】 Harada, N.; et al.; Synthesis and antitumor activity of 9-acyloxyellipticines. Chem Pharm Bull 1997, 45, 7, 1156. |
| 【2】 Tsujihara, K.; Harada, N.; Ozaki, K.; Ohashi, M.; Oda, K. (Tanabe Seiyaku Co., Ltd.); Ellipticine derivs. with antitumor activity. EP 0608876; JP 1994279441; US 5605904 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIb) | 10184 | 1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol | 2592-95-2 | C6H5N3O | 详情 | 详情 |
| (VIa) | 19943 | 5-(benzyloxy)-5-oxopentanoic acid | C12H14O4 | 详情 | 详情 | |
| (I) | 19938 | 5,8-dimethyl-9H-carbazol-3-yl methyl ether; 6-methoxy-1,4-dimethyl-9H-carbazole | C15H15NO | 详情 | 详情 | |
| (II) | 19939 | 5,8-dimethyl-9H-carbazol-3-yl pivalate | C19H21NO2 | 详情 | 详情 | |
| (III) | 19940 | 6-formyl-5,8-dimethyl-9H-carbazol-3-yl pivalate | C20H21NO3 | 详情 | 详情 | |
| (IV) | 19941 | 6-([(2,2-diethoxyethyl)[(4-methylphenyl)sulfonyl]amino]methyl)-5,8-dimethyl-9H-carbazol-3-yl pivalate | C33H42N2O6S | 详情 | 详情 | |
| (V) | 19942 | 5,11-dimethyl-6H-pyrido[4,3-b]carbazol-9-ol hydrochloride | C17H15ClN2O | 详情 | 详情 | |
| (VII) | 19944 | benzyl 5-(1H-1,2,3-benzotriazol-1-yloxy)-5-oxopentanoate | C18H17N3O4 | 详情 | 详情 | |
| (VIII) | 19945 | 1-benzyl 5-(5,11-dimethyl-6H-pyrido[4,3-b]carbazol-9-yl) pentanedioate | C29H26N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The synthesis of FK-463 can be performed as follows: The enzymatic deacylation of FR-901379 with Streptomyces anulatas No. 4811, S. anulatas No. 8703, Streptomyces strain No. 6907 or A. utahensis IFO13244 gives the deacylated lipopeptide FR-179642 (1), which is then reacylated with 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole 3-oxide (VI) by means of dimethylaminopyridine (DMAP) in DMF. The acylating compound (VI) can be obtained as follows: The cyclization of 4-pentyloxyphenylacetylene (I) with 4-(hydroxyiminomethyl)benzoic acid methyl ester (II) by means of triethylamine in hot THF gives 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in hot THF/water yielding the corresponding free acid (IV). Finally, this compound is condensed with 1-hydroxybenzotriazole (V) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDMCA) in dichloromethane.
| 【1】 Ueda, S.; Ezaki, M.; Tanaka, M.; et al.; Studies on a novel lipopeptide acylase from Streptomyces spp. for production of FR179642, a key intermediate of antifungal lipopeptide drug FK463. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-145. |
| 【2】 Fromtling, R.A.; Castañer, J.; FK-463. Drugs Fut 1998, 23, 12, 1273. |
| 【3】 Ohki, H.; Tomishima, M.; Yamada, A.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Cyclic hexapeptides having antibiotic activity. EP 0788511; JP 1998324695; JP 1998507174; US 6107458; WO 9611210 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (F- 901379) | 19224 | sodium (2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-[4-hydroxy-3-(sulfonatooxy)phenyl]ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxo-9-(palmitoylamino)tetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosine | C51H81N8NaO21S | 详情 | 详情 | |
| (FR-179642) | 19225 | (2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-Amino-20-(3-amino-1(R)-hydroxy-3-oxopropyl)-23-[1(S),2(S)-dihdyroxy-2-[4-hydroxy-3-(sulfooxy)phenyl]ethyl]-2,11,12,15-tetrahydroxy-6-(1(R)-hydroxyethyl)-16-methylperhydrodipyrrolo[2,1-c:2,1-f][1,4,7,10,13,16]hexaazacyclohenicosine-5,8,14,19,22,25-hexaone | C35H51N8NaO20S | 详情 | 详情 | |
| (I) | 19218 | 4-ethynylphenyl pentyl ether; 1-ethynyl-4-(pentyloxy)benzene | C13H16O | 详情 | 详情 | |
| (II) | 19219 | methyl 4-[(hydroxyimino)methyl]benzoate | C9H9NO3 | 详情 | 详情 | |
| (III) | 19220 | methyl 4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoate | C22H23NO4 | 详情 | 详情 | |
| (IV) | 19221 | 4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoic acid | C21H21NO4 | 详情 | 详情 | |
| (V) | 10184 | 1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol | 2592-95-2 | C6H5N3O | 详情 | 详情 |
| (VI) | 19223 | 3-(4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl)-3H-1,2,3-benzotriazol-1-ium-1-olate | C27H24N4O4 | 详情 | 详情 |