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【结 构 式】 
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【分子编号】14092 【品名】1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole 【CA登记号】4418-61-5 |
【 分 子 式 】CH3N5 【 分 子 量 】85.06852 【元素组成】C 14.12% H 3.55% N 82.33% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of 6-methylpyridine-2-carboxylic acid (I) with refluxing SOCl2 gives 6-methylpyridine-2-carbonyl chloride (II), which is condensed with 5-aminotetrazole (III) by means of triethylamine in hot DMF.
| 【1】 Takeda, M.; Honma, Y.; Tsuzurahara, K.; 2-Pyridinecarboxamide derivatives compositions containing same and method of using same. EP 0053789; ES 8303398; JP 1482289C; JP 57095984; US 4404214 . |
| 【2】 Takeda, M.; Sekine, Y.; Ono, Y.; Hashiyama, T.; Honma, Y.; Tsuzurahara, K.; Hanamoto, K.; Antiallergic agents. 3. N-(1H-Tetrazol-5-yl)-2-pyridinecarboxamides. J Med Chem 1984, 27, 2, 125-128. |
| 【3】 Serradell, M.N.; Castaner, J.; TA-5707. Drugs Fut 1984, 9, 7, 527. |
| 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) | 30380 | 6-methyl-2-pyridinecarboxylic acid | 934-60-1 | C7H7NO2 | 详情 | 详情 |
| (II) | 34352 | 6-methyl-2-pyridinecarbonyl chloride | C7H6ClNO | 详情 | 详情 | |
| (III) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 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 alkylation of 3-hydroxy-5-methoxy-1-phenylindole-2-carboxylic acid methyl ester (I) with isopropyl bromide (II) and KOH gives the corresponding 2-isopropoxy compound (III), which is hydrolyzed with KOH and HOAc, yielding the carboxylic acid (IV). The condensation of (IV) with 1H-tetrazol-5-amine (V) by means of CDI affords the expected amide (VI), which is finally treated with L-arginine to furnish the target arginine salt.
| 【1】 Unangst, P.C.; Carethers, M.E.; Indole esters as heterocyclic synthons. III. Preparation and reactions of furo[3,2-b]indoles. J Heterocycl Chem 1984, 21, 709-714. |
| 【2】 Kunz, K.; Friendlander, P.; Concerning N,N'-diphenyl-indigo. Chem Ber 1922, 55, 1597-1607. |
| 【3】 Unangst, P.C.; Conroy, M.C.; CI-949 AND RELATED INDOLECARBOXAMIDOTETRAZOLES: A NEW CLASS OF POTENTIAL ANTIALLERGY AGENTS. Drugs Fut 1990, 15, 10, 1005. |
| 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) | 42913 | methyl 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylate | C17H15NO4 | 详情 | 详情 | |
| (II) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (III) | 42914 | methyl 3-isopropoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylate | C20H21NO4 | 详情 | 详情 | |
| (IV) | 42915 | 3-isopropoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid | C19H19NO4 | 详情 | 详情 | |
| (V) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (VI) | 42916 | 3-isopropoxy-5-methoxy-1-phenyl-N-(1H-1,2,3,4-tetraazol-5-yl)-1H-indole-2-carboxamide | C20H20N6O3 | 详情 | 详情 | |
| (VII) | 42917 | L-2-Amino-5-guanidinopentanoic acid; (S)-(+)-Arginine; L-Arginine | 74-79-3 | C6H14N4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Reaction of 2-phenoxymethylpyridine (I) with diethyl ethoxymethylenemalonate (II) and n-butyllithium in THF gives ethyl 3-ethoxy-2-(ethoxycarbonyl)-4-phenoxy-4-(2-pyridyl)butyrate (III), which is cyclized to ethyl 4-oxo-1-phenoxy-4H-quinolizine-3-carboxylate (IV) by heating at 250 C in a mixture of diphenyl and diphenyl ether. Ester hydrolysis of (IV) with sodium hydroxide in methanol yields 4-oxo-1-phenoxy-4H-quinolizine-3-carboxylic acid (V), which is converted to 4-oxo-1-phenoxy-N-(1H-tetrazol-5-yl)-4H-quinolizine-3-carboxamide (VII) on treatment with carbonyldiimidazole and 5-amino-1H-tetrazole (VI) in DMF. Finally, the sodium salt of (VII) is formed by means of sodium hydroxide.
| 【1】 Kitaura, Y.; Oku, T.; Hirai, H.; Yamamoto, T.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Quinolizinone cpd., processes for preparation thereof and pharmaceutical compsns. comprising the same. AU 8547341; EP 0157346; ES 8609321; JP 1985222482; JP 1987077385; JP 1988284174; JP 1989193268; JP 1990015029; US 4650804; US 4698349 . |
| 【2】 Kitamura, S.; Okamoto, Y.; Tada, T.; Momonaga, M. (Fujisawa Pharmaceutical Co., Ltd.); Crystalline monohydrate of sodium N-(1H-tetrazol-5-yl)-1-phenoxy-4H-quinolizin-4-one-3-carboxamide. EP 0301465; JP 1989104073 . |
| 【3】 Castaner, J.; Prous, J.; Mealy, N.; Quinotolast Sodium. Drugs Fut 1994, 19, 2, 118. |
| 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) | 14087 | Phenyl 2-pyridinylmethyl ether; 2-(Phenoxymethyl)pyridine | C12H11NO | 详情 | 详情 | |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 14089 | diethyl 2-[1-ethoxy-2-phenoxy-2-(2-pyridinyl)ethyl]malonate | C22H27NO6 | 详情 | 详情 | |
| (IV) | 14090 | ethyl 4-oxo-1-phenoxy-4H-quinolizine-3-carboxylate | C18H15NO4 | 详情 | 详情 | |
| (V) | 14091 | 4-Oxo-1-phenoxy-4H-quinolizine-3-carboxylic acid | C16H11NO4 | 详情 | 详情 | |
| (VI) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (VII) | 14093 | 4-Oxo-1-phenoxy-N-(1H-1,2,3,4-tetraazol-5-yl)-4H-quinolizine-3-carboxamide | C17H12N6O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of N6-(benzyloxycarbonyl)-N2--(tert-butoxycarbonyl)-L-lysine (I) with 1H-tetrazol-5-amine (II) by means of BOP and DIEA or NMM in DMF gives the corresponding amide (III), which is hydrogenolyzed with H2 over Pd/C in etyhanol/HOAc to yield N2-(tert-butoxycarbonyl)-N1-(1H-tetrazol-5-yl)-L-lysine (IV). The reaction of (IV) with methyl acetimidate (V) by means of TEA in DMF (or ethyl acetimidate (VI) and NaOH in ethanol) affords the iminomethyl derivative (VII), which is finally deprotected with HCl in dioxane.
| 【1】 Hallinan, E.A.; Tsymbalov, S.; Dorn, C.R.; Pitzele, B.S.; Hansen, D.W. Jr.; Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J Med Chem 2002, 45, 8, 1686. |
| 【2】 Hallinan, E.A.; Hansen, D.W. Jr.; Tsymbalov, S. (Pharmacia Corp.); Aminotetrazole derivs. useful as nitric oxide synthase inhibitors. EP 0790987; EP 1113011; JP 1998508847; US 5684008; WO 9615120 . |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (III) | 54697 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1H-1,2,3,4-tetraazol-5-ylamino)hexylcarbamate | C20H29N7O5 | 详情 | 详情 | |
| (IV) | 54698 | tert-butyl (1S)-5-amino-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C12H23N7O3 | 详情 | 详情 | |
| (V) | 54699 | Methyl ethanimidoate; Methyl acetimidate | C3H7NO | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 54700 | tert-butyl (1S)-5-(ethanimidoylamino)-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C14H26N8O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The N-tetrazolyl lysinamide derivative (III) was obtained by acylation of 5-aminotetrazole (II) with Boc-L-lysine(Cbz) (I) using BOP as the coupling reagent. The N-benzyloxycarbonyl protecting group of (III) was then removed by hydrogenation over Pd/C to afford amine (IV), which was subsequently condensed with methyl acetimidate (V) producing amidine (VI). The target compound was finally obtained by N-Boc group cleavage in (VI) under acidic conditions
| 【1】 Hallinan, E.A.; Tsymbalov, S.; Dorn, C.R.; Pitzele, B.S.; Hansen, D.W. Jr.; Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor. J Med Chem 2002, 45, 8, 1686. |
| 【2】 Hallinan, E.A.; Hansen, D.W. Jr.; Tsymbalov, S. (Pharmacia Corp.); Aminotetrazole derivs. useful as nitric oxide synthase inhibitors. EP 0790987; EP 1113011; JP 1998508847; US 5684008; WO 9615120 . |
| 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) | 23159 | (2S)-6-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C19H28N2O6 | 详情 | 详情 | |
| (II) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (III) | 54697 | benzyl (5S)-5-[(tert-butoxycarbonyl)amino]-6-oxo-6-(1H-1,2,3,4-tetraazol-5-ylamino)hexylcarbamate | C20H29N7O5 | 详情 | 详情 | |
| (IV) | 54698 | tert-butyl (1S)-5-amino-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C12H23N7O3 | 详情 | 详情 | |
| (V) | 54699 | Methyl ethanimidoate; Methyl acetimidate | C3H7NO | 详情 | 详情 | |
| (VI) | 54700 | tert-butyl (1S)-5-(ethanimidoylamino)-1-[(1H-1,2,3,4-tetraazol-5-ylamino)carbonyl]pentylcarbamate | C14H26N8O3 | 详情 | 详情 |