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【结 构 式】 
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【分子编号】29482 【品名】N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate 【CA登记号】152120-54-2 |
【 分 子 式 】C14H22N4O4 【 分 子 量 】310.35324 【元素组成】C 54.18% H 7.14% N 18.05% O 20.62% |
合成路线1
该中间体在本合成路线中的序号：(V)The condensation of 1-(benzyloxycarbonyl)piperidin-4-one with N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl ester (II) by means of DBU in dichloromethane gives 2-[1-(benzyloxycarbonyl)piperidin-4-ylidene]-N-(tert-butoxycarbonyl)glycine methyl ester (III), which is selectively deprotected and reduced by hydrogenation with H2 over Pd/C in methanol yielding N-(tert-butoxycarbonyl)-2-(4-piperidyl)glycine methyl ester (IV). The reaction of (IV) with N,N'-di(tert-butoxycarbonyl)pyrazole-1-carboxamidine (V) by means of DIEA in dichloromethane gives the protected piperidine-1-carboxamidine (VI), which is treated with LiOH in methanol/water to obtain (VII) with a free carboxy group. The reaction of (VII) with O,N-dimethylhydroxylamine affords the hydroxamic ester (VIII), which is condensed with thiazole (IX) by means of butyllithium in THF yielding the fully protected intermediate (X). The deprotection of (X) with HCl in dioxane gives (XI) with free amino and amidino groups. The conddensation of (XI) with chiral acid (XII) by means of BOP and DIEA in acetonitrile yields amide (XIII) as a diastereomeric mixture that is resolved by preparative reverse-phase HPLC.
| 【1】 Plummer, J.S.; Berryman, K.A.; Cai, C.; Cody, W.L.; DiMaio, J.; Doherty, A.M.; Edmunds, J.J.; He, J.X.; Holland, D.R.; Levesque, S.; Kent, D.R.; Narasimhan, L.S.; Rubin, J.R.; Rapundalo, S.T.; Siddiqui, M.A.; Susser, A.J.; St-Denis, Y.; Winocour, P.D.; Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications. Bioorg Med Chem Lett 1998, 8, 23, 3409. |
| 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) | 26947 | benzyl 4-oxo-1-piperidinecarboxylate; N-Benzyloxycarbonyl-4-piperidone | 19099-93-5 | C13H15NO3 | 详情 | 详情 |
| (II) | 34562 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(dimethoxyphosphoryl)acetate | C10H20NO7P | 详情 | 详情 | |
| (III) | 34563 | benzyl 4-[1-[(tert-butoxycarbonyl)amino]-2-methoxy-2-oxoethylidene]-1-piperidinecarboxylate | C21H28N2O6 | 详情 | 详情 | |
| (IV) | 34564 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(4-piperidinyl)acetate | C13H24N2O4 | 详情 | 详情 | |
| (V) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (VI) | 34565 | methyl 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetate | C24H42N4O8 | 详情 | 详情 | |
| (VII) | 34566 | 2-[(tert-butoxycarbonyl)amino]-2-(1-[[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]-4-piperidinyl)acetic acid | C23H40N4O8 | 详情 | 详情 | |
| (VIII) | 34567 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino](4-[1-[(tert-butoxycarbonyl)amino]-2-[methoxy(methyl)amino]-2-oxoethyl]-1-piperidinyl)methylidenecarbamate | C25H45N5O8 | 详情 | 详情 | |
| (IX) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
| (X) | 34568 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino][4-[1-[(tert-butoxycarbonyl)amino]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinyl]methylidenecarbamate | C26H41N5O7S | 详情 | 详情 | |
| (XI) | 34569 | 4-[1-amino-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-1-piperidinecarboximidamide | C11H17N5OS | 详情 | 详情 | |
| (XII) | 34570 | (6S,8aS)-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid | C17H20N2O4 | 详情 | 详情 | |
| (XIII) | 34571 | (6S,8aS)-N-[1-[1-[amino(imino)methyl]-4-piperidinyl]-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-4-oxo-2-(3-phenylpropanoyl)octahydropyrrolo[1,2-a]pyrazine-6-carboxamide | C28H35N7O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of m-xylene-alpha,alpha'-diamine (I) with N,N'-bis(tert-butoxycarbonyl)pyrazole-1-carboxamidine (II) in THF gives the protected guanidine (III), which is acylated at the free amino group with 2,3-diphenylpropionyl chloride (IV) and triethylamine in dichloromethane affording the amide (V). The condensation of (V) with tetrahydrofuran-2-ylmethylamine (VI) in refluxing THF affords the protected amidinourea (VII), which is finally treated with TFA in dichloromethane.
| 【1】 Biftu, T.; et al.; Synthesis and SAR of oxodiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 138. |
| 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) | 19167 | 3-(aminomethyl)benzylamine; [3-(aminomethyl)phenyl]methanamine | 1477-55-0 | C8H12N2 | 详情 | 详情 |
| (II) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (III) | 29483 | tert-butyl (Z)-[[3-(aminomethyl)benzyl]amino][(tert-butoxycarbonyl)amino]methylidenecarbamate | C19H30N4O4 | 详情 | 详情 | |
| (IV) | 29484 | 2,3-diphenylpropanoyl chloride | C15H13ClO | 详情 | 详情 | |
| (V) | 29485 | tert-butyl (Z)-[(tert-butoxycarbonyl)amino][(3-[[(2,3-diphenylpropanoyl)amino]methyl]benzyl)amino]methylidenecarbamate | C34H42N4O5 | 详情 | 详情 | |
| (VI) | 27335 | Tetrahydro-2-furanylmethanamine; Tetrahydrofurfurylamine | 4795-29-3 | C5H11NO | 详情 | 详情 |
| (VII) | 29486 | tert-butyl (Z)-[(3-[[(2,3-diphenylpropanoyl)amino]methyl]benzyl)amino]([[(tetrahydro-2-furanylmethyl)amino]carbonyl]amino)methylidenecarbamate | C35H43N5O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Condensation of amine (I) with N,N’-di-Boc-thiourea (II) using HgCl2 and Et3N in DMF (1) or with di-Boc-amidinopyrazole (III) in THF gives the protected guanidine derivative (IV), which by deacetylation with methanolic sodium methoxide followed by saponification of the deacylated methyl pyranosoate (V) leads to the carboxylic acid (VI). Alternatively, acid (VI) is prepared by direct hydrolysis of compound (IV) by means of aqueous NaOH or K2CO3 in H2O/MeOH. After conversion of acid (VI) to the corresponding benzhydryl ester (VII) by treatment with diphenyldiazomethane and BF3·Et2O, selective acylation of the primary hydroxyl group with octanoyl chloride (VIII) and Et3N in CH2Cl2 yields the 9-octanoate ester (IX) (1). Finally, compound (IX) is deprotected by removal of N-Boc and O-benzhydryl protecting groups by treatment with trifluoroacetic acid in CH2Cl2, followed by basification of the obtained TFA salt with NaHCO3 (2-8). Scheme 1.
Alternatively, reaction of the 4-amino-5,6-dihydropyran derivative (X) with di-Boc-amidinopyrazole (III) provides the corresponding 4-guanidinodihydropyran, which is hydrolyzed with K2CO3 in MeOH/H2O to give carboxylic acid (VI). In an alternative strategy, carboxylic acid (VI) is prepared by hydrolysis of the 4-amino-5,6-dihydropyrancarboxylate ester (X) with NaOH followed by reaction with the amidinopyrazole derivative (III). Deprotection of di-Boc intermediate (VI) by stirring at 80 °C in MeOH gives laninamivir (XI), which is finally selectively acylated with trimethyl orthooctanoate (XII) in the presence of methanolic HCl. Laninamivir (XI) can also be obtained by hydrolysis of intermediate (X) with NaOH followed by reaction of the resulting free amine (XIII) with pyrazole-1-carboxamidine HCl (XIV) or, alternatively, by treatment of 4-amino-5,6-dihydropyran (X) with pyrazole-1-carboxamidine HCl (XIV), and then hydrolysis of the methyl ester with K2CO3 in MeOH (3). Scheme 1.
| 【1】 Honda, T., Kobayashi, Y., Masuda, T., Yamashita, M., Arai, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. EP 0823428, JP 1998330373, JP 1999279059, JP 199927968. |
| 【2】 Murakami, M., Yamaoka, M., Honda, T., Watanabe, M. (Daiichi Sankyo Co., Ltd.). Hydrates and crystals of a neuraminic acid compound. EP 1277759, US 2003105158, US 6844363, WO 200108131. |
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 【4】 Honda, T., Kubo, S., Masuda, T., Arai, M., Kobayashi, Y., Yamashita, M. Synthesis and in vivo influenza-inhibitory effect of ester prodrug of 4-guanadino-7-O-methyl-Neu5Ac2en. Bioorg Med Chem Lett 2009, 19(11): 2938-40. |
| 【5】 Honda, T., Masuda, T. Synthesis of 4-guanidino-7-modified-neu5Ac2en derivatives and their biological activities as influenza sialidase inhibitors. J Synth Org Chem Jpn 2009, 67(11): 1105. |
| 【6】 Yamashita, M., Kawaoka, Y. (University of Tokyo; Daiichi Sankyo Co., Ltd.). Drug for treatment of influenza. EP 2123271, WO 2008108323. |
| 【7】 Honda, T., Arai, M., Yamashita, M., Masuda, T., Kobayashi, Y. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 6340702. |
| 【8】 Kobayashi, Y., Honda, T., Yamashita, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 2002137791, US 6451766. |
| 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) | 65992 | C17H26N2O9 | 详情 | 详情 | ||
| (II) | 21843 | tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate | 145013-05-4 | C11H20N2O4S | 详情 | 详情 |
| (III) | 29482 | N,N-bis-Boc-1-guanylpyrazole; tert-butyl (E)-[(tert-butoxycarbonyl)amino](1H-pyrazol-1-yl)methylidenecarbamate | 152120-54-2 | C14H22N4O4 | 详情 | 详情 |
| (IV) | 65993 | C27H44N4O13 | 详情 | 详情 | ||
| (V) | 65994 | C23H40N4O11 | 详情 | 详情 | ||
| (VI) | 65995 | C22H38N4O11 | 详情 | 详情 | ||
| (VII) | 65996 | C35H48N4O11 | 详情 | 详情 | ||
| (VIII) | 11123 | Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride | 111-64-8 | C8H15ClO | 详情 | 详情 |
| (IX) | 65997 | C43H62N4O12 | 详情 | 详情 | ||
| (X) | 65998 | C14H20N2O8 | 详情 | 详情 | ||
| (XI) | 65999 | Laninamivir; (4S,5R,6R)-5-Acetamido-4-guanidino-6-((1R,2R)-2,3-dihydroxy-1-methoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid | 203120-17-6 | C13H22N4O7 | 详情 | 详情 |
| (XII) | 66000 | trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane | 161838-87-5 | C11H24O3 | 详情 | 详情 |
| (XIII) | 66001 | (4S,5R,6R)-5-acetylamino-4-amino-6-[(1R,2R)-2,3-dihydroxy-1-methoxy-propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid | 475483-21-7 | C12H20N2O7 | 详情 | 详情 |
| (XIV) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |