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【结 构 式】 
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【分子编号】66000 【品名】trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane 【CA登记号】161838-87-5 |
【 分 子 式 】C11H24O3 【 分 子 量 】204.30976 【元素组成】C 64.67% H 11.84% O 23.49% |
合成路线1
该中间体在本合成路线中的序号：(XII)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 |
合成路线2
该中间体在本合成路线中的序号：(XII)Intermediates (III) and (XII) are prepared as follows:
Trimethyl orthooctanoate (XII) is prepared by Pinner reaction of octanonitrile (XXXVII) with MeOH in the presence of HCl in MeOAc followed by treatment of the resulting methyl octanimidate hydrochloride (XXXVIII) with MeOH in methylcyclohexane (3). Scheme 5.
Intermediate (III) can be prepared by consecutive N-protection of the amidine nitrogens in pyrazole-1-carboxamidine (XIV), first by treatment with Boc2O by means of DIEA in DMF, and then reaction of the resulting monoprotected intermediate (XXXIX) with Boc2O in the presence of NaH in THF (3). Scheme 5.
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 详情 | 详情 |
| (XII) | 66000 | trimethyl orthooctanoate; 1,1,1-Trimethoxyoctane | 161838-87-5 | C11H24O3 | 详情 | 详情 |
| (XIV) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (XXXVII) | 59081 | octanenitrile | 124-12-9 | C8H15N | 详情 | 详情 |
| (XXXVIII) | 66024 | C9H19NO.HCl | 详情 | 详情 | ||
| (XXXIX) | 66025 | N-(tert-Butoxycarbonyl)-1H-pyrazole-1-carboxamidine; N-Boc-1H-pyrazole-1-carboxamidine | 152120-61-1 | C9H14N4O2 | 详情 | 详情 |