　 -Drug Synthesis Database

【结构式】

【分子编号】65992

【品名】　

【CA登记号】　

【分子式】C₁₇H₂₆N₂O₉

【分子量】402.40152

【元素组成】C 50.74% H 6.51% N 6.96% O 35.78%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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：(I)

The synthetic precursor (I) is obtained by ketalization of the α-methyl glycoside of N-acetylneuraminic acid methyl ester (XXII) with Me2C(OMe)2 in the presence of catalytic p-TsOH·H2O in acetone, followed by O-protection of the obtained 8,9-O-isopropylidene derivative (XXIII) with TBDMSCl by means of imidazole in DMF to yield the protected ether (XXIV) (3). Then, methylation of the remaining free C-7 alcohol group with Me2SO4 in the presence of NaH in DMF affords the corresponding methyl ether (XXV) (9). Treatment of either protected (XXV) (9) or unprotected (XXVI) acetamido triol (10) with Ac2O, AcOH and H2SO4 followed by ring opening of the resulting oxazoline with NaN3 in the presence of Dowex 50W provides azide (XXVII) (9, 10), which is then reduced to amine (I) by means of PPh3 (3) or H2 over Lindlar catalyst in EtOH (9, 10). Scheme 3.

参考文献中间体

合成目标

【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.
【9】 Anazawa, K., Furuhata, K., Ogura, H. Synthesis of 7-O-acetyl-n-acetylneuraminic acid derivative. Chem Pharm Bull 1988, 36(12): 4976.
【10】 Honda, T., Masuda, T., Yoshida, S., Arai, M., Kaneko, S., Yamashita, M. Synthesis and anti-influenza virus activity of 7-O-alkylated derivatives related to zanamivir. Bioorg Med Chem Lett 2002, 12(15): 1925-8.

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
(XXII)	66009	2-O-Methyl-beta-D-N-acetylneuraminic acid methyl ester	6730-43-4	C₁₃H₂₃NO₉	详情	详情
(XXIII)	66010			C₁₆H₂₇NO₉	详情	详情
(XXIV)	66011			C₂₂H₄₁NO₉Si	详情	详情
(XXV)	66012			C₂₃H₄₃NO₉Si	详情	详情
(XXVI)	66013			C₁₃H₂₃NO₉	详情	详情
(XXVII)	66014			C₁₇H₂₄N₄O₉	详情	详情

Extended Information