　 -Drug Synthesis Database

【结构式】

【分子编号】66014

【品名】　

【CA登记号】　

【分子式】C₁₇H₂₄N₄O₉

【分子量】428.39912

【元素组成】C 47.66% H 5.65% N 13.08% O 33.61%

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：(XXVII)

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

合成路线2

该中间体在本合成路线中的序号：(XXVII)

The azido acetamide intermediate (XXVII) can be prepared by several alternative methods. Alkylation of the benzyl glycoside of N-acetyl-3,6-di-O-benzyl-α-D-glucosamine (XXVIII) with iodomethane and NaH in DMF followed by catalytic benzyl group hydrogenolysis of the resulting 4-methoxy derivative (XXIX) with H2 over Pd/C yields N-acetyl-4-O-methylglucosamine (XXX), which by subsequent incubation with N-acetylneuraminic acid aldolase (N-Ac-NAA) in the presence of sodium pyruvate (XXXI) and NaN3 at pH 10-11 gives the nonuropyranosoic acid derivative (XXXII). Acid (XXXII) is esterified with MeOH in the presence of acidic cation exchange resin (Dowex 50x8) to give methyl ester (XXXIII), which by acetylation with Ac2O in pyridine and successive treatments with HCl and DBU leads to the non-2-enopyranosonate (XXXIV). Finally, compound (XXXIV) is converted to the azido acetamide intermediate (XXVII) by treatment with boron trifluoride etherate and one equivalent of MeOH in CH2Cl2 followed by NaN3 and Dowex 50x8 resin (1, 7, 8). Scheme 4.
Alternatively, solvolysis of the cyclic carbonate (XX) with methanolic NaOMe yields diol (XXXV), which is then acetylated with AcOH by means of Et3N and DMAP in EtOAc to give diacetate (XXXVI). Ring opening of oxazoline (XXXVI) with Me3SiN3 in the presence of (i-PrO)4Ti in t-BuOH furnishes the 4-azido-5,6-dihydropyran derivative (XXVII) (3). Scheme 4.

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.
【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.
【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
(XX)	66007			C₁₄H₁₇NO₈	详情	详情
(XXVII)	66014			C₁₇H₂₄N₄O₉	详情	详情
(XXVIII)	66015	Benzyl 2-Acetamido-3,6-Di-O-Benzyl-2-Deoxy-alpha-D-Glucopyranoside; 2-Acetamido-1,3,6-Tri-O-Benzyl-2-Deoxy-A-D-Glucopyranoside	55287-49-5	C₂₉H₃₃NO₆	详情	详情
(XXIX)	66016			C₃₀H₃₅NO₆	详情	详情
(XXX)	66017	Methyl 2-Acetamido-2-deoxy-alpha-D-glucopyranoside	6082-04-8	C₉H₁₇NO₆	详情	详情
(XXXI)	66018	sodium 2-oxopropanoate; Sodium pyruvate; Sodium 2-ketopropionate; 2-Oxo-propanoic acid sodium salt	113-24-6	C₃H₃NaO₃	详情	详情
(XXXII)	66019			C₁₂H₂₁NO₉	详情	详情
(XXXIII)	66020			C₁₃H₂₃NO₉	详情	详情
(XXXIV)	66021			C₁₉H₂₇NO₁₁	详情	详情
(XXXV)	66022			C₁₃H₁₉NO₇	详情	详情
(XXXVI)	66023			C₁₇H₂₅NO₉	详情	详情

Extended Information