Zanamivir, GR-121167X(former code), GG-167, 4-Guanidino-Neu5Ac2en, Relenza, -Drug Synthesis Database

【结构式】

【药物名称】Zanamivir, GR-121167X(former code), GG-167, 4-Guanidino-Neu5Ac2en, Relenza

【化学名称】N-Acetyl-2,3-didehydro-4-deoxy-4-guanidinoneuraminic acid
　　　　　　5-Acetamido-2,3-didehydro-3,4,5-trideoxy-4-guanidino-alpha-D-glycero-D-galacto-2-nonulopyranosonic acid

【CA登记号】139110-80-8

【分子式】C₁₂H₂₀N₄O₇

【分子量】332.3158

【开发单位】Biota Scientific Management (Originator), GlaxoSmithKline (Licensee), Sankyo (Licensee)

【药理作用】ANTIINFECTIVE THERAPY, Anti-Influenza Virus Drugs, Antiviral Drugs, Neuraminidase (Sialidase) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

1) The esterification of N-acetylneuraminic acid (I) with methanol/HCl gives the corresponding methyl ester (II), which is acetylated with acetic anhydride, pyridine and dimethylaminopyridine (DMAP) yielding the pentaacetate (III). The reaction of (III) with trimethylsilyl trifluoromethanesulfonate in ethyl acetate affords the 2,3-didehydro derivative (IV), which is treated with trimethylsilyl azide in butanol to give the 4-azido derivative (V). The selective deacetylation of (V) with sodium methoxide in methanol yields N-acetyl-4-azido-2,4-dideoxy-2,3-didehydroneuraminic acid methyl ester (VI), which is reduced with H2 over Lindlar catalyst (Pd-Pb) in water and treated with Dowex 8x2 resin to afford the N-acetyl-4-amino-2,4-dideoxy-2,3-didehydroneuraminic acid (VII). The reaction of (VII) with BrCN and sodium acetate in methanol gives the corresponding 4-cyanoamino derivative (VIII), which is converted into the final product by reaction with ammonium formate in aqueous NH4OH. 2) The amino derivative (VII) can be converted directly into the final product by reaction with amidinosulfonic acid (X), NaOH and K2CO3 in water. 3) The amino derivative (VII) can also be converted directly into the final product by reaction with pyrazole-1-carboxamidine (XI) and triethylamine in water.

参考文献中间体

【1】 Chandler, M.; Bamford, M.J.; Conroy, R.; et al.; Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid. J Chem Soc - Perkins Trans I 1995, 9, 7, 1173-80.
【2】 von Itzstein, M.; Wu, W.-Y.; Jin, B.; The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-N-acetylneuraminic acid: A potent influenza virus sialidase inhibitor. Carbohydr Res 1994, 259, 2, 301-5.
【3】 Fromtling, R.; Castaner, J.; Zanamivir. Drugs Fut 1996, 21, 4, 375.
【4】 Weir, N.G.; Chandler, M.; Bamford, M.J. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407885 .
【5】 Patel, V. (Glaxo Wellcome plc); Synthesis of N-acetyl neuraminic acid derivs. WO 9407886 .
【6】 Chandler, M.; Weir, N. (Glaxo Wellcome plc); Preparation of N-acetyl neuraminic derivs. WO 9312105 .

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)	15975	(2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylic acid	131-48-6	C₁₁H₁₉NO₉	详情	详情
(II)	15976	methyl (2S,4S,5R,6R)-5-(acetamido)-2,4-dihydroxy-6-[(1R,2R)-1,2,3-trihydroxypropyl]tetrahydro-2H-pyran-2-carboxylate	50998-13-5	C₁₂H₂₁NO₉	详情	详情
(III)	15977	methyl (2R,4S,5S,6R)-5-(acetamido)-2,4-bis(acetoxy)-6-[(1S,2R)-1,2,3-tris(acetoxy)propyl]tetrahydro-2H-pyran-2-carboxylate		C₂₂H₃₁NO₁₄	详情	详情
(IV)	15978	methyl (3aS,4R,7aR)-2-methyl-4-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate		C₁₈H₂₃NO₁₀	详情	详情
(V)	15979	methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₁₈H₂₄N₄O₁₀	详情	详情
(VI)	15980	methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₁₂H₁₈N₄O₇	详情	详情
(VII)	15981	(2R,3R,4S)-3-(acetamido)-4-amino-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid		C₁₁H₁₈N₂O₇	详情	详情
(VIII)	15982	(2R,3R,4S)-3-(acetamido)-4-(cyanoamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid		C₁₂H₁₇N₃O₇	详情	详情
(IX)	15983	1H-pyrazole-1-carboximidamide	4023-00-1	C₄H₆N₄	详情	详情
(X)	15984	amino(imino)methanesulfonic acid		CH₄N₂O₃S	详情	详情

合成路线2

4) The selective deacetylation of 4-O,5-N,7-O,8-O,9-O-pentaacetyl-2,3-didehydro-2-deoxyneuraminic acid (XI) with boron trifluoride ethearate in benzene/methanol gives the 4-deacetyl derivative (XII), which is treated with trifluoromethanesulfonic anhydride in dichloromethane and with sodium azide in DMF to obtain the 4-azido-4-deoxy derivative (XIII). The reduction of (XIII) with H2S in pyridine affords the corresponding 4-amino derivative (XIV), which is finally condensed with S-methylisothiourea in water and saponified through Dowex 50W x 8 in aqueous NH4OH.

参考文献中间体

【1】 Von Itzstein, L.M.; Wu, W.-Y.; Phan, T.; Danylec, B.; Derivs. and analogues of 2-deoxy-2,3-didehydro-N-acetyl neuraminic acid and their use as antiviral agents. EP 0786458; WO 9116320 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	15985	methyl (2R,3S,4S)-3-(acetamido)-4-(acetoxy)-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₂₀H₂₇NO₁₂	详情	详情
(XII)	15986	methyl (2R,3R,4S)-3-(acetamido)-4-hydroxy-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₁₈H₂₅NO₁₁	详情	详情
(XIII)	15979	methyl (2R,3R,4S)-3-(acetamido)-4-azido-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₁₈H₂₄N₄O₁₀	详情	详情
(XIV)	15988	methyl (2R,3R,4S)-3-(acetamido)-4-amino-2-[(1S,2R)-1,2,3-tris(acetoxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylate		C₁₈H₂₆N₂O₁₀	详情	详情
(XV)	10272	[[Amino(imino)methyl]sulfanyl]methane	2986-19-8	C₂H₆N₂S	详情	详情

合成路线3

The synthesis of [11C]-labeled zanamivir useful in PET studies of drug deposition has been reported: The reaction of the known amino acid GR-121158X (I) with [11C]-cyanogen bromide in 0.1 M sodium borate gives the cyanoamino derivative (II), which is finally treated with a hot solution of NH4Cl and NH4OH in water.

参考文献中间体

【1】 Sutherland, D.R.; Westerberg, G.; Bamford, M.; Langstrom, B.; Daniel, M.J.; Synthesis of 5-acetylamino-4-[C-11]guanidino-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enoic acid ([C-11]GG167) - An influenza virus neuraminidase inhibitor. J Label Compd Radiopharm 1996, 38, 6, 585.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	15981	(2R,3R,4S)-3-(acetamido)-4-amino-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid	C₁₁H₁₈N₂O₇	详情	详情
(II)	15982	(2R,3R,4S)-3-(acetamido)-4-(cyanoamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid	C₁₂H₁₇N₃O₇	详情	详情
(II)	15991	(2R,3R,4S)-3-(acetamido)-4-(cyanoamino)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid	C₁₂H₁₇N₃O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)