|
【结 构 式】 
|
【药物名称】Laninamivir octanoate；CS-8958；R-118958 【化学名称】5-(Acetamido)-4-(guanidino)-2,6-anhydro-3,4,5-trideoxy-7-O-methyl-9-O-octanoyl-D-glycero-D-galacto-non-2-enonic acid 【CA登记号】203120-46-1；203120-47-2 (monotrifluoroacetate) 【 分 子 式 】C21H36N4O8 【 分 子 量 】472.5325 |
【开发单位】Daiichi Sankyo Co., Ltd. (JP). 【药理作用】Neuraminidase Inhibitor；Treatment of Influenza |
合成路线1
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
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.
| 【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3
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.
| 【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 |
合成路线4
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 |
合成路线5
The synthetic precursor (X) is prepared by esterification of N-acetyl-2,3-didehydroneuraminic acid (XV) with MeOH in the presence of HC(OMe)3 and H2SO4 at 40 °C to yield the methyl ester (XVI), which by O-acylation with AcOH by means of H2SO4 in heptane at 40 °C followed by cyclization in the presence of NH3 and Et3N in toluene/H2O furnishes the pyrano[3,4-d]oxazole derivative (XVII). Hydrolysis of the triacetate (XVII) by means of NaOMe in MeOH gives the corresponding triol (XVIII), which is protected again at the vicinal 8,9-hydroxyl groups as the cyclic carbonate (XIX) by means of CO(OMe)2 in MeOH. Then, methylation of the free C-7 hydroxyl group with Me2SO4 in the presence of NaH in THF/DMA gives the corresponding methyl ether (XX), which is submitted to oxazoline ring opening with Me3SiN3 in the presence of (i-PrO)4Ti in t-BuOH to furnish the acetamido azide (XXI). Finally, azide (XXI) is reduced by means of PPh3 in THF or EtOAc (3). Scheme 2.
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 65998 | C14H20N2O8 | 详情 | 详情 | ||
| (XV) | 66002 | N-Acetyl-2,3-dehydro-2-deoxyneuraminic acid; 2-Deoxy-2,3-Didehydro-D-N--Acetylneuraminic Acid | 24967-27-9 | C11H17NO8 | 详情 | 详情 |
| (XVI) | 66003 | methyl (2R,3R,4S)-3-acetamido-4-hydroxy-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | 25875-99-4 | C12H19NO8 | 详情 | 详情 |
| (XVII) | 66004 | Methyl (3aR,4R,7aR)-2-methyl-4-[(1S,2R)-1,2,3-triacetoxypropyl]-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | 78850-37-0 | C18H23NO10 | 详情 | 详情 |
| (XVIII) | 66005 | methyl (3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxy-propyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | 1072449-83-2 | C12H17NO7 | 详情 | 详情 |
| (XIX) | 66006 | C13H15NO8 | 详情 | 详情 | ||
| (XX) | 66007 | C14H17NO8 | 详情 | 详情 | ||
| (XXI) | 66008 | C14H18N4O8 | 详情 | 详情 |