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【结 构 式】 
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【药物名称】PSI-7977 【化学名称】[P(S)]-2'-Deoxy-2'-fluoro-5'-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2'-methyluridine 【CA登记号】 【 分 子 式 】C22H29FN3O9P 【 分 子 量 】529.453 |
【开发单位】Gilead Sciences, Inc. (US) 【药理作用】Treatment of Hepatitis C Virus Infection;RNA-Directed RNA Polymerase (NS5B) Inhibitor |
合成路线1
Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 .
Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 .
Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 .
| 【1】 Sofia, M.J., Du, J., Wang, P., Nagarathnam, D. (Pharmasset, Inc.). Nucleoside phosphoramidate prodrugs. WO 2008121634. |
| 【2】 Sofia, M.J. Discovery and development of 2’-F-2’-C-methyl nucleosides and nucleotides for the treatment of HCV. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 259. |
| 【3】 Sofia, M.J, Bao, D., Chang, W. et al. Discovery of a β-D-2’-deoxy-2’-α-fluoro-2’-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010, 53(19): 7202-18. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 68217 | (R)-isopropyl 2-aminopropanoate hydrochloride;isopropyl L-alaninate hydrochloride | C6H13NO2.HCl | 详情 | 详情 | |
| (VIIb) | 68218 | (R)-isopropyl 2-aminopropanoate 4-methylbenzenesulfonate | C6H13NO2.C7H8O3S | 详情 | 详情 | |
| (I) | 65914 | 2'-Deoxy-2'-fluoro-2'-C-methylcytidine | 817204-33-4 | C10H14FN3O4 | 详情 | 详情 |
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (III) | 68214 | ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dioxo-3,4 -dihydropyrimidin-1(2H)-yl)-4-fluoro-4- methyltetrahydrofuran-2-yl)methyl benzoate | C24H21FN2O7 | 详情 | 详情 | |
| (IV) | 68213 | 1-((2R,3R,4S,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione | C10H13FN2O5 | 详情 | 详情 | |
| (V) | 68215 | isopropyl N-[chloro(phenoxy)phosphoryl]- Lalaninate;(2R)-isopropyl 2-((chloro(phenoxy) phosphoryl)amino)propanoate | C12H17ClNO4P | 详情 | 详情 | |
| (VI) | 68216 | 2’-deoxy-2’-fluoro-5’-O-[(O- isopropyl-L-alanino)(phenoxy)phosphoryl]-2’- methyluridine | C22H29FN3O9P | 详情 | 详情 | |
| (VIII) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
| (IX) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (X) | 42493 | Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide | 10025-87-3 | Cl3OP | 详情 | 详情 |
合成路线2
Grignard condensation of carbohydrate (VII) with MeLi in ethyl ether gives the methylated carbohydrate (VIII), which by treatment with DAST in CH2Cl2 yields the α-fluoroglycoside (IX). The debenzylation of glycoside (III) by means of Pd/C and cyclohexene, followed by reprotection of the hydroxy groups with benzoyl chloride and pyridine, yields the dibenzoate (X), which is condensed with bis(trimethylsilyl)-N-benzoyl cytosine (XI) by means of trimethylsilyl triflate in dichloroethane/toluene to provide the tribenzoylated fluorocytidine (II) .
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. et al. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 45(17): 5504-8. |
| 【1】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues, WO 2005003147. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (VII) | 65915 | (4S,5S)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxydihydrofuran-3(2H)-one | C20H22O5 | 详情 | 详情 | |
| (VIII) | 65916 | (3S,4S,5S)-4-(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyltetrahydrofuran-3-ol | C21H26O5 | 详情 | 详情 | |
| (IX) | 65917 | (3S,4S,5S)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-fluoro-2-methoxy-3-methyltetrahydrofuran | C21H25FO4 | 详情 | 详情 | |
| (X) | 65911 | ((2S,3S,4S)-3-(benzoyloxy)-4-fluoro-5-methoxy-4-methyltetrahydrofuran-2-yl)methyl benzoate | C21H21FO6 | 详情 | 详情 | |
| (XI) | 68219 | N-(2-oxo-1-(trimethylsilyl)-1,2-dihydropyrimidin-4-yl)-N-(trimethylsilyl)benzamide | C17H25N3O2Si2 | 详情 | 详情 |
合成路线3
Reaction of cytidine (XII) with benzoyl anhydride in DMF gives Nbenzoylcytidine (XIII), which is selectively protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) in pyridine to yield the silylated cytidine (XIV). Oxidation of the remaining OH group of (XIV) by means of DMSO, TFAA and TEA produces the ketone (XV), which by a Grignard condensation with MeLi, followed by a desilylation with AcOH provides the tertiary alcohol (XVI). Selective benzoylation of the primary and secondary OH groups of compound (XVI) with benzoyl chloride and pyridine results in tribenzoate (XVII) with a remaining free tertiary OH group. Finally, benzoate (XVII) is fluorinated with DAST to yield the tribenzoylated fluorocytidine (II) .
| 【1】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues, WO 2005003147. |
| 【2】 Clark, J.L., Hollecker, L., Mason, J.C. et al. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 45(17): 5504-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 65909 | N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine | C31H27N3O8 | 详情 | 详情 | |
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (XII) | 27920 | Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone | 65-46-3 | C9H13N3O5 | 详情 | 详情 |
| (XIII) | 61580 | N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide | 13089-48-0 | C16H17N3O6 | 详情 | 详情 |
| (XIV) | 65906 | N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide | 69304-43-4 | C28H43N3O7Si2 | 详情 | 详情 |
| (XV) | 65907 | N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine | 119411-03-9 | C28H41N3O7Si2 | 详情 | 详情 |
| (XVI) | 65908 | N-Benzoyl-2'-C-methyl-D-cytidine | C17H19N3O6 | 详情 | 详情 |
合成路线4
Oxidation of unsaturated ester (XVIII) with sodium permanganate and NaHCO3 produces dihydroxy ester (XIX), which is converted to the cyclic sulfite (XX) by treatment with SOCl2 in the presence of Et3N. After oxidation of sulfite (XX) to the corresponding sulfate (XXI) by means of NaOCl, addition of triethylamine trihydrofluoride in triethylamine solution at 85 °C leads the fluorolactone (XXIII) via intermediate (XXII). Subsequent acylation of diol (XXIII) with benzoyl chloride and DMAP, followed by reduction of the resulting dibenzoyloxy lactone (XXIV) with Red-Al in CH2Cl2/toluene/trifluoroethanol produces lactol (XXV), which is converted to the furanosyl chloride (XXVI) by addition of sulfuryl chloride and catalytic TBAB. Finally, silylation of N-benzoylcytosine (XXVII) by heating with hexamethyldisilazane and ammonium sulfate, followed by coupling with the glycosyl chloride (XXVII) by means of SnCl4, yields the tribenzoyl fluorocytidine derivative (II) .
| 【1】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc., F. Hoffmann-La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines, WO 2008045419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65910 | (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate | 817204-32-3 | C31H26FN3O7 | 详情 | 详情 |
| (XVIII) | 65919 | (2E)-3-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-methyl-2-propenoic acid ethyl ester | C11H18O4 | 详情 | 详情 | |
| (XIX) | 65920 | (2S,3R)-3-((4R)-2,2-Dimethyldioxolan-4-yl)-2-methyl-2,3-dihydroxypropanoic acid ethyl ester | 93635-76-8 | C11H20O6 | 详情 | 详情 |
| (XX) | 65921 | (4S,5S)-ethyl 5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide | C11H18O7S | 详情 | 详情 | |
| (XXI) | 65922 | (4S,5S)-ethyl 5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide | C11H18O8S | 详情 | 详情 | |
| (XXII) | 65923 | triethylammonium (1R,2S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-ethoxy-2-fluoro-2-methyl-3-oxopropyl sulfate | C17H34FNO8S | 详情 | 详情 | |
| (XXIII) | 65926 | (3R,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-one; (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythro-pentonic acid gamma-lactone | 879551-04-9 | C6H9FO4 | 详情 | 详情 |
| (XXIV) | 65927 | (2R)-2-Deoxy-2-fluoro-2-methyl-D-erythropentonic acid gamma-lactone 3,5-dibenzoate | 874638-80-9 | C20H17FO6 | 详情 | 详情 |
| (XXV) | 65928 | C20H19FO6 | 详情 | 详情 | ||
| (XXVI) | 65913 | C20H17ClFO5 | 详情 | 详情 | ||
| (XXVII) | 12715 | N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine | 26661-13-2 | C11H9N3O2 | 详情 | 详情 |