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【结 构 式】 
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【分子编号】68213 【品名】1-((2R,3R,4S,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione 【CA登记号】 |
【 分 子 式 】C10H13FN2O5 【 分 子 量 】260.222 【元素组成】C 46.16% H 5.04% F 7.30% N 10.76% O 30.74% |
合成路线1
该中间体在本合成路线中的序号：(IV)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 |