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【结 构 式】

【分子编号】42493

【品名】Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide

【CA登记号】10025-87-3

【 分 子 式 】Cl3OP

【 分 子 量 】153.331262

【元素组成】Cl 69.36% O 10.43% P 20.2%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(X)

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

该中间体在本合成路线中的序号:(I)

Perifosine was synthesized via a two-step process. In the first step, phosphorus oxytrichloride (I) was reacted with 4-hydroxy-1-methylpiperidine hydrochloride (II) in dichloromethane at room temperature using pyridine as auxiliary base. The resulting intermediate, without isolation, was reacted with octadecanol (III) to yield desmethyl perifosine (IV). Desmethyl perifosine was purified by recrystallization prior to methylation. The second step consisted of the methylation of desmethyl perifosine (IV), which was carried out with p-toluenesulfonic acid methyl ester in boiling ethanol using potassium carbonate as base. The crude perifosine solution that was obtained after filtration of the cooled reaction mixture was treated with ion exchange resin in order to remove remaining salts and ionic by-products. Pure perifosine was obtained after evaporation and crystallization.

1 Eibl, H.; Engel, J.; Synthesis of hexadecylphosphocholine (miltefosine). Alkylphophocholines: New drugs in cancer therapy. Prog Exp Tumor Res 1992, 34, 1-5.
2 Engel, J.; Hilgard, P.; Nossner, G.; Voss, V.; Traiser, M.; Klenner, T.; Kutscher, B.; Perifosine. Drugs Fut 2000, 25, 12, 1257.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 23403 Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate 80-48-8 C8H10O3S 详情 详情
(I) 42493 Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide 10025-87-3 Cl3OP 详情 详情
(II) 42494 4-hydroxy-1-methylpiperidinium chloride C6H14ClNO 详情 详情
(III) 21494 1-octadecanol 112-92-5 C18H38O 详情 详情
(IV) 42495 4-[[chloro(octadecyloxy)phosphoryl]oxy]-1-methylpiperidinium chloride C24H50Cl2NO3P 详情 详情
Extended Information