Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide -Drug Synthesis Database

【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 合成路线2

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 .

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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