【结 构 式】 |
【分子编号】39640 【品名】Phenyl dichlorophosphate;phenyl phosphorodichloridate 【CA登记号】770-12-7 |
【 分 子 式 】C6H5Cl2O2P 【 分 子 量 】210.983662 【元素组成】C 34.16% H 2.39% Cl 33.61% O 15.17% P 14.68% |
合成路线1
该中间体在本合成路线中的序号:(VIII)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)In the first reaction step phenyl phosphate dichloride (I) and 2-chloroethylamine hydrochloride are reacted in dichloromethane with triethylamine as base to give phenyl N,N'-di-(2-chloroethyl)phosphoric acid diamide (II). Hydrogenation of compound (II) with platinic oxide/hydrogen in methanol yields N,N'-di-(2-chloroethyl)phosphoric acid diamide (III), which directly crystallizes in the methanolic solution. 2,3,4,6-6-Tetra-O-benzyl-alpha-D-glucopyranose (IV) and trichloroacetonitrile react in ethyl acetate with sodium hydride as catalyst to yield O-(2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranosyl) trichloroacetimidate (V). A mixture of the imidate (V) and compound (III) in ethyl acetate is warmed up to 60 C. After filtration and concentration, 2,3,4,6-tetra-O-benzyl-beta-D-glucopyranosyl N,N'-di-(2-chloroethyl)phosphoric acid diamide (VI) crystallizes. Finally, compound (VI) is hydrogenated with palladium catalyst in acetone/water (80:20) to give beta-D-glucopyranosyl N,N'-di-(2-chloroethyl)phosphoric acid diamide. The solution is filtered and concentrated. The residual water is lyophilisated and the lyophilisate is crystallized in acetone/water.
【1】 Niemeyer, U.; Peter, G.; Schuessler, M.; Voss, A.; Schupke, H.; Klenner, T.; Wiessler, M.; Engel, J.; Glufosfamide. Drugs Fut 2000, 25, 8, 791. |
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) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
(II) | 39641 | Phenyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Phenoxy)Phosphoryl]Amine; Nsc318225 | 70772-68-8 | C10H15Cl2N2O2P | 详情 | 详情 |
(III) | 39642 | N,N'-bis(2-chloroethyl)phosphorodiamidic acid | C4H11Cl2N2O2P | 详情 | 详情 | |
(IV) | 30843 | (2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-ol | C34H36O6 | 详情 | 详情 | |
(V) | 39643 | (2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate | C36H36Cl3NO6 | 详情 | 详情 | |
(VI) | 39644 | C38H45Cl2N2O7P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(V)The reaction of 6-chloro-9-[2-(hydroxymethyl)cyclopropylidenemethyl]purine-2-amine (I) with methanol and K2CO3 gives of 9-[2-(hydroxymethyl)cyclopropylidenemethyl]-6-methoxypurine-2-amine (II) which is then condensed with the phosphorylated L-alanine ester (III) by means of N-methylimidazole (NMI) in pyridine/THF. The intermediate the phosphorylated L-alanine ester (III) has been obtained by condensation of L-alanine methyl ester (IV) with phenyl dichlorophosphate (V) by means of TEA in dichloromethane.
【1】 Kern, E.R.; Qiu, Y.-L.; Ptak, R.G.; Breitenbach, J.M.; Zemlicka, J.; Drach, J.C.; Cheng, Y.-C.; Lin, J.-S.; Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides. Antivir Res 1999, 43, 1, 37. |
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) | 41415 | [2-[(Z)-(2-amino-6-chloro-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H10ClN5O | 详情 | 详情 | |
(II) | 41416 | [2-[(Z)-(2-amino-6-methoxy-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C11H13N5O2 | 详情 | 详情 | |
(III) | 41417 | methyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate | C10H13ClNO4P | 详情 | 详情 | |
(IV) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
(V) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The condensation of phenyl dichlorophosphonate (I) with 2-chloroethylamine hydrochloride (II) in the presence of Et3N in cold CH2Cl2 provides phenyl N,N ’-bis(2-chloroethyl)phosphorodiamidate (III), which is finally converted to the corresponding phosphorodiamidic acid by catalytic hydrogenation over PtO2 in EtOH . In an alternative method, acylation of benzyl alcohol (IV) with POCl3 in the presence of Et3N in cold acetonitrile gives benzyl dichlorophosphonate (V), which is further condensed with 2-chloroethylamine hydrochloride (II) in the presence of Et3N to yield benzyl N,N’-bis(2-chloroethyl)phosphorodiamidate (VI). Finally, benzyl ester (VI) is then submitted to hydrogenolysis over Pd/C in acetonitrile .
【1】 Morgan, L. (Dekk-Tec, Inc.). Salts of isophosphoramide mustard and analogs thereof as anti-tumor agents. EP 1805192, JP 2008517929, US 2006089333, US 2008267945, WO 2006047575. |
【2】 Amedio, J.C., Wallner, B.P., Komarnitsky, P.B. (ZIOPHARM Oncology, Inc.). Salts of isophosphoramide mustard and analogs thereof. EP 2155682, JP 2010523571, US 2008255056, WO 2008124097. |
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) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
(II) | 21411 | 2-chloro-1-ethanamine hydrochloride | 870-24-6 | C2H7Cl2N | 详情 | 详情 |
(III) | 39641 | Phenyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Phenoxy)Phosphoryl]Amine; Nsc318225 | 70772-68-8 | C10H15Cl2N2O2P | 详情 | 详情 |
(IV) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
(V) | 66026 | Dichlorophosphoryloxymethylbenzene; Phosphorodichloridic acid, phenylmethyl ester | 52692-02-1 | C7H7Cl2O2P | 详情 | 详情 |
(VI) | 66027 | Benzyl N,N'-Bis(2-Chloroethyl)Phosphorodiamidate; 2-Chloroethyl-[(2-Chloroethylamino)-(Benzyloxy)Phosphoryl]Amine | C11H17Cl2N2O2P | 详情 | 详情 |