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【结 构 式】

【药物名称】Dapagliflozin, BMS-512148

【化学名称】(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

【CA登记号】461432-26-8

【 分 子 式 】C21H25ClO6

【 分 子 量 】408.873

【开发单位】Bristol-Myers Squibb; codeveloped with AstraZeneca

【药理作用】SGLT2 Inhibitor, Antidiabetic Agent

合成路线1

Dapagliflozin can be synthesized as follows: 2-Chloro-5-bromobenzoic acid (I) is chlorinated with oxalyl chloride and catalytic DMF in CH2Cl2 to afford the benzoyl chloride derivative (II), which is subjected to Friedel-Crafts reaction with ethoxybenzene (III) in the presence of AlCl3 in CH2Cl2 to give the benzophenone derivative (IV). Subsequent decarbonylation of ketone (IV) employing triethylsilane and boron trifluoride etherate in acetonitrile yields 5-bromo-2-chloro-4’-ethoxydiphenylmethane (V). The lithiated derivative of bisarylmethane (V) (generated by treatment with BuLi in THF/toluene at –78 ºC) is coupled with the persilylated lactone (VII) (obtained from D-gluconolactone [VI] by treatment with trimethylsilyl chloride and NMM in THF) to yield the corresponding lactol adduct, which is deprotected in situ with methanesulfonic acid in MeOH to afford the desilylated ketal (VIII) (1-3). Polyol (VIII) is peracetylated with acetic anhydride and DIEA in THF resulting in the tetraacetate (IX). The glucosidic methoxy group of (IX) is then reductively removed using triethylsilane and boron trifluoride etherate in water/acetonitrile to give the glucoside (X) (1, 2), which is finally deacetylated by treatment with LiOH in aqueous MeOH (1-3).
Alternatively, intermediate (X) can be prepared by reduction of the glucosidic methoxy group of (VIII) with trethylsilane and boron trifluoride etherate in CH2Cl2/acetonitrite, and subsequent peracetylation with Ac2O, DMAP in CH2Cl2/pyridine (3).

1 Ellsworth, B., Meng, W., Sher, P.M., Washburn, W.N., Wu, G. (Bristol-Myers Squibb Co.). C-Aryl glucoside SGLT2 inhibitors and method. EP 1506211, JP 2005531588, US 2002137903, US 6515117, WO 2003099836.
2 Crispino, G., Denzel, T.W., Deshpande, P.P. et al. (Bristol-Myers Squibb Co.). Methods of producing C-aryl glucoside SGLT2 inhibitors. CA 2512389, EP 1581543, JP 2006516257, US 2004138439, WO 2004063209.
3 Meng, W., Ellsworth, B.A., Nirschl, A.A. et al. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 2008, 51(5): 1145-9.
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) 25545 5-bromo-2-chlorobenzoic acid 21739-92-4 C7H4BrClO2 详情 详情
(II) 65743 5-Bromo-2-chlorobenzoyl chloride 21900-52-7 C7H3BrCl2O 详情 详情
(III) 65744 Phenetole; Ethoxybenzene; Ethyl phenyl ether 103-73-1 C8H10O 详情 详情
(IV) 65745 (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone 461432-22-4 C15H12BrClO2 详情 详情
(V) 65746 4-(5-Bromo-2-chlorobenzyl)phenyl ethyl ether 461432-23-5 C15H14BrClO 详情 详情
(VI) 65747 D-Gluconolactone;GLUCONIC ACID DELTA-LACTONE;D-(+)-GLUCONO-1,5-LACTONE;DELTA-LACTONE;GLUCONIC ANHYDRIDE;GLUCONIC-D-LACTONE 4253-68-3 C6H10O6 详情 详情
(VII) 65748 2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone; D-2,3,4,6-Tetrakis-O-(trimethylsilyl)-gluconic acid delta-lactone; (3R,4S,5R,6R)-3,4,5-Tris[(trimethylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]tetrahydropyran-2-one 32384-65-9 C18H42O6Si4 详情 详情
(VIII) 65749 Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-alpha-D-glucopyranoside 714269-57-5 C22H27ClO7 详情 详情
(IX) 65750     C30H39ClO11 详情 详情
(X) 65751     C29H37ClO10 详情 详情
Extended Information