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【结 构 式】 
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【分子编号】65744 【品名】Phenetole; Ethoxybenzene; Ethyl phenyl ether 【CA登记号】103-73-1 |
【 分 子 式 】C8H10O 【 分 子 量 】122.1668 【元素组成】C 78.65% H 8.25% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |
合成路线2
该中间体在本合成路线中的序号：(III)Bromination of 4-methoxy-2-methylbenzoic acid (I) with Br2 in the presence of Fe in CHCl3 yields 5-bromo-4-methoxy-2-methylbenzoicacid (II), which by chlorination with (COCl)2 in the presence of DMF in CH2Cl2 and subsequent Friedel-Crafts reaction with phenetole (III) by means of AlCl3 in CHCl3 affords the benzophenone derivative (IV). Reduction of the aryl ketone (IV) with BF3·Et2O in the presence of Et3SiH in acetonitrile/CHCl3 generates 1-bromo-5-(4-ethoxybenzyl)-2-methoxy-4-methylbenzene (V). Subsequent reaction of the aryl bromide (V) with Mg in the presence of BrCH2CH2Br in refluxing THF gives the corresponding Grignard reagent, which is then condensed with the thiolactone (VI) in THF to produce the 1-aryl-thioglucose derivative (VII), which is further reduced to the thioglucitol (VIII) using Et3SiH in the presence of BF3·Et2O in acetonitrile. Finally, thioglucitol (VIII) is debenzylated with H2 over Pd(OH)2/C in EtOAc/EtOH .
5-Bromo-4-methoxy-2-methylbenzoic acid (II) can alternatively be prepared by methylation of 4’-hydroxy-2’-methylacetophenone (IX) with methyl iodide by means of K2CO3 in acetone to give the 4’-methoxyacetophenone derivative (X), which is then treated with NaBr and oxone in acetone/water, providing a 4:1 mixture of 5’-bromo-4’-methoxy-2’-methylacetophenone (XI) and the 3’-bromo regioisomer (XII). Then, the mixture is treated with NaOCl and KOH at reflux and finally acidified with HCl .
| 【1】 Kakinuma, H., Oi, T., Hashimoto-Tsuchiya, Y. et al. (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D- glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment. J Med Chem 2010, 53(8): 3247-61. |
| 【2】 Kakinuma, H., Hashimoto, Y., Oi, T., Hirano, H. (Taisho Pharmaceutical Co., Ltd.). 1-Thio-D-glucitol derivatives. EP 1845095, JP 2010059173, US 2008132563, US 7910619, US 2011098469, US 8017792, WO 2006073197. |
| 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) | 68552 | 4-methoxy-2-methylbenzoic acid | C9H10O3 | 详情 | 详情 | |
| (II) | 68553 | 5-bromo-4-methoxy-2-methylbenzoic acid | C9H9BrO3 | 详情 | 详情 | |
| (III) | 65744 | Phenetole; Ethoxybenzene; Ethyl phenyl ether | 103-73-1 | C8H10O | 详情 | 详情 |
| (IV) | 68554 | (5-bromo-4-methoxy-2-methylphenyl)(4-ethoxyphenyl)methanone | C17H17BrO3 | 详情 | 详情 | |
| (V) | 68555 | 1-bromo-5-(4-ethoxybenzyl)-2-methoxy-4-methylbenzene | C17H19BrO2 | 详情 | 详情 | |
| (VI) | 68556 | (3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one | C34H34O5S | 详情 | 详情 | |
| (VII) | 68558 | (3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)-2-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)tetrahydro-2H-thiopyran-2-ol | C51H54O7S | 详情 | 详情 | |
| (VIII) | 68557 | (2R,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)tetrahydro-2H-thiopyran | C51H54O6S | 详情 | 详情 | |
| (IX) | 68559 | 4’-hydroxy-2’-methylacetophenone;1-(4-hydroxy-2-methylphenyl)ethanone;4'-hydroxy-2'-methyl-Acetophenone;2-Methyl-4-hydroxyacetophenone;4-Acetyl-3-methylphenol;2'-Methyl-4'-hydroxyacetophenone | 875-59-2 | C9H10O2 | 详情 | 详情 |
| (X) | 68560 | 4’-methoxyacetophenone;1-(4-methoxy-2-methylphenyl)ethanone;4'-Methoxy-2'-methylacetophenone;2'-Methyl-4'-methoxyacetophenone | 24826-74-2 | C10H12O2 | 详情 | 详情 |
| (XI) | 68561 | 5’-bromo-4’-methoxy-2’-methylacetophenone;1-(5-bromo-4-methoxy-2-methylphenyl)ethanone | C10H11BrO2 | 详情 | 详情 | |
| (XII) | 68562 | 1-(3-bromo-4-methoxy-2-methylphenyl)ethanone | C10H11BrO2 | 详情 | 详情 |