【结 构 式】 |
【分子编号】68556 【品名】(3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one 【CA登记号】 |
【 分 子 式 】C34H34O5S 【 分 子 量 】554.707 【元素组成】C 73.62% H 6.18% O 14.42% S 5.78% |
合成路线1
该中间体在本合成路线中的序号:(VI)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 |
合成路线2
该中间体在本合成路线中的序号:(VI)Thiolactone (VI) can be prepared as follows. Selective removal of the anomeric acetyl group of 1,2,3,4,6-penta-O-acetyl-5-thio-D-glucopyranose (XIII) by means of MeNHNH2 in the presence of AcOH in DMF and then protection of the resulting hydroxyl group with DHP in the presence of p-TsOH.H2O in CHCl3 affords the tetrahydropyranyl ether (XV). Zemplen deacetylation of the tetra-O-acetate (XV) with NaOMe in MeOH, and subsequent protection of the resulting hydroxyl groups with PhCH2Br by means of NaH in DMF provides the tetrabenzyl ether (XVI), which by removal of the THP-protecting group with PPTS in EtOH at 80 °C generates 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose (XVII). Finally, thioglucopyranose (XVII) is oxidized with DMSO in the presence of Ac2O .
【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 |
---|---|---|---|---|---|---|
(VI) | 68556 | (3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-one | C34H34O5S | 详情 | 详情 | |
(XIII) | 68567 | (3S,4R,5R,6S)-6-(acetoxymethyl)tetrahydro-2H-thiopyran-2,3,4,5-tetrayl tetraacetate | C16H22O10S | 详情 | 详情 | |
(XIV) | 68566 | (3S,4R,5R,6S)-2-(acetoxymethyl)-6-hydroxytetrahydro-2H-thiopyran-3,4,5-triyl triacetate | C14H20O9S | 详情 | 详情 | |
(XV) | 68565 | (2S,3R,4R,5S)-2-(acetoxymethyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-thiopyran-3,4,5-triyltriacetate | C19H28O10S | 详情 | 详情 | |
(XVI) | 68564 | 2-(((3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-yl)oxy)tetrahydro-2H-pyran | C39H44O6S | 详情 | 详情 | |
(XVII) | 68563 | (3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-thiopyran-2-ol | C34H36O5S | 详情 | 详情 |