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【结 构 式】 
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【药物名称】TAK-875 【化学名称】2-[6-[2',6'-Dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-ylmethoxy]-2,3-dihydro-1-benzofuran-3(S)-yl]acetic acid hydrate 【CA登记号】 【 分 子 式 】C29H33O7S.H2O 【 分 子 量 】542.64 |
【开发单位】Takeda Pharmaceutical Co., Ltd. (JP) 【药理作用】Free Fatty Acid Receptor FFA1 Agonist;Insulin Secretagogue;Treatment of Type 2 Diabetes |
合成路线1
Suzuki coupling of 4-bromo-3,5-dimethylphenol (I) with 3-formylphenylboronic acid (II) in the presence of Pd(PPh)3 and Na2CO3 in EtOH/toluene at 80 °C affords 4’-hydroxy-2’,6’-dimethylbiphenyl-3-carbaldehyde (III), which is then condensed with 3-(methylsulfonyl)propyl tosylate (IV) by means of K2CO3 at 90 °C in DMF to give 2’,6’-dimethyl-4’-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (V). Reduction of aldehyde (V) with NaBH4 in MeOH/THF at 0 °C produces the corresponding alcohol (VI), which upon Mitsunobu condensation with methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) in the presence of Bu3P and ADDP in toluene yields the corresponding ether (VIII). Finally, ester (VIII) is hydrolyzed with NaOH in MeOH/THF/H2O at 50 °C .
3-(Methylsulfonyl)propyl tosylate (IV) is prepared by sulfonylation of 3-(methylsulfanyl)-1-propanol (IX) using TsCl in the presence of TMHDA and Et3N in toluene to produce the corresponding tosylate (X), which is finally oxidized with oxone in MeOH/H2O .
| 【1】 Negoro, N., Sasaki, S., Mikami, S. et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010, 1: 290-4. |
| 【2】 Yasuma, T., Negoro, N., Yamashita, M., Itou, M. (Takeda Pharmaeutical Co., Ltd.). Fused cyclic compounds. CA 2656003, EP 2041123, EP 2248812, JP 2009280585, JP 2009542580, US 2010004312, US 7732626, WO 2008001931. |
| 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) | 68874 | 4-bromo-3,5-dimethylphenol；4-Bromo-3,5-xylenol | 7463-51-6 | C8H9BrO | 详情 | 详情 |
| (II) | 57061 | 3-(Dihydroxyboryl)benzaldehyde; 3-Boronobenzaldehyde; 3-Formylbenzeneboronic acid; 3-Formylphenylboronic acid; Benzaldehyde-3-boronic acid | 87199-16-4 | C7H7BO3 | 详情 | 详情 |
| (III) | 68875 | 4'-hydroxy-2',6'-dimethyl-[1,1'-biphenyl]-3-carbaldehyde | C15H14O2 | 详情 | 详情 | |
| (IV) | 68877 | 3-(methylsulfonyl)propyl tosylate;3-(methylsulfonyl)propyl 4-methylbenzenesulfonate | C11H16O5S2 | 详情 | 详情 | |
| (V) | 68876 | 2’,6’-dimethyl-4’-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde;2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-carbaldehyde | C19H22O4S | 详情 | 详情 | |
| (VI) | 68878 | (2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methanol | C19H24O4S | 详情 | 详情 | |
| (VII) | 68881 | methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 | |
| (VIII) | 68881 | methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 | |
| (IX) | 68880 | 3-Methylthiopropanol;3-(Methylthio)propanol;3-Methylthio-1-propanol；3-(methylthio)propan-1-ol；3-(methylsulfanyl)-1-propanol | 505-10-2 | C4H10OS | 详情 | 详情 |
| (X) | 68879 | Toluene-4-sulfonic acid 3-methylsulfanyl-propyl ester；3-(METHYLTHIO)-1-(TOSYLOXY)PROPANE;3-(methylthio)propyl 4-methylbenzenesulfonate | 187722-18-5 | C11H16O3S2 | 详情 | 详情 |
合成路线2
Methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) is synthesized as follows:
Cyclization of resorcinol (XI) with ethyl 4-chloroacetoacetate (XII) by means of H2SO4 gives 4-(chloromethyl)-7-hydroxychromen-2-one (XIII), which by treatment with NaOH at reflux affords (6-hydroxybenzofuran-3-yl)acetic acid (XIV). Esterification of carboxylic acid (XIV) with MeOH in the presence of H2SO4 at reflux yields the corresponding methyl ester (XV), which is hydrogenated over Pd/C in MeOH to provide (±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (XVI) . Finally, the (S)-enantiomer (VII) is isolated by preparative HPLC .
Alternatively, intermediate (XV) can be reduced by H2 in the presence of bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate and (S,S)-Et-ferrotane in the presence of NaOMe in MeOH .
| 【1】 Negoro, N., Sasaki, S., Mikami, S. et al. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett 2010, 1: 290-4. |
| 【2】 Yasuma, T., Negoro, N., Yamashita, M., Itou, M. (Takeda Pharmaeutical Co., Ltd.). Fused cyclic compounds. CA 2656003, EP 2041123, EP 2248812, JP 2009280585, JP 2009542580, US 2010004312, US 7732626, WO 2008001931. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 68881 | methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate;(S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 | |
| (XI) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (XII) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XIII) | 68882 | 4-(chloromethyl)-7-hydroxychromen-2-one;4-(chloromethyl)-7-hydroxy-2H-1-Benzopyran-2-one;4-(Chloromethyl)-7-hydroxycoumarin;4-Chloromethyl-7-hydroxy-2H-chromen-2-one;7-Hydroxy-4-(chloromethyl)coumarin | 25392-41-0 | C10H7ClO3 | 详情 | 详情 |
| (XIV) | 68883 | (6-hydroxybenzofuran-3-yl)acetic acid;2-(6-hydroxybenzofuran-3-yl)acetic acid | C10H8O4 | 详情 | 详情 | |
| (XV) | 68884 | methyl 2-(6-hydroxybenzofuran-3-yl)acetate | C11H10O4 | 详情 | 详情 | |
| (XVI) | 68885 | methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate；(±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate | C11H12O4 | 详情 | 详情 |