GPR40激动剂的合成
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摘要
以3-甲硫基丙醇(2)与对甲基苯磺酰氯(3)发生取代反应、氧化反应得3-(甲基磺酰基)丙基-4-甲基苯磺酸(5),再以间苯二酚(6)与4-氯乙酰乙酸乙酯(7)缩合成环、水解、成酯、氢化还原得6-羟基-苯并呋喃-3-乙酸甲酯(11),以4-溴-3,5-二甲基苯酚(12)与3-甲酰基苯硼酸(13)发生suzuki偶联得4'-羟基-2',6'-二甲基-[1,1'-联苯]-3-甲醛(14),再与(4)亲核取代、还原得3-(甲基磺酰基)丙基-4-甲基苯磺酸(16),(16)与(11)缩合,最终水解得到6-({2',6'-二甲基-4'-[3-(甲磺酰基)丙酰基]-联苯}甲氧基)-2,3-二氢苯并呋喃-3-乙酸(18)。
3-( methylthio) propan- 1- ol( 2) was subjected to substitution with 4- methylbenzene- 1- sulfonyl chloride( 3),and then oxidation to 3-( methylsulfonyl) propyl- 4- methylbenzensulfonate( 5),resorcinol( 6) was condensed with ethyl- 4- chloro- 3-oxobutanoate( 7),which followed byhydrol- yzed,esterified,hydrogenated to afford methyl- 2-( 6- hydroxy- 2,3- dihydrobenzofuran- 3- yl) acetate( 11). 4- bromo- 3,5- dimethylphenol( 12) subjected to suzuki reaction with 3- formylphenyl- boronic acid( 13) to get 4'-hydroxy- 2',6'- dimethylbiphenyl- 3- carbaldehyde( 14),which was substitution reaction with 5 and then reduction with Na BH4 to give( 2,6'- dimethyl- 4-( 3-( methylsulfonyl) propoxy) biphenyl- 3- yl) methanol( 16),followed by condensed,hydrolyzed to obtained 2-[6-[2',6'- Dimethyl- 4'-[3-( methylsulfonyl) propoxy]biphenyl- 3- ylmethoxy]- 2,3- dihydro- 1- benzofuran- yl] acetic acid( 18).
3-( methylthio) propan- 1- ol( 2) was subjected to substitution with 4- methylbenzene- 1- sulfonyl chloride( 3),and then oxidation to 3-( methylsulfonyl) propyl- 4- methylbenzensulfonate( 5),resorcinol( 6) was condensed with ethyl- 4- chloro- 3-oxobutanoate( 7),which followed byhydrol- yzed,esterified,hydrogenated to afford methyl- 2-( 6- hydroxy- 2,3- dihydrobenzofuran- 3- yl) acetate( 11). 4- bromo- 3,5- dimethylphenol( 12) subjected to suzuki reaction with 3- formylphenyl- boronic acid( 13) to get 4'-hydroxy- 2',6'- dimethylbiphenyl- 3- carbaldehyde( 14),which was substitution reaction with 5 and then reduction with Na BH4 to give( 2,6'- dimethyl- 4-( 3-( methylsulfonyl) propoxy) biphenyl- 3- yl) methanol( 16),followed by condensed,hydrolyzed to obtained 2-[6-[2',6'- Dimethyl- 4'-[3-( methylsulfonyl) propoxy]biphenyl- 3- ylmethoxy]- 2,3- dihydro- 1- benzofuran- yl] acetic acid( 18).
引文
[1]Arturo D Mancini,Vincent Poitout.The fatty acid receptor FFA1/GPR40 a decade later:how much do we know[J].Trends in Endocrinology and Metabolism,2013.
[2]Elisabeth C,Christian U.Discovery of potent and selective agonists for the freefatty acid receptor 1(FFA1/GPR40),a potential target for the treatment of type II diabetes[J].Journal of Medicinal Chemistry,2008,51(22):7061-7064.
[3]Yashiro H,Tsujihata Y,Takeuchi K.The effects of TAK-875,a selective G protein-coupled receptor 40/free fatty acid 1 agonist,on insulin and glucagon secretion in isolated rat and human islets[J].Journal of Pharmacology and Experimental Therapeutics,2012,340(2):483-489.
[4]武珅,陆涛峰,武爽,等.G蛋白偶联受体40研究进展[J].遗传,2013,35(1):27-34.
[5]Tsujihata Y,Suzuki M.TAK-875,an orally available GPR40/FFA1agonist enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.[J].Pharmacol Exp Ther 2011,339(1):228-375.
[6]Vakily M.,Viswanathan,P,Leifke E.A safety,tolerability,pharmacokinetics,and pharmacodynamics and preliminary food-effect study of TAK-875 GPR40 agonist,following oral administration of sequential ascending single doses to healthy subjects[J].Diabetes,2010,59(Supply 1):630.
[7]TAK-875 Free Fatty Acid Receptor FFA1 Agonist Insulin Secretagogue Treatment of Type 2 Diabetes[J].Drugs of the Future,2011,36(11):813-818.
[8]Negoro N,Sasaki S,Mikami S.Optimization of(2,3-dihydro-1-benzofuran-3-yl)acetic acids:discovery of a non-free fatty acidlike,highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent[J].Journal of Medicinal Chemistry,2012,55(8):3960-3974.
[2]Elisabeth C,Christian U.Discovery of potent and selective agonists for the freefatty acid receptor 1(FFA1/GPR40),a potential target for the treatment of type II diabetes[J].Journal of Medicinal Chemistry,2008,51(22):7061-7064.
[3]Yashiro H,Tsujihata Y,Takeuchi K.The effects of TAK-875,a selective G protein-coupled receptor 40/free fatty acid 1 agonist,on insulin and glucagon secretion in isolated rat and human islets[J].Journal of Pharmacology and Experimental Therapeutics,2012,340(2):483-489.
[4]武珅,陆涛峰,武爽,等.G蛋白偶联受体40研究进展[J].遗传,2013,35(1):27-34.
[5]Tsujihata Y,Suzuki M.TAK-875,an orally available GPR40/FFA1agonist enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.[J].Pharmacol Exp Ther 2011,339(1):228-375.
[6]Vakily M.,Viswanathan,P,Leifke E.A safety,tolerability,pharmacokinetics,and pharmacodynamics and preliminary food-effect study of TAK-875 GPR40 agonist,following oral administration of sequential ascending single doses to healthy subjects[J].Diabetes,2010,59(Supply 1):630.
[7]TAK-875 Free Fatty Acid Receptor FFA1 Agonist Insulin Secretagogue Treatment of Type 2 Diabetes[J].Drugs of the Future,2011,36(11):813-818.
[8]Negoro N,Sasaki S,Mikami S.Optimization of(2,3-dihydro-1-benzofuran-3-yl)acetic acids:discovery of a non-free fatty acidlike,highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent[J].Journal of Medicinal Chemistry,2012,55(8):3960-3974.