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【结 构 式】

【分子编号】21434

【品名】methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate

【CA登记号】

【 分 子 式 】C23H21NO4

【 分 子 量 】375.42408

【元素组成】C 73.58% H 5.64% N 3.73% O 17.05%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of L-tyrosine methyl ester (I) with 2-benzoylcyclohexanone (II) in the presence of Pd/C in boiling anisole produced the vinylogous amide intermediate (III) which, in the reaction conditions, experienced a dehydrogenation to furnish benzophenone (IV). Then, coupling of (IV) with 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (V) under Mitsunobu conditions afforded ether (VI). Finally, the ester function of (VI) was hydrolyzed with LiOH to give the title acid.

参考文献 中间体
合成目标
【1】 Martín, L.; Sorbera, L.A.; Leeson, P.A.; Castañer, J.; Farglitazar. Drugs Fut 2001, 26, 4, 354.
【2】 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel serieis of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998, 41, 25, 5020.
【3】 Willson, T.M.; Mook, R.A. Jr.; Kaldor, I.; Henke, B.R.; Deaton, D.N.; Collins, J.L.; Cobb, J.E.; Brackeen, M.; Sharp, M.J.; O'Callaghan, J.M.; Erickson, G.A.; Boswell, G.E. (Glaxo Wellcome plc); Substd. 4-hydroxy-phenylalkanoic acid derivs. with agonist activity to PPAR-gamma. EP 0888317; JP 2000507216; WO 9731907 .
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) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(II) 21432 2-benzoylcyclohexanone 3580-38-9 C13H14O2 详情 详情
(III) 21433 methyl (2S)-2-[(2-benzoyl-1-cyclohexen-1-yl)amino]-3-(4-hydroxyphenyl)propanoate C23H25NO4 详情 详情
(IV) 21434 methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate C23H21NO4 详情 详情
(V) 19874 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol C12H13NO2 详情 详情
(VI) 21436 methyl (2S)-2-(2-benzoylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate C35H32N2O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The 2-aminobenzophenone derivative (III) was prepared by condensation of L-tyrosine methyl ester (I) with 2-benzoylcyclohexanone (II) in refluxing anisole, with concomitant dehydrogenation in the presence of Pd/C. Subsequent Mitsunobu coupling of (III) with 2-(N-Boc-N-methylamino)ethanol (V), prepared from aminoalcohol (IV) and Boc2O, afforded the Boc-protected aminoethyl ether (VI). After removal of the Boc group of (VI) by treatment with trifluoroacetic acid, condensation of the resulting secondary amine (VII) with 2-fluoropyridine (VIII) yielded the 2-aminopyridine derivative (IX). Finally, the methyl ester group of (IX) was hydrolyzed to the title carboxylic acid using LiOH.

参考文献 中间体
合成目标
【1】 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel serieis of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998, 41, 25, 5020.
【2】 Willson, T.M.; Mook, R.A. Jr.; Kaldor, I.; Henke, B.R.; Deaton, D.N.; Collins, J.L.; Cobb, J.E.; Brackeen, M.; Sharp, M.J.; O'Callaghan, J.M.; Erickson, G.A.; Boswell, G.E. (Glaxo Wellcome plc); Substd. 4-hydroxy-phenylalkanoic acid derivs. with agonist activity to PPAR-gamma. EP 0888317; JP 2000507216; WO 9731907 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23767 Methoxybenzene; Methyl phenyl ether; Anisole 100-66-3 C7H8O 详情 详情
(I) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(II) 21432 2-benzoylcyclohexanone 3580-38-9 C13H14O2 详情 详情
(III) 21434 methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate C23H21NO4 详情 详情
(IV) 13324 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol 109-83-1 C3H9NO 详情 详情
(V) 34509 tert-butyl 2-hydroxyethyl(methyl)carbamate C8H17NO3 详情 详情
(VI) 34510 methyl (2S)-2-(2-benzoylanilino)-3-(4-[2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy]phenyl)propanoate C31H36N2O6 详情 详情
(VII) 34511 methyl (2S)-2-(2-benzoylanilino)-3-[4-[2-(methylamino)ethoxy]phenyl]propanoate C26H28N2O4 详情 详情
(VIII) 34512 2-fluoropyridine 372-48-5 C5H4FN 详情 详情
(IX) 34513 methyl (2S)-2-(2-benzoylanilino)-3-(4-[2-[methyl(2-pyridinyl)amino]ethoxy]phenyl)propanoate C31H31N3O4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(III)

Condensation of L-tyrosine methyl ester (I) with 2-benzoylcylohexanone (II) and subsequent dehydrogenation in refluxing anisole in the presence of Pd/C affords the benzophenone derivative (III), which is converted into carboxylic acid (V) by Mitsunobu reaction with heterocyclic alcohol (IV) by means of PPh3 and DEAD in THF followed by saponification of the resulting methyl ester with LiOH in THF/MeOH (1). Coupling of (V) with valinol (VI) by means of HOBt/Et3N and EDC·HCl in CH2Cl2 furnishes amide (VII), which is oxidized by means of 4-methylmorpholine (NMM) and TPAP in CH2Cl2 to furnish aldehyde (VIII). Finally, the desired oxazole is obtained by intramolecular cyclization of (VIII) by means of iodine, PPh3 and Et3N in CH2Cl2.

参考文献 中间体
合成目标
【1】 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel serieis of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998, 41, 25, 5020.
【2】 Cobb, J.E.; Shearer, B.G.; Lambert, M.H. III; Milburn, M.V. (Glaxo Group Ltd.); Oxazole PPAR antagonists. WO 0117994 .
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) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(II) 21432 2-benzoylcyclohexanone 3580-38-9 C13H14O2 详情 详情
(III) 21434 methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate C23H21NO4 详情 详情
(IV) 19874 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol C12H13NO2 详情 详情
(V) 48285 (2S)-2-(2-benzoylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid C34H30N2O5 详情 详情
(VI) 48289 2-amino-3-methyl-1-butanol; DL-Valinol 473-75-6 C5H13NO 详情 详情
(VII) 48287 (2S)-2-(2-benzoylanilino)-N-[1-(hydroxymethyl)-2-methylpropyl]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanamide C39H41N3O5 详情 详情
(VIII) 48288 (2S)-2-(2-benzoylanilino)-N-(1-formyl-2-methylpropyl)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanamide C39H39N3O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(III)

Condensation of L-tyrosine methyl ester (I) with 2-benzoylcylohexanone (II) and subsequent dehydrogenation in refluxing anisole in the presence of Pd/C affords the benzophenone derivative (III), which is converted into carboxylic acid (V) by Mitsunobu reaction with heterocyclic alcohol (IV) by means of PPh3 and DEAD in THF followed by saponification of the resulting methyl ester with LiOH in THF/MeOH (1). Coupling of (V) with acetic acid hydrazide (VI) by means of HOBt/Et3N and EDC.HCl in CH2Cl2 furnishes the diacyl hydrazide (VII), which is finally converted into the desired thiadiazole derivative by treatment with Lawesson's Reagent in refluxing toluene.

参考文献 中间体
合成目标
【1】 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel serieis of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998, 41, 25, 5020.
【2】 Cobb, J.E.; Shearer, B.G.; Lambert, M.H. III; Milburn, M.V. (Glaxo Group Ltd.); Oxazole PPAR antagonists. WO 0117994 .
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) 21431 methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate 1080-06-4 C10H13NO3 详情 详情
(II) 21432 2-benzoylcyclohexanone 3580-38-9 C13H14O2 详情 详情
(III) 21434 methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate C23H21NO4 详情 详情
(IV) 19874 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol C12H13NO2 详情 详情
(V) 48285 (2S)-2-(2-benzoylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid C34H30N2O5 详情 详情
(VI) 29262 acetohydrazide 1068-57-1 C2H6N2O 详情 详情
(VII) 48286 (2S)-N'-acetyl-2-(2-benzoylanilino)-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanohydrazide C36H34N4O5 详情 详情
Extended Information