2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol -Drug Synthesis Database

【结构式】

【分子编号】19874

【品名】2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol

【CA登记号】

【分子式】C₁₂H₁₃NO₂

【分子量】203.24076

【元素组成】C 70.92% H 6.45% N 6.89% O 15.74%

与该中间体有关的原料药合成路线共 7 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5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(IV)

Acetylation of N-benzoylaspartic acid beta-methyl ester (I) with acetic anhydride and subsequent decarboxylation gave the 3-benzoylamino-4-oxovalerate (II). The methyl oxazolylacetate (III) was prepared by cyclization of 4-oxovalerate (II) in the presence of Ac2O. Ester (III) was then reduced to alcohol (IV) with LiBH4 and further converted to mesylate (V) with methanesulfonyl chloride and Et3N. Coupling between mesylate (V) and 4-hydroxybenzaldehyde (VI) gave ether (VII). Knoevenagel condensation of (VII) with dimethyl malonate using piperidine acetate produced the benzylidene malonate (VIII). Finally, catalytic hydrogenation with Pd/C furnished JTP-20993. The title compound (JTT-501) is obtained by reaction of JTP-20993 with NH2OH.

参考文献中间体

合成目标

【1】 Shinkai, H.; The isoxazolidine-3,5-dione hypoglycemic agent JTT-501 and other nonthiazolidinedione insulin sensitizers. Drugs Fut 1999, 24, 8, 893.
【2】 Shinkai, H. (Japan Tobacco Inc.); Isoxazolidinedione deriv. and use thereof. EP 0684242; JP 1996517913; US 5728720; US 6057343; WO 9518125 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
JTP-20993	41516	dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]malonate		C₂₄H₂₅NO₆	详情	详情
(I)	41311	2-(benzoylamino)-4-methoxy-4-oxobutyric acid		C₁₂H₁₃NO₅	详情	详情
(II)	41312	methyl 3-(benzoylamino)-4-oxopentanoate		C₁₃H₁₅NO₄	详情	详情
(III)	41313	methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate		C₁₃H₁₃NO₃	详情	详情
(IV)	19874	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol		C₁₂H₁₃NO₂	详情	详情
(V)	41315	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate		C₁₃H₁₅NO₄S	详情	详情
(VI)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(VII)	19372	4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzaldehyde		C₁₉H₁₇NO₃	详情	详情
(VIII)	19374	dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzylidene]malonate		C₂₄H₂₃NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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3

该中间体在本合成路线中的序号：(I)

Oxazolylethanol (I) was coupled to N-Boc-L-tyrosine methyl ester (II) using Mitsunobu conditions in the presence of PPh3 and DEAD to give ether (III). Subsequent deprotection of the Boc group of (III) with trifluoroacetic acid afforded amine (IV), which was then condensed with methyl cyclohexanone-2-carboxylate (V) in boiling toluene to yield enamine (VI). Further heating of (VI) at 190 C in anisole in the presence of Pd/C resulted in aromatization of the cyclohexene ring to produce the anthranilate derivative (VII). Finally, selective hydrolysis of the aliphatic ester with LiOH under careful conditions provided the target monoester.

参考文献中间体

合成目标

【1】 Cobb, J.E.; Blanchard, S.G.; Boswell, E.G.; Brown, K.K.; Charifson, P.S.; Cooper, J.P.; Collins, J.L.; Dezube, M.; Henke, B.R.; Hull-Ryde, E.A.; Lake, D.H.; Lenhard, J.M.; Oliver, W. Jr; Oplinger, J.; Pentti, M.; Parks, D.J.; Plunket, K.D.; Tong, W.Q.; N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. J Med Chem 1998, 41, 25, 5055.

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)	19874	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol		C₁₂H₁₃NO₂	详情	详情
(II)	19875	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate	4326-36-7	C₁₅H₂₁NO₅	详情	详情
(III)	19876	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate		C₂₇H₃₂N₂O₆	详情	详情
(IV)	19877	methyl (2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propanoate		C₂₂H₂₄N₂O₄	详情	详情
(V)	19878	methyl 2-oxocyclohexanecarboxylate	41302-34-5	C₈H₁₂O₃	详情	详情
(VI)	19879	methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]-1-cyclohexene-1-carboxylate		C₃₀H₃₄N₂O₆	详情	详情
(VII)	19880	methyl 2-[((1S)-2-methoxy-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl]-2-oxoethyl)amino]benzoate		C₃₀H₃₀N₂O₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Shinkai, H.; et al.; Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents. J Med Chem 1998, 41, 11, 1927.
【2】 Shinkai, H.; The isoxazolidine-3,5-dione hypoglycemic agent JTT-501 and other nonthiazolidinedione insulin sensitizers. Drugs Fut 1999, 24, 8, 893.

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)	41311	2-(benzoylamino)-4-methoxy-4-oxobutyric acid		C₁₂H₁₃NO₅	详情	详情
(II)	41312	methyl 3-(benzoylamino)-4-oxopentanoate		C₁₃H₁₅NO₄	详情	详情
(III)	41313	methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate		C₁₃H₁₃NO₃	详情	详情
(IV)	19874	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol		C₁₂H₁₃NO₂	详情	详情
(V)	41315	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate		C₁₃H₁₅NO₄S	详情	详情
(VI)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(VII)	19372	4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzaldehyde		C₁₉H₁₇NO₃	详情	详情
(VIII)	19374	dimethyl 2-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzylidene]malonate		C₂₄H₂₃NO₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(IV)

The cyclization of methyl 4-bromo-3-oxopentanoate (I) with benzamide (II) and sodium hydrogen phosphate in refluxing ethanol gives methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (III), which is reduced with LiAlH4 in THF to yield the ethanol derivative (IV). The reaction of (IV) with methanesulfonyl chloride and TEA in dichloromethane affords the mesylate (V), which is condensed with N-(tert-butoxycarbonyl)-L-tyrosine (VI) by means of NaOH in hot DMSO/water to provide the 4-O-substituted tyrosine (VII), which is deprotected by means of HCl in dioxane to give intermediate (VIII) with a free amino group. Finally, this compound is condensed with benzoylacetone (IX) by means of trimethyl orthoformate in refluxing methanol to afford the target N-substituted tyrosine derivative.

参考文献中间体

合成目标

【1】 Oplinger, J.A.; Dezube, M.; Willson, T.M.; Collins, J.L. (Glaxo Group Ltd.); Substd. oxazoles and thiazoles derivs. as hPPAR gamma and hPPAR alpha activators. EP 1102757; WO 0008002 .

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)	49397	methyl 4-bromo-3-oxopentanoate		C₆H₉BrO₃	详情	详情
(II)	40592	Benzamide	55-21-0	C₇H₇NO	详情	详情
(III)	41313	methyl 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetate		C₁₃H₁₃NO₃	详情	详情
(IV)	19874	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-1-ethanol		C₁₂H₁₃NO₂	详情	详情
(V)	41315	2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate		C₁₃H₁₅NO₄S	详情	详情
(VI)	25395	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid	3978-80-1	C₁₄H₁₉NO₅	详情	详情
(VII)	49398	(2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid		C₂₆H₃₀N₂O₆	详情	详情
(VIII)	49399	(2S)-2-amino-3-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]propionic acid		C₂₁H₂₂N₂O₄	详情	详情
(IX)	23829	1-phenyl-1,3-butanedione	93-91-4	C₁₀H₁₀O₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(IV)

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7

该中间体在本合成路线中的序号：(IV)

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