methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate -Drug Synthesis Database

【结构式】

【分子编号】21431

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

【CA登记号】1080-06-4

【分子式】C₁₀H₁₃NO₃

【分子量】195.21816

【元素组成】C 61.53% H 6.71% N 7.17% O 24.59%

与该中间体有关的原料药合成路线共 10 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8 合成路线9 合成路线10

合成路线1

该中间体在本合成路线中的序号：(XXIII)

Tyrosine methyl ester (XXIII) was acylated with butanesulfonyl chloride (XIV) in the presence of pyridine to produce sulfonamide (XXIV). Mitsunobu coupling of pyridinyl butanol (XX) with the phenolic compound (XXIV) furnished ether (XXV). Subsequent hydrolysis of the methyl ester group of (XXV) employing LiOH afforded acid (XXVI). The title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (XXVI) in the presence of Pd/C.

参考文献中间体

合成目标

【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	26779	1-butanesulfonyl chloride	2386-60-9	C₄H₉ClO₂S	详情	详情
(XX)	59550	4-(4-pyridinyl)-1-butanol		C₉H₁₃NO	详情	详情
(XXIII)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(XXIV)	59552	methyl (2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoate		C₁₄H₂₁NO₅S	详情	详情
(XXV)	59553	methyl (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoate		C₂₃H₃₂N₂O₅S	详情	详情
(XXVI)	59554	(2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid		C₂₂H₃₀N₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of L-tyrosine methyl ester (I) with ethyl chloroformate and K2CO3 in water gives the carbamate (II), which is protected with Bn-Br and K2CO3 in DMF, yielding the benzyl ether (III). The reduction of (III) by means of LiAlH4 in refluxing THF affords the chiral 2-methylaminopropanol (IV), which is protected as its Boc derivative (V) by means of Boc2O. The oxidation of (V) by means of DMP provides the carbaldehyde (VI), which is reductocondensed with glycine methyl ester (VII) by means of NaBH3CN in methanol to give the adduct (VIII). Elimination of the Boc protecting group of (VIII) by means of TFA yields the diamine (IX), which is cyclized by means of NH4OH in ethanol to afford the piperazinone (X). Elimination of the benzyl protecting group of (X) by hydrogenation with H2 over Pd/C provides the phenol (XIa)-(XIb), which is cyclized by means of bis(acetoxy)iodobenzene in hexafluoroisopropanol to give the spiranic cyclohexadienone (XII). The hydrogenation of (XII) by means of Tes-H and CuI in dichloromethane yields the spiranic cyclohexanone (XIII), which is finally ketalized by means of ethyleneglycol (XIV) and PPTS in refluxing benzene to provide the target ethyleneketal intermediate (XV) (See scheme no. 18599903a, intermediate (XV)).

参考文献中间体

合成目标

【1】 Mizutani, H.; et al.; Facile synthesis of enantiopure (-)-TAN1251A. Tetrahedron Lett 2002, 43, 13, 2411.

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)	57099	methyl (2S)-2-[(ethoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate		C₁₃H₁₇NO₅	详情	详情
(III)	57100	methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[(ethoxycarbonyl)amino]propanoate		C₂₀H₂₃NO₅	详情	详情
(IV)	57101	(2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)-1-propanol		C₁₇H₂₁NO₂	详情	详情
(V)	57102	tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl(methyl)carbamate		C₂₂H₂₉NO₄	详情	详情
(VI)	57103	tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-oxoethyl(methyl)carbamate		C₂₂H₂₇NO₄	详情	详情
(VII)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(VIII)	57104	methyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)(methyl)amino]propyl}amino)acetate		C₂₅H₃₄N₂O₅	详情	详情
(IX)	57105	methyl 2-{[(2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)propyl]amino}acetate		C₂₀H₂₆N₂O₃	详情	详情
(X)	57106	(6S)-6-[4-(benzyloxy)benzyl]-1-methyl-2-piperazinone		C₁₉H₂₂N₂O₂	详情	详情
(XI)	57107	(6S)-6-(4-hydroxybenzyl)-1-methyl-2-piperazinone		C₁₂H₁₆N₂O₂	详情	详情
(XII)	57108			C₁₂H₁₄N₂O₂	详情	详情
(XIII)	57109			C₁₂H₁₈N₂O₂	详情	详情
(XIV)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(XV)	48806			C₁₄H₂₂N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50ºC in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.

参考文献中间体

合成目标

【1】 Grover, P.T.; et al.; Chiral mandelic acid template provides a highly practical solution for (S)-oxybutynin synthesis. J Org Chem 2000, 65, 19, 6283.
【2】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Ia)	51214	(2R)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₈O₃	详情	详情
(Ib),(IV)	51215	(2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₈O₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	51216		n/a	C₂₄H₃₁NO₆	详情	详情
(V)	12563	(2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid	17199-29-0	C₈H₈O₃	详情	详情
(VI)	19797	Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal	630-19-3	C₅H₁₀O	详情	详情
(VII)	31681	(2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(VIII)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(IX)	51217	(2S,5R)-2-(tert-butyl)-5-(1-hydroxycyclohexyl)-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₆O₄	详情	详情
(X)	51218	(2S,5S)-2-(tert-butyl)-5-(1-cyclohexen-1-yl)-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₄O₃	详情	详情
(XI)	51219	(2S)-2-(1-cyclohexen-1-yl)-2-hydroxy-2-phenylethanoic acid		C₁₄H₁₆O₃	详情	详情
(XII)	51220	(2S,5S)-2-(tert-butyl)-5-cyclohexyl-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₆O₃	详情	详情
(XIII)	30800	3-bromo-1-cyclohexene	1521-51-3	C₆H₉Br	详情	详情
(XIV)	51221	(2S,5S)-2-(tert-butyl)-5-[(1R)-2-cyclohexen-1-yl]-5-phenyl-1,3-dioxolan-4-one		C₁₉H₂₄O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

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5

该中间体在本合成路线中的序号：(II)

Coupling of N-acetyl-D-thioproline (I) with tyrosine methyl ester (II) using EDC and HOBt yielded dipeptide (III). Subsequent alkylation of the tyrosine phenolic group of (III) with 2,6-dichlorobenzyl bromide (IV) and NaH produced the dichlorobenzyl ether (V). The methyl ester group of (V) was finally hydrolyzed employing LiOH in aqueous THF.

参考文献中间体

合成目标

【1】 Head, J.C.; Warrellow, G.J.; Archibald, S.C. (Celltech Chiroscience plc); Anti-inflammatory tyrosine derivs.. EP 0984981; US 6093696; WO 9854207 .

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)	40791	(4S)-3-acetyl-1,3-thiazolidine-4-carboxylic acid	24877-72-3	C₆H₉NO₃S	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	40792	methyl (2S)-2-([[(4S)-3-acetyl-1,3-thiazolidin-4-yl]carbonyl]amino)-3-(4-hydroxyphenyl)propanoate		C₁₆H₂₀N₂O₅S	详情	详情
(IV)	40793	2-(bromomethyl)-1,3-dichlorobenzene	20443-98-5	C₇H₅BrCl₂	详情	详情
(V)	40794	methyl (2S)-2-([[(4S)-3-acetyl-1,3-thiazolidin-4-yl]carbonyl]amino)-3-[4-[(2,6-dichlorobenzyl)oxy]phenyl]propanoate		C₂₃H₂₄Cl₂N₂O₅S	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

The borinated tyrosine intermediate (VII) has been obtained as follows: The esterification of L-tyrosine (I) with SOCl2 and methanol gives the methyl ester (II), which is N-protected with Cbz-Cl and K2CO3 to yield the carbamate (III). The O-protection of (III) with benzyl bromide and Cs2CO3 affords the benzyl ether (IV), which is iodinated with I2 and Ag2SO4 to provide the 3-iodotyrosine derivative (V). Finally, the borylation of (V) by means of pinacolatodiborane (VI) catalyzed by PdCl2[bis(diphenylphosphanyl)ferrocene] (PdCl2(dppf)) gives rise to the target tyrosine intermediate (VII).

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

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)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	53339	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate	n/a	C₁₈H₁₉NO₅	详情	详情
(IV)	53340	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoate	n/a	C₂₅H₂₅NO₅	详情	详情
(V)	53341	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-iodophenyl]propanoate	n/a	C₂₅H₂₄INO₅	详情	详情
(VI)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情
(VII)	53343	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate	n/a	C₃₁H₃₆BNO₇	详情	详情

合成路线7

该中间体在本合成路线中的序号：(I)

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8

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Lin, S.N.; Danishefsky, S.J.; The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides. Angew Chem. Int Ed 2002, 41, 3, 512.

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)	48794	(S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine	60-18-4	C₉H₁₁NO₃	详情	详情
(II)	21431	methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	1080-06-4	C₁₀H₁₃NO₃	详情	详情
(III)	53339	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate	n/a	C₁₈H₁₉NO₅	详情	详情
(IV)	53340	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)phenyl]propanoate	n/a	C₂₅H₂₅NO₅	详情	详情
(V)	53341	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-iodophenyl]propanoate	n/a	C₂₅H₂₄INO₅	详情	详情
(VI)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情
(VII)	53343	methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[4-(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate	n/a	C₃₁H₃₆BNO₇	详情	详情

合成路线9

该中间体在本合成路线中的序号：(I)

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10

该中间体在本合成路线中的序号：(I)

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