2-(3,4,5-trimethoxyphenyl)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】25349

【品名】2-(3,4,5-trimethoxyphenyl)acetic acid

【CA登记号】937-52-0

【分子式】C₁₁H₁₄O₅

【分子量】226.22916

【元素组成】C 58.4% H 6.24% O 35.36%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XVII)

A further synthetic strategy was based on the Perkin condensation between 3,4,5-trimethoxyphenylacetic acid (XVII) and 3-hydroxy-4-methoxybenzaldehyde (XII). Decarboxylation of the resultant phenylcinnamic acid (XVIII) by heating with copper powder in quinoline furnished the desired stilbene, accompanied by only minor amounts of the corresponding E-isomer

参考文献中间体

合成目标

【1】 Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGrown, A.T.; Novel synthesis of cis and trans isomers of combretastatin A-4. J Org Chem 2001, 66, 24, 8135.

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)	60505	2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol	117048-60-9	C₁₈H₂₀O₅	详情	详情
(XII)	18455	3-hydroxy-4-methoxybenzaldehyde; Isovanillin	621-59-0	C₈H₈O₃	详情	详情
(XVII)	25349	2-(3,4,5-trimethoxyphenyl)acetic acid	937-52-0	C₁₁H₁₄O₅	详情	详情
(XVIII)	60513	(E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-2-propenoic acid		C₁₉H₂₀O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

3,4,5-Trimethoxyphenylacetic acid (IX) was alkylated with ethyl iodide in the presence of two equivalents of sodium bis(trimethylsilyl)amide to afford racemic trimethoxyphenylbutyric acid (X). After conversion to the corresponding acid chloride with SOCl2, condensation with (R)-4-benzyl-2-oxazolidinone (XI) in the presence of n-butyllithium gave N-acyloxazolidinone (XII) as a diastereomeric mixture that was separated by column chromatography. The required diastereoisomer was then hydrolyzed with lithium peroxide to provide (S)-2-(3,4,5-trimethoxyphenyl)butyric acid (XIII). Subsequent coupling of (XIII) with methyl (S)-pipecolate (XIV) employing 2-chloro-1-methylpyridinium iodide, followed by ester hydrolysis with LiOH, provided amide (XV). Further DCC-promoted coupling of (XV) to alcohol (VIII) provided (XVI). After acid cleavage of the tert-butyl ester, the resulting carboxylic acid was finally coupled to etylenediamine (XVII) in the presence of 1-benzotriazolyloxy tris(dimethylamino)phosphonium hexafluorophosphate to yield the title compound.

参考文献中间体

合成目标

【1】 Yang, W.; Guo, T.; Keenan, T.P.; Laborde, E.; Holt, D.A. (Ariad Pharmaceuticals Inc.); Synthetic derivs. of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains. JP 2000505475; WO 9731898 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	25348	tert-butyl 2-[3-[(1R)-3-(3,4-dimethoxyphenyl)-1-hydroxypropyl]phenoxy]acetate		C₂₃H₃₀O₆	详情	详情
(IX)	25349	2-(3,4,5-trimethoxyphenyl)acetic acid	937-52-0	C₁₁H₁₄O₅	详情	详情
(X)	25350	2-(3,4,5-trimethoxyphenyl)butyric acid		C₁₃H₁₈O₅	详情	详情
(XI)	25351	(4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone	102029-44-7	C₁₀H₁₁NO₂	详情	详情
(XII)	25352	(4R)-4-benzyl-3-[2-(3,4,5-trimethoxyphenyl)butanoyl]-1,3-oxazolidin-2-one		C₂₃H₂₇NO₆	详情	详情
(XIII)	25353	(2S)-2-(3,4,5-trimethoxyphenyl)butyric acid		C₁₃H₁₈O₅	详情	详情
(XIV)	25354	methyl (2S)-2-piperidinecarboxylate		C₇H₁₃NO₂	详情	详情
(XV)	25355	(2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]-2-piperidinecarboxylic acid		C₁₉H₂₇NO₆	详情	详情
(XVI)	25356	(1R)-1-[3-[2-(tert-butoxy)-2-oxoethoxy]phenyl]-3-(3,4-dimethoxyphenyl)propyl (2S)-1-[(2S)-2-(3,4,5-trimethoxyphenyl)butanoyl]-2-piperidinecarboxylate		C₄₂H₅₅NO₁₁	详情	详情
(XVII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,4,5-Trimethoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Shams, G.; Feller, D.R.; Zheng, W.; Konkar, A.A.; Miller, D.D.; Nikulin, V.I.; Vansal, S.S.; 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: Novel selective beta3-adrenoceptor agonists. J Med Chem 1999, 42, 12, 2287.
【2】 Miller, D.D.; Feller, D.R. (Molecular Design International, Inc. ); beta3-Adrenoreceptor agonists, agonist compsns. and methods of using. EP 1023269; WO 9916752 .

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)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(II)	30324	3-buten-2-one; methyl vinyl ketone	78-94-4	C₄H₆O	详情	详情
(III)	35230	2-(3-oxobutyl)-1H-isoindole-1,3(2H)-dione		C₁₂H₁₁NO₃	详情	详情
(IV)	35231	2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione		C₁₂H₁₀BrNO₃	详情	详情
(V)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(VI)	35232	2-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione		C₁₃H₁₁N₃O₂S	详情	详情
(VII)	35233	4-(2-aminoethyl)-1,3-thiazol-2-amine; 4-(2-aminoethyl)-1,3-thiazol-2-ylamine		C₅H₉N₃S	详情	详情
(VIII)	25349	2-(3,4,5-trimethoxyphenyl)acetic acid	937-52-0	C₁₁H₁₄O₅	详情	详情
(IX)	35238	2-(3,4,5-trimethoxyphenyl)acetyl chloride		C₁₁H₁₃ClO₄	详情	详情
(X)	35239	N-[2-(2-amino-1,3-thiazol-4-yl)ethyl]-2-(3,4,5-trimethoxyphenyl)acetamide		C₁₆H₂₁N₃O₄S	详情	详情
(XI)	35240	4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-amine; 4-(3,4,5-trimethoxybenzyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine		C₁₆H₁₉N₃O₃S	详情	详情

Extended Information