2-(2-methoxy-2-oxoethyl)acrylic acid -Drug Synthesis Database

【结构式】

【分子编号】34820

【品名】2-(2-methoxy-2-oxoethyl)acrylic acid

【CA登记号】7338-27-4

【分子式】C₆H₈O₄

【分子量】144.12712

【元素组成】C 50% H 5.59% O 44.4%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

3-Cyanobenzaldehyde (I) was converted to oxime (II) by reaction with hydroxylamine in pyridine. The intermediate nitrile oxide, generated from chlorination and further elimination of HCl, underwent a [2+3] cycloaddition with itaconic acid monomethyl ester (III) to produce the isoxazoline (IV). The carboxylate group of (IV) was then activated as the corresponding acid chloride (V) upon treatment with SOCl2. Boronic acid (VII) was prepared from N-tert-butyl benzenesulfonamide (VI) by lithiation with n-butyllithium, followed by reaction with triisopropyl borate and quenching with HCl. Subsequent Suzuki coupling of (VII) with 2-amino-5-bromopyrimidine (VIII) using Pd(PPh3)4 and Na2CO3 afforded the 2-amino-4-arylpyrimidine (IX). Condensation of amine (IX) with acid chloride (V) in the presence of Et3N gave amide (X). The N-tert-butyl group of (X) was then deprotected by means of trifluoroacetic acid to yield (XI) as the trifluoroacetate salt. The cyano group of (XI) was converted to imidate (XII) with HCl and MeOH. This was finally reacted with ammonium acetate in MeOH to furnish the title amidine.

参考文献中间体

合成目标

【1】 Quan, M.L.; Liauw, A.Y.; Ellis, C.D.; et al.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. J Med Chem 1999, 42, 15, 2752.
【2】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 .

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)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(II)	23357	3-[(hydroxyimino)methyl]benzonitrile		C₈H₆N₂O	详情	详情
(III)	34820	2-(2-methoxy-2-oxoethyl)acrylic acid	7338-27-4	C₆H₈O₄	详情	详情
(IV)	26630	3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid		C₁₄H₁₂N₂O₅	详情	详情
(V)	34821	methyl 2-[5-(chlorocarbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₁₄H₁₁ClN₂O₄	详情	详情
(VI)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(VII)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(VIII)	34822	5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine	7752-82-1	C₄H₄BrN₃	详情	详情
(IX)	34823	2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide		C₁₄H₁₈N₄O₂S	详情	详情
(X)	34824	methyl 2-[5-[[(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)amino]carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₈H₂₈N₆O₆S	详情	详情
(XI)	34825	methyl 2-[5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₄H₂₀N₆O₆S	详情	详情
(XII)	34826	methyl 2-(5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-[3-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate		C₂₅H₂₄N₆O₇S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Itaconic acid mono-tert-butyl ester (IV) was prepared via esterification of itaconic acid (I) with methanol in the presence of an acidic ion exchange resin to form the mono-methyl ester (II), which was further converted to methyl tert-butyl ester (III) upon treatment with isobutylene and sulfuric acid. Subsequent hydrolysis of the methyl ester function of (III) using LiOH furnished mono-ester (IV). Reduction of acid (IV) to the primary alcohol (V) was accomplished using the NaBH4-I2 reagent. Michael addition of p-bromothiophenol (VI) to the unsaturated ester (V) provided the thioether adduct (VII). Mitsunobu coupling of alcohol (VII) with benzo[1,2,3]triazin-4-one (VIII) yielded the 3-substituted triazinone (IX). The biphenyl system (XI) was then obtained by Suzuki coupling of the aryl bromide (IX) with (4-chlorophenyl)tributyltin (X) in the presence of palladium tetrakis(triphenylphosphine) and lithium chloride. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI) gave acid (XII), which was subsequently coupled to O-allyl hydroxylamine (XIII) to afford the allyl hydroxamate (XIV). The O-allyl group was finally removed by treatment with tributyltin hydride and a palladium catalyst.

参考文献中间体

合成目标

【1】 Le Diguarher, T.; Kucharvzyk, N.; Chollet, A.-M.; et al.; Solid-phase synthesis of alpha-substituted 3-bisarylthio N-hydroxy propionamides as specific MMP inhibitors. Bioorg Med Chem 2002, 10, 3, 531.
【2】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 .

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)	27493	2-methylenesuccinic acid	97-65-4	C₅H₆O₄	详情	详情
(II)	34820	2-(2-methoxy-2-oxoethyl)acrylic acid	7338-27-4	C₆H₈O₄	详情	详情
(III)	59619	1-(tert-butyl) 4-methyl 2-methylenesuccinate		C₁₀H₁₆O₄	详情	详情
(IV)	59620	3-(tert-butoxycarbonyl)-3-butenoic acid		C₉H₁₄O₄	详情	详情
(V)	59621	tert-butyl 2-(2-hydroxyethyl)acrylate		C₉H₁₆O₃	详情	详情
(VI)	29626	4-bromophenylhydrosulfide; 4-bromobenzenethiol	106-53-6	C₆H₅BrS	详情	详情
(VII)	59622	tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-hydroxybutanoate		C₁₅H₂₁BrO₃S	详情	详情
(VIII)	36890	1,2,3-benzotriazin-4(3H)-one		C₇H₅N₃O	详情	详情
(IX)	59623	tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate		C₂₂H₂₄BrN₃O₃S	详情	详情
(X)	59624	tributyl(4-chlorophenyl)stannane		C₁₈H₃₁ClSn	详情	详情
(XI)	59625	tert-butyl 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate		C₂₈H₂₈ClN₃O₃S	详情	详情
(XII)	59626	2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoic acid		C₂₄H₂₀ClN₃O₃S	详情	详情
(XIII)	49195	3-(aminooxy)-1-propene; O-allylhydroxylamine		C₃H₇NO	详情	详情
(XIV)	59627	N-(allyloxy)-2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanamide		C₂₇H₂₅ClN₄O₃S	详情	详情

Extended Information