2-(2-methoxyphenyl)acrylic acid -Drug Synthesis Database

【结构式】

【分子编号】37790

【品名】2-(2-methoxyphenyl)acrylic acid

【CA登记号】

【分子式】C₁₀H₁₀O₃

【分子量】178.1876

【元素组成】C 67.41% H 5.66% O 26.94%

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：(IX)

Diels-Alder reaction between (E,E)-1,4-diphenylbutadiene (I) and propiolic acid (II) in xylene in the presence of hydroxyquinone (A) yields cyclohexadiene carboxylic acid (III), which is then converted into its methyl ester derivative (IV) by treatment with MeOH in the presence of H2SO4. Condensation of methyl ester (IV) with N-trimethylsilylmethyl-N-butoxymethyl-benzylamine (V) in CH2Cl2 in the presence of TFA provides hexahydro isoindole derivative (VI), which is first treated with trifluoromethane sulfonic acid in CH2Cl2, followed by treatment with NaOH, to furnish benzo[f]isoindole derivative (VII). Debenzylation of (VII) by reaction with ammonium formate and Pd/C gives compound (VIII), which is then converted into derivative (X) by coupling with 2-(2-methoxyphenyl)acrylic acid (IX). The target product is finally obtained by hydrolysis of methyl ester (X) with NaOH in EtOH. Intermediate (IX) can be obtained as follows: Treatment of 2-methoxyphenylacetic acid (XI) with thionyl chloride in refluxing EtOH provides ethyl ester (XII), which then reacts with paraformaldehyde and tetrabutylammonium iodide (TBAI) and K2CO3 in refluxing toluene to afford acrylate (XIII). Finally, ethyl ester (XIII) is hydrolyzed by treatment with refluxing NaOH.

参考文献中间体

合成目标

【1】 Truchon, A.; Sounigo, F.; Peyronel, J.-F.; Zucco, M.; Mailliet, P.; Commercon, A.; Lebrun, A. (Aventis Pharma SA); 4,9-Ethano-benzo(f)isoindole derivs. as farnesyl transferase inhibitors. WO 9703050 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	13163	p-Dihydrobenzene; Hydroquinone	123-31-9	C₆H₆O₂	详情	详情
(I)	46199	1-[(1E,3E)-4-phenyl-1,3-butadienyl]benzene		C₁₆H₁₄	详情	详情
(II)	41770	propiolic acid	471-25-0	C₃H₂O₂	详情	详情
(III)	46200	3,6-diphenyl-1,4-cyclohexadiene-1-carboxylic acid		C₁₉H₁₆O₂	详情	详情
(IV)	46201	methyl 3,6-diphenyl-1,4-cyclohexadiene-1-carboxylate		C₂₀H₁₈O₂	详情	详情
(V)	19702	N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine		C₁₆H₂₉NOSi	详情	详情
(VI)	46202	methyl (7aS)-2-benzyl-4,7-diphenyloctahydro-3aH-isoindole-3a-carboxylate		C₂₉H₃₁NO₂	详情	详情
(VII)	46203	methyl (1R,8R,9S,13S)-11-benzyl-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₂₉H₂₉NO₂	详情	详情
(VIII)	46204	methyl (1R,8R,9S,13S)-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₂₂H₂₃NO₂	详情	详情
(IX)	37790	2-(2-methoxyphenyl)acrylic acid		C₁₀H₁₀O₃	详情	详情
(X)	46205	methyl (1R,8R,9S,13S)-11-[2-(2-methoxyphenyl)acryloyl]-1-phenyl-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₃₂H₃₁NO₄	详情	详情
(XI)	19706	2-(2-methoxyphenyl)acetic acid	93-25-4	C₉H₁₀O₃	详情	详情
(XII)	46206	ethyl 2-(2-methoxyphenyl)acetate		C₁₁H₁₄O₃	详情	详情
(XIII)	46207	ethyl 2-(2-methoxyphenyl)acrylate		C₁₂H₁₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Treatment of 3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acid (I) with methyl iodide and DBU afforded methyl ester (II). Subsequent cycloaddition of (II) with N-n-butoxymethyl-N-(trimethylsilyl)methyl benzylamine (III) in the presence of trifluoroacetic acid gave the octahydroisoindole (IV). Addition of p-tolylmagnesium bromide (V) to the keto group of (IV) produced carbinol (VI), which was converted to the tetracyclic system (VII) by intramolecular cyclization in the presence of trifluoromethanesulfonic acid. Cleavage of the N-benzyl of (VII) group to give (VIII) was effected by transfer hydrogenation with ammonium formate and Pd/C. On the other hand, condensation of (2-methoxyphenyl)acetic acid (IX) with bis(dimethylamino)methane, followed by treatment with acetic anhydride generated the 2-arylpropenoic acid (X), which was converted to acid chloride (XI) employing oxalyl chloride and a catalytic amount of DMF. Coupling of acid chloride (XI) with the tetracyclic amine (VIII) yielded the corresponding amide (XII). The methyl ester group of (XII) was finally hydrolyzed with NaOH to the title carboxylic acid.

参考文献中间体

合成目标

【1】 Dereu, N.; Sounigo-Thompson, F.; Commercon, A.; Martin, J.-P.; Bourzat, J.-D.; Capet, M.; Cheve, M.; Mailliet, P. (Aventis Pharma SA); Farnesyl transferase inhibitors. EP 0948483; WO 9829390 .

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)	37784	3-oxo-6-phenyl-1-cyclohexene-1-carboxylic acid		C₁₃H₁₂O₃	详情	详情
(II)	37785	methyl 3-oxo-6-phenyl-1-cyclohexene-1-carboxylate		C₁₄H₁₄O₃	详情	详情
(III)	19702	N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine		C₁₆H₂₉NOSi	详情	详情
(IV)	37786	methyl (4R,7aS)-2-benzyl-7-oxo-4-phenyloctahydro-3aH-isoindole-3a-carboxylate		C₂₃H₂₅NO₃	详情	详情
(V)	35657	bromo(4-methylphenyl)magnesium	4294-57-9	C₇H₇BrMg	详情	详情
(VI)	37787	methyl (4R,7R,7aS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4-phenyloctahydro-3aH-isoindole-3a-carboxylate		C₃₀H₃₃NO₃	详情	详情
(VII)	37788	methyl (1R,8R,9S,13S)-11-benzyl-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₃₀H₃₁NO₂	详情	详情
(VIII)	37789	methyl (1R,8R,9S,13S)-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₂₃H₂₅NO₂	详情	详情
(IX)	19706	2-(2-methoxyphenyl)acetic acid	93-25-4	C₉H₁₀O₃	详情	详情
(X)	37790	2-(2-methoxyphenyl)acrylic acid		C₁₀H₁₀O₃	详情	详情
(XI)	37791	2-(2-methoxyphenyl)acryloyl chloride		C₁₀H₉ClO₂	详情	详情
(XII)	37792	methyl (1R,8R,9S,13S)-11-[2-(2-methoxyphenyl)acryloyl]-1-(4-methylphenyl)-11-azatetracyclo[6.5.2.0(2,7).0(9,13)]pentadeca-2,4,6-triene-9-carboxylate		C₃₃H₃₃NO₄	详情	详情

Extended Information