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【结 构 式】 
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【分子编号】19706 【品名】2-(2-methoxyphenyl)acetic acid 【CA登记号】93-25-4 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号：(X)The condensation of racemic (3aRS,4RS,6SR,7aSR)-6-(hydroxymethyl)-4-(2-methoxyphenyl)perhydroisoindol-4-ol (I) with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in dichloromethane gives the diastereomeric amide (III), which is tosylated with tosyl chloride and submitted to chromatography yielding the (3aS,4S,6R,7aR)(S)-enantiomer (IV) as an optically pure isomer. Finally, this compound is allowed to react with potassium cyanide in hot DMSO affording RPR-111905. The starting compounds, the perhydroisoindole (I) and the propionic acid (II) have been obtained as follows: a) The cyclization of 5-(acetoxymethyl)-2-cyclohexen-1-one (V) with N-(butoxymethyl)-N-(trimethylsilylmethyl)benzylamine (VI) by means of trifluoroacetic acid (TFA) in dichloromethane gives racemic (3aRS,6SR,7aSR)-6-(acetoxymethyl)-2-benzylperhydroisoinol-4-one (VII), which is submitted to a Grignard condensation with 2-methoxyphenylmagnesium bromide (VIII) in THF yielding the racemic (3aRS,4RS,6SR,7aSR)(IX). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot ethanol affording the desired racemic diol (I). b) The condensation of 2-(2-methoxyphenyl)acetic acid (X) with (4S,5S)-4-methyl-5-phenyloxazolidin-2-one (XI) by means of NaH, pivaloyl chloride and butyllithium gives the acylated oxazolidinone (XII), which is methylated regioselectively with sodium hexamethyldisylazane (Na-HMDS) and methyl iodide in THF yielding the 2(S)-methyl derivative (XIII). Finally, the hydrolysis of the oxazolidinone group of (XIII) with LiOH in THF-water affords the desired 2(S)-(2-methoxyphenyl)propionic acid (II).
| 【1】 Mutti, S.; et al.; Practical enantiospecific synthesis of RPR 111905: A novel non-peptide substance P antagonist. Tetrahedron Lett 1996, 37, 48, 8743. |
| 【2】 Achard, D.; Peyronel, J.-F.; Tabart, M. (Aventis Pharma SA); Perhydroisoindole derivs. as antagonists of substance P. FR 2727411; JP 1998509970; US 5739351; WO 9616939 . |
| 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) | 19697 | (3aS,4R,6R,7aR)-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-1H-isoindol-4-ol | C16H23NO3 | 详情 | 详情 | |
| (II) | 19698 | (2S)-2-(2-methoxyphenyl)propionic acid | C10H12O3 | 详情 | 详情 | |
| (III) | 19699 | (2S)-1-[(4S,6R)-4-hydroxy-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-2H-isoindol-2-yl]-2-(2-methoxyphenyl)-1-propanone | C26H33NO5 | 详情 | 详情 | |
| (IV) | 19700 | [(3aR,5R,7R,7aS)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2S)-2-(2-methoxyphenyl)propanoyl]octahydro-1H-isoindol-5-yl]methyl 4-methylbenzenesulfonate | C33H39NO7S | 详情 | 详情 | |
| (V) | 19701 | [(1R)-5-oxo-3-cyclohexen-1-yl]methyl acetate | C9H12O3 | 详情 | 详情 | |
| (VI) | 19702 | N-benzyl-N-(butoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-(butoxymethyl)(phenyl)-N-[(trimethylsilyl)methyl]methanamine | C16H29NOSi | 详情 | 详情 | |
| (VII) | 19703 | [(3aR,5R,7aS)-2-benzyl-7-oxooctahydro-1H-isoindol-5-yl]methyl acetate | C18H23NO3 | 详情 | 详情 | |
| (VIII) | 19704 | bromo(2-methoxyphenyl)magnesium | C7H7BrMgO | 详情 | 详情 | |
| (IX) | 19705 | (3aS,4R,6R,7aR)-2-benzyl-6-(hydroxymethyl)-4-(2-methoxyphenyl)octahydro-1H-isoindol-4-ol | C23H29NO3 | 详情 | 详情 | |
| (X) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (XI) | 19707 | (4S,5S)-4-methyl-5-phenyl-1,3-oxazolidin-2-one | 17097-67-5 | C10H11NO2 | 详情 | 详情 |
| (XII) | 19708 | (4S,5S)-3-[2-(2-methoxyphenyl)acetyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C19H19NO4 | 详情 | 详情 | |
| (XIII) | 19709 | (4S,5S)-3-[(2S)-2-(2-methoxyphenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C20H21NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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.
| 【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3
该中间体在本合成路线中的序号：(IX)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.
| 【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 |
合成路线4
该中间体在本合成路线中的序号：(VII)A chiral process for the synthesis of the title compound was later reported. Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII), which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3. Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide, followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI). This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII). Basic hydrolysis afforded the racemic carboxylic acid (XIII), which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine. Reduction of the nitro group from the desired (S)-enantiomer (XIV), and subsequent acidic treatment then produced the title oxindole derivative.
| 【1】 Hewawasam, P.; et al.; The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels. Bioorg Med Chem Lett 2002, 12, 7, 1023. |
| 【2】 Martín, L.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; BMS-204352. Drugs Fut 2001, 26, 1, 9. |
| 【3】 Thottathil, J.K.; Pendri, Y.R.; Martinez, E.J.; Hewawasam, P. (Bristol-Myers Squibb Co.); Preparation of 3-fluoro oxindole derivs.. WO 9816222 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 19706 | 2-(2-methoxyphenyl)acetic acid | 93-25-4 | C9H10O3 | 详情 | 详情 |
| (VIII) | 39340 | 2-(5-chloro-2-methoxyphenyl)acetic acid | C9H9ClO3 | 详情 | 详情 | |
| (IX) | 39341 | methyl 2-(5-chloro-2-methoxyphenyl)acetate | C10H11ClO3 | 详情 | 详情 | |
| (X) | 39342 | 1-fluoro-2-nitro-4-(trifluoromethyl)benzene | 367-86-2 | C7H3F4NO2 | 详情 | 详情 |
| (XI) | 39343 | methyl 2-(5-chloro-2-methoxyphenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate | C17H13ClF3NO5 | 详情 | 详情 | |
| (XII) | 39344 | methyl 2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate | C17H12ClF4NO5 | 详情 | 详情 | |
| (XIII) | 39345 | 2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]acetic acid | C16H10ClF4NO5 | 详情 | 详情 | |
| (XIV) | 39346 | (2S)-2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]ethanoic acid | C16H10ClF4NO5 | 详情 | 详情 |