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【结 构 式】 
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【分子编号】35857 【品名】methyl 4-acryloylbenzoate 【CA登记号】 |
【 分 子 式 】C11H10O3 【 分 子 量 】190.1986 【元素组成】C 69.46% H 5.3% O 25.24% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Fischer esterification of 2,2,5,5-tetramethylhexanedioic acid (I) provided diethyl ester (II), which was subjected to acyloin condensation with sodium in xylene to furnish the alpha-hydroxy cyclohexanone (III). Further oxidation of (III) with CrO3 gave diketone (IV). This was condensed with 2,3-diaminopropionic acid (V) to afford, after esterification with MeOH and H2SO4, the quinoxaline ester (VI). Reduction of (VI) to alcohol (VII) employing diisobutylaluminum hydride, followed by Swern oxidation gave rise to aldehyde (VIII). Optionally, addition of vinylmagnesium bromide to (VIII), and further Swern oxidation of the allylic alcohol (IX) provided the alpha,beta-unsaturated ketone (X). Conversion to the required diketo precursor (XII) was achieved by two related strategies. Coupling of ethyl 4-formylbenzoate (XI) with the unsaturated ketone (X) using 3-benzyl-5-(2-hydroxyethyl)-4-ethylthiazolium chloride as the catalyst gave the 1,4-diketone (XII). Alternatively, addition of vinylmagnesium bromide to ethyl 4-formylbenzoate (XI) followed by oxidation with pyridinium dichromate gave unsaturated ketone (XIII). This was then coupled with quinoxaline aldehyde (VIII) in the presence of a thiazolium salt to furnish diketone (XII).
| 【1】 Tai, K.; Yamauchi, T.; Hida, T.; Kikuchi, K.; Nagia, M.; Yoshimura, H.; Tokuhara, N.; Hibi, S.; Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline derivatives with retinoic acid receptor alpha agonistic activity. J Med Chem 2000, 43, 3, 409. |
| 【2】 Kikuchi, K.; Tagami, K.; Yoshimura, H.; Hibi, S.; Nagai, M.; Abe, S.; Okita, M.; Hida, T.; Higashi, S.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Heterocyclic carboxylic acid derivs. and drugs containing the same. JP 1997071566; US 5977108; WO 9702244 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 | |
| (I) | 37002 | 2,2,5,5-tetramethylhexanedioic acid | C10H18O4 | 详情 | 详情 | |
| (II) | 37003 | diethyl 2,2,5,5-tetramethylhexanedioate | C14H26O4 | 详情 | 详情 | |
| (III) | 37004 | 6-hydroxy-2,2,5,5-tetramethylcyclohexanone | C10H18O2 | 详情 | 详情 | |
| (IV) | 37005 | 3,3,6,6-tetramethyl-1,2-cyclohexanedione | C10H16O2 | 详情 | 详情 | |
| (V) | 37006 | 2,3-diaminopropionic acid | 18635-45-5 | C3H8N2O2 | 详情 | 详情 |
| (VI) | 37007 | methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VII) | 37008 | (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)methanol | C13H20N2O | 详情 | 详情 | |
| (VIII) | 37009 | 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinecarbaldehyde | C13H18N2O | 详情 | 详情 | |
| (IX) | 37010 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-ol | C15H22N2O | 详情 | 详情 | |
| (X) | 37011 | 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one | C15H20N2O | 详情 | 详情 | |
| (XI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (XII) | 37012 | methyl 4-[4-oxo-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)butanoyl]benzoate | C24H28N2O4 | 详情 | 详情 | |
| (XIII) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 7-ethyl-4-methylbenzofuran-2-carbaldehyde (I) with 4-acryloylbenzoic acid methyl ester (II) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) in hot DMF gives the 1,4-butanedione (III), which is cyclized with ammonium acetate in refluxing methanol to yield the substituted pyrrole (IV). Finally, the ester group of (IV) is hydrolyzed with NaOH in refluxing ethanol/water.
| 【1】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 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) | 35858 | 7-ethyl-4-methyl-1-benzofuran-2-carbaldehyde | C12H12O2 | 详情 | 详情 | |
| (II) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 | |
| (III) | 35859 | methyl 4-[4-(7-ethyl-4-methyl-1-benzofuran-2-yl)-4-oxobutanoyl]benzoate | C23H22O5 | 详情 | 详情 | |
| (IV) | 35860 | methyl 4-[5-(7-ethyl-4-methyl-1-benzofuran-2-yl)-1H-pyrrol-2-yl]benzoate | C23H21NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The condensation of 2-hydroxy-3,6-dimethylbenzaldehyde (I) with 2-bromoacetaldehyde dimethyl acetal (II) by means of K2CO3 in DM gives the phenoxyacetaldehyde acetal (III), which is cyclized by means of acetic acid to yield 4,7-dimethylbenzofuran (IV). The condensation of (IV) with 4-acryloylbenzoic acid methyl ester (V) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) and TEA in DMF affords the butanedione derivative (VI), which is cyclized to the pyrrole derivative (VII) by means of NH4OAc in refluxing methanol. Finally, the methyl ester group of (VII) is hydrolyzed with NaOH in ethanol to afford the target carboxylic acid.
| 【1】 Yoshimura, H.; et al.; Discovery of novel and potent retinoic acid receptor alpha agonists: Syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem 2000, 43, 15, 2929. |
| 【2】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 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) | 50362 | 2-hydroxy-3,6-dimethylbenzaldehyde | C9H10O2 | 详情 | 详情 | |
| (II) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (III) | 50363 | 2-(2,2-dimethoxyethoxy)-3,6-dimethylbenzaldehyde | C13H18O4 | 详情 | 详情 | |
| (IV) | 35861 | 4,7-dimethyl-1-benzofuran-2-carbaldehyde | C11H10O2 | 详情 | 详情 | |
| (V) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 | |
| (VI) | 35862 | methyl 4-[4-(4,7-dimethyl-1-benzofuran-2-yl)-4-oxobutanoyl]benzoate | C22H20O5 | 详情 | 详情 | |
| (VII) | 35863 | methyl 4-[5-(4,7-dimethyl-1-benzofuran-2-yl)-1H-pyrrol-2-yl]benzoate | C22H19NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)This compound has been obtained by two related ways: 1) The Grignard reaction of 5,8-dimethylnaphthalene-2-carbaldehyde (I) with vinylmagnesium bromide in ether/THF gives the expected carbinol (II), which is oxidized with MnO2 in dichloromethane yielding the propenone (III). The condensation of (III) with 4-formylbenzoic acid methyl ester (IV) by means of 3-benzyl-5-(hydroxymethyl)-4-methylthiazolium chloride (BHMT) in refluxing ethanol affords the 1,4-butanedione (V), which is cyclized with ammonium acetate in refluxing methanol to give the substituted pyrrole (VI). Finally, the ester group of (V) is hydrolyzed with NaOH in refluxing ethanol/water. 2) 1,4-Butanedione (V) can also be obtained by condensation of 5,8-dimethylnaphthalene-2-carbaldehyde (I) with 4-acryloylbenzoic acid methyl ester (VII) by means of BHMT in hot DMF.
| 【1】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 | |
| (I) | 35852 | 5,8-dimethyl-2-naphthaldehyde | C13H12O | 详情 | 详情 | |
| (II) | 35853 | 1-(5,8-dimethyl-2-naphthyl)-2-propen-1-ol | C15H16O | 详情 | 详情 | |
| (III) | 35854 | 1-(5,8-dimethyl-2-naphthyl)-2-propen-1-one | C15H14O | 详情 | 详情 | |
| (IV) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (V) | 35855 | methyl 4-[4-(5,8-dimethyl-2-naphthyl)-4-oxobutanoyl]benzoate | C24H22O4 | 详情 | 详情 | |
| (VI) | 35856 | methyl 4-[5-(5,8-dimethyl-2-naphthyl)-1H-pyrrol-2-yl]benzoate | C24H21NO2 | 详情 | 详情 | |
| (VII) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)The reaction of 2-fluoro-5-(trifluoromethyl)phenol (I) with allyl bromide (II) by means of K2CO3 in DMF gives the phenol ether (III), which is submitted to an allylic rearrangement by heating at 190 C to yield 2-allyl-6-fluoro-3-(trifluoromethyl)phenol (IV). The cyclization of (IV) by means of MCPBA and KOH affords the dihydrobenzofuran (V), which is treated with Ac2O and pyridine to provide the acetate (VI). The dehydrogenation of (VI) by means of NBS and AIBN, followed by a treatment with tBu-OK and K2CO3 in methanol, gives 1-[7-fluoro-4-(trifluoromethyl)benzofuran-2-yl]methanol (VII), which is oxidized with oxalyl chloride and TEA in DMSO to yield the corresponding carbaldehyde (VIII). The condensation of (VIII) with 4-acryloylbenzoic acid methyl ester (IX) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (BHMT) and TEA in DMF affords the 1,4-butanedione derivative (X), which is submitted to a pyrrole synthesis by cyclization with AcONH4 in refluxing ethanol to provide the disubstituted pyrrole (XI). Finally, the ester group of (XI) is hydrolyzed with NaOH in ethanol to furnish the target carboxylic acid.
| 【1】 Yoshimura, H.; et al.; Discovery of novel and potent retinoic acid receptor alpha agonists: Syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem 2000, 43, 15, 2929. |
| 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) | 50315 | 2-Fluoro-5-(trifluoromethyl)phenol | 141483-15-0 | C7H4F4O | 详情 | 详情 |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 50316 | 2-(allyloxy)-1-fluoro-4-(trifluoromethyl)benzene; allyl 2-fluoro-5-(trifluoromethyl)phenyl ether | C10H8F4O | 详情 | 详情 | |
| (IV) | 50317 | 2-allyl-6-fluoro-3-(trifluoromethyl)phenol | C10H8F4O | 详情 | 详情 | |
| (V) | 50318 | [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol | C10H8F4O2 | 详情 | 详情 | |
| (VI) | 50319 | [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl acetate | C12H10F4O3 | 详情 | 详情 | |
| (VII) | 50320 | [7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]methanol | C10H6F4O2 | 详情 | 详情 | |
| (VIII) | 35847 | 7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde | C10H4F4O2 | 详情 | 详情 | |
| (IX) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 | |
| (X) | 35850 | methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate | C21H14F4O5 | 详情 | 详情 | |
| (XI) | 35851 | methyl 4-[5-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-1H-pyrrol-2-yl]benzoate | C21H13F4NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)From the starting carbaldehyde (I) two different pathways can be followed: 1) A solution of carbaldehyde (I) in ether is treated with the vinyl Grignard reagent (A) in THF and oxidized with activated manganese dioxide to afford enone derivative (II). The derivative is then coupled with methyl 4-formylbenzoate (III) in refluxing ethanol in presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) to yield diketone (IV). 2) Methyl 4-formylbenzoate (III) is treated with vinylmagnesium bromide (A) in THF, and oxidized with pyridinium dichromate to give methyl 4-acryloylbenzoate (V), which is coupled with carbaldehyde (I) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (B) and triethylamine in DMF to yield directly diketone (IV). The final step is the cyclization of diketone (IV) to afford the pyrrole-benzoic acid derivative by treatment of the diketone with ammonium acetate in refluxing methanol and hydrolysis with NaOH in refluxing ethanol followed by neutralization with dilute HCl.
| 【1】 Tagami, K.; Nagai, M.; Tokuhara, N.; Hida, T.; Yoshimura, H.; Hibi, S.; Yamauchi, T.; Kikuchi, K.; Tai, K.; Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as potent and selective retinoic acid receptor alpha agonists. Bioorg Med Chem Lett 2000, 10, 7, 623. |
| 【2】 Tagami, K.; Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.; Sato, T.; Okita, M.; Okamoto, Y.; Nagasaka, Y.; Kobayashi, N.; Hida, T.; Tai, K.; Tokuhara, N.; Kobayashi, S. (Eisai Co., Ltd.); Fused-ring carboxylic acid derivs.. EP 0889032; US 6110959; US 6121309; WO 9734869 . |
| 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) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (B) | 27942 | 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride | 4568-71-2 | C13H16ClNOS | 详情 | 详情 |
| (I) | 40989 | 5,8-dimethyl-2H-chromene-3-carbaldehyde | C12H12O2 | 详情 | 详情 | |
| (II) | 40990 | 1-(5,8-dimethyl-2H-chromen-3-yl)-2-propen-1-one | C14H14O2 | 详情 | 详情 | |
| (III) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (IV) | 40991 | 4-[4-(5,8-dimethyl-2H-chromen-3-yl)-4-oxobutanoyl]benzoic acid | C22H20O5 | 详情 | 详情 | |
| (V) | 35857 | methyl 4-acryloylbenzoate | C11H10O3 | 详情 | 详情 |