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【结 构 式】 
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【分子编号】10170 【品名】methyl 4-formylbenzoate 【CA登记号】1571-08-0 |
【 分 子 式 】C9H8O3 【 分 子 量 】164.16072 【元素组成】C 65.85% H 4.91% O 29.24% |
合成路线1
该中间体在本合成路线中的序号：(VI)The synthesis of [14C]-labeled BRL-26830A has been described: The reaction of copper sulfate (I) with sodium methabisulfite, followed by treatment with [14C]-labeled potassium cyanide (II) yields cuprous cyanide (III), which is condensed with methyl 4-bromobenzoate (IV) to afford methyl 4-cyanobenzoate (V). The reduction of (V) with Al/Ni and formic acid gives methyl 4-formylbenzoate (VI), which is condensed with nitroethane by means of butylamine and acetic acid in benzene to give methyl 4-(2-nitro-1-propenyl)benzoate (VII). The treatment of (VII) with Fe and HCl in refluxing methanol yields methyl 4-(acetonyl)benzoate (VIII), which is reductocondensed with (R*)-2-amino-1-phenylethanol (IX) by means of NaBH4 in refluxing benzene and crystallized in methanol to fractionate the optical diastereomers. Finally, the (R*,R*)-isomer (X) is treated with fumaric acid.
| 【1】 Freer, R.; Morecombe, D.J.; The synthesis of [14C]BRL 26830A, a novel beta-adrenoceptor agonist. J Label Compd Radiopharm 1992, 31, 9, 697. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (IV) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (V) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (V) | 44596 | methyl 4-cyanobenzoate | C9H7NO2 | 详情 | 详情 | |
| (VI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (VI) | 44597 | methyl 4-formylbenzoate | C9H8O3 | 详情 | 详情 | |
| (VII) | 10171 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VII) | 44598 | methyl 4-[(Z)-2-nitro-1-propenyl]benzoate | C11H11NO4 | 详情 | 详情 | |
| (VIII) | 10172 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (VIII) | 44599 | methyl 4-(2-oxopropyl)benzoate | C11H12O3 | 详情 | 详情 | |
| (IX) | 10173 | (1R)-2-Amino-1-phenyl-1-ethanol | 2549-14-6 | C8H11NO | 详情 | 详情 |
| (X) | 44595 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 | |
| (X) | 44600 | methyl 4-((2R)-2-[[(2R)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate | C19H23NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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3
该中间体在本合成路线中的序号：(XI)Condensation of 3-methyl-2-butanone (I) with methyl 2-methoxyacetate (II) by means of sodium in toluene gave diketone (III). Pyrazole (IV) was prepared by treatment of diketone (III) with hydrazine. Subsequent alkylation of pyrazole (IV) with isopropyl iodide in the presence of sodium hydride provided a mixture of N-alkylated regioisomers (V) and (VI). The desired minor isomer (V) was demethylated with BBr3 and the resulting alcohol (VII) was oxidized to aldehyde (VIII) using manganese dioxide. Addition of vinylmagnesium bromide to the formyl group of (VIII) produced allylic alcohol (IX), which was further oxidized to ketone (X) with MnO2. The benzoin-type condensation of unsaturated ketone (X) with aldehyde (XI) in the presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride furnished the 1,4-diketone (XII). Cyclization of (XII) to pyrrole (XIII) was carried out by treatment with ammonium acetate in refluxing MeOH. Finally, ester hydrolysis by means of NaOH gave rise to the corresponding carboxylic acid.
| 【1】 Yamauchi, T.; Tokuhara, N.; Yoshimura, H.; Nagai, M.; Hida, T.; Tai, K.; Hibi, S.; Kikuchi, K.; Novel retinoic acid receptor alpha agonists: Syntheses and evaluation of pyrazole derivatives. Bioorg Med Chem Lett 2000, 10, 7, 619. |
| 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) | 26143 | 3-methyl-2-butanone | 563-80-4 | C5H10O | 详情 | 详情 |
| (II) | 19100 | methyl 2-methoxyacetate | 6290-49-9 | C4H8O3 | 详情 | 详情 |
| (III) | 42297 | 1-methoxy-5-methyl-2,4-hexanedione | C8H14O3 | 详情 | 详情 | |
| (IV) | 42298 | (3-isopropyl-1H-pyrazol-5-yl)methyl methyl ether; 3-isopropyl-5-(methoxymethyl)-1H-pyrazole | C8H14N2O | 详情 | 详情 | |
| (V) | 42299 | 1,5-diisopropyl-3-(methoxymethyl)-1H-pyrazole; (1,5-diisopropyl-1H-pyrazol-3-yl)methyl methyl ether | C11H20N2O | 详情 | 详情 | |
| (VI) | 42300 | 1,3-diisopropyl-5-(methoxymethyl)-1H-pyrazole; (1,3-diisopropyl-1H-pyrazol-5-yl)methyl methyl ether | C11H20N2O | 详情 | 详情 | |
| (VII) | 42301 | (1,5-diisopropyl-1H-pyrazol-3-yl)methanol | C10H18N2O | 详情 | 详情 | |
| (VIII) | 42302 | 1,5-diisopropyl-1H-pyrazole-3-carbaldehyde | C10H16N2O | 详情 | 详情 | |
| (IX) | 42303 | 1-(1,5-diisopropyl-1H-pyrazol-3-yl)-2-propen-1-ol | C12H20N2O | 详情 | 详情 | |
| (X) | 42304 | 1-(1,5-diisopropyl-1H-pyrazol-3-yl)-2-propen-1-one | C12H18N2O | 详情 | 详情 | |
| (XI) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (XII) | 42305 | methyl 4-[4-(1,5-diisopropyl-1H-pyrazol-3-yl)-4-oxobutanoyl]benzoate | C21H26N2O4 | 详情 | 详情 | |
| (XIII) | 42306 | methyl 4-[5-(1,5-diisopropyl-1H-pyrazol-3-yl)-1H-pyrrol-2-yl]benzoate | C21H25N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Addition of 3-lithiopyridine (I) to methyl 4-formylbenzoate (II) in Et2O at low temperature provided carbinol (III), which was oxidized to ketone (IV) with MnO2 in refluxing THF. Then, saponification of the methyl ester of (IV) gave acid (V). Alternatively, acid (V) was obtained by Jones oxidation of silyloxymethyl compound (VI). Serinamide (IX) was prepared by coupling of N-Boc-L-serine (VII) with 4-cyclohexylbutylamine (VIII) using EDC and HOBt, followed by deprotection of the Boc group with trifluoroacetic acid in cold CH2Cl2. Compound (IX) was then coupled with acid (V) to provide amide (X), whose cyclization in the presence of PPh3, CCl4 and i-Pr2NEt produced the oxazoline (XI). Subsequent nickel peroxide oxidation yielded oxazole (XII). Finally, Wittig reaction of (XII) with phosphonate (XIII) in the presence of KO-t-Bu furnished the title compound.
| 【1】 Takeuchi, K.; Kohn, T.J.; True, T.A.; Mais, D.E.; Wikel, J.H.; Utterback, B.G.; Wyss, V.L.; Jakubowski, J.A.; Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 3. Synthesis and biological activities of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives and related compo. J Med Chem 1998, 41, 27, 5362. |
| 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) | 18261 | 3-pyridinyllithium | C5H4LiN | 详情 | 详情 | |
| (II) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (III) | 20122 | methyl 4-[hydroxy(3-pyridinyl)methyl]benzoate | C14H13NO3 | 详情 | 详情 | |
| (IV) | 20123 | methyl 4-(3-pyridinylcarbonyl)benzoate | C14H11NO3 | 详情 | 详情 | |
| (V) | 20124 | 4-(3-pyridinylcarbonyl)benzoic acid | C13H9NO3 | 详情 | 详情 | |
| (VI) | 18277 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl](3-pyridinyl)methanone | C19H25NO2Si | 详情 | 详情 | |
| (VII) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (VIII) | 20127 | 4-cyclohexyl-1-butanamine; 4-cyclohexylbutylamine | C10H21N | 详情 | 详情 | |
| (IX) | 18268 | (2S)-2-amino-N-(4-cyclohexylbutyl)-3-hydroxypropanamide | C13H26N2O2 | 详情 | 详情 | |
| (X) | 20129 | N-[(1S)-2-[(4-cyclohexylbutyl)amino]-1-(hydroxymethyl)-2-oxoethyl]-4-(3-pyridinylcarbonyl)benzamide | C26H33N3O4 | 详情 | 详情 | |
| (XI) | 20130 | (4S)-N-(4-cyclohexylbutyl)-2-[4-(3-pyridinylcarbonyl)phenyl]-4,5-dihydro-1,3-oxazole-4-carboxamide | C26H31N3O3 | 详情 | 详情 | |
| (XII) | 20131 | N-(4-cyclohexylbutyl)-2-[4-(3-pyridinylcarbonyl)phenyl]-1,3-oxazole-4-carboxamide | C26H29N3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)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6
该中间体在本合成路线中的序号：(IV)The Grignard reaction of 7-fluoro-4-(trifluoromethyl)benzofuran-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.
| 【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) | 35847 | 7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde | C10H4F4O2 | 详情 | 详情 | |
| (II) | 35848 | 1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-ol | C12H8F4O2 | 详情 | 详情 | |
| (III) | 35849 | 1-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-2-propen-1-one | C12H6F4O2 | 详情 | 详情 | |
| (IV) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (V) | 35850 | methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate | C21H14F4O5 | 详情 | 详情 | |
| (VI) | 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7
该中间体在本合成路线中的序号：(III)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 |
合成路线8
该中间体在本合成路线中的序号：(II)2-Methoxyphenethylamine (I) is condensed with methyl 4-formylbenzoate (II) to form imine (III), which is further reduced to amine (IV) with NaBH4 in MeOH. Alkylation of amine (IV) by ethyl 5-bromovalerate (V) affords the amino diester (VI). Methyl ether cleavage in (VI) by means of BBr3 gives rise to the phenol compound (VII), which is alkylated with 4-(chloromethyl)stilbene (VIII) to yield ether (IX). Catalytic hydrogenation of stilbene (IX) yields the phenethylbenzyl derivative (X). Finally, alkaline hydrolysis of the methyl ester groups of (X) leads to the title dicarboxylic acid.
| 【1】 Perzborn, E.; Stasch, J.-P.; Heil, M.; Naab, P.; Dembowsky, K.; Alonso-Alija, C.; Stahl, E.; Pernerstorfer, J.; Flubacher, D.; Wunder, F. (Bayer AG); Novel derivs. of dicarboxylic acid having pharmaceutical properties. DE 19943635; EP 1216225; WO 0119780 . |
| 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) | 57674 | 1-Amino-2-(2-methoxyphenyl)ethane; 2-(2-Aminoethyl)anisole; 2-(2-Methoxyphenyl)ethylamine; 2-Methoxyphenethylamine | 2045-79-6 | C9H13NO | 详情 | 详情 |
| (II) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (III) | 57675 | methyl 4-{[(2-methoxyphenethyl)imino]methyl}benzoate | C18H19NO3 | 详情 | 详情 | |
| (IV) | 57676 | methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate | C18H21NO3 | 详情 | 详情 | |
| (V) | 37151 | ethyl 5-bromopentanoate | 14660-52-7 | C7H13BrO2 | 详情 | 详情 |
| (VI) | 57677 | methyl 4-{[(5-ethoxy-5-oxopentyl)(2-methoxyphenethyl)amino]methyl}benzoate | C25H33NO5 | 详情 | 详情 | |
| (VII) | 57678 | methyl 4-{[(2-hydroxyphenethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate | C23H29NO5 | 详情 | 详情 | |
| (VIII) | 57679 | 4-Chloromethylstilbene | C15H13Cl | 详情 | 详情 | |
| (IX) | 57680 | methyl 4-({(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenylethenyl]benzyl}oxy)phenethyl]amino}methyl)benzoate | C38H41NO5 | 详情 | 详情 | |
| (X) | 57681 | methyl 4-[((5-methoxy-5-oxopentyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino)methyl]benzoate | C38H43NO5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)Wittig reaction of aldehyde (I) with methylene triphenylphosphorane produced olefin (II). Oxime (IV) was prepared from methyl 4-formylbenzoate (III) by treatment with hydroxylamine. The nitrile oxide generated from imine (IV) by chlorination, followed by elimination under basic conditions, underwent a [3+2] regioselective cycloaddition with alkene (II) to produce isoxazoline (V). Oxidation of the isoxazoline ring of (V) to the corresponding isoxazole derivative (VI) was accomplished by treatment with N-bromosuccinimide. Finally, ester hydrolysis with LiOH furnished the title carboxylic acid.
| 【1】 Simoni, D.; et al.; Heterocycle-containing retinoids. Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptosis-resistant cells. J Med Chem 2001, 44, 14, 2308. |
| 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) | 50713 | 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde | C15H20O | 详情 | 详情 | |
| (II) | 50714 | 1,1,4,4-tetramethyl-6-vinyl-1,2,3,4-tetrahydronaphthalene | C16H22 | 详情 | 详情 | |
| (III) | 10170 | methyl 4-formylbenzoate | 1571-08-0 | C9H8O3 | 详情 | 详情 |
| (IV) | 19219 | methyl 4-[(hydroxyimino)methyl]benzoate | C9H9NO3 | 详情 | 详情 | |
| (V) | 50715 | methyl 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5-dihydro-3-isoxazolyl]benzoate | C25H29NO3 | 详情 | 详情 | |
| (VI) | 50716 | methyl 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-3-isoxazolyl]benzoate | C25H27NO3 | 详情 | 详情 |