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【结 构 式】 
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【分子编号】28559 【品名】m-Anisic acid; 3-Methoxybenzoic acid 【CA登记号】586-38-9 |
【 分 子 式 】C8H8O3 【 分 子 量 】152.14972 【元素组成】C 63.15% H 5.3% O 31.55% |
合成路线1
该中间体在本合成路线中的序号：(I)Treatment of 3-methoxybenzoic acid (I) with methyl chloroformate and triethylamine produced the mixed anhydride (II), which was condensed with amine (III) to provide the title amide.
| 【1】 Perrone, R.; Berardi, F.; Colabufo, N.A.; Leopoldo, M.; Tortorella, V.; N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: A potent and selective dopamine D4 ligand. J Med Chem 1998, 41, 24, 4903. |
合成路线2
该中间体在本合成路线中的序号：(I)The bromination of 3-methoxybenzoic acid (I) with Br2 in refluxing acetic acid gives 2-bromo-5-methoxybenzoic acid (II), which is condensed with 3-chlorothiophenol (III) by means of cupric acetate in DMF at 150 C yielding the sulfide (IV). The cyclization of (IV) in sulfuric acid affords the thioxanthenone (V), which is condensed with 2-(diethylamino)ethylamine (VI) in pyridine at 115 C giving the corresponding 2-(diethylamino)ethylamino derivative (VII). The hydroxymethylation of (VII) with formaldehyde in hot 5N acetic acid yields the hydroxymethyl derivative (VIII), which is oxidized with MnO2 in hot toluene affording the corresponding aldehyde (IX). Finally, this compound is treated with formamide and formic acid at 170 C.
| 【1】 Perni, R.B.; Wentland, M.P.; Huang, J.I.; Powles, R.G.; Aldous, S.; Klingbeil, K.M.; Peverly, A.D.; Robinson, R.G.; Corbett, T.H.; Jones, J.L.; Mattes, K.C.; Rake, J.B.; Coughlin, S.A.; Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives. J Med Chem 1998, 41, 19, 3645. |
| 【2】 Miller, T.C.; Collins, J.C.; Wentland, M.P.; Perni, R.B.; Corbett, T.H.; Mattes, K.C. (Sanofi-Synthelabo); Thioxanthenone antitumor agents. EP 0518414; EP 0619315; EP 0882723; JP 1993178853; JP 1994340655; US 5346917 . |
| 【3】 Wentland, M.P.; et al.; Anti-solid tumor efficacy and preparation of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxo-9H-thioxanthen-4-yl]methyl]methanesulfonamide (WIN 33377) and related derivatives. Bioorg Med Chem Lett 1994, 4, 4, 609. |
| 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) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (II) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (III) | 30443 | 3-chlorophenylhydrosulfide; 3-chlorobenzenethiol | 2037-31-2 | C6H5ClS | 详情 | 详情 |
| (IV) | 30444 | 2-[(3-chlorophenyl)sulfanyl]-5-methoxybenzoic acid | C14H11ClO3S | 详情 | 详情 | |
| (V) | 30445 | 1-chloro-7-methoxy-9H-thioxanthen-9-one | C14H9ClO2S | 详情 | 详情 | |
| (VI) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VII) | 30446 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9H-thioxanthen-9-one | C20H24N2O2S | 详情 | 详情 | |
| (VIII) | 30447 | 1-[[2-(diethylamino)ethyl]amino]-4-(hydroxymethyl)-7-methoxy-9H-thioxanthen-9-one | C21H26N2O3S | 详情 | 详情 | |
| (IX) | 30448 | 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthene-4-carbaldehyde | C21H24N2O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Friedel-Crafts hydroxymethylation of 3-methoxybenzoic acid (I) using aqueous formaldehyde and HCl gave rise to 6-methoxyisobenzofuran-1-one (II). After radical bromination of (II) with N-bromosuccinimide in the presence of benzoyl peroxide, the resulting 3-bromo derivative (III) was condensed with triphenyl phosphine to afford the phosphonium salt (IV). Wittig condensation of 3,5-dichloropyridine-4-carbaldehyde (V) with the phosphonium bromide (IV) provided the 3-(pyridylmethylene)isobenzofuranone (VI). Reaction of the enol lactone function of (VI) with hydrazine produced the phthalazinone derivative (VII), which was further converted to the 4-chlorophthalazine (VIII) upon treatment with POCl3. The 4-chloro group of (VIII) was finally displaced with the sodium salt of 1,2,4-triazole (IX) to give the title compound.
| 【2】 Norcini, G.; Morazzoni, G.; Leali, G.M.; Napoletano, M.; Grancini, G.; Pellacini, F. (Zambon Group SpA); Phthalazine derivs. phosphodiesterase 4 inhibitors. EP 1097142; US 6329370; WO 0005218 . |
| 【1】 Norcini, G.; Pellacini, F.; Pradella, L.; Marchini, F.; Morazzoni, G.; Ferlenga, P.; Napoletano, M.; Phathalazine PDE4 inhibitors. Part 2: The synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives. Bioorg Med Chem Lett 2001, 11, 1, 33. |
| 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) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (II) | 50943 | 6-methoxyphthalide | C9H8O3 | 详情 | 详情 | |
| (III) | 50944 | 3-bromo-6-methoxy-2-benzofuran-1(3H)-one | C9H7BrO3 | 详情 | 详情 | |
| (IV) | 50945 | (5-methoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)(triphenyl)phosphonium bromide | C27H22BrO3P | 详情 | 详情 | |
| (V) | 35536 | 3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde | 136590-83-5 | C6H3Cl2NO | 详情 | 详情 |
| (VI) | 50946 | 3-[(Z)-(3,5-dichloro-4-pyridinyl)methylidene]-6-methoxy-2-benzofuran-1-one | C15H9Cl2NO3 | 详情 | 详情 | |
| (VII) | 50947 | 4-[(3,5-dichloro-4-pyridinyl)methyl]-7-methoxy-1(2H)-phthalazinone | C15H11Cl2N3O2 | 详情 | 详情 | |
| (VIII) | 50948 | 4-chloro-1-[(3,5-dichloro-4-pyridinyl)methyl]-6-methoxyphthalazine; 4-chloro-1-[(3,5-dichloro-4-pyridinyl)methyl]-6-phthalazinyl methyl ether | C15H10Cl3N3O | 详情 | 详情 | |
| (IX) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)10-Deacetylbaccatin III (XIV) was protected by treatment with triethylsilyl chloride and imidazole, and the resulting trisilylated compound (XV) was debenzoylated to diol (XVI) by using Red-Al(R). Selective coupling of (XVI) with m-anisic acid (XVII) yielded the m-methoxybenzoate ester (XVIII). Complete desilylation of (XVIII) with HF-pyridine, followed by selective resilylation at C-7, furnished (XIX). The 10-hydroxyl group was then selectively acylated with p-methoxyphenylacetyl chloride (XX) to afford ester (XXI). Finally, coupling of the modified baccatin (XXI) with the intermediate lactam (XIII) in the presence of lithium hexamethyldisilazide, and then deprotection with HF-pyridine, gave rise to the desired taxoid.
| 【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 | |
| (XIV) | 10467 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 32981-86-5 | C29H36O10 | 详情 | 详情 |
| (XV) | 51201 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C47H78O10Si3 | 详情 | 详情 | |
| (XVI) | 51202 | (1S,2S,3R,7R,9S,10S,12R,15S)-1,2-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-4-yl acetate | C40H74O9Si3 | 详情 | 详情 | |
| (XVII) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (XVIII) | 51203 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C48H80O11Si3 | 详情 | 详情 | |
| (XIX) | 51204 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C36H52O11Si | 详情 | 详情 | |
| (XX) | 26758 | 2-(4-methoxyphenyl)acetyl chloride | 4693-91-8 | C9H9ClO2 | 详情 | 详情 |
| (XXI) | 51213 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-12-[[2-(4-methoxyphenyl)acetyl]oxy]-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C45H60O13Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)10-Deacetylbaccatin III (I) was protected by treatment with triethylsilyl chloride and imidazole, and the resulting trisilylated compound (II) was debenzoylated to diol (III) by using Red-Al(R). Coupling of (III) with m-anisic acid (IV) yielded the m-methoxybenzoate ester (V). Complete desilylation of (V), followed by selective resilylation at C-7 with triethylsilyl chloride, furnished (VI). Acylation at C-10 and C-13 by means of Ac2O and DMAP, followed by desilylation, gave the modified baccatin (VII).
| 【1】 Strum, M.; et al.; Synthesis and SAR of new taxane reversal agents. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 131. |
| 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) | 10467 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 32981-86-5 | C29H36O10 | 详情 | 详情 |
| (II) | 51201 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C47H78O10Si3 | 详情 | 详情 | |
| (III) | 51202 | (1S,2S,3R,7R,9S,10S,12R,15S)-1,2-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-4-yl acetate | C40H74O9Si3 | 详情 | 详情 | |
| (IV) | 28559 | m-Anisic acid; 3-Methoxybenzoic acid | 586-38-9 | C8H8O3 | 详情 | 详情 |
| (V) | 51203 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12,15-tris[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C48H80O11Si3 | 详情 | 详情 | |
| (VI) | 51204 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C36H52O11Si | 详情 | 详情 | |
| (VII) | 51205 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12,15-tris(acetoxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 3-methoxybenzoate | C34H42O13 | 详情 | 详情 |