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【结 构 式】 
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【分子编号】32225 【品名】3,4,5-trimethoxybenzoic acid 【CA登记号】118-41-2 |
【 分 子 式 】C10H12O5 【 分 子 量 】212.20228 【元素组成】C 56.6% H 5.7% O 37.7% |
合成路线1
该中间体在本合成路线中的序号：(I)TMBN's have been synthesized by the method of Sastry and Lasslo by dissolving 0.05 moles of 3,4,5-trimethoxybenzoic acid (I) in 300 ml of dry benzene, to which 100 ml benzene containing 0.05 moles n-(N,N-dimethylamino) (CH2)nOH (II) was added dropwise with constant stirring. The temperature was maintained at 29-34 C. The reaction mixture was agitated for 2 additional hours at room temperature, then refluxed for 2 hours on steam bath. The product was recrystallized from benzene or from a mixture of ether and benzene. TMB-8 is considered more difficult to synthesize than TMB-6.
合成路线2
该中间体在本合成路线中的序号：(I)Prepared from 3,4,5-trimethoxybenzoic acid (I) by treatment with thionyl chloride in benzene to give the acyl chloride (II), which is treated with 2,6-pyridinedimethanol (III) in pyridine.
| 【1】 (Almirall Prodesfarma, SA); Method of preparing bis(3,4,5-trimethoxybenzoate) of pyridine-2,6-dimethanol. ES 1401608 . |
| 【2】 Williams, R.; Pirozadil. Drugs Fut 1981, 6, 5, 290. |
合成路线3
该中间体在本合成路线中的序号：(VI)A different synthetic strategy requires the precursor phthalide derivative (V), which is prepared by two related ways. 3,4,5-Trimethoxybenzoyl chloride (I) is condensed with 2-amino-2-methyl-1-propanol (II), and the resultant hydroxy amide is further cyclized with SOCl2 to the oxazoline (III). Lithiation of (III), followed by addition to veratraldehyde (IV) and acidic oxazoline hydrolysis, leads to the target lactone (V). Alternatively, isobenzofuranone (V) is obtained by direct condensation between trimethoxybenzoic acid (VI) and veratraldehyde (IV) in the presence of polyphosphoric acid.
| 【1】 Mori, S.; et al.; Convergent synthesis of S-8921, a new potent hypocholesterolemic arylnapththalene lignan analog. Tetrahedron Lett 1999, 40, 6, 1165. |
| 【2】 Mori, S.; Takechi, S.; Kida, S. (Shionogi & Co. Ltd.); Process for producing lignan cpd.. EP 0646570; WO 9424087 . |
| 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) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
| (II) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (III) | 57442 | 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2,6-dimethoxyphenyl methyl ether; 4,4-dimethyl-2-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-oxazole | C14H19NO4 | 详情 | 详情 | |
| (IV) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (V) | 57443 | 3-(3,4-dimethoxyphenyl)-4,5,6-trimethoxy-2-benzofuran-1(3H)-one | C19H20O7 | 详情 | 详情 | |
| (VI) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The condensation between benzamidoxime (I) and methyl salicylate (II) in the presence of NaOEt under microwave irradiation generated oxadiazole (III). Subsequent alkylation of the hydroxyl group of (III) with dimethylaminoethyl chloride and NaH in dioxan produced the target aminoethyl ether, which was finally isolated as the corresponding hydrochloride salt.
| 【1】 Brenner, M.; Maier, R.; Wienrich, M.; Weiser, T.; Palluk, R.; Bechtel, W.-D.; Sagrada, A.; Ensinger, H.; Pschorn, U.; Cesana, R. (Boehringer Ingelheim GmbH); Oxadiazoles, processes for their preparation and their use as medicaments. DE 19643037; EP 0934288; JP 2000505089; WO 9817652 . |
| 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) | 20438 | N'-hydroxybenzenecarboximidamide | 613-92-3 | C7H8N2O | 详情 | 详情 |
| (II) | 15754 | methyl salicylate | 119-36-8 | C8H8O3 | 详情 | 详情 |
| (III) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |
| (IV) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Treatment of 4,5-dimethoxy-2-nitro benzoic acid (I) with H2SO4 in EtOH allows formation of the corresponding ethyl ester (II), the nitro group of which is then reduced by hydrogenation over Pd/C in EtOH to provide substituted aniline (III). Finally, the desired product is obtained by condensation of (III) with acid chloride (IV) in CH2Cl2 by means of Et3N (acid chloride (IV) can be obtained by treatment of the corresponding benzoic acid (V) with SOCl2 in refluxing chloroform).
| 【1】 Isobe, Y.; Misawa, S.; Hayashi, H.; Ogita, H.; Takaku, H.; Sekine, R.; Goto, Y.; Synthesis and structure-activity relationship of diarylamide derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells. Bioorg Med Chem Lett 2001, 11, 4, 549. |
| 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) | 31789 | 4,5-dimethoxy-2-nitrobenzoic acid | 4998-07-6 | C9H9NO6 | 详情 | 详情 |
| (II) | 50082 | ethyl 4,5-dimethoxy-2-nitrobenzoate | C11H13NO6 | 详情 | 详情 | |
| (III) | 47630 | ethyl 2-amino-4,5-dimethoxybenzoate | C11H15NO4 | 详情 | 详情 | |
| (IV) | 13571 | 3,4,5Ttrimethoxybenzoyl chloride | 4521-61-3 | C10H11ClO4 | 详情 | 详情 |
| (V) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Nitrile (II) was prepared by regioselective diazotization of triaminoquinazoline (I), followed by treatment with KCN and CuSO4. Conversion of nitrile (II) into aldehyde (III) was achieved by means of Ni-Al alloy in refluxing formic acid. Subsequent reduction of aldehyde (III) with NaBH4 gave alcohol (IV), which was further brominated to (V) using HBr in HOAc. Finally, displacement of the bromide of (V) with 3,4,5-trimethoxybenzoic acid (VI) provided the target trimethoxybenzoate ester.
| 【1】 Graffner-Nordberg, M.; et al.; Design, synthesis, computational prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii. J Med Chem 2001, 44, 15, 2391. |
| 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) | 52638 | 2,4,6-quinazolinetriamine | 13741-90-7 | C8H9N5 | 详情 | 详情 |
| (II) | 52639 | 2,4-diamino-6-quinazolinecarbonitrile | C9H7N5 | 详情 | 详情 | |
| (III) | 52640 | 2,4-diamino-6-quinazolinecarbaldehyde | C9H8N4O | 详情 | 详情 | |
| (IV) | 52641 | (2,4-diamino-6-quinazolinyl)methanol | C9H10N4O | 详情 | 详情 | |
| (V) | 47618 | 6-(bromomethyl)-2,4-quinazolinediamine; 2-amino-6-(bromomethyl)-4-quinazolinylamine | C9H9BrN4 | 详情 | 详情 | |
| (VI) | 32225 | 3,4,5-trimethoxybenzoic acid | 118-41-2 | C10H12O5 | 详情 | 详情 |