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【结 构 式】 
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【分子编号】25812 【品名】2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline 【CA登记号】88-17-5 |
【 分 子 式 】C7H6F3N 【 分 子 量 】161.1265896 【元素组成】C 52.18% H 3.75% F 35.37% N 8.69% |
合成路线1
该中间体在本合成路线中的序号：(II)Condensation of methyl 2-(chlorosulfonyl)benzoate (I) with 2-(trifluoromethyl)aniline (II) in the presence of DMAP and pyridine yielded sulfonamide (III), which was then cyclized in refluxing xylene to provide the saccharin derivative (IV). Further condensation with tert-butyl acetate (V) using potassium bis(trimethylsilyl)amide as the base afforded ketoester (VI). Then, bromination with NBS in CCl4 gave (VII), which was cyclized to the benzothiazine (VIII) with K2CO3 in DMF. Treatment with trifluoromethanesulfonic anhydride and pyridine in CH2Cl2 furnished the vinyl triflate (IX), and this was then coupled with boronic acid (X) in the presence of Pd(PPh3)4 and K2CO3 to produce (XI). Finally, the tert-butyl ester was cleaved with trifluoroacetic acid in CH2Cl2.
| 【1】 Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058. |
| 【2】 Berryman, K.A.; Bunker, A.M.; Doherty, A.M.; Edmunds, J.J. (Pfizer Inc.); Benzothiazine dioxides as endothelin antagonists. EP 0811001; JP 1999501013; WO 9626195 . |
| 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) | 25811 | methyl 2-(chlorosulfonyl)benzoate | 26638-43-7 | C8H7ClO4S | 详情 | 详情 |
| (II) | 25812 | 2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline | 88-17-5 | C7H6F3N | 详情 | 详情 |
| (III) | 25813 | methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate | C15H12F3NO4S | 详情 | 详情 | |
| (IV) | 25814 | 2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C14H8F3NO3S | 详情 | 详情 | |
| (V) | 15397 | tert-butyl acetate | 540-88-5 | C6H12O2 | 详情 | 详情 |
| (VI) | 25815 | tert-butyl 3-oxo-3-(2-[[2-(trifluoromethyl)anilino]sulfonyl]phenyl)propanoate | C20H20F3NO5S | 详情 | 详情 | |
| (VII) | 25816 | tert-butyl 2-bromo-3-oxo-3-(2-[[2-(trifluoromethyl)anilino]sulfonyl]phenyl)propanoate | C20H19BrF3NO5S | 详情 | 详情 | |
| (VIII) | 25817 | tert-butyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C20H18F3NO5S | 详情 | 详情 | |
| (IX) | 25818 | tert-butyl 1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C21H17F6NO7S2 | 详情 | 详情 | |
| (X) | 25819 | 7-ethyl-1,3-benzodioxol-5-ylboronic acid | C9H11BO4 | 详情 | 详情 | |
| (XI) | 25820 | tert-butyl 4-(7-ethyl-1,3-benzodioxol-5-yl)-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C29H26F3NO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A new, more efficient synthesis has been reported for the intermediate (XVIII). The saccharin derivative (IV) was prepared by two alternative routes. Thus, 2-sulfobenzoic acid cyclic anhydride (XII) was treated with two equivalents of 2-(trifluoromethyl)aniline (II) to give the anilinium salt (XIII), which was cyclized with POCl3 to produce (IV). Also, starting from benzenesulfonyl chloride (XIV), the corresponding sulfonamide (II) was obtained by reaction with aniline (II). Ortho lithiation with n-butyllithium at low temperature, followed by CO2 quenching, afforded carboxylic acid (XVI), which upon treatment with Ac2O and methanesulfonic acid cyclized to the saccharin (IV). Then, the saccharin ring was opened by treatment with NaOMe, and subsequent treatment with methyl bromoacetate furnished diester (XVII). Finally, Claisen cyclization promoted by TiCl4 formed the key intermediate (XVIII).
| 【1】 Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 | |
| (II) | 25812 | 2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline | 88-17-5 | C7H6F3N | 详情 | 详情 |
| (III) | 25813 | methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate | C15H12F3NO4S | 详情 | 详情 | |
| (IV) | 25814 | 2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C14H8F3NO3S | 详情 | 详情 | |
| (XII) | 25821 | 2-Sulfobenzoic acid anhydride; 2,1lambda(6)-benzoxathiole-1,1,3-trione | 81-08-3 | C7H4O4S | 详情 | 详情 |
| (XIII) | 25822 | 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid | C14H10F3NO4S | 详情 | 详情 | |
| (XIV) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (XV) | 25823 | N-[2-(trifluoromethyl)phenyl]benzenesulfonamide | C13H10F3NO2S | 详情 | 详情 | |
| (XVI) | 25822 | 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid | C14H10F3NO4S | 详情 | 详情 | |
| (XVII) | 25824 | methyl 2-[[(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)anilino]sulfonyl]benzoate | C18H16F3NO6S | 详情 | 详情 | |
| (XVIII) | 25825 | methyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C17H12F3NO5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)1) Condensation of 2-trifluoromethylaniline (I) with ethyl ethoxymethylenemalonate (II) at 125 C to give ethyl-alpha-carbethoxy-beta-(2-trifluoromethylanilino)acrylate (III), m.p. 94 C; this product is cyclized by refluxing with diphenyl ether affording 3-carbethoxy-4-hydroxy-8-trifluoromethylquinoline (IV), m.p. 216 C, which in turn, is hydrolyzed with refluxing aqueous NaOH to the corresponding acid (V), m.p. 290-2 C; this acid is decarboxylated by refluxing in diphenyl ether to 4-hydroxy-8-trifluoromethylquinoline (VI), m.p. 180 C; this product by refluxing with POCl3 is converted into chloro-8-trifluoromethylquinoline (VII), m.p. 78 C; the condensation of quinoline (VII) with methyl anthranilate (A) by means of aqueous 2N HCl affords 4-(2-methoxycarbonylphenylamino)-8-trifluoromethylquinoline (VIII), m.p. 176 C (1,2). The transesterification of methyl ester (VIII) with glycerol affords the final product. (1) 2) Transesterification of methylester (VIII) with 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (B) to give the acetoneketal of floctafenine (IX), mp 108 C which is finally hydrolized with HCl. (2) 3) Condensation of the chloroquinoline (VII) with the 2,2-dimethyl-4-hydroxymethyl-2,3-dioxolane ester of anthranilic acid by means aqueous HCl to give the already obtained acetoneketal (IX), which is finally hydrolized as before. (2)
| 【1】 (Roussel-Uclaf.); DE 1815467 . |
| 【2】 Castaner, J.; Arrigoni, Martelli, E.; Floctafenine. Drugs Fut 1976, 1, 2, 59. |
| 【3】 Allais, A.; et al.; NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. Chim Ther 1973, 8, 2, 154. |
| 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) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (B) | 16476 | 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol | 100-79-8 | C6H12O3 | 详情 | 详情 |
| (I) | 25812 | 2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline | 88-17-5 | C7H6F3N | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 60720 | diethyl 2-{[2-(trifluoromethyl)anilino]methylene}malonate | C15H16F3NO4 | 详情 | 详情 | |
| (IV) | 60721 | ethyl 4-hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylate | C13H10F3NO3 | 详情 | 详情 | |
| (V) | 60722 | 4-hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid | C11H6F3NO3 | 详情 | 详情 | |
| (VI) | 60723 | 8-(trifluoromethyl)-4-quinolinol | C10H6F3NO | 详情 | 详情 | |
| (VII) | 60724 | 4-chloro-8-(trifluoromethyl)quinoline | C10H5ClF3N | 详情 | 详情 | |
| (VIII) | 60727 | methyl 2-{[8-(trifluoromethyl)-4-quinolinyl]amino}benzoate | C18H13F3N2O2 | 详情 | 详情 | |
| (IX) | 60726 | (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-{[8-(trifluoromethyl)-4-quinolinyl]amino}benzoate | C23H21F3N2O4 | 详情 | 详情 | |
| (C) | 60725 | (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-aminobenzoate | C13H17NO4 | 详情 | 详情 |