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【结 构 式】 
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【分子编号】19551 【品名】2-Fluorobenzoyl chloride 【CA登记号】393-52-2 |
【 分 子 式 】C7H4ClFO 【 分 子 量 】158.5592632 【元素组成】C 53.03% H 2.54% Cl 22.36% F 11.98% O 10.09% |
合成路线1
该中间体在本合成路线中的序号：(D)The alkylation of p-chloroaniline (V) as before yields N-(2,2,2-trifluoroethyl)aniline (VI), which is then condensed with aziridine (C) affording the substituted aniline (VII). The benzoylation of (VII) with 2-fluorobenzoyl chloride (D) yields the amide (VIII), which is cyclized with P2O5 in refluxing POCl3 giving 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine (IX). This compound is oxidized with RuO4 in CCl4 to give 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (I), which by reaction with P2S5 in refluxing dioxane gives the target compound.
| 【1】 Steinman, M.; Benzodiazepines and the process for their manufacture. DE 2138773; ES 393953; FR 2102114; GB 1345938 . |
| 【2】 Steinman, M.; 1-Polyfluoroalkyl-1,4-benzodiazepin-2-thiones for effecting tranquilization, sedation and treating colvulsions. US 3920818 . |
| 【3】 Castaner, J.; Thorpe, P.; Quazepam. Drugs Fut 1978, 3, 2, 139. |
| 【4】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (A) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |
| (I) | 33471 | 7-Chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C17H11ClF4N2O | 详情 | 详情 | |
| (V) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (VI) | 33475 | N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline | C8H7ClF3N | 详情 | 详情 | |
| (VII) | 33476 | N(1)-(4-chlorophenyl)-N(1)-(2,2,2-trifluoroethyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine | C10H12ClF3N2 | 详情 | 详情 | |
| (VIII) | 33477 | N-[2-[4-chloro(2,2,2-trifluoroethyl)anilino]ethyl]-2-fluorobenzamide | C17H15ClF4N2O | 详情 | 详情 | |
| (IX) | 33478 | 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine; 7-chloro-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine | C17H13ClF4N2 | 详情 | 详情 | |
| (C) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The condensation in DMF of 1,1-dimethyl-2-[(aminocarbonyl)amino]ethylamine (III) [prepared from 1,2-diamino-2-methylpropane (I) and urea (II)] and 2,3-epoxypropyl o-fluorobenzoate (VI) [prepared from o-fluorobenzoyl chloride (VI) and glycidol (V) in diethyl ether using triethylamine as a proton scavenger], followed by salt formation using 98% sulfuric acid in ethanol yields ACC-9089.
| 【1】 Mai, K.X.; Kam, S.T.; Matier, W.L.; O'Donnel, J.P.; Sum, C.Y.; Gorczynski, R.J.; Lee, R.J.; Stamfli, H.F.; Barcelon-Yang, C.; Anderson, W.G.; Borgman, R.J.; [(Arylcarbonyl)oxy]propanolamines. 1. Novel beta-blockers with ultrashort duration of action. J Med Chem 1984, 27, 8, 1007. |
| 【2】 Day, B.W.; Pento, J.T.; ACC-9089. Drugs Fut 1985, 10, 6, 447. |
| 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) | 29645 | 2-amino-1,1-dimethylethylamine; 2-methyl-1,2-propanediamine | 811-93-8 | C4H12N2 | 详情 | 详情 |
| (II) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (III) | 29646 | N-(2-amino-2-methylpropyl)urea | C5H13N3O | 详情 | 详情 | |
| (IV) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (V) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (VI) | 29647 | 2-oxiranylmethyl 2-fluorobenzoate | C10H9FO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(C)Formylation of 1,3-dimethoxybenzene (A) with DMF in the presence of POCl3 gives 2,4-dimethoxybenzaldehyde. Selective ether cleavage of this product with AlCl3 produces the corresponding salicylaldehyde (I), which is alkylated with ethyl chloroacetate to give (II). Ring closure of (II) under phase-transfer conditions leads to a benzofuran derivative from which the corresponding dihydrobenzofuran (III) is obtained by catalytic hydrogenation over Pd/C. Use of excess AlCl3 at room temperature during the Friedel-Crafts acylation step cleaves the methyl ether, and treatment of the crude product with HBr in acetic acid gives (IV) in 93% overall yield. The oximation reaction requires prolonged heating with excess hydroxylamine hydrochloride, but, after esterification of the crude oxime, a 90% yield (V) is obtained. In the cyclization leading to isoxazole (VI), the presence of pyridine increases the reaction rate and reduces formation of an oxazole, isomeric with (VI), which apparently occurs from a Beckman rearrangement with intramolecular capture by the phenol. Treatment of the crude oxime acetate with K2CO3 in DMF at 60 C gives isoxazole (VI) cleanly, in high yield. The remarkable step in the synthesis is the facile chlorination of (VI) with trichloroisocyanuric acid, utilizing all three chlorines from the reagent, leading to the corresponding 8-chloro derivative in nearly quantitative yield. Ester hydrolysis using KOH in water then gives A-56234.
| 【1】 Luther, R.R.; Plattner, J.J.; A-56234. Drugs Fut 1989, 14, 1, 9. |
| 【2】 Bunnell, P.R.; Plattner, J.J.; Fung, A.K.L.; et al.; Synthesis and pharmacological evaluation of Abbott (A)-53385: A new high ceiling salidiuretic and uricosuric agent. Diuretics 1984, 374-81. |
| 【3】 Plattner, J.J.; Fung, A.K.L.; Parks, J.A.; et al.; Substituted 5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acids: High-ceiling diuretics with uricosuric activity. J Med Chem 1984, 27, 8, 1016-26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 19555 | 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione | 87-90-1 | C3Cl3N3O3 | 详情 | 详情 |
| (I) | 19547 | 2-hydroxy-4-methoxybenzaldehyde | 673-22-3 | C8H8O3 | 详情 | 详情 |
| (II) | 19549 | ethyl 2-(2-formyl-5-methoxyphenoxy)acetate | C12H14O5 | 详情 | 详情 | |
| (III) | 19550 | ethyl 6-methoxy-2,3-dihydro-1-benzofuran-2-carboxylate | C12H14O4 | 详情 | 详情 | |
| (IV) | 19552 | 5-(2-fluorobenzoyl)-6-hydroxy-2,3,5,6-tetrahydro-1-benzofuran-2-carboxylic acid | C16H13FO5 | 详情 | 详情 | |
| (V) | 19553 | ethyl 5-[(2-fluorophenyl)(hydroxyimino)methyl]-6-hydroxy-2,3,5,6-tetrahydro-1-benzofuran-2-carboxylate | C18H18FNO5 | 详情 | 详情 | |
| (VI) | 19554 | ethyl 3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f][1,2]benzisoxazole-6-carboxylate | C18H14FNO4 | 详情 | 详情 | |
| (C) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)Catalytic hydrogenation of banzofuran (I) produces high yields of the dihydrobenzofuran (II) with some contamination of fully saturated material. Use of excess AlCl3 at room temperature during the Friedel Crafts' acylation step cleaves the methyl ether, and treatment of the crude product with HBr in acetic acid gives (III) in 93% overall yield. The oximation reaction requires prolonged heating with excess hydroxylamine hydrochloride, but after esterification of the crude oxime, a 90% yield of (IV) is obtained. In the cyclization leading to isoxazole (V) the presence of pyridine increases the reaction rate and reduces formation of an oxazole, isomeric with (V), which apparently occurs from a Beckmann rearrangement with intramolecular capture by the phenol. Treatment of the crude oxime acetate with K2CO3 in DMF at 60 C gives the isoxazole (V) cleanly, in high yield. The remarkable step in this synthesis is the facile chlorination of (V) with trichloroisocyanuric acid (B), utilizing all three chlorines from the reagent, leading to pure title compound in nearly quantitative yield.
| 【1】 Mannhold, R.; ABBOTT-53385. Drugs Fut 1985, 10, 5, 363. |
| 【2】 Bunnell, P.R.; Plattner, J.J.; Fung, A.K.L.; et al.; Synthesis and pharmacological evaluation of Abbott (A)-53385: A new high ceiling salidiuretic and uricosuric agent. Diuretics 1984, 374-81. |
| 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) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (B) | 19555 | 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione | 87-90-1 | C3Cl3N3O3 | 详情 | 详情 |
| (I) | 29156 | ethyl 6-methoxy-1-benzofuran-2-carboxylate | C12H12O4 | 详情 | 详情 | |
| (II) | 19550 | ethyl 6-methoxy-2,3-dihydro-1-benzofuran-2-carboxylate | C12H14O4 | 详情 | 详情 | |
| (III) | 29157 | 5-(2-fluorobenzoyl)-6-hydroxy-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H11FO5 | 详情 | 详情 | |
| (IV) | 29158 | ethyl 5-[(2-fluorophenyl)(hydroxyimino)methyl]-6-hydroxy-2,3-dihydro-1-benzofuran-2-carboxylate | C18H16FNO5 | 详情 | 详情 | |
| (V) | 19554 | ethyl 3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f][1,2]benzisoxazole-6-carboxylate | C18H14FNO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)3-Cyanobenzoic acid (Ia) is condensed with NH2OH in t-BuOH to yield oxime (IIa). Without isolation, compound (IIa) couples with 2-fluorobenzoyl chloride (III) in the presence of triethylamine to give oxime ester (IV), which is readily cyclized under reflux conditions (about 80 °C) (1).
Ataluren can also be obtained from its methyl ester precursor (V) by saponification with NaOH in t-BuOH/H2O (1) or THF/H2O (2) and subsequent acidification with H2SO4 (1) or HCl (2). Ataluren methyl ester (V) can be synthesized from methyl 3-cyanobenzoate (Ib) by subjecting it to either the same one-pot procedure as described above for 3-cyanobenzoic acid (Ia) (1) or, alternatively, to a similar non-one-pot procedure: condensation of (Ib) with NH2OH in EtOH at 100 ºC, coupling of the resulting oxime (IIb) with 2-fluorobenzoyl chloride (III) by means of DIEA in THF, and final cyclization of the isolated oxime ester (IVb) in toluene at 130 ºC (2). Methyl 3-cyanobenzoate (Ib) is prepared from the carboxylic acid (Ia) by methylation with CH3I in the presence of K2CO3 (2). Scheme 1.
| 【1】 Almstead, N.G., Hwang, P.S., Pines, S., Moon, Y.-C., Takasugi, J.J. (PTC Therapeutics, Inc.). Processes for the preparation of 1,2,4-oxadiazole benzoic acids. WO 2008030570. |
| 【2】 Karp, G.M., Amstead, N.G., Chen, G., Hwang, S. (PTC Therapeutics, Inc.). 1,2,4-Oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease. EP 1618098, JP 2006522286, US 2004204461, US 6992096, WO 2004091502. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IA) | 20406 | 3-cyanobenzoic acid | 1877-72-1 | C8H5NO2 | 详情 | 详情 |
| (IB) | 65721 | Methyl 3-cyanobenzoate | 13531-48-1 | C9H7NO2 | 详情 | 详情 |
| (IIA) | 65722 | C8H8N2O3 | 详情 | 详情 | ||
| (IIB) | 65723 | C9H10N2O3 | 详情 | 详情 | ||
| (IVA) | 65724 | C15H11FN2O4 | 详情 | 详情 | ||
| (IVB) | 65725 | C16H13FN2O4 | 详情 | 详情 | ||
| (III) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (V) | 65726 | C16H11FN2O3 | 详情 | 详情 |