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With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 20h;Product distribution / selectivity; |
Intermediate 46: N-[4-Chloro-6-(4-trifluoromethyl-phenylamino)-pyrimidin-5-yl]-2-(2,6-dichloro-Phenyl)-acetamide A solution of <strong>[6575-24-2]2,6-dichlorophenylacetic acid</strong> (4.16 g, 20.3 mmol, 1.1 eq), DMF (0.4 mL), and CH2Cl2 (40 mL) under a nitrogen atmosphere was treated with thionyl chloride (1.88 mL, 25.8 mmol, 1.4 equiv.). The resulting mixture was stirred at rt for 20 h. The mixture was concentrated afford (2,6-dichloro-phenyl)-acetyl chloride as a yellow syrup. A solution of the acid chloride in DMA (10 mL) was added to a solution of 6-chloro-N4-(4-trifluoromethyl-phenyl)-pyrimidine-4,5-diamine hydrochloride (6.0 g, 18.5 mmol, 1.0 eq) in DMA (20 mL) under a nitrogen atmosphere. After 2 h, isopropanol (50 mL) was added. The resulting solid precipitate was collected by filtration, rinsed with EtOH, and dried under vacuum at 50 C. for 18 h to give the title compound as a white solid (5.6 g, 64%). 1H NMR (d,DMSO): 9.93 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.33 (t, J=7.7 Hz, 1H), 4.24 (s, 2H). |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; benzene; at 20℃; for 3.5h; |
A solution of (2,6-dichloro-phenyl)-acetonitrile (Intermediate A1) (commercially available at Aldrich) (18.6 g, 100 mmol) in ethanol (40 mL) and water (50 mL) was treated with KOH (30 g) and the mixture was heated to 80 C. for 20 h. The mixture was quenched with HCl until pH 3. The product was extracted with chloroform (5×50 mL). The extracts were combined, dried over MgSO4, filtered and evaporated to dryness. The product was <strong>[6575-24-2](2,6-dichloro-phenyl)-acetic acid</strong>, 17 g (83%). A solution of <strong>[6575-24-2](2,6-dichloro-phenyl)-acetic acid</strong> (10 g, 49 mmol) in benzene (200 mL) was treated with oxalyl chloride (32 mL, 2M in dichloromethane) followed by a few drops of dimethyl formamide. The mixture was allowed to stir for 3.5 h at rt. The solvent was removed under vacuum to give 11.5 g of (2,6-dichloro-phenyl)-acetyl chloride (Intermediate A2). The acid chloride, Intermediate A2 (6 g, 26.8 mmol) was added via pipette to a solution of diazomethane in ether (30 mmol) (generated from Diazald by standard Aldrich diazomethane kit) at 0 C. After 35 m, HBr (conc.) (10 mL) was added at 0 C. This was allowed to react for 35 m. The ether was removed and the mixture was neutralized with sodium bicarbonate solution. The organic layer was removed and dried over MgSO4. The mixture was filtered and concentrated under reduced pressure to give 1-bromo-3-(2,6-dichloro-phenyl)-propan-2-one (Intermediate A3) (5 g, 66%). 1-Bromo-3-(2,6-dichloro-phenyl)-propan-2-one (Intermediate A3) (2.5 g) was heated in formamide for 2 h at 180 C. and 150 C. for 1 additional h. Water (50 mL) was added and the mixture was extracted with chloroform (4×50 mL). The solution was washed with brine (1×30 mL), dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel with 5% NH3-MeOH: CH2Cl2 to give the product 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4), 400 mg. A solution of 5-(2,6-dichloro-benzyl)-1H-imidazole (Intermediate A4) (0.34 g, 1.5 mmol) in THF (6 mL) and water (6 mL) was treated with NaHCO3 (1.2 g) at rt for 10 m. Phenyl chlorothionoformate (0.60 mL, 4.3 mmol) was added and stirring was continued for 3 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (6 mL) and treated with NEt3 (0.6 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 to give a white solid 4-(2,6-dichloro-benzyl)-1,3-dihydro-imidazole-2-thione (Compound 1) in 50% yield. 1H NMR (300 MHz, DMSO-d6): delta 12.0 (s, 1H), 11.7 (s, 1H), 7.50 (d, J=5.1 Hz, 2H), 7.35 (t, J=6.0 Hz, 1H), 6.04 (s, 1H), 3.98 (s, 2H). |
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With pyridine; 1,3,5-trichloro-2,4,6-triazine; In dichloromethane; at 50℃; for 0.25h;Microwave irradiation; |
General procedure: 2-Chloro-4-nitrobenzoic acid (201 mg, 1.0 mmol) and cyanuric chloride (368 mg, 2 mmol) in 2 mL CH2Cl2 were treated with pyridine (79 mg, 1.0 mmol) and irradiated in the microwave for 15 min at 50 C. Then, the resulting mixture was treated with FeCl3 (324 mg, 2.0 mmol) and irradiated in the microwave for 5 min at 30 C. Finally, 3 mL of toluene was added to the solution and irradiated in the microwave for 15 min at 70 C. Then the reaction mixture was filtered from Celite. The filtrate was washed with sodium thiosulphate followed by brine solution. The separated organic layer was dried on Na2SO4 and concentrated under reduced pressure to give pure product 6a (269.5 mg, 93% yield). Mp 110-112 C (lit. 1 111.2 C). 1H NMR (500 MHz, CDCl3): delta 2.39 (s, 3H), 7.26 (d, J = 7.45 Hz, 2H), 7.54 (d, J = 7.45 Hz, 1H), 7.61 (d, J = 6.85 Hz, 2H), 8.26 (dd, J = 6.85, 2.7 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H); 13C NMR (500 Hz, CDCl3): delta 21.4 (CH3), 122.0 (CH), 125.1 (CH), 129.6 (CH), 129.7 (CH), 130.15 (CH), 132.2 (C), 144.6 (C), 146.2 (C), 148.9 (C), 193.5 (CO); IR (cm-1): 638.3, 740.8, 801.5, 836.3, 863.0, 1000.7, 1025.9, 1052.5, 1005.1, 1133.9, 1158.3, 1180.7, 1272.5, 1294.3, 1315.8, 1349.1, 1403.2, 1449.5, 1461.2, 1528.8, 1573.3, 1595.7, 1607.9, 1673.9, 3087.5; GC/MS: 275 [M+]; HRMS: calcd for C14H10ClNO3: 275.0349. Found: 275.0467. |
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With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 20℃; |
To a solution of <strong>[6575-24-2]2-<strong>[6575-24-2](2,6-dichlorophenyl)acetic acid</strong></strong> (1 g, 4.88 mmol) in toluene (10 ml) and DMF (0.038 ml) was added dropwise thionyl chloride (0.712 ml, 9.75 mmol). The reaction mixture was stirred overnight at rt. The crude mixture was concentrated to give the title compound used without further purification in the next step. |
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General procedure: A mixture of 10 g (48.7 mmol) of 2-substituted phenyl aceticacid, 40 mL of anhydrous PhMewas treated with 11.2 g (53.8 mmol)PCl5 at ambient temperature under protection of moisture. Afterthe effervescence ceased, the resulting clear yellow solution washeated at reflux for 2 h, only in the case of 2-(2,4,6-trimethylphenyl)acetyl chloride the reaction was conducted atroom temperature overnight. Due to their hydrolytic lability, allintermedia were not analyzed, but used directly in the next step. |