* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: In a screw-cap vial, the diamine or aminothiophenol (1 mmol) was dissolved in fluorinated carboxylic acid (2 mL, 0.5 M) and the reaction was stirred at 70 °C for 16 hours. The fluorinated carboxylic acid was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product.
90%
With hydrogenchloride In water for 2 h; Heating / reflux
After a mixture of o-phenylenediamine (51.9 g, 480 mmol), difluoroacetic acid (50.7 g, 528 mmol) and 4N HCl (500 mL) was refluxed for 2 hours, the reaction mixture was neutralized by the careful addition of anhydrous sodium carbonate. The resulting precipitates were collected and washed with water to give 2-difluoromethyl-1H-benzimidazole (72.2 g) as white crystal in 90percent yield. MS m/z: 168(M+) 1H-MNR (CDCl3) δ: 6.91 (1H, t, J=54 Hz), 7.36-7.53(2H, m), 7.56 (1H, d, J=7 Hz), 7.86 (1H, d, J=7 Hz).
74.87%
at 94 - 98℃; for 3 h; Inert atmosphere
28.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98°C) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene- 1 , 2-diamine was >99percent (GC). The mixture was cooled down to room temperature, and neutralized by NaHC03 to pH = 7-8. Some solid was precipitated, filtrated, washed with water, and then dried under vacuum at 45 °C. 12.59 g white solid was obtained in 74.87percent isolated yield.
74.8%
at 94 - 98℃; for 3 h; Inert atmosphere
28.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98° C.) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was cooled down to room temperature, and neutralized by NaHCO3 to pH=7-8. Some solid was precipitated, filtrated, washed with water, and then dried under vacuum at 45° C. 12.59 g white solid was obtained in 74.87percent isolated yield.
64%
With hydrogenchloride In water for 2 h; Reflux
Preparation 8: 2-(Difluoromethyl)-lH-benzo[d]imidazoleTo a stirred solution of O-phenylenediamine (1 g, 0.00925 mol) in 4N HCI (10 mL) was added difluoroacetic acid (0.977 g, 0.01018 mol) and the resulting mixture was heated at reflux for 2 h . The reaction mixture was cooled to room temperature, neutralized with sodium carbonate and the solid obtained was collected by filtration and washed with water (30 mL), then dried under vacuum to afford the title compound ( 1 g, 64percent) . *H NMR (400 MHz, CDCI3) : δ 10.64 (brs, 1 H), 7.82-7.57 (m, 2H), 7.37 (dd, J' = 6.0 Hz, J" = 3.20 Hz, 2H), 6.92 (t, J=53.6 Hz, 1H) ; ESI-MS : Calculated mass : 168.05; Observed mass : 169.0 [M + H]+.
71.4 g DFAE (recycled from example 2) was added to 21.6 g (0.2 mol) benzene- 1 ,2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98- 100 °C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene- 1 , 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g *3) and dried under vacuum. 30.37 g light green solid was obtained in 90.36percent yield with 99percent GC purity. Total 68.3 g filtrate (DFAE) was recycled. [0026] In examples 1 -3, total 85.57 g product was obtained in above 3 batches reactions and average yield for each experiment was 85.0percent. Each product has a melting point of 162-163 °C. The product was analyzed by 1 H NM and the spectrum was as follows: 1 H NMR (300 MHz, DMSO-d6) δ: 7.16-7.42 (m, 3H), 7.68 (m, 2H), 13.3 (s, 1H). 19F NMR (282 MHz, DMSO-d6) δ: - 115.98.
53.56%
at 94 - 98℃; for 5 h; Inert atmosphere
74.4 (0.6 mol) DFAE (ethyl 2, 2-difluoroacetate) was added to 21.6 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98° C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 5 hours the conversion of benzene-1, 2-diamine was >99percent (determined by Gas Chromatography (GC)). The mixture was cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g*3), and dried under vacuum. 18 g light green solid was obtained in 53.56percent yield with 99percent GC purity. Total 70 g filtrate (DFAE) and DFMB solubilized within DFAE were recycled and used in example 2.
27.84 g (0.294 mol) DFAN (2,2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120 °C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1 , 2-diamine was 87.23percent (GC). The mixture was cooled down to 0°C, and 300 ml EA was added. The organic phase was washed with 100 ml *4 water, and then with brine 50 ml * 2. Dried with Na2S04; removed solvent. 12. lg orange solid was obtained in 73.5percent isolated yield.
73.5%
at 120℃; for 3 h; Inert atmosphere
27.84 g (0.294 mol) DFAN (2,2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120° C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was 87.23percent (GC). The mixture was cooled down to 0° C., and 300 ml EA was added. The organic phase was washed with 100 ml*4 water, and then with brine 50 ml*2. Dried with Na2SO4, removed solvent, 12.1 g orange solid was obtained in 73.5percent isolated yield.
15.3 g (0.1 1 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene- 1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 °C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 19 hrs the conversion of benzene- 1, 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3percent isolated yield.
64.3%
at 98 - 100℃; for 3 h; Inert atmosphere
15.3 g (0.11 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100° C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually.After 19 hrs the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3percent isolated yield.
33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 °C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1 , 2-diamine was >99percent (GC). The mixture was cooled down to 0 °C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8,3 g light green solid was obtained in 50.3percent isolated yield.
50.3%
at 98 - 100℃; for 3 h; Inert atmosphere
33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100° C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1, 2-diamine was >99percent (GC). The mixture was to cooled down to 0° C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8.3 g light green solid was obtained in 50.3percent isolated yield.
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 11, p. 2347 - 2353[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 11, p. 2527 - 2535
7
[ 401-67-2 ]
[ 95-54-5 ]
[ 705-09-9 ]
Reference：
[1] Chemical Research in Toxicology, 1996, vol. 9, # 7, p. 1092 - 1102
8
[ 933772-60-2 ]
[ 95-54-5 ]
[ 705-09-9 ]
Reference：
[1] Chemistry of Heterocyclic Compounds, 2015, vol. 51, # 3, p. 259 - 268[2] Khim. Geterotsikl. Soedin., 2015, vol. 51, # 3, p. 259 - 268,10
9
[ 6601-22-5 ]
[ 705-09-9 ]
[ 475111-38-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4 h;
A mixture of 2-difluoromethyl-1H-benzimidazole (72.2 g) (67.0 g, 400 mmol), 2,4-dichloro-6-morpholino-1,3,5-triazine (94.0 g, 400 mmol) and anhydrous potassium carbonate (221.1 g, 1600 mmol) in DMF (1.60 L) was stirred at room temperature for 4 hours. The resulting mixture was poured into water. White precipitates were collected and washed with DMF and then acetone successively. The solid was dried under reduced pressure to give 4-chrolo-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (131.5 g, 358.6 mmol) as white crystal in 90percent yield. MS m/z: 366 (M+) 1H-MNR(CDCl3) δ: 3.80-3.87 (4H, m), 3.94-4.01 (4H, m), 7.38-7.53 (2H, m), 7.58 (1H, t, J=54 Hz), 7.90 (1H, d, J=7 Hz), 8.42 (1H, d, J=7 Hz).
85.5%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Stage #1: With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 16 h; Stage #2: at 20℃; for 1.5 h;
(1) 11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of 2-difluoromethylbenzimidazole and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86percent) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine.(2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87percent) of the titled compound as colorless crystals. Melting point: 207-210°C NMR(CDCl3) δ : 1.34(3H, d, J=7Hz), 1.41(3H, d, J=7Hz), 3.3-3.5(1H, m), 3.7-4.0(11H, m), 4.4-4.6(2H, m), 7.3-7.5(2H, m), 7.57(1H, t, J=53Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m) MS m/z: 445(M+)
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 8h;Inert atmosphere;
the 4 - (4, 6 - dichloro pyrimidine -2 - yl) morpholine (500 mg, 2 . 14mmol), 2 - (difluoromethyl) - 1H - benzo [d] imidazole (720 mg, 4 . 27mmol), NaHCO3 (900 mg, 10 . 7mmol) dissolved in DMF (15 ml) in, replace the nitrogen air 3 times, the mixture in the 110 C stirring for 8 hours, to the reaction solution in the addition of water (50 ml), ethyl acetate extraction, concentration of the organic layer, for purification column chromatography (PE: EA=5:1), a 4 - (4 - chloro -6 - (2 - (difluoromethyl) - 1H - benzo [d] imidazole -1 - yl) pyrimidine -2 - yl) morpholine (200 mg, yield 26%).
With sodium hydrogencarbonate; In N,N-dimethyl acetamide; at 90℃; for 20h;
A mixture of 2-difluoromethyl-lH-benzimidazole (0.168 g), 4,6-dichloro-2-morpholinopyrimidine (0.233 g), sodium bicarbonate (0.168 g) and DMA (5 ml) was stirred under nitrogen and heated to 90C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The20 solid so obtained was washed with a 1 :1 mixture of isohexane and diethyl ether. There was thus obtained 6-chloro-4-(2-difluoromethylbenzimidazol- 1 -yl)-2-morpholinopyrimidine (0.075 g); NMR Spectrum: (DMSOd6) 3.7 (m, 4H), 3.78 (m, 4H), 7.2 (s, IH), 7.39-7.72 (m, 3H), 7.84 (d, IH), 7.9 (d, IH); Mass Spectrum: M+H+ 366.
With sodium hydrogencarbonate; In N,N-dimethyl acetamide; at 90℃; for 20h;
A mixture of 2-difluoromethyl-lH-benzimidazole (0.168 g), 4,6-dichloro-2-morpholinopyrimidine (0.233 g), sodium bicarbonate (0.168 g) and DMA (5 ml) was stirred under nitrogen and heated to 9O0C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 : 1 mixture of isohexane and diethyl ether. There was thus obtained 6-chloro-4-(2-difluoromethylbenzimidazol- 1 -yl)-2-morpholinopyrimidine (0.075 g); NMR Spectrum: (DMSOd6) 3.7 (m, 4H), 3.78 (m, 4H), 7.2 (s, IH), 7.39-7.72 (m, 3H), 7.84 (d, IH), 7.9 (d, IH); Mass Spectrum: M+H+ 366.
With sodium hydrogencarbonate; In N,N-dimethyl acetamide; at 90℃; for 20h;
A mixture of 2-difluoromethyl-lH-benzimidazole (0.168 g), 4,6-dichloro- 2-morpholinopyrimidine (0.233 g), sodium bicarbonate (0.168 g) and DMA (5 ml) was stirred under nitrogen and heated to 90C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 : 1 mixture of isohexane and diethyl ether. There was thus obtained 6-chloro-4-(2-difluoromethylbenzimidazol- 1 -yl)-2-morpholinopyrimidine (0.075 g); NMR Spectrum: (DMSOd6) 3.7 (m, 4eta), 3.78 (m, 4H), 7.2 (s, IH), 7.39-7.72 (m, 3H), 7.84 (d, IH), 7.9 (d, IH); Mass Spectrum: M+H+ 366.
In N,N-dimethyl acetamide; at 90℃; for 20h;
A mixture of 2-difluoromethyl-lff-benzimidazole (0.168 g), 4,6-dichloro-2-morpholin- 4-yl-rhoyrimidine (0.233 g), sodium hydrogen carbonate (0.168 g) and DMA (5 ml) was stirred <n="104"/>under nitrogen at 900C for 20 hours, filtered and evaporated. The product was purified by chromatography on silica eluting with increasing proportions of ethyl acetate in dichloromethane/iso-hexane (1:1). There was thus obtained l-(6-chloro-2-morpholin-4-yl- pyrimidin-4-yl)-2-(difluoromethyl)benzoimidazole (0.075 g); NMR Spectrum: (DMSOd6) 3.70 (m, 4H), 3.78 (m, 4H), 7.20 (s, IH), 7.39-7.72 (m, 3H), 7.84 (d, IH), 7.90 (d, IH); Mass Spectrum: M+H+ 366.
71.4 g DFAE (recycled from example 2) was added to 21.6 g (0.2 mol) benzene- 1 ,2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98- 100 C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene- 1 , 2-diamine was >99% (GC). The mixture was cooled down to 0 C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g *3) and dried under vacuum. 30.37 g light green solid was obtained in 90.36% yield with 99% GC purity. Total 68.3 g filtrate (DFAE) was recycled. [0026] In examples 1 -3, total 85.57 g product was obtained in above 3 batches reactions and average yield for each experiment was 85.0%. Each product has a melting point of 162-163 C. The product was analyzed by 1 H NM and the spectrum was as follows: 1 H NMR (300 MHz, DMSO-d6) delta: 7.16-7.42 (m, 3H), 7.68 (m, 2H), 13.3 (s, 1H). 19F NMR (282 MHz, DMSO-d6) delta: - 115.98.
53.56%
In neat (no solvent); at 94 - 98℃; for 5h;Inert atmosphere;
74.4 (0.6 mol) DFAE (ethyl 2, 2-difluoroacetate) was added to 21.6 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98 C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 5 hours the conversion of benzene-1, 2-diamine was >99% (determined by Gas Chromatography (GC)). The mixture was cooled down to 0 C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAE (17.4 g*3), and dried under vacuum. 18 g light green solid was obtained in 53.56% yield with 99% GC purity. Total 70 g filtrate (DFAE) and DFMB solubilized within DFAE were recycled and used in example 2.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H+ 169.
In toluene; at 87℃; for 41h;
A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 870C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by30 filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained <n="92"/>2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H+ 169.
In toluene; at 87℃; for 41h;
A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene 5 (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained o 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H1" 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1 ,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and TetaF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, 1eta), 7.29-7.34 (m, 2eta), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H+ 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene(350 ml) was stirred under an atmosphere of nitrogen and heated to 870C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with o a 2: 1 mixture of isohexane and methylene chloride. There was thus obtained2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H+ 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene(350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with20 a 2:1 mixture of isohexane and methylene chloride. There was thus obtained2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H1" 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1 ,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H* 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1 ,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene20 chloride (200 ml) and TetaF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, 1eta), 7.29-7.34 (m, 2eta), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H+ 169.
In toluene; at 87℃; for 41h;
The l-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-2-(difluoromethyl)benzoimidazole o used as a starting material was prepared as follows :-; A mixture of 1 ,2-phenylenediamine (54.1 g) and ethyl difluoroacetate (57.8 ml) in toluene (350 ml) was heated under nitrogen to 87C for 41 hours, filtered whilst hot and evaporated. The residue was dissolved in a mixture of THF (200 ml) and dichloromethane (200 ml), filtered through silica (30 g) and evaporated to a solid, which solid was washed with s a 2: 1 mixture of isohexane and dichloromethane. There was thus obtained 2-difluoromethyl- lF-benzimidazole (64.8 g): NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66- 7.68 (m, 2H), 13.30 (s, IH). Mass Spectrum: M+H+ 169. A mixture of the material so obtained (7.57 g), 4-(2,6-dichloropyrimidin-4-yl)morpholine (11.7 g), sodium bicarbonate (21.0 g) and DMF (100 ml) was stirred under nitrogen at 110C for 20 hours, cooled to 0 ambient temperature, filtered and evaporated. The residue was chromatographed on silica eluting with increasing proportions of ethyl acetate in dichloromethane. The solid obtained, which was a mixture of the major and minor isomeric products, was washed with a mixture of diethyl ether (400 ml) and iso-hexane (400 ml) and the washings were evaporated to a residue, [A]. The washed solid was recrystallised from dichloromethane (30 ml) by addition of iso- 5 hexane (120 ml) and the crystalline solid was filtered off, washed with a mixture of diethyl ether (300 ml) and iso-hexane (300 ml) and the washings were again evaporated to a residue, [B]. Residues [A] and [B] were combined and purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d = 0.88)] and 0 acetonitrile as eluent. There was thus obtained l-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)- 2-(difluoromethyl)benzoiniidazole (0.173 g); NMR Spectrum: (DMSOd6) 3.73 (s, 8H), 7.20 (s, <n="98"/>IH), 7.44-7.52 (m, 2H)5 7.51 (t, IH)3 7.77-7.79 (m, IH), 7.88-7.90 (m, IH). Mass Spectrum: M+H+ 366.
In toluene; at 87℃; for 41h;
A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 87C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass Spectrum: M+H" 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-lH-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1,2-phenylenediamine (54.1 g), ethyl difluoroacetate (57.8 ml) and toluene (350 ml) was stirred under an atmosphere of nitrogen and heated to 870C for 41 hours. The resultant mixture was filtered whilst hot. The filtrate was evaporated. A mixture of methylene chloride (200 ml) and THF (200 ml) was added to the residue and the solution was purified by filtration through silica (30 g). Evaporation of the solvent gave a solid which was washed with a 2:1 mixture of isohexane and methylene chloride. There was thus obtained 2-difluoromethyl-lH-benzimidazole (64.8 g); NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.3 (s, IH); Mass_Spjctrum: M+H4" 169.
In toluene; at 87℃; for 41h;
The 2-difluoromethyl-li7-benzimidazole used as a starting material was prepared as follows :-; A mixture of 1,2-phenylenediamine (54.1 g) and ethyl difluoroacetate (57.8 ml) in toluene (350 ml) was heated under nitrogen to 87C for 41 hours, filtered while hot and evaporated. The residue was dissolved in a mixture of THF (200 ml) and dichloromethane (200 ml), filtered through silica (30 g) and evaporated to a solid which was washed with a 2:1 mixture of isohexane and dichloromethane. There was thus obtained 2-difluoromethyl-lf- benzimidazole (64.8 g): NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66-7.68 (m, 2H), 13.30 (s, IH). Mass Spectrum: M+H+ 169.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 20h;
A mixture of 2-difluoromethyl-l/tauT-benzimidazole (7.57 g), 2,4-dichloro- 6-morpholinopyrimidine (11.7 g), sodium bicarbonate (21 g) and DMF (100 ml) was stirred under nitrogen and heated to 110C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methylene chloride as eluent. The solid so obtained was a mixture of major and minor isomeric products. The solid was washed with a mixture of isohexane (400 ml) and diethyl ether (400 ml). The washings were evaporated to give a Residue [A]. The washed solid was recrystallised from warm methylene chloride (30 ml) by the addition of isohexane (120 ml). The resultant crystalline solid was isolated and washed with a mixture of diethyl ether (300 ml) and <n="91"/>isohexane (300 ml) and the washings were again evaporated to give a Residue [B]. Residues [A] and [B] were combined and purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d = 0.88)] and acetonitrile as eluent. There was thus obtained a sample of the minor isomeric product, namely 2-chloro-4-(2-difluoromethylbenzimidazol-l-yl)-6-morpholinopyrimidine (0.173 g); NMR Spectrum: (DMSOd6) 3.73 (s, 8H), 7.2 (s, IH), 7.44-7.52 (m, 2H), 7.51 (t, IH), 7.77-7.79 (m, IH), 7.88-7.90 (m, IH); Mass Spectrum: M+H+ 366.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 20h;
A mixture of 2-difluoromethyl-lH-benzimidazole (7.57 g), 2,4-dichloro-6-morpholinopyrimidine (11.7 g), sodium bicarbonate (21 g) and DMF (100 ml) was stirred under nitrogen and heated to 110C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methylene chloride as eluent. The solid so obtained was a mixture of major and minor isomeric products. The solid was washed with a mixture of isohexane (400 ml) and diethyl ether (400 ml). The washings were evaporated to give a Residue [A]. The washed solid was recrystallised from warm methylene chloride (30 ml) by the addition of isohexane (120 ml). The resultant crystalline solid was isolated and washed with a mixture of diethyl ether (300 ml) and isohexane (300 ml) and the washings were again evaporated to give a Residue [B]. Residues [A] and [B] were combined and purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d = 0.88)] and acetonitrile as eluent. There was thus obtained a sample of the minor isomeric product, namely 2-chloro- 4-(2-difluoromethylbenzimidazol-l-yl)-6-morpholinopyrimidine (0.173 g); NMR Spectrum: (DMSOd6) 3.73 (s, 8H), 7.2 (s, IH), 7.44-7.52 (m, 2H), 7.51 (t, IH), 7.77-7.79 (m. IH), 7.88-7.90 (m, IH); Mass Spectrum: M+H+ 366.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 20h;
A mixture of 2-difluoromethyl-lH-benzimidazole (7.57 g), 2,4-dichloro- 6-morpholinopyrimidine (11.7 g), sodium bicarbonate (21 g) and DMF (100 ml) was stirred under nitrogen and heated to 110C for 20 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methylene chloride as eluent. The solid so obtained was a mixture of major and minor isomeric products. The solid was washed with a mixture of isohexane (400 ml) and diethyl ether (400 ml). The washings were evaporated to give a Residue [A]. The washed solid was recrystallised from warm methylene chloride (30 ml) by the addition of isohexane (120 ml). The resultant crystalline solid was isolated and washed with a mixture of diethyl ether (300 ml) and isohexane (300 ml) and the washings were again evaporated to give a Residue [B]. Residues [A] and [B] were combined and purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d = 0.88)] and acetonitrile as eluent. There was thus obtained a sample of the minor isomeric product, namely 2-chloro-4-(2-difluoromethylbenzimidazol-l-yl)-6-morpholinopyrimidine (0.173 g); NMR Spectrum: (DMSOd6) 3.73 (s, 8H), 7.2 (s, IH), 7.44-7.52 (m, 2H), 7.51 (t, IH), 7.77-7.79 (m, IH), 7.88-7.90 (m, IH); Mass Spectrum: M+H+ 366.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 110℃; for 20h;
The l-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-2-(difluoromethyl)benzoimidazole o used as a starting material was prepared as follows :-; A mixture of 1 ,2-phenylenediamine (54.1 g) and ethyl difluoroacetate (57.8 ml) in toluene (350 ml) was heated under nitrogen to 87C for 41 hours, filtered whilst hot and evaporated. The residue was dissolved in a mixture of THF (200 ml) and dichloromethane (200 ml), filtered through silica (30 g) and evaporated to a solid, which solid was washed with s a 2: 1 mixture of isohexane and dichloromethane. There was thus obtained 2-difluoromethyl- lF-benzimidazole (64.8 g): NMR Spectrum: (DMSOd6) 7.28 (t, IH), 7.29-7.34 (m, 2H), 7.66- 7.68 (m, 2H), 13.30 (s, IH). Mass Spectrum: M+H+ 169. A mixture of the material so obtained (7.57 g), 4-(2,6-dichloropyrimidin-4-yl)morpholine (11.7 g), sodium bicarbonate (21.0 g) and DMF (100 ml) was stirred under nitrogen at 110C for 20 hours, cooled to 0 ambient temperature, filtered and evaporated. The residue was chromatographed on silica eluting with increasing proportions of ethyl acetate in dichloromethane. The solid obtained, which was a mixture of the major and minor isomeric products, was washed with a mixture of diethyl ether (400 ml) and iso-hexane (400 ml) and the washings were evaporated to a residue, [A]. The washed solid was recrystallised from dichloromethane (30 ml) by addition of iso- 5 hexane (120 ml) and the crystalline solid was filtered off, washed with a mixture of diethyl ether (300 ml) and iso-hexane (300 ml) and the washings were again evaporated to a residue, [B]. Residues [A] and [B] were combined and purified using a Waters 'Xterra' preparative reversed-phase column (5 microns silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water [containing 1% aqueous ammonium hydroxide (d = 0.88)] and 0 acetonitrile as eluent. There was thus obtained l-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)- 2-(difluoromethyl)benzoiniidazole (0.173 g); NMR Spectrum: (DMSOd6) 3.73 (s, 8H), 7.20 (s, <n="98"/>IH), 7.44-7.52 (m, 2H)5 7.51 (t, IH)3 7.77-7.79 (m, IH), 7.88-7.90 (m, IH). Mass Spectrum: M+H+ 366.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;
A mixture of 2-difluoromethyl-lH-benzimidazole (2.22 g), 2,4-dichloro- 6-morpholinopyrimidine (2.81 g), potassium carbonate (6.63 g) and DMF (50 ml) was stirred under nitrogen and heated to 90C for 16 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on <n="100"/>silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1:1 mixture of isohexane and diethyl ether. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol- 1 -yl)-6-morpholinopyrimidine (3.17 g); NMR Spectrum: (DMSOd6) 3.75 (s, 8H), 7.09 (s, IH), 7.45-7.47 (m, IH), 7.50-7.54 (m, IH), 7.57-7.83 (t, IH), 7.87 (d, IH), 8.31 (d, IH); Mass Spectrum: M+H+ 366.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;
A mixture of 2-difluoromethyl-lH-benzimidazole (2.22 g), 2,4-dichloro- 6-morpholinopyrimidine (2.81 g), potassium carbonate (6.63 g) and DMF (50 ml) was stirred under nitrogen and heated to 90C for 16 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 : 1 mixture of isohexane and diethyl ether. There was thus obtained 4-chloro-2-(2-difiuoromethylbenzimidazol- 1 -yl)-6-morpholinopyrimidine (3.17 g); NMR Spectrum: (DMSOd6) 3.75 (s, 8eta), 7.09 (s, IH), 7.45-7.47 (m, IH), 7.50-7.54 (m, IH), 7.57-7.83 (t, IH), 7.87 (d, IH), 8.31 (d, IH); Mass Spectrum: M+H+ 366.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;
A mixture of 2-difluoromethyl-lH-benzimidazole (2.22 g), 2,4-dichloro- 6-morpholinopyrimidine (2.81 g), potassium carbonate (6.63 g) and DMF (50 ml) was stirred under nitrogen and heated to 90C for 16 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 : 1 mixture of isohexane and diethyl ether. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol- 1 -yl)-6-morpholinopyrimidine (3.17 g); NMR Spectrum: (DMSOd6) 3.75 (s, 8H), 7.09 (s, IH), 7.45-7.47 (m, IH), 7.50-7.54 (m, IH), 7.57-7.83 (t, IH), 7.87 (d, IH), 8.31 (d, IH); Mass Spectrum: M+H+ 366.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;
A mixture of 2-difluoromethyl-lH-benzimidazole (2.22 g), 2,4-dichloro- 6-morpholinopyrimidine (2.81 g), potassium carbonate (6.63 g) and DMF (50 ml) was stirred under nitrogen and heated to 900C for 16 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. The resultant product was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate in methylene chloride as eluent. The solid so obtained was washed with a 1 :1 mixture of isohexane and diethyl ether. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol- 1 -yl)-6-morpholinopyrirnidine (3.17 g); NMR Spectrum: (DMSOd6) 3.75 (s, 8H), 7.09 (s, IH), 7.45-7.47 (m, IH), 7.50-7.54 (m, IH), 7.57-7.83 (t, IH), 7.87 (d, IH), 8.31 (d, IH); Mass Spectrum: M+H1" 366.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;
A mixture of the material so obtained, 2-difluoromethyl-lH-benzimidazole (0.435 g), potassium carbonate (1.36 g) and DMF (15 ml) was stirred under nitrogen and heated to 1100C for 24 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol-l-yl)- 6-[(35)-3-methylmorpholin-4-yl]py?midine (0.76 g) which was used without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;
A mixture of the material so obtained, 2-difluoromethyl-lH-benzimidazole (0.435 g), potassium carbonate (1.36 g) and DMF (15 ml) was stirred under nitrogen and heated to HO0C for 24 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol-l-yl)- 6-[(31S)-3-methylmophiholin-4-yl]pyrimidine (0.76 g) which was used without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 24h;
A mixture of the material so obtained, 2-difluoromethyl-lH'-benzimidazole (0.435 g), potassium carbonate (1.36 g) and DMF (15 ml) was stirred under nitrogen and heated to 1100C for 24 hours. The resultant mixture was cooled, filtered and the filtrate was evaporated. There was thus obtained 4-chloro-2-(2-difluoromethylbenzimidazol-l-yl)- 6-[(3iS)-3-methylmorpholin-4-yl]pyrimidine (0.76 g) which was used without further purification.
General procedure: In a screw-cap vial, the diamine or aminothiophenol (1 mmol) was dissolved in fluorinated carboxylic acid (2 mL, 0.5 M) and the reaction was stirred at 70 C for 16 hours. The fluorinated carboxylic acid was then evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to yield the corresponding product.
90%
With hydrogenchloride; In water; for 2h;Heating / reflux;
After a mixture of o-phenylenediamine (51.9 g, 480 mmol), difluoroacetic acid (50.7 g, 528 mmol) and 4N HCl (500 mL) was refluxed for 2 hours, the reaction mixture was neutralized by the careful addition of anhydrous sodium carbonate. The resulting precipitates were collected and washed with water to give 2-difluoromethyl-1H-benzimidazole (72.2 g) as white crystal in 90% yield. MS m/z: 168(M+) 1H-MNR (CDCl3) delta: 6.91 (1H, t, J=54 Hz), 7.36-7.53(2H, m), 7.56 (1H, d, J=7 Hz), 7.86 (1H, d, J=7 Hz).
74.87%
at 94 - 98℃; for 3h;Inert atmosphere;
28.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98C) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene- 1 , 2-diamine was >99% (GC). The mixture was cooled down to room temperature, and neutralized by NaHC03 to pH = 7-8. Some solid was precipitated, filtrated, washed with water, and then dried under vacuum at 45 C. 12.59 g white solid was obtained in 74.87% isolated yield.
74.8%
In neat (no solvent); at 94 - 98℃; for 3h;Inert atmosphere;
28.8 g (0.6 mol) DFA (2, 2-difluoroacetic acid) was added to 10.8 g (0.2 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (94-98 C.) and maintained for 3 h under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was >99% (GC). The mixture was cooled down to room temperature, and neutralized by NaHCO3 to pH=7-8. Some solid was precipitated, filtrated, washed with water, and then dried under vacuum at 45 C. 12.59 g white solid was obtained in 74.87% isolated yield.
64%
With hydrogenchloride; In water; for 2h;Reflux;
Preparation 8: 2-(Difluoromethyl)-lH-benzo[d]imidazoleTo a stirred solution of O-phenylenediamine (1 g, 0.00925 mol) in 4N HCI (10 mL) was added difluoroacetic acid (0.977 g, 0.01018 mol) and the resulting mixture was heated at reflux for 2 h . The reaction mixture was cooled to room temperature, neutralized with sodium carbonate and the solid obtained was collected by filtration and washed with water (30 mL), then dried under vacuum to afford the title compound ( 1 g, 64%) . *H NMR (400 MHz, CDCI3) : delta 10.64 (brs, 1 H), 7.82-7.57 (m, 2H), 7.37 (dd, J' = 6.0 Hz, J" = 3.20 Hz, 2H), 6.92 (t, J=53.6 Hz, 1H) ; ESI-MS : Calculated mass : 168.05; Observed mass : 169.0 [M + H]+.
In water; at 130℃;Sealed tube; Microwave irradiation;
2-Difluoromethylbenzimidazole A2 A mixture of 1 ,2-phenylenediamine (0.50 g, 4.6 mmol, 1 equiv) and difluoroacetic acid (2.2 g, 5 equiv) in H20 (10 ml) in a sealed tube was exposed to MW irradiation (90 W, 130 C) for 10-15 minutes. The reaction mixture was diluted with H20 (50 ml), neutralized with 50% NaOH with resulting precipitate filtered, washed with H20, then dried to yield the product as orange powder. Remaining product was extracted into EtOAc, evaporated under reduced pressure and dried to yield the product (A2) as brown crystals; yield: 0.70 g, 90.3%; 1H-NMR (300 MHz, CD3OD), 7.65 (s, 2H), 7.35 (dd, J = 6.1, 3.1 Hz, 2H), 7.02 (t, J = 53.1 Hz, 1H); ESI-MS, m/z 169.2 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
A mixture of <strong>[705-09-9]2-difluoromethyl-1H-benzimidazole</strong> (72.2 g) (67.0 g, 400 mmol), 2,4-dichloro-6-morpholino-1,3,5-triazine (94.0 g, 400 mmol) and anhydrous potassium carbonate (221.1 g, 1600 mmol) in DMF (1.60 L) was stirred at room temperature for 4 hours. The resulting mixture was poured into water. White precipitates were collected and washed with DMF and then acetone successively. The solid was dried under reduced pressure to give 4-chrolo-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine (131.5 g, 358.6 mmol) as white crystal in 90% yield. MS m/z: 366 (M+) 1H-MNR(CDCl3) delta: 3.80-3.87 (4H, m), 3.94-4.01 (4H, m), 7.38-7.53 (2H, m), 7.58 (1H, t, J=54 Hz), 7.90 (1H, d, J=7 Hz), 8.42 (1H, d, J=7 Hz).
86.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 4h;
2-(Difluoromethyl)-1H-benzo[d]imidazole (7) (1.43 g, 8.51 mmol), Compound 5 (2.00 g,8.51 mmol) and K2CO3 (1.18 g, 8.51 mmol) were added to a 50 mL three-necked flask, dissolved in 25 mL of DMF, and reacted at 25 C for 4 hours. TLC (petroleum ether: ethyl acetate = 5:1) was used to detect the reaction of the starting material 5 Stop the reaction and pour the reaction solution into 80 mL of water.In the middle, a large amount of white solid was precipitated, stirred for 10 minutes, suction filtered, and the filter cake was washed with water and dried to give 2.7 g of white solid.86.5%.
85.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
4-(4-Chloro-6-(2-(difluoromethyl)-lH-benzo[d/imidazol-l-yl)-l,3,S-trw yl)morpholine- (AS) A mixture of 4-(4,6^omicroneta1thetaGammatheta-1,3,5^pi3zetaeta-2^1^omicron etaomicron1etaepsilon (A4) (0.74 g, 3.2 mmol, 1 equiv), <strong>[705-09-9]2-difluoromethylbenzimidazole</strong> (A2) (0.53 g, 1 equiv) and K2C03 (0.44 g, 1 equiv) in DMF (10 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured onto H20, filtered, washed with H20 and small amount of MeOH, then dried to yield the product AS as off-white powder, yield: 0.49 g, 42.6%; IH-NMR (300 MHz, CDC13), 8.44 (dd, J = 7.4, 1.4 Hz, 1H), 7.91 (dd, J = 7.1, 1.4 Hz, 1H), 7.58 (t, J = 53.4 Hz, 1H), 7.47 (m, 2H), 3.97 (m, 4H), 3.83 (m, 4H); LCMS (ESI): (m/z) = 367.2 [M+H]+; ESI- MS, m/z 367.8 [M+H]+; HPLC (MeCN): 8.30 min.
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 4.5h;
Step b): 4-(4-chloro-6-(2-(difluoromethvn-1 H-benzordlimidazol-l -ylVI ,3,5-triazin-2- vDmorpholine (25).Compound 24 (425 muetaetaomicronIota, 1 .0 eq.) was dissolved in DMF (2 mL) and cooled to -5C, treated with anhydrous potassium carbonate (1.44 eq.) and 2-(difluoromethyl)-1 /-/- benzo[c/]imidazole (1 .4 eq.), stirred for 30 min and further stirred at RT for 4 h. The reaction mixture was diluted with water and the precipitate was filtered and washed with small amounts of water. Purification was done by silica gel flash column chromatography.
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 4.5h;
Compound 2 (425 muetaetaomicronIota, 1.0 eq.) is dissolved in DMF (2 ml) and cooled to -5C, treated with anhydrous potassium carbonate (1 .44 eq.) and 2-(difluoromethyl)-1 H-benzo[c/]- imidazole (1 .4 eq.), stirred for 30 min and further stirred at room temperature for 4 h. The reaction mixture is diluted with water and the precipitate is filtered and washed with small amounts of water. Purification is done by silica gel flash column chromatography. Rf: 0.72 (methylene chloride/methanol, 95:5 v/v); 1H NMR (CDCI3, 400 MHz) delta 8.43 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.71 -7.43 (m, 3H), 4.00-3.95 (m, 4H), 3.86-3.80 (m, 4H); 19F NMR (CDCI3, 400 MHz) delta -1 19.20 (d, J = 53.9 Hz, 2F).
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 4.5h;Inert atmosphere;
Step b : 4-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (25) Compound 24 (425 mumol, 1.0 eq.) was dissolved in DMF (2 mL) and cooled to -5 C., treated with anhydrous potassium carbonate (1.44 eq.) and <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (1.4 eq.), stirred for 30 min and further stirred at RT for 4 h. The reaction mixture was diluted with water and the precipitate was filtered and washed with small amounts of water. Purification was done by silica gel flash column chromatography.
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 4.5h;
Compound 2 (425 mumol, 1.0 eq.) is dissolved in DMF (2 ml) and cooled to -5 C., treated with anhydrous potassium carbonate (1.44 eq.) and 2-(difluoromethyl)-1H-benzo[d]-imidazole (1.4 eq.), stirred for 30 min and further stirred at room temperature for 4 h. The reaction mixture is diluted with water and the precipitate is filtered and washed with small amounts of water. Purification is done by silica gel flash column chromatography. RF: 0.72 (methylene chloride/methanol, 95:5 v/v); 1H NMR (CDCl3, 400 MHz) delta 8.43 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.71-7.43 (m, 3H), 4.00-3.95 (m, 4H), 3.86-3.80 (m, 4H); 19F NMR (CDCl3, 400 MHz) delta -119.20 (d, J=53.9 Hz, 2 F).
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 4.5h;
General procedure: Example 2: General procedure for the preparation of compounds (IB 1-20): Cynuric chloride (1) (lOg, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at -50 C for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with di-substitued benzimidazole (7) (1.4 eq) in presence of K2C03 (1.44 eq) in DMF (20 ml) , at -5 C for 30 min and then at room temperature for 4 h led to intermediate (8) . To the solution of intermediate (8) (100 mg, 1.0 eq) in DMF (3 ml) are added K2C03 (1.4 eq) and substituted aryloxy piperidines (6) (1.44 eq).This resulting reaction mixture was stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate twice washed with 2N HC1 solution and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtained the compounds formula (1B1-20).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
4-(4,6-Dichloro-1,3,5-triazin-2-yl)morpholine was added to a 500 mL single-mouth bottle (2)11.33g (48.2mmol), anhydrous potassium carbonate 6.66g (48.2mmol), DMF 150mL2-Difluoromethyl-1H-benzimidazole (3) 8.10 g (48.2 mmol) was added with stirring.2 hours at room temperature, add 200 mL of water, let stand, precipitate solids, filter under reduced pressure, with a small amountIt was washed with water and dried to give a white powdery solid 15.21 g The crude product yield was 86.03%.
(1) 11.8 g (50 mmol) of 2,4-dichloro-6-morpholino-1,3,5-triazine, 8.41 g (50 mmol) of <strong>[705-09-9]2-difluoromethylbenzimidazole</strong> and 55.3 g (400 mmol) of anhydrous potassium carbonate added to DMF (250 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and the resulting precipitates were washed with DMF and ethanol to obtain 15.7 g (yield: 86%) of 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine.(2) 0.36 g (0.98 mmol) of the obtained 4-chloro-2-(2-difluoromethylbenzimidazol-1-yl)-6-morpholino-1,3,5-triazine, 0.16 g (1.0 mmol) of cis-2,3-dimethylmorpholine hydrochloride and 0.3 g (2.2 mmol) of anhydrous potassium carbonate added to DMF (10 ml) were stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.38 g (yield: 87%) of the titled compound as colorless crystals. Melting point: 207-210C NMR(CDCl3) delta : 1.34(3H, d, J=7Hz), 1.41(3H, d, J=7Hz), 3.3-3.5(1H, m), 3.7-4.0(11H, m), 4.4-4.6(2H, m), 7.3-7.5(2H, m), 7.57(1H, t, J=53Hz), 7.8-8.0(1H, m), 8.2-8.3(1H, m) MS m/z: 445(M+)
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 18.5h;Inert atmosphere;
Step a): 1 -(4,6-dichloropyrimidin-2-yl)-2-(difluoromethyl)-1 H-benzordlimidazole (28). Under nitrogen atmosphere an oven-dried round-bottom flask was charged with 2,4,6- trichloropyrimidine (31 .0 muIota_, 273 muetaetaomicronIota, 1 .0 eq.) in dry DMF (2 mL). The solution was cooled down to -5C and potassium carbonate (65.6 mg, 474 muetaiotaomicronIota, 1 .74 eq.) and 2- difluoromethyl-1 /-/-benzimidazole (41.3 mg, 245 muetaetaomicronIota, 0.9 eq.) were added. The reaction mixture was stirred for 30 min at -5C and then for 18 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (20% EtOAc/hexane) to yield the title compound as a white solid (60.0 mg, 70%). RF: 0.44 (hexane/EtOAc, 4:1 v/v); 1H-NMR (CDCI3, 400 MHz): delta 8.50 (d, J = 8.0 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H), 7.69 (t, J = 53.6 Hz, 1 H), 7.55-7.45 (m, 2H), 7.37 (s, 1 H); 19F-NMR (CDCI3, 400 MHz): delta -1 19.1 (d, J = 56.8 Hz, 2F); ESI-MS (Ci2H6CI2F2N4): Calc'd. 314.99 (M+), Found 315.90.
70%
With potassium carbonate; In N,N-dimethyl-formamide; at -5 - 20℃; for 18.5h;Inert atmosphere;
Step a): 1-(4,6-dichloropyrimidin-2-yl)-<strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (28) Under nitrogen atmosphere an oven-dried round-bottom flask was charged with 2,4,6-trichloropyrimidine (31.0 muL, 273 mumol, 1.0 eq.) in dry DMF (2 mL). The solution was cooled down to -5 C. and potassium carbonate (65.6 mg, 474 mumol, 1.74 eq.) and <strong>[705-09-9]2-difluoromethyl-1H-benzimidazole</strong> (41.3 mg, 245 mumol, 0.9 eq.) were added. The reaction mixture was stirred for 30 min at -5 C. and then for 18 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (20% EtOAc/hexane) to yield the title compound as a white solid (60.0 mg, 70%). RF: 0.44 (hexane/EtOAc, 4:1 v/v); 1H-NMR (CDCl3, 400 MHz): delta 8.50 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.69 (t, J=53.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.37 (s, 1H); 19F-NMR (CDCl3, 400 MHz): delta -119.1 (d, J=56.8 Hz, 2F); ESI-MS (C12H6Cl2F2N4): Calc'd. 314.99 (M+). Found 315.90.
62%
(1) 0.84 g (5 mmol) of <strong>[705-09-9]2-difluoromethylbenzimidazole</strong> dissolved in DMF (25 ml) was added and reacted with 60% sodium hydride (0.24 g, 6 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 2,4,6-trichloropyrimidine (0.92 g, 5 mmol) dissolved in DMF (25 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into water and the resulting precipitates were recrystallized from methanol to obtain 0.98 g (yield: 62%) of 4,6-dichloro-2-(2-difluoromethylbenzimidazol-1-yl)pyrimidine.
To a solution of 14a (300mg, 1.8mmol, leq) in DMF(4mL) was added NaH(60%, 75mg, 1.8mmol, leq) at 0~5C. The resulting mixture was stirred for 30min at 0~5C and to the mixture was added 68b(459mg, l.deltammol, leq) portion- wise. The reaction mixture was stirred at r.t. over a weekend. The solvent was removed and the residue was purified by column chromatography (PE:EA=4: 1) to give 68c (33Omg, yield: 50%) as a colorless oil. ES-MS m/z: 377 (M++l)
50%
Step 2: To a solution of Id (300mg, 1.8mmol, leq) in DMF (4mL) was added NaH (60%, 75mg, 1.8mmol, leq) at 0~5C. The resulting mixture was stirred for 30min at 0-5C and to the mixture was added 4b (459mg, 1.8mmol, leq) portion-wise. The reaction mixture was stirred at r.t over weekend. The solvent was removed and the residue was purified by column chromatography (PE:EA=4: 1) to give 4c (330mg, yield: 50%) as a colorless oil. ES-MS m/z: 377 (M++l)
NaH (60%, l.lg, 45.8mmol, 1.5eq) was added portion-wise to a solution of compound 14a (3.4g, 20.1mmol, 1. leq) in DMF(50mL) at O0C and the mixture was stirred at r.t for 45min. Compound 69a (5.Og, 18.3mmol, leq) was added to the mixture. The mixture was stirred at r.t. over a weekend. Water was added and the mixture was extracted with ethyl acetate, the organic layer was washed with water for 3 times, dried, concentrated and purified by column chromatography to give 69b (3.4g, yield: 45.8%) as a white solid. 1H NMR(CDCB, 300MHz, ppm): delta 10.23(s, IH), 7.72(d, IH), 7.54(d, IH) ES-MS m/z: 321(M-HH+).
45.8%
Step 2: NaH (60%, l . lg, 45.8mmol, 1.5eq) was added protion-wise to a solution of compound Id (3.4g, 20.1mmol, l .leq) in DMF(50mL) at 0C and the mixture was stirred at r.t for 45min. Compound 5a (5.0g, 18.3mmol, leq) was added to the mixture. The mixture was stirred at r.t over weekend. Water was added and the mixture was extracted with ethyl acetate, the organic layer was washed with water for 3 times, dried, concentrated and purified by column chromatography to give 5b (3.4g, yield: 45.8%) as a white solid.'H NMR(CDC13, 300MHZ, ppm): delta 10.23(s, 1H), 7.72(d, 1H), 7.54(d, 1H)ES-MS m/z: 321(M+H+).
To a solution of 14a (247mg, 1.47mmol, leq) in DMF(4mL) was added NaH(60%,70mg, 1.76mmol,l .2 eq) portion-wise at 0~5C. The resulting mixture was stirred for30min at r.t. Then 32b (400mg, 1.47mmol, leq) was added to the mixture portion- wise. The reaction mixture was stirred at r.t. overnight. The solvent was removed and the residue was purified by column chromatography (PE:EA=4:1) to give 67a(360mg, yield: 61%) as off-white solid.HNMR(CDCl3,300MHz):8.28(s,lH),8.01(s,lH),7.96~7.84(m,2H),7.70~7.63(m,2H),4.88 (m,lH),4.24~4.20(m,2H),3.71~3.63(m,2H),2.33~2.24(m,2H),2.29~2.21(m,2H).ES-MS m/z: 405.5(M++l).
61%
Step 2: To a solution of Id (247mg, 1.47mmol, leq) in DMF(4mL) was added NaH (60%, 70mg, 1.76mmol,1.2 eq) portion-wise at 0~5C. The resulting mixture was stirred for 30min at r.t. Then 3b (400mg, 1.47mmol, leq) was added to the mixture portion-wise. The reaction mixture was stirred at r.t overnight. The solvent was removed and the residue was purified by column chromatography (PE:EA=4:1) to give 3c (360mg, yield: 61%) as off-white solid.HNMR(CDCl3,300MHz):8.28(s,lH),8.01(s,lH),7.96~7.84(m,2H),7.70~7.63(m,2H),4.88 (m,lH),4.24~4.20(m,2H),3.71~3.63(m,2H),2.33~2.24(m,2H),2.29~2.21(m,2H). ES-MS m/z: 405.5(M++1).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of 14a (599mg, 3.57mmol) in DMF (2OmL) was added NaH (143mg, 3.57mmol) with ice-bath. The resulting mixture was stirred for 15min. at 0-5 0C and was added 10b (1.43g, 3.57mmol). The reaction mixture was stirred at r.t. over night and evaporated to remove DMF. The residue was purified by column chromatography (PE:EA=1 :2) to give 14b (1.13g, 59.5% yield).
59.5%
Step 2: To a solution of Id (599mg, 3.57mmol) in DMF (20mL) was added NaH (143mg, 3.57mmol) with ice-bath. The resulting mixture was stirred for 15min. at 0-5 C and was added lc (1.43g, 3.57mmol). The reaction mixture was stirred at r.t. over night and evaporated to remove DMF. The residue was purified by column chromatography (PE:EA=1 :2) to give le (1.13g, 59.5% yield).
2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 4h;
General procedure: 2-(Difluoromethyl)-1H-benzo[d]imidazole (1 mol),chloro derivative (1 mol) and K2CO3 (2 mol) were taken inDMSO (10 v). The reaction mixture was heated to 130 C,stirred for 4 h. Then the reaction mixture was cooled to roomtemperature, diluted with water (50 v) extracted with EtOAC(2 x 50 v), evaporated the solvent under reduced pressure toget the crude compound. Crude products were purified bycolumn chromatography.
Step 1 : To a solution of 3a in DMF was added NaH with ice-bath. The resulting mixture was stirred for 15min. at 0-5 0C and was added 1g. The reaction mixture was stirred at r.t. over night and evaporated to remove DMF. The residue was purified by column chromatography (PE:EA=1:2) to give 3b.
Step 3: 1 : To a solution of 6c (1.92g, 6.98mmol) in DMF (20mL) was added NaH (307mg, 7.68mmol) under ice bath. The resulting mixture was stirred at 0-50C for 30min and was added 3a (1.17g, 6.98mmol). The reaction mixture was stirred at r.t. for 2.5h and evaporated. The residue was dissolved in morpholine (30mL) and heated at 800C for 2h. After cooling to room temperature, the mixture was added IN NaOH (28mL). The resulting mixture was stirred at r.t. for 2h, evaporated. The residue was purified by column chromatography (PE:EA=1:1) to give 6 (660mg, 23% yield from 6c). 1H NMR(300MHz, CDCl3): delta=3.45 (t, 1H), 3.78-3.94 (m, 8H), 4.12-4.17 (m, 2H), 4.52-4.56 (m, 2H), 7.18 (t, 1H), 7.42-7.56 (m, 3H), 7.78 (s, 1H), 7.95-7.98 (m, 1H). LC-MS [M+H]+: 416.0.
Step 4: To a solution of Id in DMF was added NaH with ice-bath. The resulting mixture was stirred for 15min. at 0-5 C and' was added 7g. The reaction mixture was stirred at r.t. over night and evaporated to remove DMF. The residue was purified by column chromatography (PE:EA=1 :2) to give 7h.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h;Inert atmosphere;
Step d): 6-(4-chloro-6-(2-(difluoromethyl)-1 H-benzorc l imidazol-1 -yl)-1 ,3,5-triazin-2-yl)-2- oxa-6-azaspiro[3.31 heptane (22).Under nitrogen atmosphere an oven-dried round-bottom flask was charged with compound 21 (73.0 mg, 295 muiotatauiotaomicronIota, 1 .0 eq.) in dry DMF (2 ml_). The solution was cooled down to 0C and potassium carbonate (59.1 mg, 425 muiotatauiotaomicronIota, 1 .4 eq.) and 2-(difluoro- methyl)-1 /-/-benzoimidazole (69.5 mg, 414 muiotatauiotaomicronIota, 1.4 eq.) were added. The reaction mixture was stirred for 30 min at 0C and then for 2 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (1 % MeOH/DCM) to yield the title compound as a white solid (53.7 mg, 48%). RF: 0.48 (DCM/MeOH, 95:5 v/v); 1H NMR (CDCI3, 400 MHz): delta 8.48 (d, J = 7.6 Hz, 1 H), 7.90 (d, J = 7.2 Hz, 1 H), 7.64 (t, J = 53.6 Hz, 1 H), 7.46-7.44 (m, 2H), 4.90 (s, 4H),4.49 (d, J = 9.6 Hz, 4H).
48%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h;Inert atmosphere;
Step d : 6-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (22) Under nitrogen atmosphere an oven-dried round-bottom flask was charged with compound 21 (73.0 mg, 295 mumol, 1.0 eq.) in dry DMF (2 mL). The solution was cooled down to 0 C. and potassium carbonate (59.1 mg, 425 mumol, 1.4 eq.) and <strong>[705-09-9]2-(difluoro-methyl)-1H-benzoimidazole</strong> (69.5 mg, 414 mumol, 1.4 eq.) were added. The reaction mixture was stirred for 30 min at 0 C. and then for 2 h at RT. The solvent was removed under high vacuum and the remaining residue was purified directly by flash column chromatography (1% MeOH/DCM) to yield the title compound as a white solid (53.7 mg, 48%). RF: 0.48 (DCM/MeOH, 95:5 v/v); 1H NMR (CDCl3, 400 MHz): delta 8.48 (d, J=7.6 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.64 (t, J=53.6 Hz, 1H), 7.46-7.44 (m, 2H), 4.90 (s, 4H), 4.49 (d, J=9.6 Hz, 4H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
Preparation Example 1 To a solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.3 g) and <strong>[705-09-9]2-(difluoromethyl)-1H-benzimidazole</strong> (3.9 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-<strong>[705-09-9]2-(difluoromethyl)-1H-benzimidazole</strong> (5.49 g) as a white powder.
With caesium carbonate; In ISOPROPYLAMIDE; at 120℃;
PREPARATION x45: 4-(5-bromo-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-4-yl)morpholine-3-carboxylic acid A mixture of 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 3 g, 9.3 mmol), <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (1.3 g, 11.1 mmol) and Cs2CO3 (10.28 g, 47.4 mmol) in DMA (50 mL) was stirred at 120 C. overnight. The mixture was subsequently concentrated and the crude material was converted to the methyl ester of the title compound by treatment with CH2N2. The methyl ester was purified and then hydrolyzed by LiOH to give the title compound which was used without further purification (310 mg, 7.6%).
(R)-2-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13.8%
Example 211 (R)-2-(2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (24.22 mg, 0.144 mmol), cesium carbonate (64.0 mg, 0.196 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.99 mg, 0.013 mmol), and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (12.48 mg, 0.026 mmol) in DMF (500 muL) was heated to 130 C. in a microwave for 40 minutes. Additional tris(dibenzylideneacetone)dipalladium(0) (11.99 mg, 0.013 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (12.48 mg, 0.026 mmol) were added to the reaction mixture, which was subsequently heated to 130 C. in the microwave for 1 hour. After addition of EtOAc and water, the mixture was extracted with EtOAc (2*). The combined extracts were washed with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (NH-silica, gradient 30-100%, EtOAc/hexane) and then by preparatory HPLC using a 20-45% CH3CN gradient in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a yellow solid (11.3 mg, 13.8%). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.07-1.26 (m, 2H), 1.49-1.72 (m, 3H), 2.93-3.43 (m, 8H), 3.51-3.61 (m, 1H), 3.68-3.77 (m, 1H), 3.79-3.88 (m, 3H), 3.91-3.98 (m, 1H), 4.00-4.14 (m, 2H), 4.32-4.40 (m, 1H), 7.34-7.47 (m, 2H), 7.50 (s, 1H), 7.56-7.86 (m, 2H), 8.09-8.21 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C25H29F2N7O3, 514.24. found 514.3.
1-(2-(2-(difluoromethyl)-1H-benzo[c]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31.7%
Example 55 1-(2-(2-(difluoromethyl)-1H-benzo[c]imidazol-1-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone To a 5 mL microwave vial equipped with a magnetic stir-bar were added 1-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)ethanone (300 mg, 1.116 mmol), <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (179 mg, 1.063 mmol), tris(dibenzylideneacetone)dipalladium(0) (38.9 mg, 0.043 mmol) and cesium carbonate (520 mg, 1.595 mmol). The vial was evacuated and filled with nitrogen four times and then sealed. DMF (2.1 mL) was added to give an orange suspension, which was heated to 140 C. for 45 minutes. The reaction mixture was heated for an additional 30 minutes, was subsequently diluted with ACN (3 mL), and was passed through a syringe filter. The filtrate was directly purified by preparatory HPLC using a gradient of 40-60% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). Lyophilization of the collected fractions gave a TFA salt of the title compound (135 mg, 31.7%). ESI-MS m/z [M+H]+ calc'd for C19H18F2N6O2, 401.15. found 401.3.
With caesium carbonate; XPhos;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 130℃; for 1.66667h;microwave irradiation;
Example 67 (R)-2-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine A mixture of (R)-2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x10 50 mg, 0.127 mmol), <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (21.29 mg, 0.127 mmol), cesium carbonate (61.9 mg, 0.190 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 mumol) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (4.83 mg, 10.13 mumol) in DMF 253 muL was heated to 130 C. in a microwave for 40 minutes. Additional tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 mumol) and 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (4.83 mg, 10.13 mumol) were added, and the reaction mixture was heated to 130 C. in a microwave for 1 hour. EtOAc and water were added and the mixture was filtered through Celite and extracted with EtOAc (2*). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2-NH2, 30-100% EtOAc/hexane gradient) to afford the title compound as a yellow solid (14.3 mg, 21.4%). 1H NMR (400 MHz, CDCl3) delta 3.08 (s, 3H), 3.19-3.38 (m, 4H), 3.68 (td, J=12.00, 2.78 Hz, 1H), 3.83-3.92 (m, 1H), 3.94-4.02 (m, 1H), 4.11-4.20 (m, 1H), 4.44-4.63 (m, 3H), 7.36-7.75 (m, 6H), 7.93-8.01 (m, 3H), 8.17-8.23 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H24F2N6O3S, 527.16. found 527.3.
4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{(3S)-1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-6-morpholin-4-ylpyrimidin-2-amine dihydrochloride[ No CAS ]
methyl {(3R)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate[ No CAS ]
methyl {(3S)-1-[trans-4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate[ No CAS ]
15.3 g (0.1 1 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene- 1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 19 hrs the conversion of benzene- 1, 2-diamine was >99% (GC). The mixture was cooled down to 0 C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3% isolated yield.
64.3%
In neat (no solvent); at 98 - 100℃; for 3h;Inert atmosphere;
15.3 g (0.11 mol) DFAipr (isopropyl 2, 2-difluoroacetate) was added to 4.0 g (0.037 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually.After 19 hrs the conversion of benzene-1, 2-diamine was >99% (GC). The mixture was cooled down to 0 C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAipr for 3 times and dried under vacuum. 4 g light blue solid was obtained in 64.3% isolated yield.
33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 C) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1 , 2-diamine was >99% (GC). The mixture was cooled down to 0 C, and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8,3 g light green solid was obtained in 50.3% isolated yield.
50.3%
In neat (no solvent); at 98 - 100℃; for 3h;Inert atmosphere;
33.0 g (0.294 mol) DFAMe (methyl 2, 2-difluoroacetate) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (98-100 C.) and maintained for 3 hrs under nitrogen. The mixture turned to blue clear solution gradually. After 3 hrs the conversion of benzene-1, 2-diamine was >99% (GC). The mixture was to cooled down to 0 C., and solid was precipitated. After filtration, the obtained solid was washed with cool DFAMe for 3 times and dried under vacuum. 8.3 g light green solid was obtained in 50.3% isolated yield.
27.84 g (0.294 mol) DFAN (2,2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene- 1 , 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120 C) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1 , 2-diamine was 87.23% (GC). The mixture was cooled down to 0C, and 300 ml EA was added. The organic phase was washed with 100 ml *4 water, and then with brine 50 ml * 2. Dried with Na2S04; removed solvent. 12. lg orange solid was obtained in 73.5% isolated yield.
73.5%
In neat (no solvent); at 120℃; for 3h;Inert atmosphere;
27.84 g (0.294 mol) DFAN (2,2-difluoroacetamide) was added to 10.8 g (0.1 mol) benzene-1, 2-diamine at room temperature under nitrogen. Then the mixture was heated to reflux (120 C.) and maintained for several hours under nitrogen. The mixture turned to blue clear solution gradually. After 3 h the conversion of benzene-1, 2-diamine was 87.23% (GC). The mixture was cooled down to 0 C., and 300 ml EA was added. The organic phase was washed with 100 ml*4 water, and then with brine 50 ml*2. Dried with Na2SO4, removed solvent, 12.1 g orange solid was obtained in 73.5% isolated yield.
(S)-2-amino-1-(4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperazin-1-yl)-3-phenylpropan-1-one dihydrochloride[ No CAS ]
(S)-4-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)-3-methylmorpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.70 g
With sodium carbonate; In N,N-dimethyl acetamide; at 90℃; for 12h;
(S) -4- (4,6-dichloropyrimidin-2-yl) -3-methylmorpholine 4a (410 mg, 1.61 mmol)2- (difluoromethyl) -lH-benzo [d] imidazole 5a (324 mg, 1.94 mmol)And sodium carbonate (530 mg, 4.96 mmol)Was dissolved in 10 mL of dimethylacetamide,Heated to 90 C,The reaction was stirred for 12 hours.Ethyl acetate (20 mL)The aqueous phase was extracted with ethyl acetate (10 mL x 3)The organic phases were combined,Washed with saturated sodium chloride solution (30 mL)Dried over anhydrous magnesium sulfate,filter,The filtrate was concentrated under reduced pressure,(S) -4- (4-Chloro-6- (2- (difluoromethyl) -lH-benzo [d] imidazol- 1 -yl)Pyrimidin-2-yl) -3-methylmorpholine5b (0.70 g, yellow oil)The product was directly subjected to the next reaction without purification.
3-(4,6-dichloro-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane[ No CAS ]
[ 705-09-9 ]
2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of 3-(4,6-dichloro-1,3,5-triazine-2,4-diyl)(8-oxa-3-azabicyclo[3.2.1]octane) (2.61 g, 10 mmol) in acetone/ice, morpholine (900 mg, 12 mmol) and triethylamine (5 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. Separated white solid was filtered and washed with water. The crude product obtained was pure enough and taken to next step without purification. Treatment of the mixture (270 mg. 0.87 mmol) with <strong>[705-09-9]2-(difluoromethyl)-1H-benzo[d]imidazole</strong> (146 mg, 0.87 mmol) and K2CO3 (967 mg, 7 mmol) in DMF (2.5 mL) for 18 hours gave 2-(difluoromethyl)-1-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1H-benzimidazole after purification by HPLC. (M+H) 445.
4-chloro-N-(1-cyclopropylethyl)-6-morpholino-1,3,5-triazin-2-amine[ No CAS ]
[ 705-09-9 ]
N-(1-cyclopropylethyl)-4-(2-(difluoromethyl)-1Hbenzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 4h;
General procedure: 2-(Difluoromethyl)-1H-benzo[d]imidazole (1 mol),chloro derivative (1 mol) and K2CO3 (2 mol) were taken inDMSO (10 v). The reaction mixture was heated to 130 C,stirred for 4 h. Then the reaction mixture was cooled to roomtemperature, diluted with water (50 v) extracted with EtOAC(2 x 50 v), evaporated the solvent under reduced pressure toget the crude compound. Crude products were purified bycolumn chromatography.
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