With hypophosphorous acid; sodium nitrite In water at 0 - 20℃; for 0.75 h;
A solution of sodium nitrite (5.28g; 76.5 mmol) in water (17ml) was added drop wise over 5 minutes to a stirred solution of Al.4 (11.3 g; 52 mmol) in hypophosphorous acid (50 wt. percent solution in water, 15OmL) at 0° C to 50C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 40 minutes. The mixture was cooled in an ice bath (0° C to 50C ) and the pH was adjusted to >10 by the addition of aqueous sodium hydroxide (55g in 100 mL of water). The resulting suspension was filtered. The filter cake was rinsed with water and suction dried to afford 9.9 g (97percent) of A1.5 as a PiPLC: 99percent, ret. time = 0.92 min., LC/MS (M+H)+ = 202.06 (204.04, 206.02).
75%
Stage #1: With hypophosphorous acid; sodium nitrite In water at 0 - 20℃; for 2 h; Stage #2: With sodium carbonate In water at 0℃;
A1.5: 4,6-Dichloro-l -methyl- lH-imidazo[4,5-c1pyridine A1.5A solution of sodium nitrite (415 mg; 6 mmol) in 2 ml of water was added drop wise over 5 minutes to a stirred solution of A1.4 (0.87 g; 4 mmol) in 14 ml of 50percent aqueous H3PO2 at 0° C. The reaction mixture was allowed to warm to room temperature over ~2hr. After diluting the reaction mixture with water (250 ml) and re-cooling to 0° C, the ph was adjusted to ~9 by carefully adding solid sodium carbonate. The resulting suspension was filtered. The filter cake was rinsed with water and suction dried to afford 061 g (75percent) of A1.5 as a HPLC: 99percent, ret. time = 0.92 min., LC/MS (M+H)+ = 202.05 (204.04, 206.02).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 10, p. 2646 - 2649
[2] Patent: WO2006/122137, 2006, A1, . Location in patent: Page/Page column 71
[3] Patent: WO2006/53166, 2006, A1, . Location in patent: Page/Page column 57
2
[ 914942-86-2 ]
[ 122-51-0 ]
[ 887147-19-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 55℃; for 16 h;
A solution of 2,6-dichloro-4-N-methylpyridine-3,4-diamine (250 mg, 1.30 mmol, 1.00 equiv) and triethyl orthoformate (5 mL) in methanol (10 mL) was stirred for 16 h at 55° C. The reaction was quenched by water. The pH value of the solution was adjusted to 9 with sodium hydroxide (1 M). The resulting solution was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 220 mg (84percent) of the title compound as a brown solid. LC-MS (ES, m/z): 202 [M+H]+.
74%
at 20 - 80℃; for 15 h;
Ammonium chloride (787g) was added to water (5L) at room temperature. Iron (1.0 kg, 18 mol) was added and the reaction mixture heated to 90 0C. A1.5 (50Og, 2.25 mmol) was added portionwise over ~ Ih (frothing observed). The reaction mixture was maintained at 90 0C for 1 hour after which time TLC analysis of the reaction mixture showed no starting material remaining. The reaction mixture was allowed to cool to 30 0C and ethyl acetate (5L) was added to the reaction and the mixture was filtered to remove the iron. The layers were separated and the water layer washed with additional ethyl acetate. The organic layer was combined and the solvent removed under reduced pressure to provide the intermediate (3,4-diamino-2,6- dichloro-N4-methylpyridine, 36Og, 83percent), which was dissolved in ethanol (1,058 mL). Triethylorthoformate (1058 mL, 6.37 mol) was added at room temperature and the reaction mixture slowly heated to 80 0C. The reaction mixture was maintained at 80 0C for ~ 15h and cooled to 50 0C and the solvent removed by distillation under reduced pressure. n-Hexane was added and the product crystallized and was collected by filtration and dried to yield A1.7 (336g, 74percent, based on A1.5).
Reference：
[1] New Journal of Chemistry, 2016, vol. 40, # 11, p. 9194 - 9204
[2] Patent: US2015/57260, 2015, A1, . Location in patent: Paragraph 0557; 0558
[3] Patent: WO2006/122137, 2006, A1, . Location in patent: Page/Page column 74
[4] Patent: WO2006/122137, 2006, A1, . Location in patent: Page/Page column 73-74
3
[ 149-73-5 ]
[ 887147-19-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With hydrogenchloride; tin(ll) chloride In methanol; water for 1 h; Heating / reflux Stage #2: for 1 h; Heating / reflux
A1.5: 4.6-Dichloro- 1 -methyl- 1 H-imidazo|"4,5-c]pyridine; A1.5 f. A mixture of A1.7 (2.4 g; 10.8 mmol), SnCl22H20 (9.7 g; 43 mmol) and concentrated HCl (20 ml) in methanol (80 ml) was refluxed 1 hr. After removing the volatiles in vacuo, the residue was dissolved in methanol (80 ml) and trimethylorthoformate (10 ml) was added. After refluxing 30 minutes, additional trimethylorthoformate (10 ml) was added and heating was continued for 30 minutes. After removing the volatiles in vacuo, the residue was partitioned between ethyl acetate (200 ml) and 2N NaOH (150 ml). The organic layer was washed with 2N NaOH (150 ml) and brine (100 ml). Drying (MgSO4) and concentration afforded 2.12 g (97percent) of A1.5 as a tan solid. HPLC (A): 98percent, ret. time = 0.94 min., LC/MS(M+H)+ = 202.05 (204.04, 206.02).
In ethanol; at 110℃; for 1.5h;Microwave irradiation;
A1.8: 4-Methylamino-6-chloro- 1 -methyl- 1 H-imidazo[4,5-c]pyridine; A1.8A mixture of A1.5 (0.47 g; 2.3 mmol) and 8M methylamine in ethanol (5 ml) was heated to 110 C. in a microwave apparatus for 1.5 hr. After removing the volatiles in vacuo, the residue was triturated with water, filtered and dried to afford59 EPO <DP n="61"/>0.44 g (98%) of A1.8 as a tan solid. HPLC (A): 99%, ret. time = 0.76 min., LC/MS (M+H)+ = 197.14 (199.06).
90 - 93%
In ethanol; at 82 - 120℃; for 3 - 24h;Product distribution / selectivity;
A mixture of A1.5 (9.9 g; 49 mmol) and methylamine (8M solution in ethanol,80mmol, 100 ml) was heated to 82 C for 24 hr. After removing the volatiles in vacuo, the residue was triturated with water (30 mL), filtered and dried to afford 8.89 EPO <DP n="76"/>g (93%) of A1.8 as a tan solid. HPLC (A): 99%, ret. time = 0.98 min., LC/MS (M+H)+ = 197.16 (199.06).Alternate preparation: A1.7 (26Og, 1.3 mol) and methylamine 40% in ethanol (3.0 L) were placed in an autoclave and heated between 110-120 0C for 3h. The reaction mixture was allowed to cool to room temperature and the solvent was removed by distillation under reduced pressure. The residue was triturated with water (15 L) and then washed with hexane (5L) and dried to yield A1.8 (228g, 90%).
With hypophosphorous acid; sodium nitrite; In water; at 0 - 20℃; for 0.75h;Product distribution / selectivity;
A solution of sodium nitrite (5.28g; 76.5 mmol) in water (17ml) was added drop wise over 5 minutes to a stirred solution of Al.4 (11.3 g; 52 mmol) in hypophosphorous acid (50 wt. % solution in water, 15OmL) at 0 C to 50C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 40 minutes. The mixture was cooled in an ice bath (0 C to 50C ) and the pH was adjusted to >10 by the addition of aqueous sodium hydroxide (55g in 100 mL of water). The resulting suspension was filtered. The filter cake was rinsed with water and suction dried to afford 9.9 g (97%) of A1.5 as a PiPLC: 99%, ret. time = 0.92 min., LC/MS (M+H)+ = 202.06 (204.04, 206.02).
75%
A1.5: 4,6-Dichloro-l -methyl- lH-imidazo[4,5-c1pyridine A1.5A solution of sodium nitrite (415 mg; 6 mmol) in 2 ml of water was added drop wise over 5 minutes to a stirred solution of A1.4 (0.87 g; 4 mmol) in 14 ml of 50% aqueous H3PO2 at 0 C. The reaction mixture was allowed to warm to room temperature over ~2hr. After diluting the reaction mixture with water (250 ml) and re-cooling to 0 C, the ph was adjusted to ~9 by carefully adding solid sodium carbonate. The resulting suspension was filtered. The filter cake was rinsed with water and suction dried to afford 061 g (75%) of A1.5 as a HPLC: 99%, ret. time = 0.92 min., LC/MS (M+H)+ = 202.05 (204.04, 206.02).
A1.5: 4.6-Dichloro- 1 -methyl- 1 H-imidazo|"4,5-c]pyridine; A1.5 f. A mixture of A1.7 (2.4 g; 10.8 mmol), SnCl2»2H20 (9.7 g; 43 mmol) and concentrated HCl (20 ml) in methanol (80 ml) was refluxed 1 hr. After removing the volatiles in vacuo, the residue was dissolved in methanol (80 ml) and trimethylorthoformate (10 ml) was added. After refluxing 30 minutes, additional trimethylorthoformate (10 ml) was added and heating was continued for 30 minutes. After removing the volatiles in vacuo, the residue was partitioned between ethyl acetate (200 ml) and 2N NaOH (150 ml). The organic layer was washed with 2N NaOH (150 ml) and brine (100 ml). Drying (MgSO4) and concentration afforded 2.12 g (97%) of A1.5 as a tan solid. HPLC (A): 98%, ret. time = 0.94 min., LC/MS(M+H)+ = 202.05 (204.04, 206.02).
A solution of 2,6-dichloro-4-N-methylpyridine-3,4-diamine (250 mg, 1.30 mmol, 1.00 equiv) and triethyl orthoformate (5 mL) in methanol (10 mL) was stirred for 16 h at 55 C. The reaction was quenched by water. The pH value of the solution was adjusted to 9 with sodium hydroxide (1 M). The resulting solution was extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 220 mg (84%) of the title compound as a brown solid. LC-MS (ES, m/z): 202 [M+H]+.
74%
In ethanol; at 20 - 80℃; for 15h;Product distribution / selectivity;
Ammonium chloride (787g) was added to water (5L) at room temperature. Iron (1.0 kg, 18 mol) was added and the reaction mixture heated to 90 0C. A1.5 (50Og, 2.25 mmol) was added portionwise over ~ Ih (frothing observed). The reaction mixture was maintained at 90 0C for 1 hour after which time TLC analysis of the reaction mixture showed no starting material remaining. The reaction mixture was allowed to cool to 30 0C and ethyl acetate (5L) was added to the reaction and the mixture was filtered to remove the iron. The layers were separated and the water layer washed with additional ethyl acetate. The organic layer was combined and the solvent removed under reduced pressure to provide the intermediate (3,4-diamino-2,6- dichloro-N4-methylpyridine, 36Og, 83%), which was dissolved in ethanol (1,058 mL). Triethylorthoformate (1058 mL, 6.37 mol) was added at room temperature and the reaction mixture slowly heated to 80 0C. The reaction mixture was maintained at 80 0C for ~ 15h and cooled to 50 0C and the solvent removed by distillation under reduced pressure. n-Hexane was added and the product crystallized and was collected by filtration and dried to yield A1.7 (336g, 74%, based on A1.5).
In methanol; for 1h;Heating / reflux;Product distribution / selectivity;
A mixture of A1.7 (2.4 g; 10.8 mmol), SnCl2»2H20 (9.7 g; 43 mmol) and concentrated HCl (20 ml) in methanol (80 ml) was refluxed 1 hr. After removing the volatiles in vacuo, the intermediate (3,4-diamino-2,6-dichloro-N4-methylpyridine) was dissolved in methanol (80 ml) and trimethylorthoformate (10 ml) was added. After refluxing 30 minutes, additional trimethylorthoformate (10 ml) was added and heating was continued for 30 minutes. After removing the volatiles in vacuo, the EPO <DP n="75"/>residue was partitioned between ethyl acetate (200 ml) and 2N NaOH (150 ml). The organic layer was washed with 2N NaOH (150 ml) and brine (100 ml). Drying (MgSO4) and concentration afforded 2.12 g (97%) of A1.5 as a tan solid. HPLC (A):98%, ret. time = 0.94 min., LC/MS (M+H)+ = 202.05 (204.04, 206.02).
Exam le 17V,iV-dicyclopropyl-6-ethyl-l-methyl-4-(thiazol-2-ylamino)-l,6-dihydroimidazo [4,5- d] pyrrolo [2,3-b] pyridine-7-carboxamide1A Preparation of 6-chloro-N-(2.4-dimethoxybenzyl)- 1 -methyl- 1H- imidazor4,5-c1 pyridin-4-ami[00123] In a 200 mL round bottom flask, 4,6-dichloro-l-methyl-lH-imidazo[4,5- c]pyridine (15 g, 74.2 mmol) (prepared as per WO2006122137 example A1.5) was dissolved in 2,4-dimethoxybenzylamine (25 mL, 166 mmol). The reaction mixture was heated to 110 C for 3 h and cooled to room temperature. Water was added and a tan colored solid precipitated out. Vacuum filtration yielded a tan solid. The solid was washed with ethyl acetate and hexane to yield 6-chloro-N-(2,4- dimethoxybenzyl)- 1 -methyl- lH-imidazo[4,5-c]pyridin-4-amine (23.459 g, 95 % yield) as a cream colored solid.[00124] MS (ESI) m/z 333.0 (Mu+Eta)[00125] 1H MR (500 MHz, DMSO-d6) delta ppm 8.05 (s, 1 H), 7.17 (t, 1 H, J=6.19 Hz), 7.06 (d, 1 H, J=8.25 Hz), 6.87 (s, 1 H), 6.55 (d, 1 H, J=2.47 Hz), 6.42 (dd, 1 H, J=8.52, 2.47 Hz), 4.54 (d, 2 H, J=5.77 Hz), 3.82 (s, 3 H), 3.74 (s, 3 H), 3.72 (s, 3 H)
at 110℃; for 3h;Sealed tube;
1.3. Intermediate 4 /Intermediate 5 1.3.1. Step i): (6-Chloro-l-methyl-lH-imidazo[4,5-c]pyridin-4-yl)-(2,4- dimethoxybenzyl)amine (intermediate 4) 4,6-Dichloro-l-methyl-lH-imidazo[4,5-c]pyridine (1 eq, 5.0 g) is dissolved in 2,4-dimethoxybenzylamine (2.24 eq, 8.3 mL) in a 20 mL sealed tube. The solution is heated to 110C and left stirring for 3 h. The reaction is diluted with water and extracted with DCM (3 x 100 mL). The combined organic layers are washed with sat. brine (100 mL), dried over Na2S04 and concentrated in vacuo. Trituration of the obtained residue in MeOH yields the desired product.
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