Hydrochloric Acid → HCID 178462260, compound

Temperature

60 °C

(R)-3,5-Dichloro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole was suspended in acetonitrile (40 mL) and treated with formalin (1 mL). The reaction was treated with sodium cyanoborohydride (0.83 g, 13.2 mmol). The reaction was treated with ca. 0.5 mL acetic acid over ca. 10 min. The reaction was treated with tetrahydrofuran (20 mL), and additional portions of formalin (0.5 mL) and sodium cyanoborohydride (0.2 g) and stirred for 30 min. The reaction was concentrated to remove most of the organics (but not to dryness), partitioned between a minimum of dichloromethane/saturated sodium bicarbonate, and poured into a separatory funnel. The mixture was diluted with diethyl ether and the layers separated. The organics were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in ethanol (125 mL) and heated at reflux for 30 h. The reaction was concentrated to give viscous foam. The crude product was pumped on high vaccuum overnight. The resulting solid was dissolved in methanol and loaded onto a phenomenex strata strong cation exchange cartridge (giga tube, 20 g/60 mL). The tube was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give the crude product (3.5 g). The material was dissolved in 15 mL of isopropanol at 60° C. and water added until the mixture went cloudy (only about 9 mL water). The mixture was seeded with a crystal of product. At first the material appeared to oil out, but it was stirred vigorously for a couple of minutes which gave a white precipitate. An additional 6 mL of water was added. The mixture was incubated at 50° C. for 2 h (occasionally stirring to agitate the bed of product). The material was warmed to 60° C., incubated at that temperature for 15 min, and then re-cooled to 50° C. and incubated at that temperature 2 h longer. The suspension was allowed to gradually warm to room temperature in the water bath and was filtered. The resulting precipitate was rinsed with cold 1:1 isopropanol/water and air dried to give crystalline freebase (2.45 g, 64%). 1H-NMR (CDCl3, 500 MHz) δ 9.50 (bs, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.8, 5.2 Hz, 2H), 7.07 (dd, J=8.8, 8.6 Hz, 2H), 7.02 (d, J=1.8 Hz, 1H), 4.50 (q, J=6.6 Hz, 1H), 3.43 (d, J=8.7 Hz, 1H), 3.29 (d, J=8.7 Hz, 1H), 2.59 (m, 1H), 2.53 (m, 1H), 2.29 (m, 1H), 2.21 (s, 3H), 2.20 (m, 1H), 2.12 (m, 1H), 2.09 (m, 1H), 1.99 (m, 1H), 1.90 (m, 1H), 1.41 (d, J=6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=247 Hz), 139.1, 137.0, 134.3, 128.6 (d, J=7.8 Hz), 128.3, 126.9, 125.2, 122.1, 117.7, 115.6 (d, J=21 Hz), 78.9, 78.1, 51.8, 51.7, 46.2, 40.3, 32.9, 32.6, 22.1. Mass spec.: 436.1 (MH)+. A portion of the material was converted to the hydrochloride salt by suspending the product (1.2 g, 2.75 mmol) in ethanol (10 mL), cooling to 0° C., and treatment with ethanolic hydrochloric acid (1.25M, 2.2 mL). The mixture was concentrated to give (R)-3,5-dichloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole hydrochloride (1.30 g, 100%). 1H-NMR (CD3OD, 500 MHz) δ 7.46 (m, 1H), 7.40 (dd, J=9.2, 5.2 Hz, 1.5H), 7.31 (dd, J=8.9, 5.2 Hz, 0.5H), 7.08 (dd, J=8.9, 8.5 Hz, 1.5H), 6.98 (m, 1.2 H), 6.93 (d, J=1.5 Hz, 0.3H), 4.68 (q, J=6.4 Hz, 0.3H), 4.63 (q, J=6.7 Hz, 0.7H), 3.82 (d, J=9.8 Hz, 0.2H), 3.59 (q, J=7.0 Hz, 0.3H), 3.37-3.52 (m, 3H), 3.36 (d, J=9.2 Hz, 1H), 3.21 (d, J=9.2 Hz, 1H), 2.90 (s, 0.7H), 2.80 (m, 1.7H), 2.73 (s, 2.2H), 2.61 (m, 1.8H), 2.41 (m, 0.2H), 1.95-2.25 (m, 2H), 1.43 (m, 3H), 1.15 (m, 1.6H); 13C NMR (126 MHz, CD3OD) δ ppm 162.3 (d, J=246 Hz), 162.0 (d, J=245 Hz), 141.1, 137.6, 135.5, 133.5, 129.4 (d, J=8.6 Hz), 129.14, 129.05, 127.8 (d, J=7.7 Hz), 12.72, 125.3, 125.1, 121.7, 117.24, 117.20, 115.8 (d, J=21 Hz), 115.0 (d, J=21 Hz), 79.0, 75.99, 75.85, 72.7, 65.9, 57.4, 51.5, 51.4, 50.84, 50.76, 42.8, 42.2, 40.5, 38.1, 30.1, 29.9, 29.5, 29.1, 21.20, 21.16, 17.4, 14.5.

1. concentrationThe reaction was concentrated
2. customto remove most of the organics (but not to dryness),
3. custompartitioned between a minimum of dichloromethane/saturated sodium bicarbonate
4. additionpoured into a separatory funnel
5. additionThe mixture was diluted with diethyl ether
6. customthe layers separated
7. washThe organics were washed with brine
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated
10. dissolutionThe resulting residue was dissolved in ethanol (125 mL)
11. temperatureheated
12. temperatureat reflux for 30 h
13. concentrationThe reaction was concentrated
14. customto give viscous foam
15. customThe tube was flushed with several volumes of methanol which
16. washThe product was eluted with 2 M ammonia in methanol
17. customto give the crude product (3.5 g)
18. stirringit was stirred vigorously for a couple of minutes which
19. customgave a white precipitate
20. waitThe mixture was incubated at 50° C. for 2 h
21. stirring(occasionally stirring
22. stirringto agitate the bed of product)
23. waitincubated at that temperature for 15 min
24. temperaturere-cooled to 50° C.
25. customincubated at that temperature 2 h
26. filtrationwas filtered
27. washThe resulting precipitate was rinsed with cold 1:1 isopropanol/water and air
28. customdried
29. customto give crystalline freebase (2.45 g, 64%)
30. temperaturecooling to 0° C.
31. concentrationThe mixture was concentrated

ORD record

ord-f6f2d689744a4d72b4300dd968a63076

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026257B2