Hydrochloric Acid → Azd-9496

Temperature

50 °C

(E)-Methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (350 g, 766.69 mmol) was charged a 5 L fixed vessel. Isopropyl alcohol (2.80 L) was added to the vessel. Sodium hydroxide (5M, 460 ml, 2.30 mol) was added in one portion and the mixture was stirred at 21 C for 16 hrs. The dark solution was screened through a filter to remove particulates. The filtrate was returned to the reactor vessel. The filter and filtrate collection vessel were washed with isopropanol (700 ml) and the washings were added to the reactor vessel. The reaction mixture was agitated and water (1.75 L) was added. Concentrated hydrochloric acid (37% w/w, 165 ml, 1.92 mol) was charged to the vessel. Further hydrochloric acid (21.5 ml) was added to the vessel to adjust the pH between 4.0 and 4.5. The solution was heated to 50° C. Water (1.92 L) added to the vessel over 1 hour maintaining the internal temperature between 50-53° C. The jacket temperature was raised to 70° C. to maintain the reactor temperature in this range during the addition. Within 10 minutes of completion of the water addition, the mixture self seeded and started to crystallise. The mixture was held at 50-52° C. for 1.5 hours (jacket set temperature 58° C.). The resulting yellow suspension was cooled to 5° C. (jacket temperature) over 6 hours. The slurry was held at 5° C. (jacket temperature) for 11 hrs. The resultant yellow solid was isolated by filtration. The cake was pasted with a spatula to prevent cracking of the cake. The vessel was washed with water (1.05 L). The washings were used to wash the cake. The cake was pulled dry in air then dried in vacuo to constant weight over 4 days (oven temperature=30° C.). (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid was thus isolated as a yellow crystalline solid, “Form B” (319.45 g, 94%). 1H NMR (500 MHz, DMSO, 27° C.) 1.05 (3H, d), 1.08-1.28 (6H, m), 2.35 (1H, dd), 2.58 (1H, dd), 2.8-2.97 (2H, n), 3.47-3.57 (1H, m), 5.22 (1H, s), 6.67 (1H, d), 6.91-7.06 (2H, m), 7.19 (1H, d), 7.41 (1H, d), 7.46 (2H, d), 7.54 (1H, d), 10.58 (1H, s), 12.62 (1H, s).

1. filtrationa filter
2. customto remove particulates
3. filtrationThe filter
4. customfiltrate collection vessel
5. washwere washed with isopropanol (700 ml)
6. additionthe washings were added to the reactor vessel
7. stirringThe reaction mixture was agitated
8. additionwater (1.75 L) was added
9. temperaturemaintaining the internal temperature between 50-53° C
10. temperatureThe jacket temperature was raised to 70° C.
11. temperatureto maintain the reactor temperature in this range
12. additionduring the addition
13. customto crystallise
14. waitThe mixture was held at 50-52° C. for 1.5 hours
15. custom(jacket set temperature 58° C.)
16. temperatureThe resulting yellow suspension was cooled to 5° C. (jacket temperature) over 6 hours
17. customwas held at 5° C.
18. customfor 11 hrs
19. customThe resultant yellow solid was isolated by filtration
20. washThe vessel was washed with water (1.05 L)
21. washto wash the cake
22. customThe cake was pulled dry in air
23. customthen dried in vacuo to constant weight over 4 days (oven temperature=30° C.)

ORD record

ord-1cc9202b87164d4db57b4a93e5af7167

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09155727B2