Methanesulfonic Acid → HCID 87279909, compound

Temperature

20 °C

(1S,2R)-PNE (20.3 g, 18.0 mmol) in THF/toluene (9:1-w/w, 18.2%-w/w) was charged under a nitrogen atmosphere to a dry, jacketed 150 mL-reactor with agitator. Diethylzinc in toluene (29.9%-w/w, 6.48 g, 15.7 mmol) was added by syringe keeping the temperature at 17 to 22° C. and the mixture was aged for 30 min at 17° C. Cyclopropylacetylene in toluene (69.6%-w/w, 6.84 g, 72.0 mmol) was added at 17° C. and the resulting mixture was aged for about 60 min at 20° C. To the reaction mixture BuLi in toluene (3.06 mol/kg, 19.9 g, 60.9 mmol) and (1-(4-aminobiphenyl-3-yl)-2,2,2-trifluoroethanone (CN46225, compound of formula IV, wherein R1 is trifluoromethyl, R8 is 5-phenyl, R9 is hydrogen and R10 is hydrogen) (43.0%-w/w, 37.0 g, 60 mmol) in THF/toluene (1:1-w/w) were added in parallel over a period of 3 h at 20° C. The addition of BuLi was started about 10 min in advance of the CN46225 addition. After complete addition of BuLi and CN46225, the reaction mixture was stirred for 30 min at 20° C., then heated over a period of 1 h to 30° C. and aged for 6 h at 30° C. The reaction mixture was stirred overnight at 0° C. HPLC indicated 94.3% conversion and 95.6% ep, according to Method B. The reaction mixture was diluted with toluene (27.6 g) at room temperature and quenched by adding aqueous citric acid (1 M, 45.3 g). The phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 (5%-w/w, 24.2 g) and water (12.0 g). The organic phase was heated under reduced pressure to partly remove THF while toluene is added to finally reach a THF poor residue (54.5 g) of (R)-2-(4-aminobiphenyl-3-yl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol (CN46630, compound of formula II, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 5-phenyl, R9 is hydrogen and R10 is hydrogen). The residue was diluted with isopropyl alcohol (16.7 g) and toluene (60.0 g). A first portion of methanesulfonic acid (5.48 g, 57.0 mmol) was added by a syringe pump over a period of 30 min at 30° C. Seeding crystals (a small portion between 1 and 10 mg) were added and the mixture was aged for 30 min at 30° C. A second portion of methanesulfonic acid (2.88 g, 30.0 mmol) was added by syringe pump over a period of 45 min at 30° C. The mixture was stepwise aged and cooled over 1 h 45 min to finally reach 5° C. The product was filtered, and the filter cake was washed with toluene/isopropyl alcohol (10:1-w/w, 27.0 g) and dried in vacuo at 40° C. The dry product (R)-2-(4-aminobiphenyl-3-yl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (1:1 mol/mol, CN46630-MSA) (15.2 g, 35.6 mmol, 59% yield) was obtained as an off-white solid (99.4% purity and 99.7% ep, according to Method B). The combined mother liquor and wash liquor was concentrated (46.7 g residue). During storage overnight at 3° C. a white solid crystallized from the residue. The product was filtered, washed with toluene, and then toluene/isopropyl alcohol (10:1-w/w, 10 g) was added. After stirring the slurry for 60 min at 30° C. the mixture was cooled to 3° C. and filtered. The product was washed with toluene/isopropyl alcohol (10:1-w/w) and dried in vacuo at 40° C. CN46630-MSA (second crop, 3.8 g, 8.0 mmol, 13% yield) was obtained as off-white solid (89.7% purity at 99.7% ep, according to Method B).

1. customat 17 to 22° C.
2. waitthe resulting mixture was aged for about 60 min at 20° C
3. additionwas started about 10 min in advance of the CN46225 addition
4. temperatureheated over a period of 1 h to 30° C.
5. waitaged for 6 h at 30° C
6. stirringThe reaction mixture was stirred overnight at 0° C
7. customquenched
8. additionby adding aqueous citric acid (1 M, 45.3 g)
9. customThe phases were separated
10. washThe organic phase was successively washed with water (9.1 g), aqueous NaHCO3 (5%-w/w, 24.2 g) and water (12.0 g)
11. temperatureThe organic phase was heated under reduced pressure to partly remove THF while toluene
12. additionis added
13. additionThe residue was diluted with isopropyl alcohol (16.7 g) and toluene (60.0 g)
14. additionSeeding crystals (a small portion between 1 and 10 mg) were added
15. waitthe mixture was aged for 30 min at 30° C
16. temperaturecooled over 1 h 45 min to finally reach 5° C
17. filtrationThe product was filtered
18. washthe filter cake was washed with toluene/isopropyl alcohol (10:1-w/w, 27.0 g)
19. customdried in vacuo at 40° C

ORD record

ord-3b27f51d1a3449eda6cfeeee1a53145f

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08957204B2