Cyclopropylacetylene → HCID 56962560, compound

Temperature

20 °C

A solution of (1R,2S)-PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature range for 30 min. A solution of cyclopropylacetylene (compound of formula III, wherein R2 is cyclopropyl) in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was added at 18° C. and the resulting mixture was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of 1-(2-amino-5-methylphenyl)-2,2,2-trifluoroethanone (CN46217, compound of formula IV, wherein R1 is trifluoromethyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) (36.5%-w/w, 33.4 g, 60.0 mmol) in toluene/THF (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN46217 addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid (1 M, 73.9 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g). The organic phase was partially concentrated (60 g residual solution), diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue was diluted with toluene (65 g), cooled to 5° C. and aged over night. The crystals were filtered, washed with cold (approx. 5° C.) toluene (10 g) and dried under vacuum at 40° C. The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep according to method B. The crude product was purified by slurring it in a mixture of toluene (10 mL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at 40° C. in vacuo. The product (compound of formula II, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) was obtained as white solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to method B. The assay was 97.0%-w/w according to 1H-NMR.

1. customfor 30 min
2. additionwas started 10 min in advance of the CN46217 addition
3. additionaddition of CN46217 the reaction mixture
4. temperatureheated to 30° C. over a period of 60 min
5. waitaged for 6 h at 30° C
6. stirringThe reaction mixture was stirred at 0° C. overnight
7. customquenched by addition of aqueous citric acid (1 M, 73.9 g)
8. stirringAfter stirring for 15 min the phases
9. customwere separated
10. washThe organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g)
11. concentrationThe organic phase was partially concentrated (60 g residual solution)
12. additiondiluted with toluene (30 g)
13. concentrationpartially concentrated again (52 g residue)
14. additionThe residue was diluted with toluene (65 g)
15. temperaturecooled to 5° C.
16. waitaged over night
17. filtrationThe crystals were filtered
18. washwashed with cold (approx. 5° C.) toluene (10 g)
19. customdried under vacuum at 40° C

ORD record

ord-f282dbe5a8b64607bb6677572e05dc12

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08957204B2