4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbaldehyde → (R)-5-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-methyl-morpholine-3-thione

In a 5 ml-reaction tube under an inert atmosphere a mixture of (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione (48 mg, 0.2 mmol) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (20 mg, 0.11 mmol) in methanol (0.3 ml) was stirred at room temperature for 1 hour. Then decaborane (24 mg, 0.2 mmol) was added in one portion and the mixture warmed to 45° C. for 15 hours. For the workup, the light yellow solution was quenched with sodium carbonate (10% solution), the methanol removed at reduced pressure and then the residue extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude product was purified by preparative HPLC using a gradient of water (+0.1% triethylamine) and acetonitrile (90:10 to 10:90). The (R)-5-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-methyl-morpholine-3-thione was obtained as a colourless foam (49 mg, 60%); (calculated) C16H16ClF3N4OS [404.84]; (found) [M+H]+=405.

1. customIn a 5 ml-reaction tube under an inert atmosphere
2. temperaturethe mixture warmed to 45° C. for 15 hours
3. customFor the workup, the light yellow solution was quenched with sodium carbonate (10% solution)
4. customthe methanol removed at reduced pressure
5. extractionthe residue extracted three times with ethyl acetate
6. dry with materialThe combined organic layers were dried over sodium sulphate
7. customevaporated at reduced pressure
8. customThe crude product was purified by preparative HPLC

ORD-Eintrag

ord-3166208b241646a6b25f36fae3a24cc6

Quelldatensatz

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09242943B2