Diisopropylethylamine → methyl 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxylate

Temperature

-78 °C

To a stirring solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.00 g, 19.32 mmol) in THF (85 mL) was added DIEA (3.37 mL, 19.32 mmol). The resulting mixture was cooled to −78° C. in a dry ice/acetone bath. A solution of (1S,3R)-3-aminocyclohexanol (2.448 g, 21.25 mmol; prepared as described in Tetrahedron: Asymmetry 15:2051-2056 (2004)) in 40 mL THF was added at such a rate that the temperature remained at −78° C. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then concentrated to dryness and diluted with 200 mL ethyl acetate and 75 mL of a 1:1 mixture of water and an aqueous saturated sodium bicarbonate solution. The layers were separated and the aqueous layer back-extracted with 100 mL ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing. The solid was triturated with diethyl ether (5 mL), filtered, rinsed with diethyl ether (5 mL) and dried in vacuo to afford methyl 2-chloro-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxylate (3.7 g, 12.95 mmol, 67% yield) that was used without further purification. MS (ESI) m/z 286.0 [M+1]+.

1. customremained at −78° C
2. concentrationThe reaction mixture was then concentrated to dryness
3. additiondiluted with 200 mL ethyl acetate and 75 mL of a 1:1 mixture of water
4. customThe layers were separated
5. extractionthe aqueous layer back-extracted with 100 mL ethyl acetate
6. washThe combined ethyl acetate layers were washed with 50 mL of a saturated aqueous sodium chloride solution
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated to an oil that
10. customThe solid was triturated with diethyl ether (5 mL)
11. filtrationfiltered
12. washrinsed with diethyl ether (5 mL)
13. customdried in vacuo

ORD record

ord-bf06a6a5301a40f4a83e96d32d22e27e

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09139534B2