Citric Acid → HCID 54676814, compound

Temperature

-40 °C

A flask was charged with the dibenzoyl-L-tartaric acid salt of {circle around (R)}-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one (this material contained 1.5 eq DBTA counterion, 4.00 g, theor. 0.00454 mol), 2-MeTHF (40 mL), MTBE (40 mL), and water (20 mL). A solution of 5% aq NaHCO3 (about 20 mL) was added until the pH was 7.4. The solution pH was back-adjusted to pH=7.2 with a small amount of 40% citric acid solution. The phases were separated and the aqueous layer was extracted with 2-MeTHF (25 mL). The combined organic layers were dried with Na2SO4 and concentrated to an oil. The oil was used directly in the subsequent condensation. To the crude {circle around (R)}-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one was added methanol (32 mL) and the solution cooled to −40° C. To the cold solution was added pyridine-borane complex (1.30 mL, 0.01287 mol) and 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (1.41 g, 0.00800 mol). The solution was warmed to 0° C. over 45 min then stirred for an additional 2 h. The reaction was quenched by the addition of water (10 mL) and the mixture stirred at rt overnight. To the mixture was added 1M HCl (10 mL), and the solution was stirred for 3 h. Isopropyl acetate (57 mL) was added and the pH adjusted to 7 by the addition of 1M NaOH. The phases were separated and the organic layer extracted with water (25 mL×2). The aqueous phases were extracted further with CH2Cl2 (100 ml, 2×25 mL). The combined IPAc and CH2Cl2 layers were dried (Na2SO4), filtered, and concentrated to yield 3.41 g of crude {circle around (R)}-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one. To the residue was added isopropyl acetate (46 mL) and EtOH (2.5 mL) and the mixture heated to reflux until homogeneous. The solution was allowed to cool slowly to rt and stirred overnight. The slurry was filtered, the solids rinsed with IPAc (13 mL), and dried to provide 1.74 g (76%) of {circle around (R)}-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one as an off-white solid.

1. customThe phases were separated
2. extractionthe aqueous layer was extracted with 2-MeTHF (25 mL)
3. dry with materialThe combined organic layers were dried with Na2SO4
4. concentrationconcentrated to an oil
5. customThe oil was used directly in the subsequent condensation
6. temperatureThe solution was warmed to 0° C. over 45 min
7. customThe reaction was quenched by the addition of water (10 mL)
8. stirringthe mixture stirred at rt overnight
9. additionTo the mixture was added 1M HCl (10 mL)
10. stirringthe solution was stirred for 3 h
11. additionIsopropyl acetate (57 mL) was added
12. additionthe pH adjusted to 7 by the addition of 1M NaOH
13. customThe phases were separated
14. extractionthe organic layer extracted with water (25 mL×2)
15. extractionThe aqueous phases were extracted further with CH2Cl2 (100 ml, 2×25 mL)
16. dry with materialThe combined IPAc and CH2Cl2 layers were dried (Na2SO4)
17. filtrationfiltered
18. concentrationconcentrated

ORD record

ord-409d262fb16d4e1fa7dab91873d72c8e

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07807838B2