Bicarbonate Ion → 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carboxamide

HRID 2280785Notes

Reaction equation

HRID 2280785 reaction equation
[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][CH:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:11]=2)[CH2:3]1.C(O)(C(F)(F)F)=[O:24].C(=O)(O)[O-]>CS(C)=O.[OH-].[Na+].OO>[OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]([NH2:17])=[O:24])=[CH:14][N:13]=[C:12]([NH:18][C:19]3([CH3:22])[CH2:21][CH2:20]3)[N:11]=2)[CH2:3]1

Participants

7

Reactant 3

HCID 769Bicarbonate IonHCID 6422Trifluoroacetic acidHCID 709813154-((3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carbonitrile

Product 1

HCID 712373884-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carboxamideYield 36%

Reagents, catalysts & solvents 3

HCID 784Hydrogen PeroxideCatalystHCID 14798Sodium HydroxideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
50 °C

Procedure

4-((3R,4R)-3-Hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carbonitrile (0.181 g, 0.601 mmol) was dissolved in DMSO (6 mL). Ten drops of 50% aqueous sodium hydroxide (0.047 mL, 0.901 mmol) and ten drops of 30% aqueous hydrogen peroxide were added at room temperature. The reaction mixture was stirred at 50° C. for 1 h. Upon completion of reaction, as indicated by LCMS and TLC, the reaction mixture was cooled to room temperature and was poured into 300 mL of the ice water. The aqueous layer was extracted with 20% iPrOH/chloroform (×3) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by reverse-phased semi-preparative HPLC (0-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting residue was redissolved in methanol (5 mL), passed over Varian StratoSpheres HCO3 resin SPE tubes for TFA removal (0.9 mmol bicarbonate equiv. per tube), and then concentrated under reduced pressure to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(1-methylcyclopropylamino)pyrimidine-5-carboxamide (0.069 g, 36% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79-8.92 (m, 1H), 8.28-8.39 (m, 1H), 7.32-7.48 (m, 1H), 4.56 (s, 1H), 3.83-3.97 (m, 1H), 2.89-3.08 (m, 1H), 2.18-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.61-1.74 (m, 1H), 1.35 (s, 4H), 1.05-1.26 (m, 1H), 0.94 (d, J=6.64 Hz, 5H), 0.66 (s, 3H), 0.54 (br. s., 3H); MS (ESI) m/z 320.2 [M+1]+.

Workup

  1. customUpon completion of reaction
  2. temperaturethe reaction mixture was cooled to room temperature
  3. extractionThe aqueous layer was extracted with 20% iPrOH/chloroform (×3)
  4. dry with materialthe combined organic layers were dried over anhydrous magnesium sulfate
  5. concentrationconcentrated
  6. customThe crude mixture was purified
  7. customHPLC (0-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min)
  8. additionFractions containing product
  9. concentrationwere concentrated under reduced pressure
  10. dissolutionThe resulting residue was redissolved in methanol (5 mL)
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-2a7fc5a45d8c44a2a13ba96e3b458a7e
Source dataset
uspto-grants-2015_09
Patent number
US09139534B2

Reaction notes

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