Sodium hydride → 2-(4-((1R,2S)-2-(2-(5-(1H-1,2,3-triazol-1-yl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-5-chloropyrimidine

HRID 1798837Notes

Reaction equation

HRID 1798837 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[CH:25][N:24]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][CH2:20][O:21][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)=[CH:25][N:24]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 581285562-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridineHCID 581286112-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol

Product 1

HCID 444671832-(4-((1R,2S)-2-(2-(5-(1H-1,2,3-triazol-1-yl)pyridin-2-yloxy)ethyl)cyclopropyl)piperidin-1-yl)-5-chloropyrimidine

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
0 °C

Procedure

A suspension of NaH (720 mg; 60 wt %; 432 mg NaH contained; 17.99 mmol) in DMF (9 mL) at 0° C. was treated with a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (3.9 g; 13.84 mmol) in DMF (9 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was treated with a solution of 2-fluoro-5-(1H-1,2,3-triazol-1-yl)pyridine (2.499 g; 15.22 mmol) in DMF (10 mL). The reaction was stirred at 0° C. for 45 minutes, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture partitioned between ethyl acetate and water. The organic layer was washed twice more with water, dried over sodium sulfate, filtered and evaporated to a residue. The residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane). The fractions containing the desired product were combined and evaporated to a white solid. Crystalline solid was also recovered from the chromatography fractions. The solid isolated from chromatography was recrystallized from EtOH/heptane. The solid (4 g) was suspended in EtOH (150 ml), then heated until completely dissolved, allowed to cool to RT and heptane (100 ml) was added. The mixture was aged at RT overnight, cooled to 0° C. for 5 minutes and filtered to provide the title compound). LCMS: calc. 425.17 obs: 426.09 (M+1). 1H NMR (CDCl3): δ 8.48 (d, 1H), 8.20 (s, 2H), 7.97 (dd, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.26 (s, CDCl3), 6.89 (d, 1H), 4.47 (br t, 2H), 4.47 (t, 2H), 2.87 (m, 2H), 2.15 (m, 1H), 1.86 (br t, 2H), 1.58 (m, 1H), 1.57 (S, H2O), 1.37 (m, 2H), 1.12 (m, 1H), 0.94 (m, 1H), 0.70 (m, 1H), 0.61 (m, 1H), −0.08 (q, 1H).

Workup

  1. stirringThe reaction was stirred at 0° C. for 45 minutes
  2. temperatureto warm to room temperature
  3. stirringstirred overnight
  4. customThe reaction was quenched with saturated aqueous NH4Cl
  5. customthe mixture partitioned between ethyl acetate and water
  6. washThe organic layer was washed twice more with water
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. customevaporated to a residue
  10. customThe residue was chromatographed (Horizon 65i silica cartridge; 30% to 45% ethyl acetate/heptane)
  11. additionThe fractions containing the desired product
  12. customevaporated to a white solid
  13. customCrystalline solid was also recovered from the chromatography fractions
  14. customThe solid isolated from chromatography
  15. customwas recrystallized from EtOH/heptane
  16. temperatureheated
  17. dissolutionuntil completely dissolved
  18. temperatureto cool to RT
  19. additionheptane (100 ml) was added
  20. waitThe mixture was aged at RT overnight
  21. temperaturecooled to 0° C. for 5 minutes
  22. filtrationfiltered

Sources & evidence

ORD record
ord-fceee92f2e7e4f2daffaa4bb0e4198de
Source dataset
uspto-grants-2013_01
Patent number
US08343990B2

Reaction notes

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