Triphenylphosphine → 2-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile

HRID 2278687Notes

Reaction equation

HRID 2278687 reaction equation
[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]([CH2:28][C:29]#[N:30])[CH:26]([CH2:31][CH3:32])[C:25]([C:33]([F:36])([F:35])[F:34])=[N:24]4)=[CH:19][CH:18]=3)[CH:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(C1C(CC#N)N(C2C=CC(O)=CC=2)N=C1C(F)(F)F)C.ClC1C(N2CC[C@H](O)[C@H](C)C2)=CC(OC)=NC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]#[N:30])[C@H:26]([CH2:31][CH3:32])[C:25]([C:33]([F:36])([F:34])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[CH:12]([CH3:37])[CH2:11]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1

Participants

8

Reactant 6

HCID 11776TriphenylphosphineHCID 516892Sodium BicarbonateHCID 6034084Di-tert-butyl diazene-1,2-dicarboxylateHCID 86719424(3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-olHCID 867194262-(1-(4-((1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrileHCID 867194272-(4-ethyl-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile

Product 1

HCID 867194252-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrileYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

2-(1-(4-((1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile: To a solution of 2-(4-ethyl-1-(4-hydroxyphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (174 mg, 0.58 mmol) and (3R,4S)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (150 mg, 0.58 mmol) in THF (195 μl) was added triphenylphosphine (215 mg, 0.82 mmol). The reaction vessel was then lowered into a sonication bath and sonicated for several minutes (to allow for mixing) giving a clear and highly viscous solution. While sonicating, (E)-di-tert-butyl diazene-1,2-dicarboxylate (161 mg, 0.70 mmol) was added dropwise to the reaction mixture, and the reaction mixture was sonicated for 120 min. LCMS showed the desired mass of product. Then, sat. aq. NaHCO3 (10 mL) was added slowly to the reaction mixture. The mixture was then extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried (Na2SO4), filtered, and concentrated. Purification by chromatography gave 2-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-ethyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetonitrile (80 mg, 0.15 mmol, 26% yield) an oil. LC-MS Anal. Calc'd for C26H29ClF3N5O2 535.20. found [M+H] 536.0.

Workup

  1. customThe reaction vessel was then lowered into a sonication bath
  2. customsonicated for several minutes
  3. addition(to allow for mixing)
  4. customgiving a clear and highly viscous solution
  5. customWhile sonicating
  6. customthe reaction mixture was sonicated for 120 min
  7. extractionThe mixture was then extracted with EtOAc (2×10 mL)
  8. washthe combined organic extracts were washed with water (20 mL) and brine (20 mL)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification by chromatography

Sources & evidence

ORD record
ord-fb6d7b18a39748de9c1a49ab2630ed5f
Source dataset
uspto-grants-2015_09
Patent number
US09133163B2

Reaction notes

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