Hydrochloric Acid → Diethylamine

HRID 2407027Notes

Reaction equation

HRID 2407027 reaction equation
[CH:1]1([N:6]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:22][CH:23]=2)[C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:62][CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66].C(N(CC)C(C)C)(C)C>C1COCC1.[NH4+].[Cl-].CO>[C:11](=[O:13])=[O:12].[CH2:1]([NH:6][CH2:7][CH3:16])[CH3:2].[CH:1]1([N:6]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)=[N:22][CH:23]=2)[C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:62][CH2:63][CH2:64][C:65]([O:67][CH3:68])=[O:66])=[O:12])=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67983468HCID 67983468, compound

Product 3

HCID 280Carbon DioxideHCID 8021DiethylamineYield 0.1%HCID 67980752HCID 67980752, compound

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (+/−)-methyl 6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinate (972 mg, 2.13 mmol) in THF (10 mL) was added 2N aqueous LiOH (10.7 mL, 21.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was neutralized by addition of 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL). HATU (1.19 g, 3.15 mmol) was added. The mixture was stirred for 45 min. Methyl 3-aminopropanoate hydrochloride (435 mg, 3.15 mmol) and N,N-diisopropylethylamine (1.08 g, 8.4 mmol) were added. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous NH4Cl. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to give crude (+/−)-methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate (1.2 g). Resolution by SFC (Column: AD 250 mm*20 mm*5 μm, Mobile phase: 45:55 CO2:methanol, Flow rate: 80 mL/min, Modifier: 0.1% diethylamine) to give methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 1 (Retention time 1.36 min, 450 mg) and methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate, Isomer 2 (Retention time 3.50 min, 460 mg).

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe combined organic layers were dried over Na2SO4
  3. concentrationconcentrated under reduced pressure
  4. dissolutionThe residue was dissolved in DMF (5 mL)
  5. stirringThe mixture was stirred for 45 min
  6. stirringThe resulting mixture was stirred at room temperature for 2 h
  7. washThe organic layer was washed with water
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated under reduced pressure
  10. customto give crude (+/−)-methyl 3-(6-(cyclopentyl(2-(4-(trifluoromethyl)phenyl)pyrimidin-5-yl)methylamino)nicotinamido)propanoate (1.2 g)

Sources & evidence

ORD record
ord-cd570dffab4c44cf8834d53b888f167e
Source dataset
uspto-grants-2014_08
Patent number
US08809342B2

Reaction notes

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