Diisopropylethylamine → (R)-N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide

HRID 931203Notes

Reaction equation

HRID 931203 reaction equation
[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:5]3[O:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 825972691-(3-Methyl-1,2-oxazol-5-yl)cyclopropane-1-carboxylic acidHCID 89854051(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride2×

Product 1

HCID 117966665(R)-N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamideYield 53.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe residue was dissolved in dichloromethane
  3. additionA saturated aqueous solution of sodium bicarbonate was added
  4. customThe organics were collected
  5. extractionthe aqueous layer was extracted with dichloromethane
  6. washThe combined organics were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified via flash chromatography (0-12% methanol in dichloromethane)

Sources & evidence

ORD record
ord-5fb77bcc076a43018cf0659eaeb4b1e3
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

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