Triethylamine → (R)-ethyl 3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate

HRID 1055108Notes

Reaction equation

HRID 1055108 reaction equation
[NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([F:24])=[C:18](Cl)[N:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]([F:24])=[CH:20][C:21]=1[C:22]#[N:23]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27338492,6-Dichloro-5-fluoro-3-pyridinecarbonitrileHCID 86714738Ethyl 3-amino-3-(1-methylcyclopentyl)propanoate2×

Product 1

HCID 86714767(R)-ethyl 3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction mixture was stirred at 90° C. in a pressure tube for 18 hours. The reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (25% EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=9.7 Hz, 1H), 5.56 (d, J=8.9 Hz, 1H), 4.68 (td, J=9.6, 3.6 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.77-1.62 (m, 4H), 1.61-1.49 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.26 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H) 354.98. The racemic mixture was submitted to SFC chiral separation to give the individual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.

Workup

  1. filtrationThe reaction mixture was filtered
  2. concentrationthe resulting filtrate was concentrated in vacuo
  3. customThe product was purified by silica gel chromatography (25% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-ded39e4d06894f22866d710fa6ff6504
Source dataset
uspto-grants-2016_07
Patent number
US09394302B2

Reaction notes

Loading…