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

HRID 2171903Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2171903
[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]

Komponenten

5

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

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.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-4de390f7599c4786b26e9d4fe5745b64
Quelldatensatz
uspto-grants-2015_06
Patentnummer
US09051319B2

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