Acetic Acid → 4-[(2S)-(2-amino-2-cyanoethyl)]-3-fluorobenzonitrile

HRID 239856

Reaktionsgleichung

Reaktionsgleichung von HRID 239856
[C:1]([CH:3]([N:14]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13])#[N:2].O.C(O)(=O)C>O1CCCC1>[NH2:14][C@H:3]([C:1]#[N:2])[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:13]

Komponenten

5

Edukt 3

HCID 176Acetic AcidHCID 962WaterHCID 866481454-{2-Cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile

Produkt 1

HCID 684437434-[(2S)-(2-amino-2-cyanoethyl)]-3-fluorobenzonitrile

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

A solution of 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile from step 2 (24.5 g) in tetrahydrofuran (190 ml) is treated with water (45 ml) then with acetic acid (90 ml) and let stir for 24 h at 40° C. Approximately 75% of the volatiles were then removed under reduced pressure. The residual solution is diluted with water (100 ml) and 1 N hydrochloric acid (25 ml), extracted with 2 portions (100 ml each) of diethyl ether then was made basic with 8N potassium hydroxide and aqueous potassium phosphate until pH 9-10 was reached. The aminonitrile was extracted with three portions (300 ml each) of ethyl acetate. The pooled organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The orange product gum was dissolved in ethanol (20 ml) and diluted with hexanes (20 ml). Aliquots of 500 mg were injected on chiralcel AD column using 50% ethanol:50% hexanes isocratic conditions. The faster nitrile is the wrong enantiomer (Rt=19 min) while after evaporation and coupling (step 4) the slower enantiomer (t=24 min) will lead to the potent diastereomer of the (2S)—N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-4-fluoro-4-methyl-2-({1(S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino) pentanamide that is assumed to be of S configuration.

Aufarbeitung

  1. customApproximately 75% of the volatiles were then removed under reduced pressure
  2. additionThe residual solution is diluted with water (100 ml) and 1 N hydrochloric acid (25 ml)
  3. extractionextracted with 2 portions (100 ml each) of diethyl ether
  4. extractionThe aminonitrile was extracted with three portions (300 ml each) of ethyl acetate
  5. washThe pooled organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. dissolutionThe orange product gum was dissolved in ethanol (20 ml)
  9. additiondiluted with hexanes (20 ml)
  10. customafter evaporation and coupling (step 4) the slower enantiomer (t=24 min)

Quellen und Nachweise

ORD-Eintrag
ord-dbe2f5965a184b85a2a3d8bf15bddcb6
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08642799B2

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