Urea → benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

HRID 1850740Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1850740
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([CH3:29])=[CH:27][C:26]([NH2:30])=[CH:25][N:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:41][CH2:42][N:43]=[C:44]=[O:45].NC(N)=O.[H-].[Na+]>C1COCC1>[CH3:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)=[N:24][CH:25]=[C:26]([N:30]2[CH2:41][CH2:42][NH:43][C:44]2=[O:45])[CH:27]=1

Komponenten

7

Edukt 5

HCID 1176UreaHCID 160352-Chloroethyl isocyanateHCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 70856037benzyl 4-((1R,2S)-2-{2-[(5-amino-3-methylpyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate

Produkt 1

HCID 70856309benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

To a solution of benzyl-4-((1R,2 S)-2-{2-[(5-amino-3-methylpyridin-2yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (39 mg, 0.106 mmol) in THF (2.5 ml) at RT under nitrogen was added DIPEA (0.037 ml, 0.213 mmol), followed by 2-chloroethyl isocyanate (0.014 ml, 0.160 mmol). And the resulting solution stirred at room temperature overnight. LC/MS showed clean conversion to the uncyclized urea intermediate. The mixture was cooled to 0° C. and NaH (8.51 mg, 0.213 mmol) was added. The mixture was removed from the ice bath after ca. 15 minutes. LC/MS at 1 h showed complete conversion to the desired product. Formic acid (50 μl) was added and the reaction mixture stirred for 30 minutes. The material was concentrated under reduced pressure and the residue was purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate to afford the title compound. MS (ESI) m/z 479 [M+H]+.

Aufarbeitung

  1. temperatureThe mixture was cooled to 0° C.
  2. customThe mixture was removed from the ice bath after ca. 15 minutes
  3. waitLC/MS at 1 h showed complete
  4. additionFormic acid (50 μl) was added
  5. stirringthe reaction mixture stirred for 30 minutes
  6. concentrationThe material was concentrated under reduced pressure
  7. customthe residue was purified by RP HPLC on a Gilson
  8. washOBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes
  9. waithold at 100% for 1 minute, at 20 ml/min flow rate

Quellen und Nachweise

ORD-Eintrag
ord-86d99a8512a54b769caf6b3d9011cdcb
Quelldatensatz
uspto-grants-2015_02
Patentnummer
US08957062B2

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