Acetic Acid → tert-Butyl cis(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate tert-Butyl trans(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate

HRID 43866Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 43866
[CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:8]2[NH:9][C:10]([CH2:11][CH3:12])=[C:6]([Cl:5])[N:7]=2)=[O:14])[C@H:21]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]

Komponenten

6

Edukt 4

HCID 176Acetic AcidHCID 69828Cyclopropylamine2×HCID 5003444Sodium cyanoborohydrideHCID 68406285tert-Butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate

Produkt 1

HCID 131730874tert-Butyl cis(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylate tert-Butyl trans(+/-)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(cyclopropylamino)piperidine-1-carboxylateAusbeute 15 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
50 °C

Versuchsvorschrift

Cyclopropylamine (249 μL, 3.59 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (190 mg, 0.512 mmol) in tetrahydrofuran (6 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Cyclopropylamine (71.0 μL, 0.102 mmol), sodium cyanoborohydride (97.0 mg, 1.54 mmol) and acetic acid (293 μL, 5.12 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 34 mg of the cis isomer of the title compound (16%) as a pale yellow oily substance and 32 mg of the trans isomer of the title compound (15%) as a pale yellow oily substance.

Aufarbeitung

  1. temperaturethe mixture was heated
  2. concentrationThe reaction solution was concentrated under reduced pressure
  3. additiontetrahydrofuran (3 mL) and methanol (3 mL) were added
  4. concentrationThe reaction solution was concentrated under reduced pressure
  5. additionSaturated aqueous sodium bicarbonate solution was added to the residue
  6. extractionfollowed by extraction with ethyl acetate
  7. washThe resulting organic layer was washed with brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. customthe insoluble matter was separated by filtration
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customthe resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v)

Quellen und Nachweise

ORD-Eintrag
ord-7deb4565f1c8464fb28a61d93eaa5250
Quelldatensatz
uspto-grants-2013_09
Patentnummer
US08536197B2

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