Sodium cyanoborohydride → 3-Bromo-N-[(2S)-4-{3-[4-(cyclopropylcarbonyl)piperazin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-N-methyl-5-(trifluoromethyl)benzamide dihydrochloride

HRID 2063300Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2063300
[ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(C3CC3)=O)CC2)C1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([CH:26]3[CH2:27][CH2:28]3)=[O:29])[CH2:23][CH2:24]2)[CH2:18]1)[CH3:10])=[O:8]

Komponenten

6

Edukt 3

HCID 5003444Sodium cyanoborohydrideHCID 16124373Methanone, [4-(3-azetidinyl)-1-piperazinyl]cyclopropyl-HCID 866483133-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(6-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide dihydrochloride

Produkt 1

HCID 866483153-Bromo-N-[(2S)-4-{3-[4-(cyclopropylcarbonyl)piperazin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-N-methyl-5-(trifluoromethyl)benzamide dihydrochlorideAusbeute 61,8 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 3007855ZincchlorideKatalysatorHCID 887MethanolLösungsmittel2×

Versuchsvorschrift

To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 450 mg, 1.0 mmol) and 1-azetidin-3-yl-4-(cyclopropylcarbonyl)piperazine (see Method 14; ˜0.9 mmol) in methanol (50 mL) was added a solution of sodium cyano borohydride (250 mg, 4.0 mmol) and zinc chloride (270 mg, 2.0 mmol) in methanol (30 mL). The reaction mixture was stirred at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The product was purified by means of silica gel chromatography first eluting with ethyl acetate and then with a mixture of ethyl acetate, methanol and triethylamine (9:1:1). The proper fractions were combined and concentrated on a rotavapor and then the residue was co-evaporated twice using methylene chloride. The residue was dissolved in methylene chloride and to the solution was added HCl-saturated diethyl ether (1 mL). The solvent was removed by evaporation and then the residue was co-evaporated twice with methylene chloride. There was obtained 220 mg (30%) of the title compound. 1H NMR (400 MHz, CDCl3): 0.8-1.0 (cm, 4H), 1.2-4.7 (cm, 24H), 6.9-8.0 (cm, 7H): m/z 640 (M+1)+.

Aufarbeitung

  1. customthe solvent was removed by evaporation
  2. customThe residue was partitioned between ethyl acetate (50 mL) and water (20 mL)
  3. washThe organic solution was washed with brine
  4. dry with materialdried over Na2SO4
  5. customThe solvent was removed by evaporation
  6. dissolutionthe residue was dissolved in ethyl acetate
  7. customThe product was purified by means of silica gel chromatography
  8. washfirst eluting with ethyl acetate
  9. additionwith a mixture of ethyl acetate, methanol and triethylamine (9:1:1)
  10. concentrationconcentrated on a rotavapor
  11. dissolutionThe residue was dissolved in methylene chloride and to the solution
  12. additionwas added HCl-saturated diethyl ether (1 mL)
  13. customThe solvent was removed by evaporation

Quellen und Nachweise

ORD-Eintrag
ord-7ebf1b2d840c48579c4e7dd4d9f46942
Quelldatensatz
uspto-grants-2012_10
Patentnummer
US08288370B2

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