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

HRID 2063297Notes

Reaction equation

HRID 2063297 reaction equation
[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]C[CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(=O)CC)CC2)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[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[CH2:20][CH2:21][N:22]([C:25](=[O:29])[CH2:26][CH3:27])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 161232931-Propanone, 1-[4-(3-azetidinyl)-1-piperazinyl]-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

Product 1

HCID 866483143-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-propionylpiperazin-1-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide dihydrochlorideYield 85.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 165 mg, 0.4 mmol) and 1-azetidin-3-yl-4-propionylpiperazine (see Method 7; 80 mg, 0.41 mmol) were dissolved in methylene chloride (10 mL) together with a small amount of dry methanol (0.2 mL). Sodium triacetoxyborohydride (157 mg, 0.74 mmol) was added together with DIPEA (143 mg, 1.11 mmol). The reaction mixture was stirred at RT for 2.5 h and then diluted with methylene chloride. The solution was washed twice with aqueous NaHCO3 and then with brine. The organic phase was separated by means of a phase separator column and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride 5:95). The oily product was dissolved in 2M hydrochloric acid and the solvent was then removed by freeze-drying. There was obtained 120 mg (48%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): 1.2-3.8 (cm, 28H), 6.8-7.8 (cm, 7H); LCMS: m/z 628 (M+1)+.

Workup

  1. washThe solution was washed twice with aqueous NaHCO3
  2. customThe organic phase was separated by means of a phase separator column
  3. customthe solvent was removed by evaporation
  4. customThe product was purified by chromatography on silica gel (methanol-methylene chloride 5:95)
  5. dissolutionThe oily product was dissolved in 2M hydrochloric acid
  6. customthe solvent was then removed
  7. customby freeze-drying

Sources & evidence

ORD record
ord-75ec5f6612a645179e49d32c5c774e9c
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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