Diisopropylethylamine → N-[(2S)-4-{3-[4-(Azetidin-1-ylcarbonyl)piperidin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-3-bromo-N-methyl-5-(trifluoromethyl)benzamide

HRID 426077Notes

Reaction equation

HRID 426077 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=O)[CH3:8])=[O:6].[NH:28]1[CH2:31][CH:30]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]([N:40]3[CH2:43][CH2:42][CH2:41]3)=[O:39])[CH2:34][CH2:33]2)[CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[N:40]1([C:38]([CH:35]2[CH2:36][CH2:37][N:32]([CH:30]3[CH2:29][N:28]([CH2:12][CH2:11][C@@H:10]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:9][N:7]([CH3:8])[C:5](=[O:6])[C:4]4[CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:23]=[C:2]([Br:1])[CH:3]=4)[CH2:31]3)[CH2:33][CH2:34]2)=[O:39])[CH2:41][CH2:42][CH2:43]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 159506583-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamideHCID 236587781-Azetidin-3-yl-4-(azetidin-1-ylcarbonyl)piperidine

Product 1

HCID 23582759N-[(2S)-4-{3-[4-(Azetidin-1-ylcarbonyl)piperidin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-3-bromo-N-methyl-5-(trifluoromethyl)benzamideYield 59.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.16 g, 0.36 mmol) and 1-azetidin-3-yl-4-(azetidin-1-ylcarbonyl)piperidine (see method 2; 0.10 g, 0.47 mmol) were dissolved in methylene chloride (10 mL) together with a small amount of dry methanol (0.2 mL). To the resultant solution were added DIPEA (0.14 g, 1.08 mmol) and sodium triacetoxyborohydride (0.15 g, 0.72 mmol). The mixture was stirred under nitrogen for 4 h at RT. The mixture was diluted with methylene chloride and washed twice with saturated aqueous NaHCO3 and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1). There was obtained 0.14 g (59%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): δ 1.4-1.8 (cm, 6H), 2.1 (m, 1H) 2.2 (qn, 2H), 2.3-2.4 (cm, 2H), 2.5-3.5 (cm, 14H), 3.6 (d, 1H), 3.9 (t, 2H), 4.1 (t, 2H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 654 (M+1)+.

Workup

  1. washwashed twice with saturated aqueous NaHCO3
  2. filtrationThe organic phase was filtered through a phase separator
  3. customthe solvent was removed by evaporation
  4. customThe product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1)

Sources & evidence

ORD record
ord-36a02cae85d54ad9bc3cf9d666967ab1
Source dataset
uspto-grants-2012_01
Patent number
US08106208B2

Reaction notes

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