Triethylamine → N-{(2S)-2-(4-Fluorophenyl)-4-[3-(4-fluoropiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-3,5-bis(trifluoromethyl)benzamide

HRID 749410Notes

Reaction equation

HRID 749410 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH:29]=O)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH:33]1[CH2:36][CH:35]([N:37]2[CH2:42][CH2:41][CH:40]([F:43])[CH2:39][CH2:38]2)[CH2:34]1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH2:29][N:33]2[CH2:36][CH:35]([N:37]3[CH2:42][CH2:41][CH:40]([F:43])[CH2:39][CH2:38]3)[CH2:34]2)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 5003444Sodium cyanoborohydrideHCID 211841351-(Azetidin-3-YL)-4-fluoropiperidine dihydrochlorideHCID 58683524N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide

Product 1

HCID 11157448N-{(2S)-2-(4-Fluorophenyl)-4-[3-(4-fluoropiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-3,5-bis(trifluoromethyl)benzamideYield 48.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent2×

Procedure

N-[(2S)-2-(4-Fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (see Method 20; 189 mg, 0.43 mmol), 1-azetidin-3-yl-4-fluoropiperidine dihydrochloride (see WO 97/27185; 139 mg, 0.56 mmol) and triethylamine (154 mg, 1.52 mmol) were dissolved in methanol (10 mL). A methanol solution (5 mL) of sodium cyanoborohydride (191 mg, 3.04 mmol) and zinc chloride (178 mg, 1.30 mmol) was added and the mixture stirred at room temperature for 20 minutes. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The organic solution was washed with aqueous NaHCO3 (1 M) and then brine. The solution was dried over Na2SO4 and then the solvent was removed by evaporation. The product was chromatographed on silica gel using a gradient of methanol and CH2Cl2 (0% MeOH-20% MeOH). There was obtained 120 mg (48%) of the title compound as a gum. 1H NMR (500 MHz, CDCl3): 1.4-1.9 (cm, 6H), 2.1-2.4 (cm, 6H), 2.6-3.5 (cm, 10H), 3.6-3.8 (m, 1H), 4.6-4.8 (bd, 1H), 6.8-7.5 (m, 6H), 7.8 (s, 1H); LCMS: m/z 578 (M+1)+.

Workup

  1. customThe solvent was removed by evaporation
  2. customthe residue partitioned between water and ethyl acetate
  3. washThe organic solution was washed with aqueous NaHCO3 (1 M)
  4. dry with materialThe solution was dried over Na2SO4
  5. customthe solvent was removed by evaporation
  6. customThe product was chromatographed on silica gel using a gradient of methanol and CH2Cl2 (0% MeOH-20% MeOH)

Sources & evidence

ORD record
ord-ecd116f66d9e48a893d2466161575ed8
Source dataset
uspto-grants-2008_07
Patent number
US07402581B2

Reaction notes

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