Diisopropylethylamine → 3,5-dichloro-N-[(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]-N-methylbenzamide

HRID 749413Notes

Reaction equation

HRID 749413 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:28][CH2:29]N2CC(N3CCC(O)CC3)C2)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16](C(F)(F)F)[CH:15]=[C:14](C(F)(F)F)[CH:13]=2)=[CH:4][CH:3]=1.[ClH:41].[ClH:42].[NH:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:41][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([Cl:42])[CH:15]=1)[C:11]([N:10]([CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:28][CH2:29][N:43]1[CH2:46][CH:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44]1)[CH3:27])=[O:26]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 11455933N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-hydroxypiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-3,5-bis(trifluoromethyl)benzamideHCID 220613264-(Azetidin-3-yl)morpholine dihydrochloride

Product 1

HCID 112604303,5-dichloro-N-[(2S)-2-(4-fluorophenyl)-4-(3-morpholin-4-ylazetidin-1-yl)butyl]-N-methylbenzamideYield 63%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

3,5-Dichloro-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methylbenzamide (see Method 21; 146 mg, 0.40 mmol) was dissolved in CH2Cl2 (8 mL) and to the resultant solution were added 4-azetidin-3-ylmorpholine dihydrochloride (see WO 00/63168; 62 mg, 0.44 mmol) and DIPEA (179 mg, 1.39 mmol) together with 5 drops of acetic acid. The mixture was stirred for 25 minutes and then sodium triacetoxyborohydride (118 mg, 0.55 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated NaHCO3 aq. The phases were separated and the aqueous solution was extracted with ethyl acetate. The combined organic solutions were dried over MgSO4 and the solvent was removed by evaporation. The residue was chromatographed on silica gel using a mixture of methanol and CH2Cl2 as eluent (gradient 0 to 20% methanol). There was obtained 124 mg (63%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3): 1.4-1.8 (cm, 2H), 2.2-3.8 (cm, 21H), 6.7 (s, 1H), 6.8-7.2 (m, 5H), 7.3 (s, 1H); LCMS: m/z 494 (M+1)+.

Workup

  1. stirringThe mixture was stirred at room temperature overnight
  2. customThe solvent was evaporated
  3. customthe residue was partitioned between ethyl acetate and saturated NaHCO3 aq. The phases
  4. customwere separated
  5. extractionthe aqueous solution was extracted with ethyl acetate
  6. dry with materialThe combined organic solutions were dried over MgSO4
  7. customthe solvent was removed by evaporation
  8. customThe residue was chromatographed on silica gel using
  9. additiona mixture of methanol and CH2Cl2 as eluent (gradient 0 to 20% methanol)

Sources & evidence

ORD record
ord-b6d39ddb8f4a4ca2847adcbddaa04e48
Source dataset
uspto-grants-2008_07
Patent number
US07402581B2

Reaction notes

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