Acetic Acid → Racemic 6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7, 8-dihydro[1,2,4]triazolo[4,3-b]pyridazine

HRID 2381145Notes

Reaction equation

HRID 2381145 reaction equation
C(O)(=O)C.[F:5][C:6]([F:34])([F:33])[C:7]1[N:11]2[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](=O)[CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15][C:10]2=[N:9][N:8]=1.[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36].[O-]S([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH:28]([CH3:29])[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH:19]3[CH2:20][CH2:21][N:16]([C:13]4[CH2:14][CH2:15][C:10]5[N:11]([C:7]([C:6]([F:34])([F:33])[F:5])=[N:8][N:9]=5)[N:12]=4)[CH2:17][CH2:18]3)=[CH:32][CH:31]=2)[CH2:40][CH2:39]1)(=[O:37])[CH3:36]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 24083Sulfuric acid magnesium salt (1:1)HCID 837951-AcetylpiperazineHCID 5049666Sodium triacetoxyborohydrideHCID 684994251-(4-{1-[3-(Trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)propan-2-one

Product 1

HCID 68499797Racemic 6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7, 8-dihydro[1,2,4]triazolo[4,3-b]pyridazineYield 26.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Acetic acid (0.081 mL, 1.41 mmol) was added to 1-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)propan-2-one (595 mg, 1.41 mmol), N-acetylpiperazine (199 mg, 1.55 mmol) and a catalytic amount of MgSO4 in THF (5 mL). The resulting mixture was stirred at ambient temperature for 1 hour, then sodium triacetoxyborohydride (359 mg, 1.69 mmol) was added and stirring was continued for a further 16 hours. The reaction mixture was concentrated, diluted with DCM (25 mL), washed with saturated NaHCO3 (25 mL) and then filtered through a PTFE cup. The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford racemic 6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (199 mg, 26.4%) as a gum.

Workup

  1. stirringstirring
  2. waitwas continued for a further 16 hours
  3. concentrationThe reaction mixture was concentrated
  4. additiondiluted with DCM (25 mL)
  5. washwashed with saturated NaHCO3 (25 mL)
  6. filtrationfiltered through a PTFE cup
  7. customThe organic layer was evaporated
  8. customto afford crude product
  9. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM
  10. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-31b2e5ee775942d6bc6d26f8a96d735f
Source dataset
uspto-grants-2012_09
Patent number
US08258140B2

Reaction notes

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