Hydrochloric Acid → 6-(3-(2,4-Difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine

HRID 1929994Notes

Reaction equation

HRID 1929994 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)[N:10]=1.FC1C=C(F)C=CC=1C1N(C2CCN(C(OC(C)(C)C)=O)C2)N=CC=1C1C=CC2N(C(C(C)C)=NN=2)N=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 57929860tert-butyl 3-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylateHCID 57929884tert-butyl 3-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Product 1

HCID 579298656-(3-(2,4-Difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazineYield 74%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

To a round bottom flask was added tert-butyl 3-(3-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and tert-butyl 3-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (0.446 g, 0.875 mmol, Preparation #X.1.1.1) as a mixture of regioisomers followed by 1,4-dioxane (10 mL) and concentrated hydrochloric acid (3.50 mL, 17.5 mmol). The reaction mixture was heated to about 85° C. for about 20 min. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM (50 mL). The organic layer was isolated and the aqueous layer extracted with DCM (2×50 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH with 5% 2.0 M ammonia in EtOH gradient from 1:0 to 80:20) to give the title compound (0.265 g, 74%): LC/MS (Table 1, Method g) Rt=1.75 min; MS m/z: 410.3 (M+H)+.

Workup

  1. additionas a mixture of regioisomers
  2. customThe reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM (50 mL)
  3. customThe organic layer was isolated
  4. extractionthe aqueous layer extracted with DCM (2×50 mL)
  5. dry with materialThe combined organic layers were dried with MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH with 5% 2.0 M ammonia in EtOH gradient from 1:0 to 80:20)

Sources & evidence

ORD record
ord-907de110e8174209ad6c033d6c937c42
Source dataset
uspto-grants-2012_05
Patent number
US08188083B2

Reaction notes

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