Hydrochloric Acid → 1-{2-[6-(3,3-Difluoropyrrolidin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile

HRID 2039498Notes

Reaction equation

HRID 2039498 reaction equation
Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:17])[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:37]=[C:38]([N:44]1[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[CH:45]1)[C:39](OCC)=[O:40])C.Cl>O>[F:11][C:12]1([F:17])[CH2:16][CH2:15][N:14]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([N:8]3[C:39](=[O:40])[C:38]([N:44]4[CH:48]=[C:47]([C:49]#[N:50])[N:46]=[CH:45]4)=[CH:37][NH:9]3)[CH:7]=2)[CH2:13]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 81531Diisopropylethylamine2×HCID 2472224-Chloro-6-hydrazinylpyrimidineHCID 249034823,3-Difluoropyrrolidine hydrochloride2×HCID 66726020Ethyl 3-(N,N-dimethylamino)-2-(4-cyano-1H-imidazol-1-yl)acrylate

Product 1

HCID 444651261-{2-[6-(3,3-Difluoropyrrolidin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
100 °C

Procedure

A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 238 mg (1.7 mmol) of 3,3-difluoropyrrolidine hydrochloride and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 16 h. Following the addition of 53 μl (79 mg, 0.7 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. 1 ml of 1 N hydrochloric acid is added to the reaction mixture. The resulting precipitated hydrochloride of the crude product is filtered off, washed with diethyl ether and dried. The crude product still contains unreacted starting material (compound from Example 11A). Accordingly, the crude product is reacted with 108 μl (80 mg, 0.6 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine, 10 mg (0.1 mmol) of 3,3-difluoropyrrolidine hydrochloride and 2 ml of water in a single mode microwave (Emrys Optimizer) at 170° C. for 15 min The reaction solution purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 30 mg (6% of theory)

Workup

  1. stirringthe reaction mixture is stirred at 100° C. for 16 h
  2. customThe resulting precipitated hydrochloride of the crude product
  3. filtrationis filtered off
  4. washwashed with diethyl ether
  5. customdried
  6. custompurified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient)

Sources & evidence

ORD record
ord-d19f2ba2716e409c9137f98ef07a0c9c
Source dataset
uspto-grants-2013_11
Patent number
US08580778B2

Reaction notes

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