Potassium Carbonate → 3-Cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile

HRID 1853004Notes

Reaction equation

HRID 1853004 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41](B(O)O)[CH:42]=2)[CH2:37]1)=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].C(Cl)Cl.C(O)(C(F)(F)F)=O>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:41]4[CH:42]=[C:43]5[C:38](=[CH:39][CH:40]=4)[CH2:37][NH:36][CH2:45][CH2:44]5)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1

Participants

8

Reactant 5

HCID 11430Potassium CarbonateHCID 21863450Trifluoroacetic acid methylene chlorideHCID 23677046Sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonateHCID 67455510(2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acidHCID 866853033-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile

Product 1

HCID 682318263-Cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrileYield 31%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropyl-propanenitrile (Preparation M; 50 mg, 0.16 mmol) in dioxane (5 mL) was added K2CO3 (66 mg, 0.48 mmol), diacetoxypalladium (1.8 mg, 0.0080 mmol), 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (89 mg, 0.32 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (8.2 mg, 0.016 mmol). The reaction mixture was degassed with argon, sealed and heated to 80° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to give the intermediate product, to which was added DCM/TFA (1 mL/1 mL). The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (20 mg, 31% yield). MS (apci) m/z=410.3 (M+H).

Workup

  1. customThe reaction mixture was degassed with argon
  2. customsealed
  3. temperatureThe reaction was cooled to ambient temperature
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by silica gel chromatography (DCM/MeOH 10:1)
  6. customto give the intermediate product
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1)

Sources & evidence

ORD record
ord-5e1a74434f264a3ba664f8a68b524780
Source dataset
uspto-grants-2015_02
Patent number
US08962596B2

Reaction notes

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