Triethylamine → {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

HRID 1617346Notes

Reaction equation

HRID 1617346 reaction equation
[C:1]([CH2:3][C:4]1([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[CH:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].Br[C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[N:55]=[CH:54][CH:53]=[CH:52]2.C(N(CC)CC)C>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.C(O)(C(F)(F)F)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:25][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[C:49]1[CH:50]=[C:51]2[C:56](=[CH:57][CH:58]=1)[N:55]=[CH:54][CH:53]=[CH:52]2)[C:14]([N:11]1[CH2:10][CH2:9][CH:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:26]3[CH:30]=[C:29]([C:31]4[C:32]5[CH:39]=[CH:38][NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH:28]=[N:27]3)[CH2:7]2)[CH2:13][CH2:12]1)=[O:15]

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 792436-BromoquinolineHCID 58431411{4-[(4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid

Product 1

HCID 53380439{1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Reagents, catalysts & solvents 4

HCID 11430Potassium CarbonateCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 21863450Trifluoroacetic acid methylene chlorideSolvent

Conditions

Temperature
140 °C

Procedure

To a solution of {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid (50 mg, 0.08 mmol) in DMF (2 mL) were added 6-bromoquinoline (15 mg, 0.076 mmol), triethylamine (0.021 mL, 0.15 mmol) and 3 drops of 2 N K2CO3 aqueous solution. The mixture was degased and bis(triphenylphosphine)palladium(II) chloride (5.4 mg, 0.0076 mmol) was added. The reaction mixture was stirred at 140° C. in a microwave oven for 25 minutes, then cooled to room temperature and filtered. The filtrate was purified by HPLC to afford a white powder. The white powder was dissolved in a 5 mL of DCM/TFA (1:2). After being stirred at room temperature for 1 hour, the solution was concentrated. The residue was dissolved in 5 mL of 10% ethylenediamine in THF. After being stirred at room temperature for 2 hours, the solution was concentrated. The residue was purified by HPLC (method B) to afford the title compound {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 612.2 (M+H)+.

Workup

  1. customThe mixture was degased
  2. temperaturecooled to room temperature
  3. filtrationfiltered
  4. customThe filtrate was purified by HPLC
  5. customto afford a white powder
  6. stirringAfter being stirred at room temperature for 1 hour
  7. concentrationthe solution was concentrated
  8. dissolutionThe residue was dissolved in 5 mL of 10% ethylenediamine in THF
  9. stirringAfter being stirred at room temperature for 2 hours
  10. concentrationthe solution was concentrated
  11. customThe residue was purified by HPLC (method B)

Sources & evidence

ORD record
ord-aabc0dfeb3784f26a2cf554bae537055
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

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