Diisopropylethylamine → 4-[4-{2-[1-(1-methyl-L-prolyl)piperidin-4-yl]ethoxy}-3-(trifluoromethyl)phenyl]-7-(tetrahydrofuran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride

HRID 522299Notes

Reaction equation

HRID 522299 reaction equation
[CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[ClH:43].[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[C:60]4[CH:69]=[CH:68][N:67]([CH2:70][CH:71]5[CH2:75][CH2:74][CH2:73][O:72]5)[C:61]=4[N:62]=[C:63]([C:65]#[N:66])[N:64]=3)=[CH:55][C:54]=2[C:76]([F:79])([F:78])[F:77])[CH2:46][CH2:45]1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O.O>[ClH:43].[CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([N:44]1[CH2:45][CH2:46][CH:47]([CH2:50][CH2:51][O:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[C:60]4[CH:69]=[CH:68][N:67]([CH2:70][CH:71]5[CH2:75][CH2:74][CH2:73][O:72]5)[C:61]=4[N:62]=[C:63]([C:65]#[N:66])[N:64]=3)=[CH:55][C:54]=2[C:76]([F:77])([F:78])[F:79])[CH2:48][CH2:49]1)=[O:6]

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 643474N-Methyl-L-prolineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1178996134-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-(tetrahydrofuran-2-yl methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride

Product 1

HCID 1180472894-[4-{2-[1-(1-methyl-L-prolyl)piperidin-4-yl]ethoxy}-3-(trifluoromethyl)phenyl]-7-(tetrahydrofuran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochlorideYield 79.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

1-Methyl-L-proline (33 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg), and N,N-diisopropylethylamine (64 μL) were added to a solution of 4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7-(tetrahydrofuran-2-yl methyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (80 mg) in DMF (1.6 mL) at room temperature, and the mixture was stirred at the same temperature overnight. After the reaction mixture was diluted with EtOAc, a saturated aqueous NaHCO3 solution and water were added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (Hex:CHCl3=50:50 to 0:100). The obtained product was dissolved in EtOAc (1 mL), then a 4 M solution of hydrogen chloride in EtOAc (31 μL) was added thereto at room temperature, and the mixture was stirred at the same temperature for 1 hour. The precipitate was collected by filtration, whereby 4-[4-{2-[1-(1-methyl-L-prolyl)piperidin-4-yl]ethoxy}-3-(trifluoromethyl)phenyl]-7-(tetrahydrofuran-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (77 mg) was obtained as a pale yellow solid.

Workup

  1. extractionextraction
  2. washthe extract was washed with saturated brine
  3. dry with materialThe organic layer was dried over Na2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customThe residue was purified by basic silica gel column chromatography (Hex:CHCl3=50:50 to 0:100)
  7. dissolutionThe obtained product was dissolved in EtOAc (1 mL)
  8. additiona 4 M solution of hydrogen chloride in EtOAc (31 μL) was added
  9. stirringat room temperature, and the mixture was stirred at the same temperature for 1 hour
  10. filtrationThe precipitate was collected by filtration

Sources & evidence

ORD record
ord-2144b2668e714530a4574c1cde7d14bb
Source dataset
uspto-grants-2016_05
Patent number
US09328118B2

Reaction notes

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