Diisopropylethylamine → 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide

HRID 2363335Notes

Reaction equation

HRID 2363335 reaction equation
C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]2[CH2:58][CH2:57]2)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]3[CH2:58][CH2:57]3)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 67391464{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochlorideHCID 866757555-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide

Product 1

HCID 712080905-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamideYield 59%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
125 °C

Procedure

N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide (58 mg, 0.21 mmol) in NMP (2.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (80 mg, 59%). LCMS (M+H)+: m/z=653.2.

Workup

  1. extractionextracted with dichloromethylene (3×20 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%)

Sources & evidence

ORD record
ord-ad05e779449844e5970247f0269b54d0
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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