Cesium carbonate → HCID 90404695, compound

HRID 1505667Notes

Reaction equation

HRID 1505667 reaction equation
Cl.[F:2][C:3]([F:34])([F:33])[CH2:4][C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]#[N:31])=[CH:24]5)[CH2:16][CH2:15]3)[C:7]=2[CH:6]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:30]([C:25]1[N:26]([CH2:36][C:37]([NH2:39])=[O:38])[C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:12]3[C:7]4[CH:6]=[C:5]([CH2:4][C:3]([F:33])([F:2])[F:34])[S:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]1)=[CH:29][CH:28]=2)#[N:31]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 696322-BromoacetamideHCID 90405412HCID 90405412, compound

Product 1

HCID 90404695HCID 90404695, compoundYield 40.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

760 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride (1.5 mmol) and 207 mg of bromoacetamide (1.5 mmol) were dissolved in 3.6 mL of dry DMF. 1.96 g of cesium carbonate (6 mmol) was added and reaction mixture was stirred for 4 hs. Then it was quenched with 50 mL of water and extracted with DCM-MeOH 10:1. Combined organic extracts were evaporated with silica gel and loaded on column. The product was eluted with DCM-MeOH 10:1 mixture. After evaporation of product containing fractions it was recrystallized from MeOH to produce 319 mg of 2-(2-cyano-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide, which was converted to hydrochloride salt by dissolving in 5 mL of MeOH, adding of 1 eq of 1M HCl in water. Hydrochloride salt can be recrystallized further from MeOH. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.44 (s, 1H), 7.91 (s, 1H), 7.57 (m, 2H), 7.41 (s, 1H), 5.10 (s, 2H), 4.53 (m, 1H), 4.47 (s, 1H), 3.89 (q, 2H, J=10.3 Hz), 3.62 (m, 2H), 3.24 (m, 2H), 2.35 (m, 2H), 1.93 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 171.07, 157.66, 153.62, 140.17, 130.77, 129.55, 127.95, 127.10, 125.64, 123.46, 121.90, 118.31, 114.76, 113.69, 113.52, 112.60, 61.96, 52.67, 49.60, 47.98, 47.40, 35.52 (q, J=33 Hz), 29.96. ESI MS [MH+]: 528.1783.

Workup

  1. customreaction mixture
  2. customThen it was quenched with 50 mL of water
  3. extractionextracted with DCM-MeOH 10:1
  4. customCombined organic extracts were evaporated with silica gel
  5. washThe product was eluted with DCM-MeOH 10:1 mixture
  6. customAfter evaporation of product
  7. additioncontaining fractions it
  8. customwas recrystallized from MeOH

Sources & evidence

ORD record
ord-cec61d2f03bb4282b7f2c15000ce4063
Source dataset
uspto-grants-2015_12
Patent number
US09216993B2

Reaction notes

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