Tin tetrachloride → 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile

HRID 1505655Notes

Reaction equation

HRID 1505655 reaction equation
[C:1]([C:3]1[N:4](C(OC(C)(C)C)=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12]Br)=[CH:7][CH:6]=2)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[C:29]3[CH:36]=[C:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[F:40][C:38]([F:39])([F:41])[CH2:37][C:35]1[S:34][C:30]2[N:31]=[CH:32][N:33]=[C:28]([NH:27][CH:24]3[CH2:23][CH2:22][N:21]([CH2:12][C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[NH:4][C:3]([C:1]#[N:2])=[CH:11]5)[CH2:26][CH2:25]3)[C:29]=2[CH:36]=1

Participants

6

Reactant 4

HCID 24287Tin tetrachlorideHCID 81531DiisopropylethylamineHCID 90404208tert-butyl 5-(bromomethyl)-2-cyano-1H-indole-1-carboxylateHCID 90404759N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine

Product 1

HCID 862970775-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrileYield 68%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

16.7 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate (0.05 mmol) and 15.8 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.05 mmol) were dissolved in 0.6 mL of DCM. 12.9 mg of DIPEA (0.1 mmol) was added to that solution and reaction mixture was stirred for 18 hs. Then reaction mixture was directly loaded on silica gel column and the product was eluted with DCM-MeOH 30:1. After evaporation of solvent boc-protected intermediate was dissolved in 0.5 mL of ACN and 0.06 mL of SnCl4 (0.5 mmol) was added. The homogenous reaction mixture was stirred for 1 h and then all volatiles were removed in vacuo. The residue was quenched ammonia and extracted with ethyl acetate. Combined organic fractions were dried over MgSO4 and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate-MeOH 1:1:0.1 to produce 16 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 (Compound 175). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. The hydrochloride salt was recrystallized from methanol. 1H NMR (600 MHz, DMSO-d6): δ 12.62 (s, 1H), 10.74 (br, 1H), 8.33 (s, 1H), 8.07 (d, 1H, J=7 Hz), 7.93, s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=12 Hz), 7.56 (d, 1H, J=12 Hz), 7.45 (s, 1H), 4.36 (s, 1H), 4.30 (m, 1H), 4.03 (q, 2H, J=11 Hz), 3.41 (m, 2H), 3.11 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H).

Workup

  1. customThen reaction mixture
  2. washthe product was eluted with DCM-MeOH 30:1
  3. customAfter evaporation of solvent boc-
  4. dissolutionwas dissolved in 0.5 mL of ACN
  5. stirringThe homogenous reaction mixture was stirred for 1 h
  6. customall volatiles were removed in vacuo
  7. customThe residue was quenched ammonia
  8. extractionextracted with ethyl acetate
  9. dry with materialCombined organic fractions were dried over MgSO4
  10. concentrationconcentrated
  11. customThe residue was purified on silica gel column

Sources & evidence

ORD record
ord-f2a99b018a4044c385a4c2b7f3d0b899
Source dataset
uspto-grants-2015_12
Patent number
US09216993B2

Reaction notes

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