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Triethylamine → 2,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile

HRID 75342
Notes
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Reaction equation

HRID 75342 reaction equation
[F:1][C:2]1([F:19])[CH2:5][N:4]([C:6]2[CH:7]=[C:8]3[N:17]([CH3:18])[CH:16]=[CH:15][C:9]3=[N:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH2:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:14][CH:12]([C:11]2[N:10]=[C:9]3[CH:15]=[CH:16][N:17]([CH3:18])[C:8]3=[CH:7][C:6]=2[N:4]2[CH2:5][C:2]([F:1])([F:19])[CH2:3]2)[CH3:13])[N:22]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 867080081-(6-(3,3-Difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamineHCID 867080212,4-Diamino-6-chloropyrimidine-5-carbonitrile

Product 1

HCID 730557082,4-Diamino-6-((1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile

Reagents, catalysts & solvents 2

HCID 6228
Dimethylformamide
Solvent
HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a 10 mL vial were added 1-(6-(3,3-difluoroazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (61 mg, 0.23 mmol) in DMF (2 mL) along with 2,4-diamino-6-chloropyrimidine-5-carbonitrile (38.8 mg, 0.229 mmol) and Et3N (0.064 mL, 0.46 mmol). The resulting yellow solution was heated to 90° C. and stirred for 5 hours. The reaction mixture was diluted with EtOAc and washed with saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was precipitated with ether, filtered, and purified by silica gel column chromatography, eluting with 1:1 EtOAc/hexane to 100% EtOAc to 9:1 EtOAc/MeOH gradient. The resulting yellow foam was further purified by preparative HPLC eluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate). The fractions containing the desired product were combined and lyophilized to give the title compound (racemate) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.43 (m, 3 H), 3.74-3.85 (m, 3 H), 4.18-4.37 (m, 2 H), 4.41-4.59 (m, 2 H), 5.38-5.52 (m, 1 H), 6.39-6.56 (m, 3 H), 6.57-6.65 (m, 2 H), 6.68-6.76 (m, 1H), 7.39-7.45 (m, 1 H), 7.46-7.53 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C18H19F2N9, 400.2; found 400.4.

Workup

  1. washwashed with saturated NH4Cl (3×)
  2. dry with materialThe combined organic layers were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe product was precipitated with ether
  6. filtrationfiltered
  7. custompurified by silica gel column chromatography
  8. washeluting with 1:1 EtOAc/hexane to 100% EtOAc to 9:1 EtOAc/MeOH gradient
  9. customThe resulting yellow foam was further purified by preparative HPLC
  10. washeluting with 20-40% ACN in water (with 0.05% ammonium bicarbonate)
  11. additionThe fractions containing the desired product

Sources & evidence

ORD record
ord-5b9ee2d9a1034312ac5451cf1998f473
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08835420B2

Reaction notes

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