Triethylamine → 2,4-Diamino-6-((1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile

HRID 75343Notes

Reaction equation

HRID 75343 reaction equation
[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:18]([NH2:20])[CH3:19])=[C:8]([N:11]3[CH2:17][C:13]4([CH2:16][O:15][CH2:14]4)[CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][CH:18]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:17][C:13]3([CH2:16][O:15][CH2:14]3)[CH2:12]2)[CH3:19])[N:23]=1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 867080131-(1-Methyl-6-(2-oxa-6-azaspiro[3,3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamineHCID 867080212,4-Diamino-6-chloropyrimidine-5-carbonitrile

Product 1

HCID 730560002,4-Diamino-6-((1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)pyrimidine-5-carbonitrile

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

To a 10 mL vial were added 1-(1-methyl-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (81 mg, 0.30 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol) and Et3N (0.083 mL, 0.60 mmol) in DMF (2 mL). 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 desired compound 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 product were combined and lyophilized to give the title compounds (racemate) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28-1.40 (m, 3 H), 3.71-3.82 (m, 3 H), 3.96-4.07 (m, 2 H), 4.14-4.25 (m, 2 H), 4.72-4.85 (m, 4 H), 5.44-5.58 (m, 1 H), 6.37-6.45 (m, 1 H), 6.45-6.55 (m, 2H), 6.55-6.66 (m, 2 H), 6.68-6.79 (m, 1 H), 7.08-7.16 (m, 1 H), 7.37-7.45 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H23N9O, 406.2; found 406.5.

Workup

  1. washwashed with saturated NH4Cl (3×)
  2. dry with materialThe combined organic layers were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe desired compound 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 product

Sources & evidence

ORD record
ord-86ee6b270e7a423fa6cdbe175ac798e7
Source dataset
uspto-grants-2014_09
Patent number
US08835420B2

Reaction notes

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