Triethylamine → tert-Butyl (S)-3-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate

HRID 2205612Notes

Reaction equation

HRID 2205612 reaction equation
[NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:3].[NH2:26][C:27]1[N:32]=[C:31](Cl)[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1.C(N(CC)CC)C>CS(C)=O>[NH2:26][C:27]1[N:32]=[C:31]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15]2)[CH3:3])[C:30]([C:34]#[N:35])=[C:29]([CH3:36])[N:28]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 754124462-Amino-4-chloro-6-methyl-5-pyrimidinecarbonitrileHCID 118207715tert-Butyl 3-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate

Product 1

HCID 118214752tert-Butyl (S)-3-(5-((S)-1-((2-amino-5-cyano-6-methylpyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
85 °C

Procedure

To a 25 mL pear flask were added the mixture of diastereomers of tert-butyl 3-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyrrolidine-1-carboxylate (0.057 g, 0.17 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.042 g, 0.25 mmol) in DMSO (1 mL). Triethylamine (0.069 mL, 0.50 mmol) was added and the mixture was heated to 85° C. for 14 hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by liquid chromatography (SiO2, 25-100% EtOAc/hexanes). The product-containing fractions from two different peaks were pooled separately and concentrated in vacuo to give the title diastereomers. Peak 1 (shorter retention time, 19 mg, 24%): 1H NMR (400 MHz, CDCl3) δ ppm 0.69-0.85 (m, 5H), 1.32-1.51 (m, 22H), 2.15-2.40 (m, 8H), 3.33-3.49 (m, 2H), 3.52-3.86 (m, 8H), 4.70 (dd, J=10.74, 7.45 Hz, 1H), 5.27 (br s, 1H), 5.62-5.75 (m, 1H), 5.82-5.96 (m, 2H), 6.60 (br s, 2H), 6.73 (d, J=8.84 Hz, 1H), 7.19 (s, 2H), 7.33-7.45 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477. Peak 2 (longer retention time, 41 mg, 52%): 1H NMR (400 MHz, CDCl3) δ ppm 0.66-0.90 (m, 3H), 1.39-1.52 (m, 15H), 1.88-2.07 (m, 3H), 2.21-2.40 (m, 5H), 3.30-3.89 (m, 10H), 5.02-5.20 (m, 2H), 5.65 (t, J=6.44 Hz, 1H), 6.61 (d, J=3.03 Hz, 1H), 7.14-7.24 (m, 2H), 7.28-7.46 (m, 2H); ESI-MS m/z [M+H]+ calc'd for C25H32N8O2, 477. found 477.

Workup

  1. additionTo a 25 mL pear flask were added
  2. customThe reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate
  3. extractionThe aqueous layer was extracted with ethyl acetate
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by liquid chromatography (SiO2, 25-100% EtOAc/hexanes)
  8. concentrationconcentrated in vacuo
  9. customto give the title diastereomers

Sources & evidence

ORD record
ord-e265a59fbd65405e8feabfac9350c6d7
Source dataset
uspto-grants-2016_06
Patent number
US09371321B2

Reaction notes

Loading…