(3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidine → tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate

HRID 1775014Notes

Reaction equation

HRID 1775014 reaction equation
F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:39]5[CH2:40][CH2:41][C@@H:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:38]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1

Participants

4

Reactant 2

HCID 1514397(3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidineHCID 712534393-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine

Product 1

HCID 86676687tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamateYield 86.7%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (50.0 mg, 0.13 mmol) and (R)-3-(Boc-amino)pyrrolidine (246.1 mg, 1.32 mmol) in DMSO (2.6 mL) in a sealed tube was stirred at 95° C. under N2 for 3 days. The cooled reaction mixture was diluted into 1:1 ether-ethyl acetate. The organic layer was washed with 10% aqueous citric acid until pH ˜4 to 5, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate) to give tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate as a foam (61.4 mg, 85.3%). 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.79 (s, 1H), 8.05 (broad s, 1H), 7.97 (s, 1H), 7.62-7.50 (m, 2H), 6.37 (d, J=7.9 Hz, 1H), 5.86 (dd, J=8.5, 2.2 Hz, 1H), 4.79 (s, 1H), 4.44 (s, 1H), 4.07-3.95 (m, 4H), 3.92-3.84 (m, 1H), 3.84-3.69 (m, 3H), 3.63-3.51 (m, 1H), 2.64-2.49 (m, 1H), 2.37 (td, J=13.6, 7.7 Hz, 1H), 2.17 (d, J=9.8 Hz, 2H), 2.11-2.01 (m, 1H), 1.89-1.68 (m, 3H), 1.46 (s, 9H). LC/MS: m/z 545.3 [M+1].

Workup

  1. customThe cooled reaction mixture
  2. washThe organic layer was washed with 10% aqueous citric acid until pH ˜4 to 5, water and brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customThe crude product was purified
  7. washflash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate)

Sources & evidence

ORD record
ord-7ae5fe45493049c19de4d96e1c81e0a6
Source dataset
uspto-grants-2016_02
Patent number
US09260425B2

Reaction notes

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