Acryloyl chloride → (-)-1-(3-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)piperidin-1-yl)prop-2-en-1-one

HRID 928173Notes

Reaction equation

HRID 928173 reaction equation
[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(OCC)(=O)C>[CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:31](=[O:34])[CH:32]=[CH2:33])[CH2:21]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 1180737239-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-3-yl)-9H-purin-6-amine

Product 1

HCID 118073654(-)-1-(3-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)piperidin-1-yl)prop-2-en-1-oneYield 16%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To 9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(piperidin-3-yl)-9H-purin-6-amine from the previous reaction was added sat. aq. NaHCO3 (12 mL) and ethyl acetate (30 mL). The mixture was stirred for 10 min, and acryloyl chloride (148 μL, 1.8 mmol) was added and stirred at ambient temperature for 15 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organics were dried over Na2SO4 and evaporated to give a foamy solid (600 mg) that was subjected to chiral SFC purification to separate the two enantiomers (Chiralcel OJ-H 4.6×250 mm column, 20% EtOH, 140 bar, 3.0 mL/min). Peak 1(+) eluted at 3.18 min. Peak 2 (−) as the title product eluted at 5.03 min) (86.4 mg, ˜98% ee, 16% yield in 3 steps). [α]D22=−76.0° (c 0.14, EtOH). 1H NMR (700 MHz, DMSO-17 mm) δ ppm 9.87 (br. s., 1 H) 8.28 (br. s., 1 H) 7.96-8.13 (m, 1 H) 7.74 (d, J=7.26 Hz, 1 H) 6.76-6.91 (m, 1 H) 5.99-6.17 (m, 1 H) 5.53-5.75 (m, 1 H) 4.69-4.84 (m, 2 H) 4.03-4.30 (m, 2 H) 3.84 (s, 3 H) 2.74-3.02 (m, 2 H) 2.11-2.28 (m, 1 H) 1.75-2.01 (m, 2 H) 1.54 (d, J=2.64 Hz, 7 H). m/z (APCI+) for C20H26N8O 395.1 (M+H)+.

Workup

  1. stirringstirred at ambient temperature for 15 min
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was extracted with ethyl acetate (30 mL)
  4. dry with materialThe combined organics were dried over Na2SO4
  5. customevaporated

Sources & evidence

ORD record
ord-2091507bfcc747b3be6f0bb3e7848660
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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