tert-Butanol → tert-Butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate

HRID 877892Notes

Reaction equation

HRID 877892 reaction equation
Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12].[F-].[Cs+].C(O)(C)(C)C>C1CCC(P([C]2[CH][CH][CH][CH]2)C2CCCCC2)CC1.C1CCC(P([C]2[CH][CH][CH][CH]2)C2CCCCC2)CC1.Cl[Pd]Cl.[Fe].O>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[C:2]([C:28]2[CH:27]=[N:26][N:25]([C:14]3([CH2:13][C:11]#[N:12])[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:17]3)[CH:29]=2)=[N:7][CH:6]=1

Participants

7

Reactant 4

HCID 6386tert-ButanolHCID 25953Cesium fluorideHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-HCID 67457197tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Product 1

HCID 78323640tert-Butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylateYield 99%

Reagents, catalysts & solvents 2

HCID 71777680Dichloro [1,1\'-bis(dicyclohexylphosphino) ferrocene]palladium(II)CatalystHCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4, 39.6 g, 257.6 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 100 g, 257.6 mmol, 1.0 equiv), cesium fluoride (136.9 g, 901.4 mmol, 3.5 equiv), tert-butanol (250 mL), water (250 mL), and [1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (Pd-127, 351.4 mg, 0.46 mmol, 0.0018 equiv) at ambient temperature. The resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to reflux and maintained at reflux under nitrogen for 20-24 hours. When HPLC showed the reaction was complete, the reaction mixture was cooled to 45-55° C. in 30 minutes, the two phases were separated, and the aqueous phase was discarded. To the organic phase was added n-heptane (125 mL) in 30 minutes at 45-55° C. The resulting mixture was slowly cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 2 hours. The solids were collected by filtration, washed with n-heptane (100 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-azetidine-1-carboxylate (5, 96.8 g, 97.7 g theoretical, 99%) as a pale yellow solid. For 5: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.06 (d, J=3.6 Hz, 1H), 4.62-4.41 (m, 2H), 4.31-4.12 (m, 2H), 3.67 (s, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.40, 152.60, 150.63, 149.15, 139.76, 129.53, 127.65, 122.25, 116.92, 113.21, 99.71, 79.45, 58.34 (br), 56.80, 27.99, 26.83 ppm; C19H21N7O2 (MW 379.4), LCMS (EI) m/e 380 (M++H).

Workup

  1. customTo a 1-L flask equipped with a nitrogen inlet
  2. customThe resulting reaction mixture
  3. customwas de-gassed
  4. additionrefilled with nitrogen for 3 times
  5. temperaturebefore being heated
  6. temperatureto reflux
  7. temperaturemaintained
  8. temperatureat reflux under nitrogen for 20-24 hours
  9. customthe two phases were separated
  10. additionTo the organic phase was added n-heptane (125 mL) in 30 minutes at 45-55° C
  11. temperatureThe resulting mixture was slowly cooled to ambient temperature in one hour
  12. filtrationThe solids were collected by filtration
  13. washwashed with n-heptane (100 mL)
  14. customdried under vacuum at 50° C. with nitrogen sweeping to constant weight

Sources & evidence

ORD record
ord-004c05a385a84f4296eb5f93d800a4c1
Source dataset
uspto-grants-2015_03
Patent number
US08987443B2

Reaction notes

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