Trifluoroacetic acid → 3-(6-Chloro-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

HRID 1093178Notes

Reaction equation

HRID 1093178 reaction equation
[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]3[N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:17]=[CH:18][C:10]=13)[CH2:2]2.F[C:33](F)(F)[C:34](O)=O.FC(F)(F)C([O-])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:60]([N:62](CC)[CH2:63]C)[CH3:61]>ClCCl>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:61]4[CH:60]=[N:62][CH:63]=[CH:33][CH:34]=4)[CH2:23][CH2:24]3)[N:17]=[CH:18][C:10]2=[C:9]([N:3]2[CH2:2][CH:1]3[O:8][CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[N:14]=1

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 84468TrifluoroacetateHCID 5049666Sodium triacetoxyborohydrideHCID 86629367tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

Product 1

HCID 866293693-(6-Chloro-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octaneYield 100%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

Tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (0.20 g, 0.45 mmol) was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL). When LC/MS analysis revealed the deprotection of the Boc group, the mixture was concentrated to dryness under reduced pressure. Diethyl ether was evaporated three times from the crude material in order to afford a solid residue. The trifluoroacetate salt was dissolved in dichloromethane (10 mL) and then treated with triethylamine (0.18 mL). The mixture was concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (10 mL) and treated with 3-pyridinecarboxaldehyde (0.064 mL). The mixture was allowed to stir for 10 minutes before the addition of sodium triacetoxyborohydride (0.15 g, 0.68 mmol). After stirring overnight, the mixture was diluted with dichloromethane and washed with 1 M aqueous sodium hydroxide solution. The aqueous phase was back extracted once with dichloromethane and then the combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. 3-(6-Chloro-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.20 g, 100%) was thus obtained as a yellow crystalline solid. MS (ES+): 440.0, 441.2 (M+H)+

Workup

  1. concentrationthe mixture was concentrated to dryness under reduced pressure
  2. customDiethyl ether was evaporated three times from the crude material in order
  3. customto afford a solid residue
  4. concentrationThe mixture was concentrated to dryness under reduced pressure
  5. additiontreated with 3-pyridinecarboxaldehyde (0.064 mL)
  6. washwashed with 1 M aqueous sodium hydroxide solution
  7. extractionThe aqueous phase was back extracted once with dichloromethane
  8. dry with materialthe combined organics were dried over anhydrous magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-aae8893ceeaf448594236f84cf8e8676
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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