Triphenylphosphine → Tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-D]pyrimidin-1-YL)piperidine-1-carboxylate

HRID 1931588Notes

Reaction equation

HRID 1931588 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Cl:48][C:49]1[N:54]=[CH:53][N:52]=[C:51]2[NH:55][N:56]=[CH:57][C:50]=12>O1CCCC1.C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:41]1[CH2:46][CH2:45][CH:44]([N:55]2[C:51]3=[N:52][CH:53]=[N:54][C:49]([Cl:48])=[C:50]3[CH:57]=[N:56]2)[CH2:43][CH2:42]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]

Participants

7

Reactant 4

HCID 11776TriphenylphosphineHCID 2210954-Chloro-1H-pyrazolo[3,4-d]pyrimidine3×HCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 5363146Diisopropyl azodicarboxylate

Product 1

HCID 57964905Tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-D]pyrimidin-1-YL)piperidine-1-carboxylateYield 39%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of triphenylphosphine (30.5 g, 116.3 mmol) in anhydrous tetrahydrofuran (450 mL) was cooled to 0° C. under nitrogen. Diisopropylazodicarboxylate (22.9 mL, 116.3 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min and then 1-Boc-4-hydroxy-piperidine (Aldrich, 20.3 g, 100 mmol) was added. The mixture was stirred at 0° C. for 10 min and then solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 13.0 g, 84 mmol) was added in portions. The flask containing Intermediate 30 was rinsed with THF and the washings were added to the reaction mixture. The reaction mixture was stirred in the ice-bath for 3 h, and then stored in the refrigerator overnight. The reaction mixture was evaporated to dryness and the residue was taken up in a mixture of ether and hexanes (2:1; 1 L). The mixture was stirred at room temperature for 20 min, and then the white solid was filtered off and washed with a mixture of ether and hexanes (2:1). The filtrate was evaporated to dryness to give a yellow solid. This was taken up in toluene with warming, applied to a column of flash silica gel (90 mm×6″) and eluted with 20-25% ethyl acetate/hexanes to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.0 g, 39%) along with mixed fractions which were repurified by flash chromatography.

Workup

  1. stirringThe mixture was stirred at 0° C. for 10 min
  2. washwas rinsed with THF
  3. additionthe washings were added to the reaction mixture
  4. stirringThe reaction mixture was stirred in the ice-bath for 3 h
  5. customstored in the refrigerator overnight
  6. customThe reaction mixture was evaporated to dryness
  7. additionthe residue was taken up in a mixture of ether and hexanes (2:1; 1 L)
  8. stirringThe mixture was stirred at room temperature for 20 min
  9. filtrationthe white solid was filtered off
  10. washwashed with a mixture of ether and hexanes (2:1)
  11. customThe filtrate was evaporated to dryness
  12. customto give a yellow solid
  13. temperaturewith warming
  14. washeluted with 20-25% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-5aed1fa39f234064b5732cfc6099cf1b
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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