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

HRID 1931589Notes

Reaction equation

HRID 1931589 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[C:38](C=O)=[C:37](Cl)[N:36]=[CH:35][N:34]=1.C1(C)C=CC=CC=1>O1CCCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:37]3=[N:36][CH:35]=[N:34][C:33]([Cl:32])=[C:38]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 4

HCID 1140TolueneHCID 81531DiisopropylethylamineHCID 8196914,6-Dichloro-5-pyrimidinecarbaldehyde2×HCID 20824232Tert-butyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate2×

Product 1

HCID 57964905Tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-D]pyrimidin-1-YL)piperidine-1-carboxylateYield 70%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15; 1.80 g, 5.71 mmol), diisopropylethylamine (2.0 mL, 11.3 mmol), and 4,6-dichloropyrimidine-5-carbaldehyde (Intermediate 16; 1.00 g, 5.65 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. for 30 min, then it was warmed up to rt and stirred for 4 h. The solid was filtered. The filtrate was washed with brine (10 mL) and the aqueous layer was extracted with methyl tert-butyl ether (1×10 mL). The combined organic layers were washed with brine (1×10 mL) and concentrated to give an orange-red semi-solid. Toluene (10 mL) was added and the solution was heated to 110° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated to give a semi-solid. This crude solid was dissolved in the minimum amount of dichloromethane and passed through a pad of silica gel, eluting with 9% ethyl acetate/hexanes. Concentration of fractions homogeneous for the product gave 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.33 g, 70%) as a cream white solid. 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.9-2.1 (m, 2H), 2.25 (qd, 2H, J=12.6, 4.5 Hz), 2.97 (t, 2H, J=12.0 Hz), 4.30 (br, 2H), 4.96 (tt, 1H, J=11.4, 4.2 Hz), 8.15 (s, 1H), 8.75 (s, 1H).

Workup

  1. filtrationThe solid was filtered
  2. washThe filtrate was washed with brine (10 mL)
  3. extractionthe aqueous layer was extracted with methyl tert-butyl ether (1×10 mL)
  4. washThe combined organic layers were washed with brine (1×10 mL)
  5. concentrationconcentrated
  6. customto give an orange-red semi-solid
  7. temperaturethe solution was heated to 110° C. for 6 h
  8. temperatureThe reaction mixture was cooled to room temperature
  9. concentrationconcentrated
  10. customto give a semi-solid
  11. washeluting with 9% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-518852e827804da1b92bca5d81cda26b
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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