Isopropyl chloroformate → HCID 25122895, compound

HRID 418260Notes

Reaction equation

HRID 418260 reaction equation
[CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[N:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[N:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:20][CH2:19]4)[N:16]=[CH:17][C:10]=23)=[CH:6][CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 7917Isopropyl chloroformateHCID 8471TriethylamineHCID 57544435HCID 57544435, compound

Product 1

HCID 25122895HCID 25122895, compound

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(2-methylpyridin-3-yloxy)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine from Example 18A (44 mg, 0.14 mmol) in 2 mL of methylene chloride was added triethylamine (0.024 mL, 0.17 mmol) and isopropyl chloroformate (0.14 mL of a 1M solution in toluene, 0.14 mmol). The resulting mixture was allowed to stir at RT overnight. The mixture was diluted with ethyl acetate, washed with sat'd aq sodium bicarbonate and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to an oil. The residue was purified by silica gel chromatography (12 g ISCO cartridge, 0-100% ethyl acetate/hexane, 15 min gradient) to afford isopropyl 4-(4-(2-methylpyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate free base (10 mg). Took up in 2 mL ether, added 2N hydrochloric acid (0.07 mL, 0.14 mmol), concentrated to a solid, triturated with hexane and dried in vacuo to afford 8 mg (14%) of Example 18 as an off-white solid. 1H NMR (500 MHz, CD3OD) δ ppm 1.28 (d, J=6.05 Hz, 6H) 2.00-2.06 (m, 2H) 2.16-2.25 (m, 2H) 2.64 (s, 3H) 3.05-3.16 (m, 2H) 4.26-4.33 (m, 2H) 4.90-4.94 (m, 1H) 5.06-5.13 (m, 1H) 7.94 (dd, J=8.25, 5.50 Hz, 1H) 8.36 (s, 1H) 8.47-8.50 (m, 2H) 8.69 (d, J=4.40 Hz, 1H). LRMS (ESI): 397.2 (M+H)+.

Workup

  1. washwashed with sat'd aq sodium bicarbonate and brine
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered through a pad of silica gel
  4. concentrationconcentrated in vacuo to an oil
  5. customThe residue was purified by silica gel chromatography (12 g ISCO cartridge, 0-100% ethyl acetate/hexane, 15 min gradient)

Sources & evidence

ORD record
ord-c955d8fada7f4dafa3073afbf3cbb422
Source dataset
uspto-grants-2012_01
Patent number
US08093257B2

Reaction notes

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