Tetrahydrofuran → 4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trifluoro-1-methyl-ethyl ester

HRID 1931715Notes

Reaction equation

HRID 1931715 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](N(C(C)C)CC)(C)C.[O:43]1CCC[CH2:44]1>>[F:1][C:2]([F:7])([F:6])[CH:3]([O:4][C:44]([N:29]1[CH2:28][CH2:27][CH:26]([N:23]2[C:19]3=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=4)=[C:18]3[CH:25]=[N:24]2)[CH2:31][CH2:30]1)=[O:43])[CH3:34]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 669153264-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt2×

Product 1

HCID 579650574-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trifluoro-1-methyl-ethyl esterYield 28%

Procedure

Triphosgene (1.6 g, 5.5 mmol) was added in portions to a solution of 1,1,1-trifluoro-2-propanol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 0.45 mL, 5 mmol) in a mixture of pyridine (0.48 mL, 6 mmol) and carbon tetrachloride (25 mL) under nitrogen. The solution was stirred at 60° C. for 5.5 h and then cooled using an ice bath. 1 M aqueous hydrochloric acid (4 mL) was added and then the mixture was diluted with water and the layers were separated. The organic layer was dried (sodium sulfate), and filtered to give approximately 20 mL of solution, of which 6 mL were used directly in the next reaction without further purification. The solution (6 mL) as added to a mixture of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27; 250 mg, 0.5 mmol) in tetrahydrofuran (1 mL). Diisopropylethylamine (0.5 mL, 2.8 mL) was added slowly and the mixture was stirred for 10 min and then evaporated to dryness and chromatographed using a 30 mm×3″ column of silica gel, eluting with 66-75% ethyl acetate/hexanes, to give 4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid 2,2,2-trifluoro-1-methyl-ethyl ester (72 mg, 28%) as a white solid.

Workup

  1. customof which 6 mL were used directly in the next reaction without further purification
  2. customevaporated to dryness
  3. customchromatographed
  4. washeluting with 66-75% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-c24c0c3a82af4d91a8007db58ef3f2a6
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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