Hydrochloric Acid → 1-piperidin-4-yl-4-(2,4,5-trifluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride

HRID 1931625Notes

Reaction equation

C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1

Participants

Conditions

Temperature: 40 °C

Procedure

A mixture of 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 35; 66 mg, 0.15 mmol) and 4M HCl in 1,4-dioxane (10 mL) was stirred at 40° C. for 1 h. The solvent was evaporated under vacuum to provide 1-piperidin-4-yl-4-(2,4,5-trifluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride as a solid which was used directly in the next step without purification. Dichloromethane (5 mL) was added, and the mixture was cooled to about 0° C. using an ice-water bath. Isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 0.22 mL, 1.0 M in toluene, 0.22 mmol) was added, followed by triethylamine (0.13 mL, 0.96 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. Water and dichloromethane were added and the aqueous phase was extracted twice with each of the following solvents: dichloromethane, ether and hexane. The combined organic phases were evaporated and the resulting residue was purified by C18 reversed phase HPLC using a gradient of 20-100% acetonitrile/water to give 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (47 mg, 73%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.28 (d, 6H, J=6.2 Hz), 1.98-2.05 (m, 4H), 2.18-2.25 (m, 2H), 3.00-3.10 (m, 2H), 4.08-4.15 (m, 2H), 4.80-4.82 (m, 1H), 5.00-5.05 (m, 1H), 7.88-7.94 (m, 2H), 8.47 (s, 1H), 8.59 (s, 1H). Mass spectrum MH+=436. HRMS Calcd. For C20H21F3N5O3 (MH+): 436.1591. Found: 436.1589.

Workup

customThe solvent was evaporated under vacuum

Sources & evidence

ORD record: ord-aba7b99d35ef4b288875943e9f82ff92
Source dataset: uspto-grants-2012_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08188098B2

Reaction notes

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