Sodium Iodide → N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide

HRID 898015Notes

Reaction equation

HRID 898015 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.Br[CH2:39][CH:40]([F:42])[F:41].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:39][CH:40]([F:42])[F:41])[CH2:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 11430Potassium CarbonateHCID 1361862-Bromo-1,1-difluoroethane3×HCID 20817350HCID 20817350, compound

Product 1

HCID 22347012N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamideYield 81%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

N2-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (250 mg, 0.503 mmol), 2-bromo-1,1-difluoroethane (91 mg, 0.629 mmol), Potassium carbonate (87 mg, 0.629 mmol) and Sodium iodide (10 mg, 0.066 mmol) were mixed in DMF (3 mL). The reaction mixture was heated at 80° C. overnight. HPLC showed only about fifty percent conversion. The bath temperature was lowered to 55° C. and more 2-bromo-1,1-difluoroethane (0.1 mL) was added. After stirring at 55° C. overnight, more 2-bromo-1,1-difluoroethane (0.1 mL) was added and the reaction mixture was stirred at 55° C. overnight. HPLC showed most of starting material was converted to product. The crude reaction mixture was purified by reverse phase preparative HPLC using acetonitrile/water (50 mM ammonium acetate buffer) as mobile phase to give N2-(4-{4-amino-1-[1-(2,2-difluoroethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide (227 mg, 81%). 1H NMR (DMSO-d6) δ 1.89 (m, 2H), 2.27 (m, 2H), 2.42 (m, 2H), 2.80 (m, 1H), 3.05 (m, 2H), 3.96 (s, 3H), 4.04 (s, 3H), 4.69 (m, 1H), 6.17 (t t, J=55.81 Hz, J=4.35 Hz, 1H), 7.15 (m, 1H), 7.33 (m, 4H), 7.78 (d, J=7.94 Hz, 1H), 7.70 (d, J=7.94 Hz, 1H), 8.11 (d, J=8.19 Hz, 1H), 8.25 (s, 1H), 9.44 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 0.8 mL/min.): RT=3.32 min. MH+=561.3.

Workup

  1. customwas lowered to 55° C.
  2. stirringthe reaction mixture was stirred at 55° C. overnight
  3. customThe crude reaction mixture
  4. customwas purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-21f15849c5cc406f824cbe8aacf17c9f
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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