Sodium t-butoxide → 4-[4-(2-Methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1931617Notes

Reaction equation

HRID 1931617 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]([N:32]2[CH:36]=[N:35][CH:34]=[N:33]2)[N:26]=1.CC(C)([O-])C.[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(CN1P2N(CC(C)C)CCN(CCN2CC(C)C)CC1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:31][C:30]4[C:25]([CH3:24])=[N:26][C:27]([N:32]5[CH:36]=[N:35][CH:34]=[N:33]5)=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 3

HCID 23676156Sodium t-butoxideHCID 532992722-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine2×HCID 57964905Tert-butyl 4-(4-chloro-1H-pyrazolo[3,4-D]pyrimidin-1-YL)piperidine-1-carboxylate2×

Product 1

HCID 579649544-[4-(2-Methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl esterYield 26%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 45712432,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecaneCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamine (Intermediate 7, Step 2; 26 mg, 0.15 mmol), palladium(II) acetate (0.3 mg, 0.01 eq), triisobutylphosphatrane (1 mg, 0.02 eq) and sodium tert-butoxide (34 mg, 0.36 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. The mixture was filtered through a PTFE filter with a 0.45 μM pore size to remove the catalyst, and the solid was rinsed with ethyl acetate. Ethyl acetate and water were added to the combined filtrate and washings, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated to give 4-[4-(2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (18 mg, 26%) as a light yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.75-2.07 (m, 4H), 2.99 (br s, 2H), 3.98-4.15 (m, 2H), 4.77-5.00 (m, 1H), 7.77 (d, 1H, J=8.5 Hz), 8.04-8.15 (m, 2H), 8.30 (s, 2H), 9.33 (s, 1H), 10.00 (br s, 1H). Mass spectrum (ES) MH+=477. HRMS Calcd. for C23H29N10O2 (MH+): 477.2470. Found: 477.2468.

Workup

  1. filtrationThe mixture was filtered through a PTFE
  2. filtrationfilter with a 0.45 μM pore size
  3. customto remove the catalyst
  4. washthe solid was rinsed with ethyl acetate
  5. additionEthyl acetate and water were added to the combined filtrate and washings
  6. extractionthe aqueous layer was extracted twice with ethyl acetate
  7. customevaporated
  8. custompurified by preparative C18 HPLC
  9. washeluting with 10-100% acetonitrile/water
  10. additionSamples containing the product
  11. extractionwere extracted twice with dichloromethane
  12. customthe solvent was evaporated

Sources & evidence

ORD record
ord-f844dfc021ba408c91e6406e241ddaa9
Source dataset
uspto-grants-2012_05
Patent number
US08188098B2

Reaction notes

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