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Dichloromethane → Tert-butyl (4-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]-2-pyridyl]-4-cyano-piperidine-1-carboxylate)

HRID 331496
Notes
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Reaction equation

HRID 331496 reaction equation
[C:1]([C:3]1([C:16]2[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.Br[C:50]1[N:51]=[C:52]([C:71]#[C:72][Si](C)(C)C)[C:53]([N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[N:54][CH:55]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:16]2[CH:21]=[C:20]([C:50]3[CH:55]=[N:54][C:53]([N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:63])=[C:52]([C:71]#[CH:72])[N:51]=3)[CH:19]=[CH:18][N:17]=2)([C:1]#[N:2])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 6

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 58070279Tert-butyl N-tert-butoxycarbonyl-N-[5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl]carbamateHCID 69929701Tert-butyl 4-cyano-4-(4-iodo-2-pyridyl)piperidine-1-carboxylate

Product 1

HCID 86680960Tert-butyl (4-[4-[5-[bis(tert-butoxycarbonyl)amino]-6-ethynyl-pyrazin-2-yl]-2-pyridyl]-4-cyano-piperidine-1-carboxylate)Yield 51%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

tert-butyl 4-cyano-4-(4-iodo-2-pyridyl)piperidine-1-carboxylate (1.01 g, 2.444 mmol) was dissolved in dioxane (15 mL) and bis(pinacolato)diboron (934.0 mg, 3.678 mmol) followed by potassium acetate (721.9 mg, 7.356 mmol) were added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles. [PdCl2(dppf)].dichloromethane (199.6 mg, 0.2444 mmol) was then added and the reaction heated to 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature and tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.150 g, 2.444 mmol) and a 2 M aqueous solution of sodium carbonate (3.666 mL of 2 M, 7.332 mmol) were added. The reaction mixture was degassed with 3× vacuum/nitrogen cycles then Pd(PPh3)4 (283.2 mg, 0.2451 mmol) was added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles and then heated to 90° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate/water. The aqueous layer was extracted with ethyl acetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column), loaded in dichloromethane eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as a beige solid (749 mg, 51% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.33 (s, 18H), 1.38 (s, 9H), 2.07 (dt, 2H), 2.21 (d, 2H), 3.01 (br s, 2H), 4.10 (br d, 2H), 4.99 (s, 1H), 8.11 (dd, 1H), 8.25 (s, 1H), 8.78 (d, 1H) and 9.40 (s, 1H) ppm; LC/MS m/z 605.3 [M+H]+.

Workup

  1. additionwere added
  2. customThe reaction mixture was degassed with 5× vacuum/nitrogen cycles
  3. temperatureThe reaction mixture was cooled to ambient temperature
  4. customThe reaction mixture was degassed with 3× vacuum/nitrogen cycles
  5. customThe reaction mixture was degassed with 5× vacuum/nitrogen cycles
  6. temperatureheated to 90° C. for 2 hours
  7. temperatureThe reaction mixture was cooled to ambient temperature
  8. additiondiluted with ethyl acetate/water
  9. extractionThe aqueous layer was extracted with ethyl acetate (×1)
  10. washthe combined organic extracts washed with brine (×2)
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe residue was purified by column chromatography (ISCO Companion, 120 g column)
  15. washeluted with 0 to 50% ethyl acetate/petroleum ether
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4bf3d048624a46b58170eac44940daad
Source dataset
uspto-grants-2014_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08877759B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes