Formic Acid → HCID 68283515, compound

HRID 1052124Notes

Reaction equation

HRID 1052124 reaction equation
C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)=O.CCN(CC)CC.C([O:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:45](=[O:59])[CH2:46][N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([C:56](=[O:58])[CH3:57])=[N:48]1)=[O:38])C=C>CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:56]([C:49]1[C:50]2[C:51](=[N:52][CH:53]=[CH:54][CH:55]=2)[N:47]([CH2:46][C:45]([N:40]2[C@H:39]([C:37]([OH:38])=[O:36])[CH2:44][C@@H:43]3[C@H:41]2[CH2:42]3)=[O:59])[N:48]=1)(=[O:58])[CH3:57]

Participants

7

Reactant 4

HCID 284Formic AcidHCID 8471TriethylamineHCID 27349372-(Di-tert-butylphosphino)-2'-methyl-1,1'-biphenylHCID 68283908HCID 68283908, compound

Product 1

HCID 68283515HCID 68283515, compound

Reagents, catalysts & solvents 2

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 6228DimethylformamideSolvent2×

Procedure

Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under an argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by Et3N (1.86 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.4 mL). The reaction mixture was stirred at 10° C. for 1 h. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions c): 1.84 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H).

Workup

  1. temperatureAfter cooling the reaction mixture to 10° C.
  2. stirringThe reaction mixture was stirred at 10° C. for 1 h
  3. customDMF was evaporated
  4. additionThe residue was poured into NH4Cl (sat. aq. solution)
  5. extractionextracted with EtOAc (3×50 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in MeOH
  10. filtrationfiltered over a PL-Thiol cartridge
  11. concentrationThe filtrate was concentrated
  12. customthe crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA)
  13. custom1.84 min

Sources & evidence

ORD record
ord-97669ff4acf049e887cfe57b96b0c56b
Source dataset
uspto-grants-2016_07
Patent number
US09388199B2

Reaction notes

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