Hydrochloric Acid → HCID 67959763, compound

HRID 1529272Notes

Reaction equation

HRID 1529272 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[CH:27]=[N:26][CH:25]=2)[C:5]([F:8])=[N:6][CH:7]=1.Cl.CC(O)C>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[CH:25]=[N:26][CH:27]=[C:28]([O:30][C@@H:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)[N:29]=2)[C:5]([F:8])=[N:6][CH:7]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 3776IsopropanolHCID 67959750(3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

Product 1

HCID 67959763HCID 67959763, compound

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

(3R)-tert-butyl 3-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate 10a (270 mg, 0.48 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (97 mg, 0.56 mmol) (Combi-Blocks, Catalog# BB-3818), potassium phosphate tribasic (308 mg, 1.45 mmol) (Sigma-Aldrich, Catalog# P5629-25G, Lot#069K0110), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.8 mg, 0.03 mmol) (Strem, Catalog#15-1149, Batch# A0183078), and Pd2(dba)3 (13.3 mg, 0.02 mmol) (Strem, Catalog#46-3000, Lot# A8761089) were weighed into a 10 mL glass microwave vial. The vial was purged with argon, the solids were treated with dioxane (4 mL) and water (1 mL) and the vial was sealed. The contents were heated in Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 115° C. for 30 min. The reaction mixture was treated with 2 mL of water and extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated, affording (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate as a light yellow solid. MS (ESI, pos. ion) m/z: 609.2 (M+1). The material was used without purification. To a solution of (3R)-tert-butyl 3-(6-(5-(5-chloro-2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (292 mg, 0.48 mmol) in THF (2.2 mL) and EtOH (2.2 mL) was added HCl, 5-6N in IPA (0.8 mL, 26.40 mmol). The solution was heated in an oil bath at 65° C. for 1 h. The crude reaction was concentrated to a yellow solid that was dissolved in 5 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% [0.1% TFA in ACN] in [0.1% TFA in water]. The desired fractions were collected, concentrated, and basified with 1 N NaOH, extracted with EtOAc. The EtOAc solution was washed with brine, dried with Na2SO4 and concentrated to afford (R)-5-(5-chloro-2-fluoropyridin-3-yl)-3-(6-(piperidin-3-yloxy)pyrazin-2-yl)-1H-indazole as an off white crystalline solid. MS (ESI, pos. ion) m/z: 425.1 (M+1).

Workup

  1. customThe material was used without purification
  2. customThe crude reaction
  3. concentrationwas concentrated to a yellow solid
  4. dissolutionthat was dissolved in 5 mL of DMSO
  5. custompurified on a reverse phase HPLC
  6. customThe desired fractions were collected
  7. concentrationconcentrated
  8. extractionextracted with EtOAc
  9. washThe EtOAc solution was washed with brine
  10. dry with materialdried with Na2SO4
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-8aaadd72c2b04549b22867268f666c49
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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