tert-Butyl methyl ether → tert-Butyl 4-((6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate

HRID 1529286Notes

Reaction equation

HRID 1529286 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.COC(C)(C)C.CC(C)([O-])C.[Na+].[CH3:76][NH:77][CH:78]1[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1COCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[N:7]=[C:2]([N:77]([CH3:76])[CH:78]2[CH2:79][CH2:80][N:81]([C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[CH2:82][CH2:83]2)[CH:3]=[N:4][CH:5]=1

Participants

8

Reactant 5

HCID 15413tert-Butyl methyl etherHCID 15380702tert-Butyl 4-(methylamino)piperidine-1-carboxylateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 23676156Sodium t-butoxideHCID 867097633-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 86709764tert-Butyl 4-((6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 66572931HCID 66572931, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

To a glass microwave vial was added 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.200 g, 0.469 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 6.57 mg, 0.014 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dipropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (6.57 mg, 0.014 mmol), RuPhos precatalyst (10.28 mg, 0.014 mmol), and sodium tert-butoxide (0.144 mL, 1.174 mmol). The vial was placed under vacuum and flushed with argon. tert-Butyl 4-(methylamino)piperidine-1-carboxylate (0.121 g, 0.563 mmol, CNH Technologies) and THF (1.565 mL) were added and the reaction mixture was stirred at 85° C. overnight. Reaction was cooled to RT. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 100% EtOAc in hexane. The desired tert-Butyl 4-((6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate was obtained and then treated with 5-6 M HCl in IPA. The reaction mixture was heated at 80° C. for 1 h and then contracted to dryness. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in ACN/H2O, gradient 15% to 100% over 15 min. The title compound was obtained. MS (ESI, pos. ion) m/z: 421.1 (M+1).

Workup

  1. customflushed with argon
  2. customReaction
  3. temperaturewas cooled to RT
  4. customchromatographed through a Biotage pre-packed silica gel column (40S)
  5. washeluting with a gradient of 10% to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-69294e21bd054f98b91f0665b5ad830f
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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