Toluene → HCID 178434520, compound

HRID 1516445Notes

Reaction equation

HRID 1516445 reaction equation
[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31](I)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][NH:36][N:35]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([C:38]6[C:34]([CH3:33])=[N:35][NH:36][CH:37]=6)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1

Participants

6

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 67425529HCID 67425529, compoundHCID 178434487HCID 178434487, compound

Product 1

HCID 178434520HCID 178434520, compoundYield 11.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (4-hydroxy-piperidin-1-yl)-{4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl-amino]-cyclohexyl}-methanone (274 mg) and 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (9 mL, degassed) and EtOH (0.7 mL) was bubbled with argon in a screw cap pressure flask for 10 min. To this was added Pd(PPh3)4 (18 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was allowed to cool to RT, then additional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) were added, the flask sealed, and heated again at 110° C. for 6 h. An additional portion of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Pd(PPh3)4 (20 mg) was added, and the mixture stirred at 110° C. overnight. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a crude solid (311 mg). The crude product (52 mg) was chromatographed on silica, and eluted with 0-60% Magic Base/DCM, titurated in Et2O overnight, filtered, and dried to yield (4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 11, 28 mg). mp=190-195° C.; M+H=502.

Workup

  1. customwas bubbled with argon in a screw
  2. customcap pressure flask for 10 min
  3. additionTo this was added Pd(PPh3)4 (18 mg)
  4. customthe flask sealed
  5. temperatureto cool to RT
  6. additionadditional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) were added
  7. customthe flask sealed
  8. temperatureheated again at 110° C. for 6 h
  9. additionAn additional portion of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Pd(PPh3)4 (20 mg) was added
  10. stirringthe mixture stirred at 110° C. overnight
  11. temperatureThe reaction mixture was then cooled to RT
  12. additiondiluted in water
  13. extractionextracted in DCM
  14. washwashed with water and brine
  15. dry with materialdried over Na2SO4
  16. customto yield a crude solid (311 mg)
  17. customThe crude product (52 mg) was chromatographed on silica
  18. washeluted with 0-60% Magic Base/DCM
  19. waittiturated in Et2O overnight
  20. filtrationfiltered
  21. customdried

Sources & evidence

ORD record
ord-489a7e8eb4814e8fafefbe2836abde84
Source dataset
uspto-grants-2012_07
Patent number
US08227478B2

Reaction notes

Loading…