Toluene → (4-Hydroxy-piperidin-1-yl)-{4-[4-(4-pyridin-4-yl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanone

HRID 1516446Notes

Reaction equation

HRID 1516446 reaction equation
Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)[N:12]=1.C[C:34]1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)[O:35]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>O.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.CCO>[NH4+:6].[OH-:25].[CH3:34][OH:35].[OH:32][CH:29]1[CH2:30][CH2:31][N:26]([C:24]([CH:21]2[CH2:20][CH2:19][CH:18]([NH:17][C:13]3[N:12]=[C:11]([N:6]4[C:7]5[C:3](=[C:2]([C:41]6[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=6)[CH:10]=[CH:9][CH:8]=5)[CH:4]=[CH:5]4)[CH:16]=[CH:15][N:14]=3)[CH2:23][CH2:22]2)=[O:25])[CH2:27][CH2:28]1

Participants

9

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 27346484-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 67426733{4-[4-(4-Bromo-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-(4-hydroxy-piperidin-1-yl)-methanone

Product 2

HCID 21894508Ammonium hydroxide methanolYield 1%HCID 46834350(4-Hydroxy-piperidin-1-yl)-{4-[4-(4-pyridin-4-yl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanoneYield 74.9%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of {4-[4-(4-bromo-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-(4-hydroxy-piperidin-1-yl)-methanone (0.3 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-pyridine (0.135 g) and Na2CO3 (2 M aq, 0.9 mL, degassed), toluene (12 mL, degassed) and EtOH (3 mL) was added to a screw cap pressure flask. To this was added Pd(PPh3)4 (0.02 g), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield an oil. The oil was flash chromatographed on silica, eluting with DCM:1% NH4OH-MeOH (1000:50) to provide (4-hydroxy-piperidin-1-yl)-{4-[4-(4-pyridin-4-yl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanone (Compound 16, 0.112 g, 30%) as a white powder. Mp=258-259° C.; M+H=497.

Workup

  1. additionwas added to a screw
  2. customcap pressure flask
  3. customthe flask sealed
  4. extractionextracted in DCM
  5. washwashed with water and brine
  6. dry with materialdried over Na2SO4
  7. customto yield an oil
  8. customchromatographed on silica
  9. washeluting with DCM

Sources & evidence

ORD record
ord-4d3728214a31429e9134d692ffbee617
Source dataset
uspto-grants-2012_07
Patent number
US08227478B2

Reaction notes

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