1,2-Dimethoxyethane → Sonidegib

HRID 1022832Notes

Reaction equation

HRID 1022832 reaction equation
[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:17]=[C:18]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH2:33][CH:32]([CH3:34])[O:31][CH:30]([CH3:35])[CH2:29]2)=[CH:26][CH:27]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.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>[CH3:34][C@H:32]1[CH2:33][N:28]([C:25]2[N:24]=[CH:23][C:22]([NH:21][C:19]([C:18]3[C:17]([CH3:16])=[C:39]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=4)[CH:38]=[CH:37][CH:36]=3)=[O:20])=[CH:27][CH:26]=2)[CH2:29][C@@H:30]([CH3:35])[O:31]1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 27343864-(Trifluoromethoxy)phenylboronic acidHCID 66898722HCID 66898722, compound

Product 1

HCID 24775005SonidegibYield 61.1%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
130 °C

Procedure

A mixture of 4-(trifluoromethoxy)phenylboronic acid (254 mg, 1.24 mmol), 3-bromo-N-[6-(2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-4-methyl-benzamide 5 (250 mg, 0.62 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), Na2CO3 (2.0M aqueous solution, 1.23 mL, 2.4 mmol) and DME (4.5 mL) in a sealed tube was heated at 130° C. overnight. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative mass triggered HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4′-(trifluoromethoxy)biphenyl-3-carboxamide (183.5 mg, 61.1% yield). LC-MS m/z: 486.2 (M+1).

Workup

  1. extractionThe aqueous layer was extracted with EtOAc
  2. washThe combined organic layer was washed with brine
  3. concentrationconcentrated
  4. customto give the crude product which
  5. customwas then purified by preparative mass
  6. washHPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA)

Sources & evidence

ORD record
ord-2640c321e51b41f48e6d1d76015374b0
Source dataset
uspto-grants-2014_05
Patent number
US08722672B2

Reaction notes

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