Cesium carbonate → [4-Difluoromethoxy-2-ethyl-8-fluoro-3-(4-pyrimidin-2-yl-benzyl)quinolin-5-yloxy]acetic acid

HRID 1922089Notes

Reaction equation

HRID 1922089 reaction equation
C[O:2][C:3](=[O:39])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.Br[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:38][CH:36]([F:37])[O:35][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:39])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:41]2[N:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[CH:24][CH:25]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 783452-BromopyrimidineHCID 67458783{4-Difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester

Product 1

HCID 25096075[4-Difluoromethoxy-2-ethyl-8-fluoro-3-(4-pyrimidin-2-yl-benzyl)quinolin-5-yloxy]acetic acidYield 23.7%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.10 g), 2-bromopyrimidine (0.076 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.016 g), 1,4-dioxane (2.0 mL) and 2.0 M aqueous cesium carbonate solution (0.38 mL) was heated by microwave irradiation at 90 to 130° C. for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and then filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.38 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 0.1 M aqueous hydrochloric acid solution and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.021 g).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. filtrationfiltered
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. dissolutionthe residue dissolved in tetrahydrofuran (5.0 mL)
  5. additionThe mixture was acidified by the addition of 0.1 M aqueous hydrochloric acid solution
  6. concentrationconcentrated under reduced pressure
  7. customPurification of the residue by preparative reverse-phase HPLC

Sources & evidence

ORD record
ord-fee6ad59a9f9497db09df21599f9b02c
Source dataset
uspto-grants-2012_05
Patent number
US08173812B2

Reaction notes

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