Toluene → ethyl 1-benzyloxymethyl-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate

HRID 2097523Notes

Reaction equation

HRID 2097523 reaction equation
[CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]1[CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]1([O:34][C:35]2[CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:39][C:40]=2[O:41][CH:42]([F:44])[F:43])[CH2:33][CH2:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.O>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:37]2[CH:38]=[CH:39][C:40]([O:41][CH:42]([F:44])[F:43])=[C:35]([O:34][CH:31]3[CH2:32][CH2:33]3)[CH:36]=2)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]1[CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 1140TolueneHCID 62657Potassium Phosphate, TribasicHCID 666028342-(3-Cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolaneHCID 86627046ethyl 1-benzyloxymethyl-5-bromo-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate

Product 1

HCID 86627031ethyl 1-benzyloxymethyl-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylateYield 99.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneCatalystHCID 962WaterSolvent2×

Conditions

Temperature
100 °C

Procedure

To 4.04 g (8.52 mmol) of ethyl 1-benzyloxymethyl-5-bromo-4-(2-fluorobenzyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 36-(e) were added 3.62 g (11.1 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a), 7.23 g (34.0 mmol) of potassium phosphate, 60 ml of toluene and 3.6 ml of water, the mixture was degassed under reduced pressure and replaced with argon. Further, 40 mg (0.178 mmol) of palladium acetate and 128 mg (0.356 mmol) of butyl-di-1-adamantylphosphine were added to the mixture, and the mixture was stirred at 100° C. for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=19:1→9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 5.01 g of the title compound as a yellowish oil substantially quantitatively.

Workup

  1. additionwas added to the reaction mixture
  2. extractionthe mixture was extracted with ethyl acetate
  3. customThe organic layer after separation
  4. washwas washed with a saturated aqueous solution of sodium chloride
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. additionthe fractions containing the desired compound
  8. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-9f855c3fbcef4427b3c94017582395ea
Source dataset
uspto-grants-2013_05
Patent number
US08450319B2

Reaction notes

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