Cesium carbonate → HCID 68568769, compound

HRID 1435127Notes

Reaction equation

HRID 1435127 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH3:25])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:13][C:14]2[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH3:25])[CH:15]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 509994811-Bromo-4-chloro-5-fluoro-2-nitrobenzeneHCID 57848967HCID 57848967, compound2×

Product 1

HCID 68568769HCID 68568769, compoundYield 64%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 1-bromo-4-chloro-5-fluoro-2-nitrobenzene (6.0 g, from a different batch prepared analogous to Example 67, Step A, 23.0 mmol) and methyl 5-amino-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 30, 11.0 g, 35.0 mmol) in toluene (70 mL) was added tris(dibenzylideneacetone)dipalladium (0) chloroform complex (595 mg, 0.58 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xantphos (665 mg, 1.20 mmol) and Cs2CO3 (22.5 g, 69.0 mmol)) with vigorous stirring. The reaction flask was sealed and carefully evacuated and refilled with N2 three times and the reaction mixture was stirred at 60° C. for 15 h. The reaction mixture was filtered through a pad of silica gel washing with copious amounts of 20% EtOAc in hexanes. The volatiles were evaporated under reduced pressure to give methyl 5-[(4-chloro-5-fluoro-2-nitrophenyl)amino]-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate 7.24 g (64%). This intermediate was dissolved in acetic acid (25 mL) and added via an addition funnel to a solution of iron power (4.0 g, 75 mmol) and acetic acid (20 mL) at 55° C. with vigorous stirring. The reaction mixture was then cooled to rt, diluted with EtOAc and filtered through celite and the resulting filtrate was neutralized with 6N MaOH solution and saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried over Na2SO4 and the volatiles were evaporated under reduced pressure to give methyl 5-[(2-amino-4-chloro-5-fluorophenyl)amino]-3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-2-thiophenecarboxylate. To this material was added trimethylorthoformate (150 mL) and formic acid (10 mL) and the resulting reaction mixture was stirred at 40° C. for 1 h. Silica gel was added and the volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography (0 to 15% EtOAc:hexane) to afford 4.7 g (67%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.58-7.83 (m, 2H), 7.38-7.50 (m, 2H), 7.44 (s, 1H), 7.25-7.37 (m, 1H), 5.99 (q, J=8.2 Hz, 1H), 3.82 (s, 3H), 1.62 (d, J=6.2 Hz, 3H), MS (ESI): 467 [M+H]+.

Workup

  1. customThe reaction flask was sealed
  2. customcarefully evacuated
  3. additionrefilled with N2 three times
  4. filtrationThe reaction mixture was filtered through a pad of silica gel washing with copious amounts of 20% EtOAc in hexanes
  5. customThe volatiles were evaporated under reduced pressure

Sources & evidence

ORD record
ord-7ac7dda26ccb4da2bc5d77eadb173a27
Source dataset
uspto-grants-2009_11
Patent number
US07615643B2

Reaction notes

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