Structure of 64747-71-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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| CAS No. : | 64747-71-3 |
| Formula : | C10H10F2O2 |
| M.W : | 200.18 |
| SMILES Code : | O=C(OCC)C1=CC=C(C(F)F)C=C1 |
| English Name : | Ethyl 4-(difluoromethyl)benzoate |
| MDL No. : | MFCD09996892 |
| InChI Key : | WISBDSSXPQJMIG-UHFFFAOYSA-N |
| Pubchem ID : | 21407902 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: water; potassium carbonate / methanol / 2 h / 25 °C / Inert atmosphere 2: potassium fluoride / N,N-dimethyl-formamide / 12 h / 170 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: potassium carbonate / 26 h / 20 °C 2: potassium fluoride / N,N-dimethyl-formamide / 12 h / 170 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: copper(l) iodide; potassium fluoride / dimethyl sulfoxide / 15 h / 60 °C / Inert atmosphere 2: water; potassium carbonate / methanol / 2 h / 25 °C / Inert atmosphere 3: potassium fluoride / N,N-dimethyl-formamide / 12 h / 170 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With potassium fluoride In N,N-dimethyl-formamide at 170℃; for 12h; Inert atmosphere; | 4 Preparation of aromatic difluoromethyl compound According to the above scheme, 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoic acid (Compound 4d; 73.3 mg, 0.3 mmol), potassium fluoride (87.2 mg, 1.5 mmol) DMF (1.2 mL) was added, and the mixture was stirred at 170 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 4-(difluoromethyl)benzoate (compound 5d) in a yield of 57% |
| With potassium fluoride In N,N-dimethyl-formamide at 170℃; for 12h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77 %Spectr. | Stage #1: Ethyl 4-bromobenzoate; 2,2-difluoro-1-phenylethanone With potassium phosphate monohydrate; C28H41ClNPPd In toluene at 100℃; for 30h; Sealed tube; Stage #2: With water; potassium hydroxide In toluene at 20℃; for 2h; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With styrene; bis-triphenylphosphine-palladium(II) chloride; iron(III)-acetylacetonate; potassium carbonate; hydroquinone; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 24h; Schlenk technique; Glovebox; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 61% | With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; copper(l) iodide at 60℃; for 24h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | Stage #1: 4-iodobenzoic acid ethyl ester With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: C8H18F4N2Zn In 1,4-dioxane at 120℃; for 6h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 76% | Stage #1: Ethyl 4-bromobenzoate With 1,1'-bis-(diphenylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 20℃; for 0.5h; Inert atmosphere; Stage #2: C8H18F4N2Zn In 1,4-dioxane at 120℃; for 6h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; hydroquinone; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 48h; Inert atmosphere; Sealed tube; | General procedure for palladium-catalysed difluoromethylation of ArB(OH)2 or Ar-Beg with ClCF2H. General procedure: To a 25 ml sealed tube were added anhydrous K2CO3 (powder, 4.0 equiv.), hydroquinone (2.0 equiv.), Pd2(dba)3 (2.5 mol%), Xantphos (7.5 mol%) and ArB(OH)2 (0.3 or 0.5 mmol) or Ar-Beg (0.3 or 0.5 mmol) under argon. A solution of ClCF2H in 1,4-dioxane (2.0 M, 1.5 ml for 0.3 mmol scale or 2.5 ml for 0.5 mmol scale, 10 equiv.) and fresh distilled 1,4-dioxane (1.0 ml for 0.3 mmol scale or 2.5 ml for 0.5 mmol scale) were added subsequently. The sealed tube was screw capped and heated to 110 °C (oil bath). After stirring for 48 h, the reaction was cooled to room temperature and fluorobenzene (1.0 equiv.) was added. The yield was determined by 19F NMR before working up. The reaction mixture was then diluted with ethyl acetate, filtered through a pad of Celite and concentrated. The residue was purified with silica gel chromatography to provide the desired product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 83% | With dmap; dibromobis(triphenylphosphine)nickel(II); potassium carbonate In tetrahydrofuran at 80℃; for 17h; Schlenk technique; Inert atmosphere; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 96% | Stage #1: 4-(difluoromethyl)benzoic acid With thionyl chloride for 0.5h; Reflux; Stage #2: ethanol for 1h; Reflux; | Intermediate 201 ethyl 4-(difluoromethyl)benzoate 4-(difluoromethyl)benzoic acid (5.00 g, 29.0 mmol) was suspended in thionyl chloride (15 ml, 210 mmol) and refluxed for 30 minutes. After cooling to ambient temperature the mixture was concentrated under reduced pressure. The remaining material was resolved in ethanol (50 ml, 860 mmol) and the mixture was refluxed for 1Hour. After cooling to ambient temperature, the mixture was concentrated under reduced pressure; the remaining residue was resolved in dichloromethane and washed with water (2x). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to yield 5.57 g (96%) of the desired product.1H-NMR (400 MHz, dimethylsulfoxide-d6) δ [ppm]: -0.014 (1.55), 1.316 (7.29), 1.334 (16.00), 1.345 (9.92), 1.352 (9.81), 1.363 (4.50), 3.334 (3.11), 4.316 (2.45), 4.333 (7.73), 4.345 (5.91), 4.351 (8.54), 4.362 (4.82), 4.369 (3.81), 4.380 (1.50), 6.999 (2.02), 7.009 (1.36), 7.138 (3.87), 7.148 (2.59), 7.277 (1.95), 7.287 (1.33), 7.714 (5.37), 7.732 (7.17), 8.076 (6.10), 8.094 (6.57), 8.106 (4.09). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 20 °C 2: isopropyl alcohol / 95 °C 3: sodium phenoxide; tris-(dibenzylideneacetone)dipalladium(0); Xantphos / 1,4-dioxane / 85 °C / Inert atmosphere; Sealed tube |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 20 °C 2: isopropyl alcohol / 95 °C 3: sodium phenoxide; tris-(dibenzylideneacetone)dipalladium(0); Xantphos / 1,4-dioxane / 1.5 h / 85 °C / Inert atmosphere; Sealed tube 4: tetrahydrofuran / 0 - 20 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 6 steps 1: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 20 °C 2: hydrazine hydrate / ethanol / 95 °C 3: acetic acid / 140 °C 4: caesium carbonate / N,N-dimethyl-formamide / 20 °C 5: hydrazine hydrate / ethanol / 90 °C 6: sodium phenoxide; tris-(dibenzylideneacetone)dipalladium(0); Xantphos / 1,4-dioxane / 1.5 h / 85 °C / Inert atmosphere; Sealed tube |

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