Structure of 195447-25-7
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CAS No. : | 195447-25-7 |
Formula : | C9H15F2NO2 |
M.W : | 207.22 |
SMILES Code : | O=C(N1CC(F)(F)CC1)OC(C)(C)C |
MDL No. : | MFCD06797010 |
InChI Key : | ULFWNKDACVUZOD-UHFFFAOYSA-N |
Pubchem ID : | 18542424 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
71% | With diethylamino-sulfur trifluoride; In benzene; at 0 - 20℃; for 72.0h; | 2) 3, 3-Difluoropyrrolidine-1-carboxylic acid tert-butyl ester Under a nitrogen atmosphere, (diethylamino)sulfur trifluoride (1.45 mL) was added to a solution of N-tert-butoxycarbonyl-3-pyrrolidinone (846 mg) in benzene (30 mL) under ice cooling, and the resultant mixture was stirred for 3 days at room temperature. Diethyl ether was added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel thin layer chromatography (ethyl acetate-hexane), to obtain 3, 3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (669 mg, 71%) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 1.45(9H, s), 2.26-2.36(2H, m), 3.57-3.65(4H, m). |
54.7% | With diethylamino-sulfur trifluoride; In toluene; at 0 - 20℃; for 23.0h; | [0357] Part B: To a solution of part A compound (1.8 g, 9.7 mmol) in 2 mL of toluene was added a solution of (diethylamino)sulfur trifluoride (1.3 mL, 9.7 mmol) at 0 C. The mixture was stirred at 0 C. for 1 h and at room temperature for 22 h. The resulting mixture was then poured onto ice and extracted with ethyl acetate (3×). The organic layer was washed with saturated sodium bicarbonate aqueous solution, brine and dried over magnesium sulfate. The crude product was purified over silica gel to afford 1.1 g (54.7%) of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate: 1H-NMR (CDCl3, δ) 3.62 (4H, m), 2.34 (2H, m), 1.48 (9H, s). |
41.92% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0℃; for 0.6h;Inert atmosphere; | To a stirred solution of tert-butyl 3-oxopyrrolidine-l-carboxylate (step 1, 3.44 g, 18.59 mmol) in DCM (40 ml) under N2atmosphere at 0 C, was added DAST (2.7 ml, 20.45 mmol) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of ice cold water. The solution was extracted with DCM (2x100 mL) and the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc and hexane (1 :9) to afford the desired compound (1.61 g, yield: 41.92%) as an oil. 1H MR (300 MHz, CDC13): δ 3.65-3.55 (m, 4H), 2.38-2.24 (m, 2H), 1.46 (s, 9H). |
41.92% | With diethylamino-sulfur trifluoride; In dichloromethane; at 0℃; for 6.0h;Inert atmosphere; | To a stirred solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (step 1, 3.44 g, 18.59 mmol) in DCM (40 ml) under N2 atmosphere at 0 C., was added DAST (2.7 ml, 20.45 mmol) and stirred for about 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of ice cold water. The solution was extracted with DCM (2*100 mL) and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc and hexane (1:9) to afford the desired compound (1.61 g, yield: 41.92%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.65-3.55 (m, 4H), 2.38-2.24 (m, 2H), 1.46 (s, 9H). |
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0 - 20℃; for 11.0h; | To a solution of 3-OXO-PYRROLIDINE-1-CARBOXYLIC acid ter-butyl ester (1G) in CH2CI2 (10ML) is added [bis (2-methoxyethyl) amino] sulfer trifluoride (2mL) at 0C, and stirred for 11 HR at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with Et20. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil. To a solution of the oil in ET20 (1 OmL) was added HCI in EtOAc (4N, 5mL) and stirred for 3hr at room temperature. The reaction mixture is concentrated in vacuo, and the residue is suspended in Et20. White precipitate in the Et20 is collected by filtration to to provide the title compound. | |
With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃; for 16.0h; | A mixture of Example 70B (6.35 g, 34.29 mmol) in 100 mL of dichloromethane was cooled to -50 C. followed by the addition of (diethylamino)sulfur trifluoride (1.6 eq., 9.94 mL). The mixture was slowly allowed to come to room temperature and stirred for 16 hours. Saturated aqueous NaHCO3 solution was added slowly, and the mixture extracted with methylene chloride (3*25 mL). The combined organic extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (10% ethyl acetate/hexane) to provide the titled product. MS (CI) m/z+208 [M+H]+. | |
With diethylamino-sulfur trifluoride; In dichloromethane; at -50 - 20℃; for 16.0h;Product distribution / selectivity; | As shown in Scheme 13, compounds of formula 25 when treated under oxidative conditions of oxalyl chloride in DMSO followed by the addition of triethylamine will provide the ketone of formula 26. The ketone of formula 26 when treated with DAST ((diethylamino)sulfur trifluoride) in dichloromethane will provide difluoro compounds of formula 27. The Boc group of compounds of formula 27 may be removed using trifluoroacetic acid in dichloromethane to provide compounds of formula 28. ; Example 70C 3,3-Difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of Example 70B (6.35 g, 34.29 mmol) in 100 mL of dichloromethane was cooled to -50 C. followed by the addition of (diethylamino)sulfur trifluoride (1.6 eq., 9.94 mL). The mixture was slowly allowed to come to room temperature and stirred for 16 hours. Saturated aqueous NaHCO3 solution was added slowly, and the mixture extracted with methylene chloride (3*25 mL). The combined organic extracts were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (10% ethyl acetate/hexane) to provide the titled product. MS (CI) m/z+208 [M+H]+. | |
With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 5.0h; | DAST (4.03 g, 67.6 mmol, 2.5 eq.) was added to a solution of tert-butyl 3- oxopyrrolidine-l-carboxylate (5 g, 27.0 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction was stirred for 5 hours at room temperature. The reaction mixture was poured into ice cold sat. NaHCCL solution (100 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude Boc-3,3-difluoropyrrolidine (5.9 g, quantitative yield), which was then treated with 6 N HC1 in dioxane to give 3,3-difluoropyrrolidine hydrochloride (4.1 g, quantitative yield). LC-MS m/z [M+H]+ calc’d for C4H8CIF2N, 110; found, 110. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 1.66667h; | [0358] Part C: To a solution of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate (0.868 g, 4.19 mmol) in 1.5 mL of 1,4-dioxane was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 11 mL, 44 mmol) at 0 C. The mixture was stirred at 0 C. for 40 min, at room temperature for 1 h and was then concentrated to afford 0.65 g (100%) of 3,3-difluoropyrrolidine hydrochloride: 1H-NMR (CD3OD) δ 3.54 (2H, t, J=11.9 Hz), 3.43 (2H, t, J=7.8 Hz), 2.40 (2H, m). |
100% | With hydrogenchloride; In 1,4-dioxane; for 2.0h; | To a stirred solution of <strong>[195447-25-7]tert-butyl 3,3-difluoropyrrolidine-1-carboxylate</strong> (step 2, 1.61 g, 7.77 mmol) in dioxane (15 ml), was added 6N HCl in dioxane (20 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (1.11 g, yield: 100%). Next reaction was carried out without any further purification. |
With hydrogenchloride; In 1,4-dioxane; for 0.2h; | To a stirred solution of tert-butyl 3,3-difluoropyrrolidine-l-carboxylate (step 2, 1.61 g, 7.77 mmol) in dioxane (15 ml), was added 6N HCl in dioxane (20 ml) and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the desired product (1.11 g, yield: 100%). Next reaction was carried out without any further purification. |
4.1 g | With hydrogenchloride; In water; | DAST (4.03 g, 67.6 mmol, 2.5 eq.) was added to a solution of tert-butyl 3- oxopyrrolidine-l-carboxylate (5 g, 27.0 mmol, 1.0 eq.) in dichloromethane (30 mL). The reaction was stirred for 5 hours at room temperature. The reaction mixture was poured into ice cold sat. NaHCCL solution (100 mL) and extracted with dichloromethane for three times. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude Boc-3,3-difluoropyrrolidine (5.9 g, quantitative yield), which was then treated with 6 N HC1 in dioxane to give 3,3-difluoropyrrolidine hydrochloride (4.1 g, quantitative yield). LC-MS m/z [M+H]+ calc’d for C4H8CIF2N, 110; found, 110. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In diethyl ether; ethyl acetate; at 20℃; for 3.0h; | To a solution of 3-OXO-PYRROLIDINE-1-CARBOXYLIC acid ter-butyl ester (1G) in CH2CI2 (10ML) is added [bis (2-methoxyethyl) amino] sulfer trifluoride (2mL) at 0C, and stirred for 11 HR at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with Et20. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil. To a solution of the oil in ET20 (1 OmL) was added HCI in EtOAc (4N, 5mL) and stirred for 3hr at room temperature. The reaction mixture is concentrated in vacuo, and the residue is suspended in Et20. White precipitate in the Et20 is collected by filtration to to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 3.0h; | Example 70C (1.315 g, 36.34 mmol) in a mixture of trifluoroacetic acid (4 mL) in methylene chloride (4 mL) was stirred at room temperature for 3 hours and concentrated under reduced pressure to provide the desired amine as the trifluoroacetate salt. MS (CD) m/z 108 [M+H]+. | |
In dichloromethane; at 20℃; for 3.0h;Product distribution / selectivity; | As shown in Scheme 13, compounds of formula 25 when treated under oxidative conditions of oxalyl chloride in DMSO followed by the addition of triethylamine will provide the ketone of formula 26. The ketone of formula 26 when treated with DAST ((diethylamino)sulfur trifluoride) in dichloromethane will provide difluoro compounds of formula 27. The Boc group of compounds of formula 27 may be removed using trifluoroacetic acid in dichloromethane to provide compounds of formula 28. ; Example 70D 3,3-Difluoro-pyrrolidine Example 70C (1.315 g, 36.34 mmol) in a mixture of trifluoroacetic acid (4 mL) in methylene chloride (4 mL) was stirred at room temperature for 3 hours and concentrated under reduced pressure to provide the desired amine as the trifluoroacetate salt. MS (CI) m/z 108 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.47 g (58%) | C. 3,3-Difluoro-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester A solution of the title compound of Step (B) (0.74 g; 4 mmol) in 1 ml of toluene was added to a solution of diethylaminosulfur trifluoride (0.53 ml; 4 mmol) in 1 ml of toluene at 0 C. After stirring 1 hr at 0 C., and 20 hr at room temperature, the reaction mixture was carefully poured onto ice. After the ice melted, the aqueous mixture was extracted with EtOAc (50 ml). The organic layer was washed with saturated NaHCO3 solution (50 ml) and brine (50 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 5*10 cm silica gel column using Hex:EtOAc, 9:1 as the mobile phase. The pure fractions were concentrated to afford 0.47 g (58%) of the title compound of this step as a light yellow liquid. 1 H NMR (CDCl3): δ 1.47 (s, 9H), 2.30 (m, 2H), 3.55 (m, 2H), 3.68 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In methanol; at 20℃; | Add 3,3-difluoropyrrolidine hydrochloride (3.52g, 24.50mmol) to a 100mL bottle and dissolve it in MeOH (51mL),Add K2CO3 (6.74g, 48.80mmol) under ice bath, stir evenly,Then slowly add di-tert-butyl dicarbonate (6.4mL, 28.00mmol) dropwise,Move to room temperature and react overnight. The insoluble matter was removed by filtration, diluted with water, extracted with EtOAc, combined the organic phases, washed with H2O and saturated NaCl solution, dried with anhydrous Na2SO4, concentrated under reduced pressure, and the concentrated solution was separated by silica gel column chromatography (eluent: PE/EtOAc( v/v)=1/10) to obtain a colorless transparent liquid (4.50g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | With ruthenium trichloride; sodium periodate; In water; ethyl acetate; at 20℃; for 24.0h;Cooling with ice; | Add <strong>[195447-25-7]tert-butyl 3,3-difluoropyrrolidine-1-carboxylate</strong> (3.80g, 18.3mmol) to a 250mL bottle, dissolve it in a mixed solvent of EtOAc (80mL) and H2O (80mL), and add ruthenium trichloride (0.23 g, 1.1 mmol), then slowly add sodium periodate (15 g, 70.130 mmol) in batches under ice bath, and stir the reaction at room temperature for 24 h. Dilute with H2O (80mL), extract with EtOAc, combine the organic phases, wash with saturated NaCl solution, add IPA (40mL), stir for 3h, dry with anhydrous Na2SO4, concentrate under reduced pressure, and separate the concentrate by silica gel column chromatography (eluent : PE/EtOAc (v/v)=1/8) to give a pale yellow oil (2.41 g, 59.4%). |
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