* 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.
With diethylamino-sulfur trifluoride In dichloromethane for 15 h;
To a solution of 1, 1-dimethylethyl (4-oxocyclohexyl) carbamate (1 g, 4.69 MMOL, 1 equiv) in CH2CI2 (15 ml) was added DAST (1.05 MI, 7.98 mmol, 1.7 equiv) and the resulting mixture was stirred for 15 h. A saturated aqueous NAHC03 solution was added and the resulting biphasic mixture was stirred vigorously for 1 h. The two layers were separated and the aqueous phase extracted with CH2CI2. The combined organic phase were dried over MGS04 and concentrated in vacuo to give 1, 1-dimethylethyl (4, 4-difluorocyclohexyl) carbamate (D277) (1.03 g, 93percent) as a beige solid which was used in the next step without further purification.
56%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at -5 - 20℃; Inert atmosphere Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; Stage #3: at 0 - 20℃;
To a solution of tert-butyl 4-oxocyclo- hexylcarbamate (2.13 g, 10 mmol) in dry DCM (25 mL) was added DAST (2.58 g, 16 mmol) dropwise at -5 °C under nitrogen protection. After addition, the reaction mixture was stirred at r.t overnight. The reaction mixture was poured into ice water slowly and extracted by DCM ( 3 x 100 mL). The combined organic layers were washed with 2 N aq. NaHC03 and brine, dried over anhydrous Na2SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography using petroleum ether / EtOAc (V: V, 5: 1) as eluent to afford a mixture of the title compound (-70percent) and the byproduct tert-butyl 4-fluorocyclohex-3-enylcarbamate (-30percent) as a light-yellow solid.
54.7%
Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Cooling with ice Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 5 - 20℃; Cooling with ice Stage #3: With sodium tetrahydroborate In methanol at 20℃; Cooling with ice
Step B: tert-butyl (4,4-difluorocyclohexyl)carbamateDiethylaminosulfur trifluoride (8.54 g, 52.981 mmol) was added dropwise to the methylene chloride containing tert-butyl 4-oxocyclohexylcarbamate (7.96 g, 37.323 mmol) while stirring in an ice salt bath. In a (200 mL) solution, slowly warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with saturated aqueous ammonium chloride under an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.Separation of tert-butyl (4,4-difluorocyclohexyl)carbamate by column chromatography (about 70percent)With tert-butyl 4-fluorocyclohexyl-3-enylcarboxylate (about 30percent).Under ice-cooling, m-CPBA (6.9 g, 40.0 mmol) was slowly added dropwise to the methylene chloride solution of the above mixture while keeping the system temperature below 5°C. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. Quench with saturated aqueous sodium thiosulfate under an ice bath and stir at room temperature for half an hour, extract three times with methylene chloride, wash the combined organic phases with brine, dry over sodium sulfate, filter, and concentrate in vacuo, directly without purification. Used for the next step.The above concentrated residue was dissolved in methanol, and sodium borohydride (630 mg, 16.662 mmol) was added in small portions in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was concentrated in vacuo, methanol, and quenched with water under an ice bath. The mixture was quenched with stirring at room temperature for half an hour. Ethyl acetate was extracted three times. The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo gave tert-butyl (4,4-difluorocyclohexyl)carbamate (4.8 g, 54.7percent yield).
43%
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; for 16 h;
To a solution of 1, 1-dimethylethyl (4-oxocyclohexyl) carbamate (3.56 g, 16.7 MMOL, 1 equiv) in CH2CI2 (50 mi) was added DAST (4.6 MI, 35.1 mmol, 2.1 equiv) and the resulting mixture was stirred at room temperature for 16 h. A saturated aqueous NAHC03 solution (20 mi) was added and the biphasic mixture was vigorously stirred at room temperature for 1 h. The layers were separated and the aqueous phase extracted with CH2CI2. The combined organic layers were dried over MGS04 and concentrated in vacuo. Trituration of the residue with hexane gave 1, 1-dimethylethyl (4,4- difluorocyclohexyl) carbamate (D52) (1.7 g, 43percent) as a white solid which was used in the next step without further purification.
With diethylamino-sulfur trifluoride In dichloromethane at -5 - 20℃; Inert atmosphere
Step C: Tert-butyl 4,4-difluorocyclohexylcarbamate. To a solution of /3 and brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography using petroleum ether / EtOAc (V:V, 5: 1) as eluent to afford a mixture of the title compound (-70percent) and the byproduct tert-butyl 4-fluorocyclohex-3-enylcarbamate (-30percent) as a light-yellow solid.
With diethylamino-sulfur trifluoride In dichloromethane at 20℃; Cooling with ice
Step B: tert-butyl (4,4-difluorocyclohexyl)carbamateDiethylaminosulfur trifluoride (8.54 g, 52.981 mmol) was added dropwise to the methylene chloride containing tert-butyl 4-oxocyclohexylcarbamate (7.96 g, 37.323 mmol) while stirring in an ice salt bath. In a (200 mL) solution, slowly warm to room temperature and stir the reaction mixture overnight. The mixture was carefully quenched with saturated aqueous ammonium chloride under an ice bath and extracted three times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.Separation of tert-butyl (4,4-difluorocyclohexyl)carbamate by column chromatography (about 70percent)With tert-butyl 4-fluorocyclohexyl-3-enylcarboxylate (about 30percent).Under ice-cooling, m-CPBA (6.9 g, 40.0 mmol) was slowly added dropwise to the methylene chloride solution of the above mixture while keeping the system temperature below 5°C. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred overnight. Quench with saturated aqueous sodium thiosulfate under an ice bath and stir at room temperature for half an hour, extract three times with methylene chloride, wash the combined organic phases with brine, dry over sodium sulfate, filter, and concentrate in vacuo, directly without purification. Used for the next step.The above concentrated residue was dissolved in methanol, and sodium borohydride (630 mg, 16.662 mmol) was added in small portions in an ice bath. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was concentrated in vacuo, methanol, and quenched with water under an ice bath. The mixture was quenched with stirring at room temperature for half an hour. Ethyl acetate was extracted three times. The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo gave tert-butyl (4,4-difluorocyclohexyl)carbamate (4.8 g, 54.7percent yield).
Reference：
[1] Patent: TW2017/36341, 2017, A, . Location in patent: Paragraph 0489; 0492; 0493
Preparation 30; 4,4-difluoro-cyclohexylamine; Allow the solution of (4,4-difluoro-cyclohexyl)-carbamic acid tert-butyl ester in 20 mL of TFA to stand at room temp for overnight. Concentrate the mixture under vacuum. Pass the residue through a SCX column to yield 251 mg of the title product: mass spectrum (m/z): 136 (M+l).
With hydrogenchloride; In methanol;
Step D: 4,4-Difluorocyclohexanamine hydrochloride A mixture of tert-butyl 4,4-difluorocyclo-hexylcarbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product which was directly used in next step without further purification. 1H NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+1)+.
With hydrogenchloride; In methanol; at 20℃; for 2h;
Step D: 4,4-Difluorocyclohexanamine hydrochloride. A mixture of fe/ -butyl 4,4-difluorocyclo- hexylcarbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product which was directly used in next step without further purification. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+l)+.
With hydrogenchloride; In methanol; at 20℃; for 2h;
A mixture of tert-butyl 4,4-difluoro- cyclohexylcarbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at r.t. for 2 hr. The solvent was concentrated to give the crude product which was directly used in next step without further purification. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+l)+.
With hydrogenchloride;
Step D: 4,4-Difluorocyclohexanamine hydrochloride A mixture of tert-butyl 4,4-difluorocyclo-hexylcarbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product which was directly used in next step without further purification. 1H NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+1)+.
With hydrogenchloride; In methanol; at 20℃; for 2h;
A mixture of tert-butyl 4,4-difluorocyclo-hexylcarbamate (6.0 g, 25.5 mmol) and 6N HC1/MeOH (60 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product which was directly used in next step without further purification.?H NMR (400 IVIHz, CD3OD): 4.89 (s, 211), 3.32-3.26 (m, 111), 2.14-2.01 (m, 411), 2.02-1.85 (m, 211), 1.74-1.65 (m, 211). MS: 136.1 (M+1).
With hydrogenchloride; In methanol; at 20℃; for 2h;
Step D: 4,4-Difluorocyclohexanamine hydrochloride. A mixture of iert-butyl4,4-difluorocyclo- hexyl carbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product which was directly used in next step without further purification. NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). M S: 136.1 (M + l)+.
With hydrogenchloride;
Step D: 4,4-Difluorocyclohexanamine hydrochloride A mixture of tert-butyl 4,4-difluorocyclohexylcarbamate (6.0 g, 25.5 mmol) and 6 N HCl/MeOH (60 mL) was stirred at r.t. for 2 hr. The solvent was concentrated to give the crude product which was directly used in next step without further purification. 1H NMR (400 MHz, CD3OD): delta 4.89 (s, 2H), 3.32-3.26 (m, 1H), 2.14-2.01 (m, 4H), 2.02-1.85 (m, 2H), 1.74-1.65 (m, 2H). MS: 136.1 (M+1)+.
With hydrogenchloride; In methanol; at 20℃; for 2h;
A mixture of tert-butyl (4,4-difluorocyclohexyl)carbamate (1.4 g, 5.950 mmol) and 6N HCl/MeOH (14 mL) was stirred at room temperature for 2 hours.Concentration in vacuo gave 4,4-difluorocyclohexylamine hydrochloride (1.02 g, yield 100%) which was directly used for next step without purification.
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 3h;
A solution of hydrogen chloride in dioxane (4M, 1. [6ML)] was added at [20C] to a stirred solution of Intermediate 62 (140mg, 0.6mmol), in dioxane (1. [6ML).] After 3h, the reaction mixture was concentrated in vacuo to afford intermediate 63 (96. [5MG)] containing 4- [JLUORO-3-CYCLOHEXEN-1-AMINE. LH] NMR [(400MHZ] in d6-DMSO, [27C,] bppm) Minor component: [68.] 22 (br, 3H excess), 5.18 (dm, [16HZ,] 1H), 3.28-3. 13 (m, 1H excess), 2.41- 1.53 (m's, 6H excess). Major component: [58.] 22 (br, 3H excess), 3.28-3. 13 (m, 1H excess), 2.41-1. 53 (m's, 8H excess). Impurities are also present.
With thionyl chloride In methanol at 20℃; for 0.5h;
4.A Example 4 5,6-bis(4-chlorophenvl)-A^-('4,4-difluorocvclohexvl)pvrazme-2-carboxamide; Step A (4,4-difluorocyclohexyl)amine
To a solution of ./V-4-Boc-cyclohexanone (600 mg, 2.81 mmol) in DCM (3ml) at 0 °C wasadded DAST (455 mg, 2.81 mmol) dropwise. After 70 minutes the temperature wasincreased to room temperature and after 3 hours to reflux for 5 minutes. The solvent was removed in vacuo and the product was purified with a flash column (silica gel, toluene, 100% to EtOAc, 100%). The suspension of the Boc-protected material in methanol (5ml) ws treated with a solution of thionyl chloride (2 ml, 27.57 mmol) in methanol (20ml) dropwise. The reaction was continued at room temperature for 30 minutes. The solvent was evaporated in vacuo. The crude material was retaken in pyridine (5ml) and treated with a solution of benzylchloroformate (532 mg, 3.12 mmol) in 1 ml DCM. The mixture was stirred for 58 hours. It was washed with HC1 (aq) and KiCOs (aq). The Z-protected compound was purified by flash chromatography (SiOa, toluene), 212 mg (28%). The Z-group was removed by stirring under Ha atmosphere in THF (10 ml) with palladium on activated carbon (40 mg, 10wt% Pd) for 4h. It was filtered through Celite 521 and evaporated in vacuo to give a crude material.
With trifluoroacetic acid In dichloromethane at 20℃; for 2h;
2
A solution of N-(4,4-difluorocyclohexyl)(t-butoxy) carboxamide (6.51 mmol) in CH2Cl2 (20 mL) was treated with TFA (10 mL) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed with chloroform. The acidic aqueous phase was cooled at 0°C and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2Cl2, dried, and filtered yielding the title compound which was used without further purification as a 0.3 M solution in CH2Cl2
With potassium hydroxide; trifluoroacetic acid In dichloromethane; water
2 Step 2.
Step 2. Synthesis of 4,4-difluorocyclohexylamine A solution of N-(4,4-difluorocyclohexyl)(t-butoxy)carboxamide (6.51 mmol) in CH2Cl2 (20 mL) was treated with TFA (10 mL) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed with chloroform. The acidic aqueous phase was cooled at 0° C. and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2Cl2, dried, and filtered yielding the title compound which was used without further purification as a 0.3 M solution in CH2Cl2.
With hydrogenchloride In ethyl acetate at 20℃; for 1h;
049.1 Step 1. Synthesis of Compound WX049-2
WX049-1 (4 g, 17.00 mmol, 1 eq) was dissolved in ethyl acetate (30 mL), and hydrochloric acid/ethyl acetate (4M, 21.25 mL, 5 eq) was added. The system was stirred at 20° C. for 1 hour. The reaction solution was allowed to stand and filtered, and the filter cake was dried to give WX049-2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.68 (m, 2H) 1.83-2.12 (m, 6H) 3.18 (br d, J=4.77 Hz, 1H).
With triethylamine; In dichloromethane; at 20 - 50℃; for 5h;
Stage 1: tert-Butoxy-(4,4-difluorocyclohexylamino)-methanol: 2.5 g of <strong>[675112-70-6]4,4-difluorocyclohexylamine hydrochloride</strong> in the presence of 3.2 g of (t-BuOCO)2O and 2.5 ml of triethylamine in 50 ml of dichloromethane. After one night at room temperature, the reaction medium is left at 50 C. for 5 hours. The medium is evaporated to dryness and then extracted with ethyl acetate. The organic phase is washed with a saturated NaCl solution and then dried over sodium sulfate. 3.3 g of expected product are obtained after chromatography (dichloromethane as a gradient up to 1% methanol) on silica.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
