3,3-Difluorocyclobutanamine hydrochloride

3, 3-Difluoro-cyclobutylamine (hydrochloride). A mixture of (3, 3-Difluoro-cyclobutyl)- carbamic acid benzyl ester (1.47 g, 6.1 mmol) and 10percent Pd/C (1 g) in MeOH (20 ml) was stirred overnight under HPreparation 88 To a solution of 4.79 g (25.1 mmol, 97% purity) of ethyl 2-amino-4-methylthiophene-3-carboxylate in 144 ml of dichloromethane were added 8.13 g (50.2 mmol) of CDI and 14 ml (100 mmol) of triethylamine, and the mixture was stirred at RT for 3 days. Then 7.20 g (50.2 mmol) of General procedure: A mixture the tricycle and amine (1 - 10 equivalents) with or without an excess of base (1508) (triethylamine or DIPEA) was dissolved/suspended in either anhydrous DMF or acetonitrile. The reaction was then heated at ~70 C, 90 C, or 140 C for a period of 15 min to 1 hour in a sealed vial or under an atmosphere of N2. The reaction mixture was then cooled to room temperature and either (1) filtered and purified by reverse phase HPLC or (2) worked up and purified by reverse phase HPLC or normal phase column chromatography unless otherwise noted.To a mixture of To a solution of intermediate 481 (42 mg, 0.0900 mmol) in DCM (3 mL) triethylamine (0.038 mL, 0.270 mmol) was added followed by 3, 3-difluorocyclobutan-l-amine hydrochloride (19 mg, 0.135 mmol). The solution was stirred at room temperature for 20 minutes. Saturated aqueous NH4CI solution (5 mL) was added to the reaction. The organic layer was separated and dried (MgS04). The solvent was removed to give a solid. Purification by flash column chromatography eluting with 0 to 40% of EtOAc in heptane gradient gave the title compound as a white solid (33 mg, 100% pure. 68% yield): LCMS [M+H]+ 538, RT 1.96 minutes (Method 12).To a stirring solution of Intermediate 182 (50 mg, 0.1118 mmol) was dissolved in N, N-dimethylformamide (3 ml) and triethylamine (0.070 mL, 0.51 mmol) and A solution of (2R, 3R, 4R, 5R)-2-(acetoxymethyl)-5-(5, 7-dichloro-6-cyano-3H-imidazo[4, 5- b]pyri din-3 -yl)tetrahydrofuran-3, 4-diyl diacetate (110 mg, 0.23 mmol), 3, 3-difluoro (1585) cyclobutanamine hydrochloride (40.2 mg, 0.28 mmol) and triethylamine (70.9 mg, 0.7 mmol) in ethanol (6 mL) in a sealed tube was stirred at 50 C for 16 hours. Then 7 N ammonia in methanol (3 mL) was added and the mixture was stirred at 50 C for 3 days. After cooling to ambient temperature, solvent was removed under reduced pressure to give 5-chloro-7-((3, 3- difluorocyclobutyl)amino)-3-((2R, 3R, 4S, 5R)-3, 4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-3H-imidazo[4, 5-b]pyridine-6-carbonitrile (80 mg, 84% yield) which was used for next step directly.The solution of compound 1 (5.0 g, 0.0348 moles) and 7.5 mL of formic acid was slowly added trimethyl amine (5.30 g, 0.0521 moles), obtained solution was stirred at 60-65C for 1-2 hrs, the reaction progress was monitored by GC, then mass was cooled to 20-25C, product was partitioned with Ethyl acetate and water mixture, distilled off solvent completely under reduced pressure to produce compound 2 as a white solid, 3.10 g (65.95%), HPLC Purity: 98.45%.Compound 1 (100 gm, 0.6965 moles) was suspended in ethylformate 152 mL followed by addition of triethylamine (105.72 g, 1.0447 moles) the reaction mixture was refluxed for the 3- 4 hrs, added 150 mL toluene and distilled off solvent under vacuum at 50-55C till residue volume reached up to 200-250 mL, cool reaction mass to 20-25C, Charged MDC (700 mL) at 25-35C added tri ethyl amine (282 g, 2.7868 moles). The resulting solution was cooled to 0 to 5 C and added POCh(l39.0 gm, 0.9065 mole). Reaction mass was stirred until completion (Monitored by GC) at 5-l0C. After completion of reaction it was quenched by aqueous ammonia solution (200 mL 30% aqueous ammonia solution and 1100 mL water. Organic layer was distilled off and charged 2, 2, 2 trifluoroethanol (600 mL) and it was cooled to 0-10C and added compound 6 ((l-(2-chlorophenyl)-N-(5-fluoropyri din-3 -yl)methanimine) (131 g, 0.5582 mole)) and compound 7 (((S)-5-oxopyrrolidine-2-carboxylic acid) ( 81.0 g, 0.6273mole)) at 0- lOC and stirred for lh (monitored by HPLC) at 0-l0C and raised temperature to 20-25C then stirred for 4-5 hrs. After completion of reaction trifluoroethanol was distilled off under vacuum at 50-55C till residue volume reached up to 300-350 mL, and charged toluene and distilled off again. Charged 1000 mL Toluene at 40-45C, organic layer was washed with 1% diluted HC1, 5% sodium carbonate solution at 40-50C, then cooled to 20-25C and added piperidine in to it under stirring and reaction mass was heated to 70-80 0C. Cooled and filter the precipitated product and washed it with 1% Piperidine in toluene solution. Obtained solid was slurred in 0.5% HC1 in water (660ml X2) solution. Further solid was washed with 660ml of water twice. The product was dried under vacuum to afford solid. (Wt. 90-l05gm, HPLC purity > 99.0%, Chiral Purity: >99.9%)

3-Halo substituted cyclobutanamine used in the preparation of piperazinyl antiviral agents as well as kinase inhibitors.

Molecular Weight:143.56
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Exact Mass:143.0313333
Monoisotopic Mass:143.0313333
Topological Polar Surface Area:26
Heavy Atom Count:8
Complexity:73.8
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes