3-OXO-CYCLOBUTANECARBONITRILE

Step 1. 3-Oxocyclobutane-l-carbonitrile. Sodium periodate (9.2 g, 42.96 mmol) was added to a mixture of 3-methylenecyclobutane-l-carbonitrile (1.0 g, 10.74 mmol), ruthenium (III) chloride hydrate (50 mg, 0.24 mmol) CHExample 277A 3 -oxocyclobutanecarbonitrile [1266] A mixture of 3-methylenecyclobutanecarbonitrile (9.39 g, 101 mmol), dichloromethane (200 mL), water (300 mL), acetonitrile (200 mL), and ruthenium(III) chloride hydrate (0.500 g, 2.218 mmol) was cooled to <5 °C, followed by portionwise addition of sodium periodate (88 g, 413 mmol) at <20 °C, and stirred for 10 minutes. The mixture was diluted with dichloromethane and partitioned. The organic phase was filtered through a silica pad, dried ( aExample 125A Example 133A To a solution of 3-methylene cyclobutanecarbonitrile (60a) (5 g, 54.3 mmol) in water (60 mL) and 1, 4-dioxane (150 mL) was added 0.2 M Os0Sodium periodate (43.0 mmol, 9.20 g) was added portion-wise to a solution of 3- methylenecyclobutanecarbonitrile (21.5 mmol, 2.00 g) and ruthenium trichloride (0.47 mmol, 98 mg) in (0880) dichloromethane : acetonitrile : water (1:1:1.5; 175 mL) . The resulting suspension was vigorously stirred (0881) overnight. The organic phase was separated then the aqueous phase was further extracted with dichloromethane (3 x 50 mL) . The combined organic extracts were dried (MgSOi) then passed through a silica plug. The solvents were removed under reduced pressure to give the title compound as a dark solid (1.58 g, 74percent).Compound 10-1 (10g, 0.108mol) was dissolved in a mixed solvent of 50mL of MeOH and 50mL of DCM. To the reaction system was blown Ointo a 500-mL 3-necked round-bottomflask, was placed a solution of 3-methylidenecyclobutane-1-carbonitrile (1.5 g, 16.11 mmol, 1.00 eq.) and RuC13.H20 (360 mg, 1.60 mmol, 0.10 eq.) in DCMIACN/H20 (60/60/90 mL). This was followed by the addition of sodium periodate (5.2 g, 24.31 mmol, 1.50 eq.), in portions at 10°C in 15 mm. The resulting solution was stirred for 2 hours at 25 °C. The solids were filtered out. The resulting solution was extracted with dichloromethane (3x100 mL) andthe organic layers combined. The resulting mixture was washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.1 g (72percent) of 3- oxocyclobutane-1-carbonitrile as a yellow solid.Step 1 : oxocyclobutane-l-carbonitrile: into a 500-mL 3-necked round-bottom flask, was placed a solution of 3-methylidenecyclobutane-l-carbonitrile (1.5 g, 16.1 1 mmol, 1.00 eq.) and RuClinto a 500-mL 3-necked round-bottom flask, was placed a solution of 3-methylidenecyclobutane-l-carbonitrile (1.5 g, 16.11 mmol, 1.00 eq.) and RuClinto a 500-mL 3-necked round-bottom flask, was placed a solution of 3-methylidenecyclobutane-l-carbonitrile (1.5 g, 16.11 mmol, 1.00 eq.) and RuClA mixture of S-methylenecyclobutanecarbonitrile (10.0 g, 0.1074 mol), and 0.2 M of osmium tetroxide in water (2 mL) in water (100 mL) and 1, 4-dioxane (300 mL), was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (48.2 g, 0.225 mol) was added in portions over a period of 30 min. The mixture was stirred for an additional 1.5 h. The mixture was extracted with EtOAc and combined organic layers were dried over MgSOA mixture of water (40 mL, 2 mol) and 1, 4-dioxane (100 mL, 1 mol), 3-methylenecyclobutanecarbonitrile (3.30 g, 0.0354 mol) (commercially available from Bepharma Ltd., China), and 0.2 M of osmium tetraoxide in water (0.7 mL) was stirred for 5 min, during which time the mixture became brown. (a) Example 58A To a solution of compound 21-1 (5 g, 62 mmol) and RuC (0.25 g, 1.4 mmol) in CHStep 1 (0730) To a solution of compound 21-1 (5 g, 62 mmol) and RuClDiethylaminosulfur trifluoride (32.10 mmol, 4.24 mL) was added drop-wise to a solution of 3- oxocyclobutanecarbonitrile (16.00 mmol, 1.52 g) in dichloromethane (50 mL) under N2 over 5 minutes. The mixture was allowed to warm to room temperature then stirred overnight. A further 2.12 mL of (0885) diethylaminosulfur trifluoride was added then the mixture was heated at reflux for 4 hours then allowed to cool to room temperature. The mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution with vigorous stirring. The organics were isolated by phase separator cartridge then concentrated under reduced pressure without external heating. The crude product was purified by column chromatography (silica gel, diethyl ether) to give the title compound as brown oil (1.72 g, 92%).3, 3-difluorocyclobutanecarbonitrile[1268] Example 125 A (8.21 g, 86 mmol) in dichloromethane (135 mL) was stirred at room temperature, cooled to <10 C, added DAST (1 1.41 mL, 86 mmol), warmed to room temperature, and stirred for 2 hours. The mixture was poured into saturated aqeuous NaHCC (200 mL) and partitioned. The aqueous phase was extracted with 2 x 50 mL dichloromethane. The combined organic phase was dried (Na2S04), filtered, and concentrated to give Example 125B (9.14 g, 78 mmol, 90 % yield) as a brown oil. XH NMR (400 MHz, CDC13) ' 3.06 - 2.91 (m, 5H).Example 125B 3, 3-difluorocyclobutanecarbonitrile Example 125A (8.21 g, 86 mmol) in dichloromethane (135 mL) was stirred at room temperature, cooled to <10 C., added DAST (11.41 mL, 86 mmol), warmed to room temperature, and stirred for 2 hours. The mixture was poured into saturated aqeuous NaHCO3 (200 mL) and partitioned. The aqueous phase was extracted with 2*50 mL dichloromethane. The combined organic phase was dried (Na2SO4), filtered, and concentrated to give Example 125B (9.14 g, 78 mmol, 90% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) delta 3.06-2.91 (m, 5H).Example 59A 3, 3-Difluorocyclobutanecarbonitrile Under argon, 14.57 g (153.2 mmol) of Example 37c 3, 3-Difluoro-cyclobutanecarbonitrile Neat DAST (94.9 g, 0.59 mol) was added drop wise to a solution of Compound 10-2 (8.0g, 84.21mmol) was dissolved in DCM (80mL) at 0C, added DAST (27g, 0.168mol). The reaction mixture was stirred overnight at room temperature, and the end of the reaction was monitored by TLC (petroleum ether/ethyl acetate = 3: 1). Ice water was added to the reaction solution, extracted with DCM, washed with saturated brine, and then dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 150: 1-30:1) to give the crude Compound 10-3 (8.1g) as a brown oil.After cooling a solution of 1.0 g (3.37 mmol) of the synthesized N-(4-(4-aminocyclohex-1-en-1-yl)-1H-pyrrolo[2, 3-b]pyridin-6-yl)cyclopropanecarboxamide), 1.0 g (3.37 mmol) of the synthesized N(4-(4-aminocyclohex- 1-en-i -yl)- 1 H-pyrrolo [2, 3-b jpyridin-6-yl)cyclopropanecarboxamide and 3-oxocyclobutane-i-carbonitrile were dissolved in THF solution, and then NaBH(OAc) and DIPEA were inserted thereinto and stirred at room temperature for a day. Once the reaction was completed, water was added thereto and an extraction using dichloromethane was performed. A solution extracted therefrom was dried by means of magnesium sulfate anhydrous and concentrated under reduced pressure, from which a residue was accordingly obtained. The residue was separated via silica gel column chromatography, and finally N(4-( 1 -(3-cyanocyclobutyl)- 1 , 2, 3, 6-tetrahydropyridin-4-yl)- 1H-pyrrolo[2, 3-bjpyridin-6- yl)cyclopropanecarboxamide was accordingly obtained.MS(ESI+) mlz 362 (M+H) +

Molecular Weight:95.10
XLogP3:-0.6
Hydrogen Bond Acceptor Count:2
Exact Mass:95.037113783
Monoisotopic Mass:95.037113783
Topological Polar Surface Area:40.9
Heavy Atom Count:7
Complexity:133
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes