oxetan-3-amine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was dissolved in a mixed liquid of pyridine (0.5 ml) and N-methylpyrrolidone (0.5 ml). A methanol solution (45%; 1.5 ml) of 3-aminooxetane was added to the resultant solution. The mixture was stirred at 70° C. for 18 hours. The reaction mixture was acidified with a 3% aqueous solution (20 ml) of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol. Ether (5 ml) was added to the residue to conduct filtration, thereby obtaining the title compound (48 mg) as a pale yellow powder. formed were collected by filtration The solids were subjected to azeotropic distillation with ethanol Ether (5 ml) was added to the residue filtration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 250 mL round-bottomed flask, 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (1.54 g, 4.92 mmol, Eq: 1.00) was combined with CH3 CN (60 ml) to give a light yellow solution. To this oxetan-3-amine (432 mg, 5.91 mmol, Eq: 1.20) and dropwise DIPEA (1.14 g, 1.55 ml, 8.86 mmol, Eq: 1.80) were added and the reaction mixture was stirred at room temperature for 24 hr. to give a light yellow solution

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid (189.8 mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0 mL) was added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2 drops). The reaction was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) and N,N-diisopropylethylamine (0.122 mL, 0.699 mmol). After stirring at room temperature for 16 hours, the reaction was quenched with methanol (2.0 mL), then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes) provided the title compound as a colorless oil. concentrated in vacuo The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL) After stirring at room temperature for 16 hours the reaction was quenched with methanol (2.0 mL) concentrated in vacuo Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid (189.8 mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0 mL) was added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2 drops). The reaction was stirred at room temperature for 3.5 hours, then concentrated in vacuo. The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) and N,N-diisopropylethylamine (0.122 mL, 0.699 mmol). After stirring at room temperature for 16 hours, the reaction was quenched with methanol (2.0 mL), then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes) provided the title compound as a colorless oil. concentrated in vacuo The sulfonyl chloride intermediate was dissolved in dichloromethane (5.0 mL) After stirring at room temperature for 16 hours the reaction was quenched with methanol (2.0 mL) concentrated in vacuo Purification of the residue by chromatography on silica gel (4 g SiO2, 0%-50% EtOAc in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-methyl (1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperidin-4-yl)carbamate (44 mg, 0.039 mmol) was dissolved in DMF (2.5 ml) and methanol (1 ml). oxetan-3-amine (20 μl, 0.039 mmol) and trimethyl orthoformate (0.25 ml, 2.262 mmol) were added. Acetic acid (0.05 ml, 0.873 mmol) was added drop wise until pH ˜5. The reaction mixture was stirred at room temperature for 10 minutes. sodium cyanoborohydride (21 mg, 0.334 mmol) was added and stirring at room temperature continued for 1 hour. Formaldehyde (50 μl, 0.672 mmol) and additional sodium cyanoborohydride (21 mg, 0.334 mmol) and acetic acid (0.05 ml, 0.873 mmol) were added and the mixture stirred at room temperature for 3 hours, then evaporated in a nitrogen stream overnight. The crude mixture of the 2 diastereomeric products was dissolved in DMSO, filtered and purified by prep HPLC with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10-mM ammonium acetate; Gradient: 50-90% B over 30 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.7 mg) (Example 750) and methyl ((3S,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-(methyl(oxetan-3-yl)amino)piperidin-4-yl)carbamate (1.9 mg) (Example 751) stirring at room temperature continued for 1 hour the mixture stirred at room temperature for 3 hours evaporated in a nitrogen stream overnight The crude mixture of the 2 diastereomeric products was dissolved in DMSO filtered purified by prep HPLC with the following conditions Gradient: 50-90% B over 30 minutes a 5-minute hold Fractions containing the desired product dried via centrifugal evaporation

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propyl)pyrimidine-4-carboxamide (347 mg, 1 mmol) in i-PrOH (5 mL) was added oxetan-3-amine (73.1 mg, 1 mmol) and DIPEA (129 mg, 1 mmol). The resulting mixture was stirred at 110° C. for 16 hours, at which time LCMS showed the completion of the reaction. After evaporation of the solvent, the residue was purified by preparative HPLC to give the target compound (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide (62.5 mg, yield: 16.3%). 1H NMR (400 MHz, MeOD-d4) δ 8.24 (s, 1H), 7.15-7.05 (m, 4H), 7.02-6.98 (m, 1H), 5.09 (s, 1H), 4.95 (t, J=6.8 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 4.10-4.03 (m, 1H), 3.72 (s, 2H), 3.56-3.46 (m, 2H), 2.96-2.91 (m, 2H), 2.87-2.80 (m, 2H), 2.65 (d, J=6.3 Hz, 2H). LCMS (m/z): 384.1 [M+H]+. the completion of the reaction After evaporation of the solvent the residue was purified by preparative HPLC

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 8-[1-(2-chloro-ethyl)-1H-pyrazol-4-yl]-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.416 mmol) and 3-oxetanamine (0.608 g, 2.08 mmol) in 5 mL of DMF was added potassium carbonate (0.287 g, 2.08 mmol) and potassium iodide (0.069 g, 0.416 mmol). The reaction mixture was heated at 50° C. for approximately 4 hours. The heated was increased to 70 C and the reaction was continued another 15 hours to give the desired product as determined by LCMS. The crude material was purified by RP-HPLC to cleanly give 461. MS: (ESI+)=518.3 The heated was increased to 70 C

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 335 mg (4.50 mmol) of oxetan-3-amine, and then the reaction mixture was stirred at 80 for 3 days. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 59.7 mg (55% of theory) The solvent was removed under reduced pressure the crude product was purified by means of preparative HPLC