4-Aminotetrahydropyran

To a stirred solution of compound 2.2 (1.0 g, 8.7 mmol) in methanol (50 mL) was added Raney Ni (10percent), and the resulting mixture was stirred at room temperature under hydrogen for 5 h. The progress of the reaction was monitored by TLC. Upon completion of reaction, the methanol solvent was filtered and concentrated in vacuo to give compound 2.3 (0.5 g, 57percent).A mixture of dihydro-2H-pyran-4(3H)-one (2.3 ml, 25 mmol) and methanol (54 ml) wastreated with ammonium formate (15.8 g, 250 mmol) and H20 (6 ml). The resulting mixture wasmaintained at RT with vigorous stirring until it became homogeneous. The mixture was then treatedwith palladium on carbon (2.5 g), and maintained at RT overnight. The mixture was filtered and10 concentrated to remove the volatile organics, then the aqueous later was exhaustively extracted withethyl acetate. The combined organics were dried (MgS04), filtered and concentrated to afford15tetrahydro-2H-pyran-4-amine (2.2 g, 88percent) as an oil: 1H NMR (400 MHz, MeOD-d4) 8 3.89-3.99 (m, 2H), 3.35-3.51 (m, 2 H), 2.81-2.95 (m, 1 H), 1.75- 1.90 (m, 2 H), 1.31- 1.48 (m, 2 H);General procedure: Ni-Al alloy (200 mg) and cyclohexanone (35 μL, 0.34 mmol) were suspended in 28–30percent NH(2) cooling the 4-formamide tetrahydropyran mixed solution prepared in the step 1 to a temperature of 5 ° C, adding a NaOH solution, After stirring uniformly, NaBrO solution was added dropwise thereto. After the completion of the dropwise addition, the reaction was continued at this temperature for 2 hours, and then the temperature was raised to 50 ° C for 1 hour, then cooled to room temperature, extracted with dichloromethane, and the organic phase was combined. After dichloromethane was removed by pressure distillation, recrystallization was carried out to obtain 4-aminotetrahydropyran.Preferably, the molar volume ratio of tetrahydropyran-4-carboxylic acid to water in the step (1) is 5 mol/L.The concentration of ammonia water in the step (1) is 13 mol/L; the amount of tetrahydropyran-4-carboxylic acid and ammonia in the step (1)The molar volume ratio is 10:1 mol/L.The mass concentration of the NaOH solution in the step (2) is 40percent, the 4-formamide tetrahydropyran mixed solution and the NaOH solutionThe volume-to-volume ratio was 7:1; the mass concentration of the NaBrO solution in the step (2) was 15percent.The molar ratio of tetrahydropyran-4-carboxylic acid to NaBrO was 1:1.5.The obtained 4-aminotetrahydropyran had a purity of 99.2percent and a product yield of 91.8percent.Three-neck flask equipped with mechanical stirrer, thermometer, dropping funnel, 250ml of water was added to the flask, stirring was added 4-cyano-tetrahydropyran 111.14g (1mole), cooled to 0 ~ 5 ° C, was added at a concentration of 10 minutes 13.8percent sodium hydroxide solution, a total of 290 g (1 mole), temperature controlled at 0 ~ 10 ° C, after each addition incubated for 15 to 20 minutes, all the alkali was added, stirred for 1 to 3 hours, the reaction was complete by gas detecting material, controlling the temperature of 0 ~ 5 ° C, was slowly added to a concentration of 10percent sodium hypochlorite solution 1116.6g (1.5mole), plus Bi, 0 ~ 5 ° C for 1 hour, heated at reflux temperature for 2 hours to complete the reaction intermediate vapor detection, water cooling to 10 ~ 40 ° C, with 500ml dichloromethane and 50ml methanol solvent mixture and extracted 3 times, the combined extracts were recovered by distillation of methylene chloride, methylene chloride was distilled off to make, distillation to give 4-amino-tetrahydropyran 75.3 g, with a purity of 99.1percent, a yield of 73.7percent.A mixture of the amine (Step A) (13.2 g, 49.4 mmol), 4 N HCl/dioxane (12.5 ML, 49.4 mmol), Pd/C 10percent (1. 1 g), dioxane (30 mL), and ETOH (120 mL) was placed on a Parr Apparatus and hydrogenated at 35 lb pressure of H2 overnight. The reaction mixture was filtered through celite and concentrated to dryness. The concentrate was stirred in DCM. The precipitate was filtered and dried to yield Intermediate 3 (4. 9 G, 72.2percent). 1H NMR (400MHZ, CD30D) 8 3.99 (dd, J=12.1 Hz, 5.1 Hz, 2H), 1.89 (td, J=11. 9 Hz, 2.1 Hz, 2H), 3.38-3. 32 (m, 1H), 1.96-1. 92 (m, 2H), 1.70-1. 59 (m, 2H).A mixture of the amine (Step A, Intermediate 3) (13.2 g, 49.4 mmol), 4N HCl/dioxane (12.5 mL, 49.4 mmol), Pd/C 10percent (1.1 g), dioxane (30 mL), and EtOH (120 mL) was placed under par-shaker and shook at 35 Lb pressure overnight. The reaction mixture was filtered through celite and concentrated to dryness. The concentrate was stirred in DCM. The precipitate was filtered and dried to yield Intermediate 3 (4.91g, 72.2percent). 1H NMR (400MHz, CD30D) 5 3.99 (dd, J=12. 1 Hz, 5.1 Hz, 2H), 1.89 (td, J=11. 9 Hz, 2.1 Hz, 2H), 3.38-3. 32 (m, 1H), 1.96-1. 92 (m, 2H), 1.70-1. 59 (m, 2H).To a flask having an inner volume of 30 ml, made of glass and equipped with a stirring device, a thermometer and a reflux condenser were charged 260 mg (2.08 mmol) of 4-hydrazinotetrahydropyran with a purity of 93percent synthesised in the same manner as in the above-mentioned (1), 92 mg of developed Raney nickel and 2.5 ml of ethanol, and the mixture was reacted at 75°C for 6 hours under hydrogen atmosphere. EXAMPLE 21

Molecular Weight:101.15
XLogP3:-0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:101.084063974
Monoisotopic Mass:101.084063974
Topological Polar Surface Area:35.2
Heavy Atom Count:7
Complexity:50
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes