TETRAHYDRO-2H-PYRAN-4-CARBOXAMIDE

White solid

A mixture of methyl tetrahydro-2/-/-pyran-4-carboxylate (7 g , 48.6 mmol) and 30percent aqueous ammonia (20 mL) was stirred in a closed bottle at r.t. for 18 h. The ammonia excess was removed under reduced pressure and the residue was crystallized from ethanol affording 5.6 g (89percent) of tetrahydro-2/-/-pyran-4-carboxamide. Tetrahydro-2H-pyran-4-carboxamide A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7.0 g, 48.6 mmol) and concentrated ammonia (20 ml) was stirred at 22° C. for 18 h. The excess ammonia was then removed under reduced pressure and the residue was crystallized from ethanol to give 4.94 g (78percent yield) of the title amide as white crystals: mp 179-181° C. Production Tetrahydro-2H-pyran-4-carboxamide; To methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) was added concentrated ammonia water (50 mL), and the reaction mixture was stirred at room temperature for 43.5 hours. Thereafter, the reaction mixture was cooled in an ice water bath, and the precipitate was filtrated. Then, the precipitate was dried at 40° C. under reduced pressure, to obtain 33.4 g of a title compound (yield: 74.6percent). [0511] Concentrated aqueous ammonia (50 mL) was added to methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reaction mixture was stirred for 43.5 hours at room temperature. The reaction mixture was then cooled in an ice water bath, after which the precipitate was filtered out and dried under reduced pressure at 40° C. to afford 33.4 g of the title compound (74.6percent yield). [0512] 1H NMR (400 MHz, DMSO-d6) δ 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz, 1H), 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H), 6.74 (br s, 1H), 7.21 (br s, 1H).Methyl tetrahydro-2H-pyran-4-carboxylate (10 g, 69 mmol) was stirred in ammonium hydroxide(35percent, 500 mL) for 2 d. The reaction mixture was concentrated in vacuo. The white residual solid wasrecrystallized from ethanol to give oxane-4-carboxamide (6.1 g, 69 percent) as colourless plates.1H-NMR (CDCl3, 500 MHz): 3.86 (2H, dt, J 11.4, 3.3, 2×2-HA), 3.38–3.29 (2H, m, 2×2-HB), 2.43–2.31(1H, m, 4-H), 1.71–1.56 (4H, m, 2×3-H2);13C-NMR (CDCl3, 75 MHz): 180.3, 68.3, 42.5, 30.4;HRMS (ESI+): Calculated for C6H11NaNO ([M+Na]+): 152.0682. Found: 152.0678, Δ –2.6 ppm.Intermediate 30 oxane-4-carboxamide To a stirred solution of oxane-4-carboxylic acid (800 mg, 6.15 mmol) in chloroform (5 mL) were added triethylamine (1.28 mL, 9.22 mmol) and isobutyl chloro formate (884 μ, 7.37 mmol) dropwise at 0°C under argon. The reaction mixture was stirred at 0°C for 2 h and then ammonia gas was passed through the solution for 15 min. The reaction mixture was concentrated. The residue was dissolved in propan-2-ol/chloroform (1 :4, 25 mL) and washed with water, 5percent aHC03(aq) and then 1M HClExample B5 Example B5 Example 6Synthesis of tetrahydropyran-4-carboxylic acid amide; In a vessel made of a glass, having an inner volume of 100 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 6.30 g (38.5 mmol) of tetrahydropyran-4-carboxylic acid chloride synthesized in the same method as in Example 5 and 20 g (329 mmol) of 28percent by weight aqueous ammonia, and the mixture was reacted at 0° C. for 6 hours under stirring. After completion of the reaction, the reaction mixture was filtered, and the obtained filtrate was dried to obtain 4.84 g (Isolation yield; 62percent) of tetrahydropyran-4-carboxylic acid amide was white crystals.Physical properties of the tetrahydropyran-4-carboxylic acid amide were as follows.A mixture of methyl tetrahydro-2/-/-pyran-4-carboxylate (7 g , 48.6 mmol) and 30percent aqueous ammonia (20 mL) was stirred in a closed bottle at r.t. for 18 h. The ammonia excess was removed under reduced pressure and the residue was crystallized from ethanol affording 5.6 g (89percent) of tetrahydro-2/-/-pyran-4-carboxamide. 1H NMR (401 MHz, DMSO-d6) delta ppm 7.21 (br. s., 1 H), 6.73 (br. s., 1 H), 3.90 - 3.80 (m, 2 H), 3.30 -3.23 (m, 2H), 2.36 - 2.24 (m, 1 H), 1.66 - 1.47 (m, 4 H)Tetrahydro-2H-pyran-4-carboxamide A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7 g, 48.6 mmol) and 30percent aqueous ammonia (20 mL) was stirred in a closed bottle at r.t. for 18 h. The ammonia excess was removed under reduced pressure and the residue was crystallized from ethanol affording 5.6 g (89percent) of tetrahydro-2H-pyran-4-carboxamide. 1H NMR (401 MHz, DMSO-d6) delta ppm 7.21 (br. s., 1H), 6.73 (br. s., 1H), 3.90-3.80 (m, 2H), 3.30-3.23 (m, 2H), 2.36-2.24 (m, 1H), 1.66-1.47 (m, 4H)A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7.0 g, 48.6 mmol) and concentrated ammonia (20 ml) was stirred at 22° C. for 18 h. The excess ammonia was then removed under reduced pressure and the residue was crystallized from ethanol to give 4.94 g (78percent yield) of the title amide as white crystals: mp 179-181° C. 1HNMR 400 MHz (CDCl3) delta (ppm): 1.81 (4H, m, 2.x.CH2), 2.42 (1H, m, CH), 3.44 (2H, m, OCH2), 4.04 (2H, m, OCH2), 5.55 and 5.8 (2.x.1H, broad, NH2).Production Tetrahydro-2H-pyran-4-carboxamide; To methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) was added concentrated ammonia water (50 mL), and the reaction mixture was stirred at room temperature for 43.5 hours. Thereafter, the reaction mixture was cooled in an ice water bath, and the precipitate was filtrated. Then, the precipitate was dried at 40° C. under reduced pressure, to obtain 33.4 g of a title compound (yield: 74.6percent). 1H NMR (400 MHz, DMSO-d6) delta 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz, 1H) 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H), 6.74 (br s, 1H), 7.21 (br s, 1H)[0511] Concentrated aqueous ammonia (50 mL) was added to methyl tetrahydro-2H-pyran-4-carboxylate (50 g, 347 mmol) and the reaction mixture was stirred for 43.5 hours at room temperature. The reaction mixture was then cooled in an ice water bath, after which the precipitate was filtered out and dried under reduced pressure at 40° C. to afford 33.4 g of the title compound (74.6percent yield). [0512] 1H NMR (400 MHz, DMSO-d6) delta 1.45-1.62 (m, 4H), 2.28 (tt, J=11.1, 4.4 Hz, 1H), 3.26 (ddd, J=11.4, 11.4, 2.7 Hz, 2H), 3.82 (br d, J=11.4 Hz, 2H), 6.74 (br s, 1H), 7.21 (br s, 1H).Methyl tetrahydro-2H-pyran-4-carboxylate (10 g, 69 mmol) was stirred in ammonium hydroxide(35percent, 500 mL) for 2 d. The reaction mixture was concentrated in vacuo. The white residual solid wasrecrystallized from ethanol to give oxane-4-carboxamide (6.1 g, 69 percent) as colourless plates.1H-NMR (CDCl3, 500 MHz): 3.86 (2H, dt, J 11.4, 3.3, 2×2-HA), 3.38'3.29 (2H, m, 2×2-HB), 2.43'2.31(1H, m, 4-H), 1.71'1.56 (4H, m, 2×3-H2);13C-NMR (CDCl3, 75 MHz): 180.3, 68.3, 42.5, 30.4;HRMS (ESI+): Calculated for C6H11NaNO ([M+Na]+): 152.0682. Found: 152.0678, Delta '2.6 ppm.Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydropyranyl acetate (20 mL, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydropyran-4- carboxamide as a white solid.Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2H- pyran-4-carboxylate (20 ML, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 ML) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydro- 2H-PYRAN-4-CARBOXAMIDE as a white solid.Preparation 110; Tetrahydro-pyran-4-carboxylic acid amide; In a 5L flask, charge methyltetrahydropyran-4-carboxylate (500ml, 3. 75mol) and concentrated ammonium hydroxide (1.3L) and stir the reaction at room temperature for 48 hours. Filter the reaction and dry the white solid in a vacuum oven at 60°C overnight. to obtained 36.33g white solid of the title compound.Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2//- pyran-4-carboxylate (20 tnL, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1 1.4 g of tetrahydro- 2H-pyran-4-carboxamide as a white solid.Example 6Synthesis of tetrahydropyran-4-carboxylic acid amide; In a vessel made of a glass, having an inner volume of 100 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 6.30 g (38.5 mmol) of tetrahydropyran-4-carboxylic acid chloride synthesized in the same method as in Example 5 and 20 g (329 mmol) of 28percent by weight aqueous ammonia, and the mixture was reacted at 0° C. for 6 hours under stirring. After completion of the reaction, the reaction mixture was filtered, and the obtained filtrate was dried to obtain 4.84 g (Isolation yield; 62percent) of tetrahydropyran-4-carboxylic acid amide was white crystals.Physical properties of the tetrahydropyran-4-carboxylic acid amide were as follows.1H-NMR (CDCl3, delta (ppm)); 1.46 to 1.62 (4H, m), 2.26 to 2.52 (1H, m), 3.28 to 3.34 (2H, m), 3.81 to 3.87 (2H, m), 6.77 to 7.24 (2H, d)CI-MS (m/e); 130 (M+1)Thionyl chloride (10.0 mL, 137 mmol) was added to A suspension of d) Tetrahydropyran-4-carbonitrile can be prepared as follows: Slowly add 10 cm3 of thionyl chloride to 3 g of (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.

Molecular Weight:129.16
XLogP3:-0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:129.078978594
Monoisotopic Mass:129.078978594
Topological Polar Surface Area:52.3
Heavy Atom Count:9
Complexity:108
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes