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CAS No. : | 110238-91-0 | MDL No. : | MFCD01075170 |
Formula : | C7H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CNCMVGXVKBJYNU-UHFFFAOYSA-N |
M.W : | 144.17 | Pubchem ID : | 2773520 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.02 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.87 cm/s |
Log Po/w (iLOGP) : | 1.97 |
Log Po/w (XLOGP3) : | 0.43 |
Log Po/w (WLOGP) : | 0.59 |
Log Po/w (MLOGP) : | 0.35 |
Log Po/w (SILICOS-IT) : | 1.22 |
Consensus Log Po/w : | 0.91 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.87 |
Solubility : | 19.3 mg/ml ; 0.134 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.74 |
Solubility : | 26.0 mg/ml ; 0.18 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.83 |
Solubility : | 21.3 mg/ml ; 0.148 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: With lithium aluminium tetrahydride In diethyl ether for 3.75 h; Heating / reflux Stage #2: With sodium hydroxide; water In diethyl ether |
Preparation 5: (Tetrahydropyran-4-yl)methanoI; OHTo a suspension of LiAltL, (56g, 1.47mol) in diethyl ether (2L) under argon was added methyl tetrahydro-2H-pyran-4-carboxylate (270g, 1.88mol) in diethyl ether (ca. 200mL) under reflux over a period of 1.75h. After addition was complete reflux was continued for a further lh. TLC (diethyl ether) indicated a small amount of ester remained, so further LiAltLt (lOg, 0.26mol) was added and reflux continued for lh. Water (66mL) was added, then 15percent NaOH solution (66mL), followed by further water (198mL). The solid was filtered and dried to give the crude product, which was redissolved in DCM (800 ml), dried (MgS04),filtered and the solvent removed to afford the title compound (207 g, 94percent yield). NMR was consistent with the above structure. |
94% | Stage #1: With lithium aluminium tetrahydride In diethyl ether for 3.75 h; Heating / reflux Stage #2: With sodium hydroxide; water In diethyl ether |
Preparation 3: (Tetrahydropyran-4-yl)methanol To a suspension Of LiAlH4 (56g, 1.47mol) in diethyl ether (2L) under argon was added methyl tetrahydro-2H-pyran-4-carboxylate (27Og, 1.88mol) in diethyl ether (ca.20OmL) under reflux over a period of 1.75h. After addition was complete reflux was continued for a further Ih. TLC (diethyl ether) indicated a small amount of ester remained, so further LiAlH4 (1Og, 0.26mol) was added and reflux continued for Ih. Water (66mL) was added, then 15percent NaOH solution (66mL), followed by further water (198mL). The solid was filtered and dried to give the crude product, which was redissolved in DCM (800 ml), dried(MgSO4), filtered and the solvent removed to afford the title compound (207g, 94percent yield). NMR was consistent with the above structure. |
94% | Stage #1: With lithium aluminium tetrahydride In diethyl ether for 3.75 h; Heating / reflux Stage #2: With sodium hydroxide; water In diethyl ether |
Preparation 3: (Tetrahydropyran-4-yl)methanoI; To a suspension of LiAlFL, (56g, 1.47mol) in diethyl ether (2L) under argon was added methyl tetrahydro-2H-pyran-4-carboxylate (270g, 1.88mol) in diethyl ether (ca. 200mL) under reflux over a period of 1.75h. After addition was complete reflux was continued for a further lh. TLC (diethyl ether) indicated a small amount of ester remained, so further LiAlFL, (lOg, 0.26mol) was added and reflux continued for lh. Water (66mL) was added, then 15percent NaOH solution (66mL), followed by further water (198mL). The solid was filtered and dried to give the crude product, which was redissolved in DCM (800 ml), dried (MgS04),filtered and the solvent removed to afford the title compound (207 g, 94percent yield). NMR was consistent with the above structure. |
91% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; Inert atmosphere Stage #2: With water; sodium hydroxide In tetrahydrofuranCooling with ice |
Step 1: Synthesis of (Tetrahydro-pyran-4-yl)-methanol To a solution of 250 mL of LiAlH4 (2.3M solution in THF, 0.575 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of tetrahydro-pyran-4-carboxylic acid methyl ester in THF (900 mL) under nitrogen atmosphere (CAUTION: highly exothermic[reaction]). The temperature is kept at 40-45° C. with an ice-bath. Upon complete addition, the reaction is stirred at room temperature for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aqueous NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of (tetrahydro-pyran-4-yl)-methanol as a clear oil. Yield: 91percent; 1H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20-1.39 (2H, m), 1.56-1.83 (3H, m), 2.03 (1H, br. s.), 3.29-3.52 (4H, m), 3.89-4.05 (2H, m), |
91% | With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; Inert atmosphere | To a solution of 250 mL of LiAlH4 (2.3M solution in THF, 0.575 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of Compound 5 in THF (900 mL) under nitrogen atmosphere. The temperature is kept at 40-45° C. with an ice-bath. Upon complete addition, the reaction is stirred at room temperature for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aqueous NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of Compound 6 as a colorless oil. Yield: 91percent; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20-1.39 (2H, m), 1.56-1.83 (3H, m), 2.03 (1H, br. s.), 3.29-3.52 (4H, m), 3.89-4.05 (2H, m). |
91% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; for 1.5 h; Inert atmosphere Stage #2: With water; sodium hydroxide In tetrahydrofuranCooling with ice |
Synthesis of 2-Methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionic acid Step 1: Synthesis of (Tetrahydro-pyran-4-yl)-methanol To a solution of 250 mL of LiAlH4 (2.3M solution in THF, 0.575 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of tetrahydro-pyran-4-carboxylic acid methyl ester in THF (900 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction.). The temperature is kept at 40-45 °C with an ice-bath. Upon complete addition, the reaction is stirred at room temperature for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aqueous NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of (tetrahydro-pyran-4-yl)-methanol as a colorless oil. Yield: 91percent; 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 1.20 - 1.39 (2 H, m), 1.56 - 1.83 (3 H, m), 2.03 (1 H, br. s.), 3.29 - 3.52 (4 H, m), 3.89 - 4.05 (2 H, m) |
91% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; for 1.5 h; Inert atmosphere Stage #2: With water; sodium hydroxide In tetrahydrofuran |
Acid Method B:Synthesis of Compound B6Step 1: Synthesis of Compound B2To a solution of 250 mL of LiAlH4 (2.3M solution in THF, 0.575 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of compound B l in THF (900 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction.). The temperature is kept at 40-45 °C with an ice-bath. Upon complete addition, the reaction is stirred at room temperature for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aqueous NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of compound B2 as a clear oil. Yield: 91percent; ]H-NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 - 1.39 (2 H, m), 1.56 - 1.83 (3 H, m), 2.03 (1 H, br. s.), 3.29 - 3.52 (4 H, m), 3.89 - 4.05 (2 H, m) |
91% | Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; for 1.5 h; Inert atmosphere; Cooling with ice; Exothermic reaction Stage #2: With water; sodium hydroxide In tetrahydrofuran |
Step 1: Synthesis of compound B-2 To a solution of 250 mL of LiAlH4 (2.3 M solution in THF, 0.575 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of compound B-l in THF (900 mL) under nitrogen atmosphere (CAUTION: highly exothermic reaction.). The temperature is kept at 40-45 °C with an ice-bath. Upon complete addition, the reaction is stirred at room temperature for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aqueous NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite.(R). and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of compound B-2 as a colorless oil. Yield: 91 percent; *H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20 - 1.39 (2 H, m), 1.56 - 1.83 (3 H, m), 2.03 (1 H, br. s.), 3.29 - 3.52 (4 H, m), 3.89 - 4.05 (2 H, m) |
91% | With lithium aluminium tetrahydride In tetrahydrofuran; water at 20 - 45℃; for 1.5 h; Inert atmosphere | To 250 mL of LiAlH4 (2.3 M solution in THF, 0.58 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of tetrahydro-pyran-4-carboxylic acid methyl ester in THF (900 mL) under nitrogen atmosphere. The temperature is kept at 40-45° C. with an ice-bath. Upon complete addition, the reaction is stirred at RT for 1.5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aq. NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite® and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of (tetrahydro-pyran-4-yl)-methanol. Yield: 91percent |
91% | With lithium aluminium tetrahydride In tetrahydrofuran at 20 - 45℃; for 1.5 h; Inert atmosphere | To 250 mL of LiAIH4 (2.3 M solution in THF, 0.58 mol) in THF (200 mL) is added dropwise a solution of 130 mL (0.974 mol) of tetrahydro-pyran-4-carboxylic acid methyl ester in THF (900 mL) under nitrogen atmosphere. The temperature is kept at 40-45 °C with an ice-bath. Upon complete addition, the reaction is stirred at RT for 1 .5 h. The reaction is cooled in an ice-bath and quenched with addition of water (22 mL), 15percent aq. NaOH solution (21 mL) and water (66 mL). The resulting precipitate is removed by filtration through Celite® and is rinsed with THF (300 mL). The filtrate is concentrated under reduced pressure to afford 102.5 g of (tetrahydro- pyran-4-yl)-methanol. Yield: 91 percent |
87% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere | To a solution of methyl tetrahydro-2H-pyran-4-carboxylate (3 g, 21 mmol) in tetrahydrofuran (30 mL) undernitrogen atmosphere was slowly added lithium aluminum hydride (1.18g, 31 mmol) in batches at 0°C. The reaction wasstirred at 0°C for 1 hour, then carefully quenched with H2O (1.2 mL), NaOH (1.2 mL, 15percent), H2O (3.6 mL) successivelyand stirred for 20 minutes. The mixture was filtered and the filtrate was concentrated to give the title compound (2.1 g,87percent yield) as a colorless liquid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 4.00 (dd, J=4.02, 11.04 Hz, 1H), 3.51 (t,J=5.77 Hz, 1H), 3.41 (dt, J=1.76, 11.67 Hz, 1H), 1.70-1.81 (m, 1H), 1.66 (d, J=13.05 Hz, 2H), 1.27-1.40 (m, 3H). |
80% | With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; for 3 h; | Methyl tetrahydro-2H-pyran-4-carboxylate (5 g, 34.68 mmol, 1.0 equiv) was dissolved in THE (60 mL) and methanol (10 mL). Sodium borohydride (2.62 g, 69.36 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.22a (3.2 g, 80 percent yield). 1H NMR (400 MHz, DMSO) 6 3.96 — 3.75 (m, 2H), 3.66 — 3.58 (m, 2H), 3.36 (dd, J = 6.9, 4.7 Hz, 2H), 3.33—3.17 (m, 2H), 1.81—1.70 (m, 2H), 1.63—1.48 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With ammonia In water at 20℃; for 18 h; | 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) δ 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) |
89% | With ammonia In water at 20℃; for 18 h; Sealed tube | 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) δ 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) |
78% | With ammonia In water at 22℃; for 18 h; | 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) δ (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). |
74.6% | With ammonia In water at 20℃; for 43.5 h; | Production Example 2; 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) 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) |
74.6% | With ammonia In water at 20℃; for 43.5 h; | [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). |
69% | for 48 h; Inert atmosphere | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetone for 3 h; Heating / reflux | Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol) was slowly added to a stirred suspension of anhydrous potassium carbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethyl sulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h. The inorganic salts were then removed by filtration and washed with acetone, and the filtrate was dried and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 99percent), which was used in the next step without further purification. GC-MS m/z 145 (MH+); 1H NMR (300 MHz, CDCl3) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H), 3.65 (s, 3H), 3.88-3.95 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | at 70 - 75℃; for 10 h; Inert atmosphere | In a 300 ml glass flask equipped with stirrer, thermometer and reflux condenser, 22.8 g (197.4 mmol) of 4-cyanotetrahydropyran having a purity of 99percent synthesized in Example 5, 60percent (98 mmol) 98percent sulfuric acidas well as130 ml (3.21 mol) of methanol was added under nitrogen atmosphere, the mixture was reacted at 70 to 75°C. for 10 hours with stirring. After completion of the reaction, 100 ml of water was added, the reaction solution was cooled to room temperature. The organic layer and aqueous layer were separated. Then,the aqueous layer was extracted three times with 200 ml of ethyl acetate, the organic layer and the ethyl acetate extract were mixed, and concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (75 to 76 ° C., 1.2 to 13 kPa) to obtain 18.3 g of methyl tetrahydropyran-4-carboxylate as a colorless liquid having a purity of 98.7percent (area percentage by gas chromatography) (isolation yield: 63.5percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.75 h; Stage #2: at -78 - 20℃; |
[1749] At -78° C., 22.1 ml ofn-butyllithium (35.4 mmol,1.6M in hexane) were slowly added dropwise to a solution of4.91 ml (35.0 mmol) of diisopropylamine in 45 ml oftetrahydrofuran,and the mixture was stirred at -78° C. for another 10min and at oo C. for another 25 min. Subsequently, at -78° C.,a solution of 5.00 g (34.7 mmol) of methyl tetrahydro-2Hpyran-4-carboxylate in 45 ml oftetrahydrofuran was added,and the mixture was stirred at -78° C. for another 15 min andat oo C. for another 30 min. At -78° C., 2.16 ml (34.7 mmol)of methyl iodide were added dropwise, and the reaction mixturewas slowly warmed to -25° C. and then to room temperatureovernight. The reaction was terminated by additionof 80 ml of O.lN hydrochloric acid, and the phases wereseparated. The aqueous phase was extracted twice with ethylacetate, the combined organic phases were dried over magnesiumsulphate and filtered and the solvent was removedunder reduced pressure. The resulting suspension was trituratedwith 20 ml of methyl tert-butyl ether, the precipitate wasfiltered off with suction and the mother liquor was concentratedunder reduced pressure, giving the title compound.Yield: 5.88 g (purity 95percent, quant.)[1750] 1H-NMR (400 MHz, DMSO-d6): o [ppm]=3.70-3.64 (m, 2H), 3.64 (s, 3H), 3.37-3.30 (m, 2H), 1.94-1.88 (m,2H), 1.45-1.37 (m, 2H), 1.16 (s, 3H). |
100% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - 0℃; for 1.83333 h; Stage #2: at -78 - 0℃; |
At -78 C, 22.1 ml of n-butyllithium (35.4 mmol, 1.6Min hexane) were slowly added dropwise to a solution of 4.91 ml (35.0 mmol) ofdiisopropylamine in 45 ml of tetrahydrofuran, and the mixture was stirred at-78 C for another 10 mm and at 0 C for another 25 min. Subsequently, at -78 C, a solution of 5.00 g (34.7 mmol) of methyltetrahydro-2H-pyran-4-carboxylate in 45 ml of tetrahydrofuran was added, andthe mixture was stirred at -78 C for another 15 min and at 0 C for another 30mm. At -78 C, 2.16 ml (34.7 mmol) of methyl iodide were added dropwise, and thereaction mixture was slowly warmed to -25 C and then to room temperatureovernight. The reaction was terminated by addition of 80 ml of 0.1Nhydrochloric acid, and the phases were separated. The aqueous phase wasextracted twice with ethyl acetate, the combined organic phases were dried overmagnesium sulphate and filtered and the solvent was removed under reducedpressure. The resulting suspension was triturated with 20 ml of methyltert-butyl ether, the precipitate was filtered off with suction and the motherliquor was concentrated under reduced pressure, giving the title compound.Yield: 5.88 g (purity 95percent, quant.) |
44% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: for 1 h; |
Methyl tetrahydro-2H-pyran-4-carboxylate (2.50 g, 17.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium diisopropylamide solution (2M n-hexane solution, 10.4 mL, 20.8 mmol) was slowly added dropwise at -78° C. under the protection of nitrogen. The reaction solution was stirred at -78° C. for 1 hour. Iodomethane (4.92 g, 34.7 mmol) was added slowly, and stirred for 1 hour. The reaction was quenched by adding water (20 mL). The reaction solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (10:1 petroleum ether/ethyl acetate, Rf-0.4) to give methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.20 g, yellow oil) with a yield of 44percent. 1H NMR: (400 MHz, Methonal-d4) δ3.79-3.75 (m, 2H), 3.71 (s, 3H), 3.48-3.42 (m, 2H), 2.06-2.02 (m, 2H), 1.51-1.44 (m, 2H), 1.20 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With isopropylmagnesium chloride In tetrahydrofuran at -30 - -5℃; for 1 h; | Step 1 Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) was added thereto, and the mixture was stirred. A THF solution (15.0 mL, 30.0 mmol) of 2.0 mol/L isopropyl magnesium chloride was added dropwise to the reaction mixture at -30°C under an argon atmosphere, and the mixture was stirred at -5°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was purified by distillation under reduced pressure, whereby N-methoxy-N-methyl tetrahydropyran-4-carboxylic acid amide (1.00 g, 58percent) was obtained. Boiling point: 125 to 129°C/8.0 hPa 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H) |
58% | With isopropylmagnesium chloride In tetrahydrofuran at -30 - -5℃; for 1 h; Inert atmosphere | Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto , then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at -30°C, and the mixture was stirred at -5°C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58percent). Boiling point: 125-129 °C / 8.0 hPa, 1H NMR (CDCl3, δ ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H). |
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