Reference：
[1] Helvetica Chimica Acta, 2003, vol. 86, # 5, p. 1371 - 1396
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 18, p. 4093 - 4102
[3] Yakugaku Zasshi, 1957, vol. 77, p. 232,234[4] Chem.Abstr., 1957, p. 11344
[5] Tetrahedron, 1981, vol. 37, p. 781 - 787
[6] Farmaco, Edizione Scientifica, 1984, vol. 39, # 3, p. 171 - 188
2
[ 124391-75-9 ]
[ 89364-31-8 ]
Reference：
[1] ACS Catalysis, 2018, vol. 8, # 7, p. 6738 - 6744
[2] Bulletin of the Chemical Society of Japan, 2009, vol. 82, # 8, p. 1000 - 1002
[3] Synthetic Communications, 1999, vol. 29, # 17, p. 2937 - 2942
[4] Organic Process Research and Development, 2017, vol. 21, # 9, p. 1388 - 1393
3
[ 79710-86-4 ]
[ 89364-31-8 ]
Reference：
[1] Patent: US6881851, 2005, B1, . Location in patent: Page/Page column 3-5
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 463 - 477
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 3905,3907
6
[ 1445651-64-8 ]
[ 89364-31-8 ]
Reference：
[1] Patent: WO2013/93850, 2013, A1,
7
[ 67-56-1 ]
[ 89364-31-8 ]
[ 53662-85-4 ]
Yield
Reaction Conditions
Operation in experiment
67%
for 18 h; Reflux
To a solution of tetrahydro-3-furancarboxylic acid (20.00 g, 172 mmol) in MeOH (350 mL) was added sulfuric acid (27.54 mL, 517 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (15.0 g, 67percent yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d) δ ppm 3.85 (t, J=8.4 Hz, 1H), 3.77-3.66 (m, 3H), 3.62 (s, 3H), 3.07-3.22 (m, 1H), 1.97-2.12 (m, 2H).
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 8, p. 2690 - 2694
[2] Patent: US2018/201610, 2018, A1, . Location in patent: Paragraph 0076; 0077
[3] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 463 - 477
Stage #1: With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 1 h; Stage #2: With hydrazine In tetrahydrofuran at 20℃; for 1 h;
(S)-Tetrahydrofuran-3-carbohydrazide and (R)-tetrahydrofuran-3-carbohydrazide, Example 6.1 (1014) To a mixture of tetrahydro-3-furanoic acid (2.0 mL, 20.9 mmol) and TEA (5.8 mL, 42 mmol) in THF (42 mL) was added dropwise isobutyl chloroformate (2.86 mL, 23.00 mmol). The resulting mixture was stirred at 0° C. for 1 h before hydrazine (0.67 mL, 23.00 mmol) was added. The resulting mixture was allowed to stir at RT for 1 h. The mixture was then concentrated, and chloroform (200 mL) and water (20 mL) were added to dissolve the residue. The organic layer was separated, and the aqueous phase was lyophilized. EtOH (50 mL×3) was used to triturate the solid 3 times. The combined EtOH solution was concentrated and dried to give tetrahydrofuran-3-carbohydrazide (2.27 g). LCMS ESI (pos) m/z=131.1 (M+H)+.
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h;
To a solution of tetrahydrofuran-3-carboxylic acid (0.247 mL, 2.58 mmol) in THF (13 mL) at 0 °C was added slowly lithium aluminium hydride (1 .0 M in THF, 5.2 mL, 5.16 mmol), stirred for 10 minutes then allowed to attain room temperature and stirred for a further 3 hours. The reaction mixture was cooled to 0 °C and diluted with diethyl ether (15 mL), then treated sequentially with water (0.2 mL), NaOH (15percent solution, 0.2 mL) and water (0.6 mL) and stirred for 30 minutes. The white suspension was then treated with sodium sulfate, stirred for a further 20 minutes, filtered over celite, washed with diethyl ether (2x 20 mL) and concentrated in vacuo to yield 224 mg (85percent) of the title compound as a colourless oil which was carried forward to the next stage without further purification. -NMR Spectrum: δΗ (500 MHz, CDCI3): 3.90-3.84 (2H, m), 3.78-3.73 (1H, m), 3.66-3.63 (2H, m), 3.61-3.57 (1H, m), 2.51-2.46 (1H, m), 2.08-2.01 (1H, m), 1.69-1.62 (1H, m)
38%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 65℃; for 12 h; Stage #2: at 65℃; for 2 h;
Step 1 : To a solution of tetrahydrofuran-3-carboxylic acid (600 mg, 5.17 mmol) in THF (15 mL) was added a solution of 1 M BH3 THF in THF (10.3 mL, 10.3 mmol) at 0 °C. The reaction was heated to 65 °C and stirred for 12 hours. The solution was then cooled to 20 °C and MeOH (4 mL) was added. The reaction was then stirred at 65 °C for 2 hours before cooling to RT and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and petroleum ether to give (tetrahydrofuran-3-yl)methanol 200 mg (38percent)
>99.9 %Chromat.
at 199.84℃; for 10 h; Autoclave
General procedure: The hydrogenation of carboxylic acids or other substrates was performed in a high-pressure stainless-steel autoclave (Xinyuan Chemical Machinery, Series CJK, 300 mL) with a maximum stirring rate of 1500 r/min. In a typical experiment, 0.2 g of catalyst (or without catalyst for the control experiment), 3 mmol of the substrate, and 100 mL alkane solvent (n-hexane, n-heptane, i-octane, or n-dodecane) were well mixed in the autoclave and purged with pure nitrogen at room temperature. The gas supply and discharge were carried out manually through needle valves. The autoclave was rapidly heated to the desired temperature and hydrogen was introduced at 2 MPa to initiate the reaction. The reaction pressure was kept at 2 MPa with a small negative deviation (∼0.2 MPa) owing to the consumption of hydrogen. Samples of the liquid phase were continuously taken through a sampling tube with a filter at certain intervals. The stirring rate was kept at 750 r/min during the reaction.
Reference：
[1] Patent: WO2017/55860, 2017, A1, . Location in patent: Page/Page column 211; 212
[2] Patent: WO2016/55618, 2016, A1, . Location in patent: Page/Page column 43
[3] Tetrahedron, 1981, vol. 37, p. 781 - 787
[4] Farmaco, Edizione Scientifica, 1984, vol. 39, # 3, p. 171 - 188
[5] Chinese Journal of Catalysis, 2018, vol. 39, # 2, p. 250 - 257
To a solution of tetrahydro-3-furancarboxylic acid (20.00 g, 172 mmol) in MeOH (350 mL) was added sulfuric acid (27.54 mL, 517 mmol). The reaction was heated to reflux for 18 h. The reaction was then cooled to rt and concentrated. The residue was partitioned between water (500 mL) and DCM (200 mL). The phases were separated and the aqueous fraction was extracted with DCM (200 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated to afford methyl tetrahydro-3-furancarboxylate (15.0 g, 67% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d) delta ppm 3.85 (t, J=8.4 Hz, 1H), 3.77-3.66 (m, 3H), 3.62 (s, 3H), 3.07-3.22 (m, 1H), 1.97-2.12 (m, 2H).
With oxygen In water at 68 - 125℃; for 0 - 6.53333h;
1; 2; 3; 4; 5; 6; 7; 8
EXAMPLES; The operation of the process of the present invention is further illustrated by the following examples wherein all percentages given are by weight unless otherwise specified. The oxidation experiments were carried out in a stainless steel, 100 ml volume, high pressure autoclave reactor (Autoclave Engineers EZ-Seal) equipped with a high pressure gas manifold inlet system capable of adding oxygen-containing gas streams to the liquid phase reaction medium. The gas stream was added below the liquid level within the reactor near the impeller/stirrer. The stirrer was maintained at 1500 RPM to ensure rapid and even mixing of the oxygen-containing gas stream with the liquid 3-FTHF/solvent medium within the reactor. In order to maintain constant pressure within the reactor body, a high pressure, total reflux column served to vent the gas stream from the reactor body. A back pressure regulator was used to maintain the overall reactor pressure at the desired pressure. The 3-FTHF solution was added to the solvent and oxygen-containing gas stream of the autoclave by means of a high pressure syringe pump to initiate the thermal oxidation reaction. Microliter-sized samples of the liquid phase reaction medium were taken at different time intervals by means of a capillary dip tube maintained in the liquid level of the reactor.In a typical experiment, the reactor was charged with 40 g of water and 12 drops of an internal GC standard, tetramethylene sulfone, and sealed. The desired gas phase composition of oxygen with optional inert gas diluent was flowed through the reactor and the desired reaction pressure set using the back pressure reactor at the exit of the reflux condenser. The reactor was then heated to the desired reaction temperature using a band heater tightly wrapped around the exterior of the reactor body. The stir rate of the solution was set at 1500 RPM to ensure rapid and uniform mixing at all reaction conditions. The pressure was raised to 8.6 bara (125 pounds per square inch-psia) using a pre-determined gas flow composition of O2 and He to give the desired O2 partial pressure. Constant pressure was maintained in the autoclave reactor by the back pressure regulator after the gaseous reactor effluent was cooled to 2° C. in a total reflux-type of stainless steel coiled condenser.After the reactor was heated to the desired temperature, 10.0 g of a 50% solution of 3-FTHF in water quickly was added at high pressure through the syringe pump into the reactor to give a total volume of approximately 50 mls solution, which defined time=0 for the kinetic experiments. Each reaction typically was run for 5 to 6 hours, samples were taken periodically using the dip tube in the reactor and were subsequently analyzed by gas chromatography (GC). In one experiment, off gases were collected in a gas sample bomb and analyzed for CO2 using a different GC, which had been calibrated for CO2. Negligible amounts of CO2-were observed at all reaction times, confirming that combustion of feed and product were not occurring during the thermal oxidation reaction.; Example 1; 3-FTHF was oxidized over a period of 5 hours at 100° C. and 8.6 bara (125 psia) overall pressure (5.0 bara {72.5 psia} O2 and 3.6 bara {52.5 psia} He) according to the procedure described above. The course of the reaction was observed by periodically sampling the reaction mixture and analyzing for 3-FTHF. The results are shown in Table I wherein Time is the time (minutes) of the reaction measure as described above and 3-FTHF is the normalized micromoles of unreacted 3-FTHF present in the reaction mixture.; Example 2; The procedure of Example 1 was repeated except that after 150 minutes of reaction time of a second aliquot of 10.0 grams of 50% aqueous 3-FTHF solution was pumped into the autoclave reactor. The course of the reaction was observed by periodically sampling the reaction mixture and analyzing for 3-FTHF. The results are shown in Table II wherein Tim is the time (minutes) of the reaction measured as described above and 3-FTHF is the normalized micromoles of unreacted 3-FTHF present in the reaction mixture.; Examples 3-5; The procedure of Example 1 was repeated using different reaction temperatures as shown in Table III wherein Temp is the temperature (° C.) at which the experiment was carried out and Time has the meaning given above in Example 1. In these examples, the O2 pressure was maintained constant at 8.6 bara (125 psia) at a total reaction pressure of 8.6 bara1(25 psia). The samples taken periodically were analyzed for 3-FTHF and 3-THFA. Table III also reports the Conversion of 3-FTHF and the Selectivity to 3-THFA at each point of Time. Conversion is the percent conversion of FTHF to all products: Selectivity is the percent selectivity to THFA defined as; Examples 6-8; The procedure of Example 1 was repeated at 100° C. and 8.6 bara (125 psia) overall pressure except that different oxygen partial pressures were used as shown in Table IV wherein O2 Press is the oxygen partial pressure (bara-psia) at which the experiment was carried out and Time has the meaning given above in Example 1. The samples taken periodically were analyzed for 3-FTHF and 3-THFA. Conversion and Selectivity have the meanings provided in Examples 3-5.; Example 9; The basic procedure of Example 1 was repeated except that the starting material was 75 g of a 50% aqueous 3-FTHF solution and the oxidation was carried out over a time of 3 hours. The results are shown in Table V wherein Time, Conversion and Selectivity have the meanings provided in the preceding examples.
With Jones reagent In acetone at 20℃; Cooling with ice;
With potassium carbonate; In N,N-dimethyl-formamide; at 32℃; for 5h;
To a solution of tetrahydrofuran-3-carboxylic acid (50 g, 0.431 mol) and potassium carbonate (89.2 g, 0.647 mol) in A^N-dimethylformamide (500 mL) was added iodomethane (73.4 g, 0.517 mol) at 32 C and stirred for 5 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo to afford crude product (53 g, 95% yield). NMR (400 MHz, CDC13): delta 3.98 - 3.76 (m, 4 H), 3.69 (s, 3 H), 3.11 - 3.04 (m, 1 H), 2.23 - 2.09 (m, 2 H).
N-(3-chloropyrazin-2-yl)tetrahydrofuran-3-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;
Step 1 : To a solution of tetrahydrofuran-3-carboxylic acid (1 .0 g, 8.6 mmol) in DMF (15 ml) was added HATU (3.60 g, 9.47 mmol), DIPEA (1 .22 g, 1 .66 ml, 9.47 mmol) and finally <strong>[63286-28-2]2-chloro-3-hydrazinylpyrazine</strong> (1 .37 g, 9.47 mmol). The mixture was stirred for 3 hours at RT. The reaction mixture was poured into sat. aq. Na2CO3 (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic phases were washed with brine (3x25 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography using a gradient of ethyl acetate and heptane to yield 1 .1 g (53%) A/'-(3-chloropyrazin-2-yl)tetrahydrofuran-3- carbohydrazide.
(S)-N-(2,6-Dimethoxyphenyl)tetrahydrofuran-3-carboxamide and (R)-N-(2,6-dimethoxyphenyl)tetrahydrofuran-3-carboxamide, Example 7.1 (1021) An ice-cooled solution of tetrahydro-3-furoic acid (Sigma-Aldrich, 3.0 g, 26.1 mmol) in DMF (52 mL) was treated with TEA (10.9 mL, 78 mmol) via syringe followed by HATU (10.9 g, 28.7 mmol) directly. After 5 min, <strong>[2734-70-5]2,6-dimethoxyaniline</strong> (Amfinecom Inc., 4.0 g, 26.1 mmol) was added. The resulting orange solution was warmed to RT and stirred for 60 min. The mixture was then partitioned between brine (100 mL) and EtOAc (4×). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% EtOAc in hexanes) to provide 7.1 (2.50 g, 38% yield) as a white solid. LCMS-ESI (pos) m/z: 252.2 (M+H)+.
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