* 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.
Stage #1: With sodium hydride In diethyl ether at 20℃; for 0.5 h; Stage #2: at 0℃; for 1 h;
To a stirred slurry of sodium hydride (2.2 g, 55 mmol) in dry ether (40 mL) at room temperature (rt) was added methyl glycolate (4.5 g, 50 mmol) dropwise. The reaction mixture was stirred for 14 h, then it was concentrated under vacuo. To the solid was added methyl acrylate (5.2 g, 55 mmol) in DMSO (20 mL) at O0C and the mixture was stirred for 15 min, and the cool bath was removed and it was stirred for 45 min. The mixture was poured into 5percent H2SO4 (60 mL), and it was extracted with ether (150 mL). The organic layer was dried, concentrated and purified by column chromatography to give 1.7 g (24percent) of the title compound. 1H NMR (CDCl3): 4.51-4.40 (m, 2H), 4.03 (q, J = 8.1 Hz, 2H), 3.80 (s, 3H), 3.54 (t, J = 8.1 Hz, IH).
31%
With sodium In dimethyl sulfoxide
Synthesis of 2,5-dihydro furan 3,4-dicarboxylic acid 2.3 g (0.1 mol) sodium was pulverized under toluene and the solvent was replaced with 75 ml ether. 11 ml (0.1 mol) methylglycolate was added to the mixture under stirring until the evolution of hydrogen gas had ceased. To the dry sodium derivative remaining after destination of the ether, a solution of 10 ml (0.12 mol) distilled methylacrylate in 50 ml DMSO was added while the reaction was kept at 4° C. After 15 minutes the solution was stirred for an additional 30-40 min at room temperature and poured into aqueous H2SO4 at 4° C. and extracted with ether. Washing of the organic layer with a saturated NaCl solution, drying over NaSO4 and removal of the ether was followed by destination under reduced pressure to give 4.5 g (31percent) of 4-oxo-tetrahydro furane 3-carboxylic acidmethyl ester.
Stage #1: With sodium hydride In diethyl ether Stage #2: at 0 - 20℃; Stage #3: With hydrogenchloride In water; dimethyl sulfoxide
To a suspension of NaH (6.66g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0 oC and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10percent HCl and extract with ether (3X). Combine organic extracts and wash with brine. Dry the organic solution (NA2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SI02, 40 ML/MIN, 0-50percent ethyl acetate/hexane for 20 minutes and then 50percent ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9g, 89.2 mmol, 54percent) as a colorless OIL. 1H NMR (8, 400 MHz, CDCL3) : 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4. 05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4Hz). MS calcd. 144; found (EI) 144.
Stage #1: With sodium hydride In diethyl ether at 20℃; for 2 h; Stage #2: at 0 - 20℃; for 1.25 h;
Sodium hydride (4 g, 60percent w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 °C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26percent yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25percent ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60percent w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 °C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 °C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23percent yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25percent ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).
(e) 1-(3-Tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile A mixture of 3-tetrahydrofuranylhydrazine hydrochloride (6.2 g, 0.045 mol), sodium methoxide (2.4 g, 0.045 mol) and ethanol (70 ml) was refluxed under argon for 10 minutes. The reaction mixture was cooled to room temperature and 1-ethoxyethylidene malononitrile (6.1 g, 0.045 mol) was added. The reaction mixture was heated to reflux and stirred for 21 hours. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from water to afford 4.7 g (54percent) of 1-(3-tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as yellow crystals, m.p. 134°-135° C. when dried at 90° C. in high vacuum.
To a stirred slurry of sodium hydride (2.2 g, 55 mmol) in dry ether (40 mL) at room temperature (rt) was added methyl glycolate (4.5 g, 50 mmol) dropwise. The reaction mixture was stirred for 14 h, then it was concentrated under vacuo. To the solid was added methyl acrylate (5.2 g, 55 mmol) in DMSO (20 mL) at O0C and the mixture was stirred for 15 min, and the cool bath was removed and it was stirred for 45 min. The mixture was poured into 5% H2SO4 (60 mL), and it was extracted with ether (150 mL). The organic layer was dried, concentrated and purified by column chromatography to give 1.7 g (24%) of the title compound. 1H NMR (CDCl3): 4.51-4.40 (m, 2H), 4.03 (q, J = 8.1 Hz, 2H), 3.80 (s, 3H), 3.54 (t, J = 8.1 Hz, IH).
4.5 g (31%)
With sodium; In dimethyl sulfoxide;
Synthesis of 2,5-dihydro furan 3,4-dicarboxylic acid 2.3 g (0.1 mol) sodium was pulverized under toluene and the solvent was replaced with 75 ml ether. 11 ml (0.1 mol) methylglycolate was added to the mixture under stirring until the evolution of hydrogen gas had ceased. To the dry sodium derivative remaining after destination of the ether, a solution of 10 ml (0.12 mol) distilled methylacrylate in 50 ml DMSO was added while the reaction was kept at 4 C. After 15 minutes the solution was stirred for an additional 30-40 min at room temperature and poured into aqueous H2SO4 at 4 C. and extracted with ether. Washing of the organic layer with a saturated NaCl solution, drying over NaSO4 and removal of the ether was followed by destination under reduced pressure to give 4.5 g (31%) of 4-oxo-tetrahydro furane 3-carboxylic acidmethyl ester.
To a suspension of NaH (185 g, 4.6 mol, 60% weight) in THF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 C. After the addition, the reaction mixture was stirred for 30 mm at ambient temperature and then re-cooled to 0 C. A solution of methylacrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 C. The resulting reaction mixture was stirred for 30 mm at 0 C and for 2 h at 20 C. After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5% H2S04 (slowly) and extracted with EtOAc (3 L). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification. ?H NMR (CDC13, 400 MHz) : 4.3 5-4.45 (m, 2H), 3.86-3.97 (m, 2H), 3.72 (s, 3H), 3.47 (t, 1H).
To a suspension of NaH (185 g, 4.6 mol, 60 weight) in T HF (4 L) was charged methyl 2-hydroxyacetate (380 g, 4.2 mol) dropwise at 0 . After the addition, the reaction mixture was stirred for 30 min at ambient temperature and then re-cooled to 0 . A solution of methyl acrylate (400 g, 4.64 mol) in DMSO (2 L) was added dropwise over 2 hours at 0 . The resulting reaction mixture was stirred for 30 min at 0 and for 2 h at 20 . After TLC showed that the start material was consumed completely, the mixture was quenched with 1.5 L of 5 H2SO4(slowly) and extracted with EtOAc (3 L) . The combined organic layers were washed with brine (1 L) , dried over Na2SO4, filtered and concentrated to afford Methyl 4-oxotetrahydrofuran-3-carboxylate (11) as a liquid. The crude oil was used in the next step without further purification.1H NMR (CDCl3, 400 MHz) delta: 4.35-4.45 (m, 2H) , 3.86-3.97 (m, 2H) , 3.72 (s, 3H) , 3.47 (t, 1H) .
With potassium hydroxide; In water; at 20℃; for 6.08333h;Heating / reflux;
To a stirred solution of potassium hydroxide (1.97 g, 31.7 mmol) and 2-methyl-2- thiopseudourea sulfate (4.41 g, 31.7 mmol) in water (15 mL) was added dropwise of methyl tetrahydro-4-oxofuran-3-carboxylate (1.59 g, 15.9 mmol) over 5 min. The mixture was stirred at rt for 3 h and refluxed for 3 h. It was evaporated to dryness to give 4.1 g of crude product and used for next reaction without further purification.
To a suspension of NaH (6.66g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0 oC and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3X). Combine organic extracts and wash with brine. Dry the organic solution (NA2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SI02, 40 ML/MIN, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9g, 89.2 mmol, 54%) as a colorless OIL. 1H NMR (8, 400 MHz, CDCL3) : 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4. 05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4Hz). MS calcd. 144; found (EI) 144.
Example 1 5,7-dihydrofuro[3,4-d]pyrimidine-2,4(1H,3H)-dione: To Methyl 4-oxotetrahydrofuran-3-carboxylate (18.30 g), urea (11.44 g), methanol (100 mL) and concentrated hydrochloric acid (5 mL) were added. The mixture was refluxed with heating for two hours. The obtained suspension was stirred for 15 minutes in an ice-bath. The precipitate was filtered under reduced pressure, and washed with water (20 mL x 2 times). 2 mol/L aqueous solution of sodium hydroxide (100 mL) and water (30 mL) were added to the obtained precipitate. The mixture was refluxed with heating for 1 hour. Concentrated hydrochloric acid was dropped to the reaction solution in an ice-bath. The precipitate was filtered under reduced pressure, and then the precipitate was washed with water and acetone, dried under reduced pressure to give the title compound (15.7 g) having the following physical data. TLC: Rf 0.32 (methanol: ethyl acetate = 10 : 1); 1H-NMR (300MHz, DMSO-d6). delta 11.23, 11.44-11.10, 11.00, 4.70.
In diethyl ether; dimethyl sulfoxide; at 0 - 20℃; for 1.75h;
EXAMPLE 13; 4-Oxo-tetrahydro-furan-3-carboxylic acid methyl ester. To a stirred slurry of sodium hydride (1.67 g, 60% in mineral oil, 44.0 mmol) in dried ether was added with ethyl glycolate, dropwise over 15 minutes. The reaction was warmed up to room temperature for 30 min while stirring and concentrated in vacuo to provide white solid. The solid was treated with methyl acrylate (4.16 g, 49 mmol) in DMSO (20 mL) at 0 C. for 15 minutes and room temperature for 45 minutes. The mixture was poured into 5% H2SO4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over Mg2SO4 and concentrated to give 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester as a colorless oil. MS (ES): [M-1]- cal'cd for C6H7O3, 143; found: 143.
4-cyano-tetrahydro furane 3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium cyanide; sulfuric acid; In water;
To a stirred solution of 3.9 g (60 mmol) KCN in 5.5 ml of water at 4 C., a solution of 2.9 g (20 mmol) of 4-oxo-tetrahydro furane 3-carboxylic acid methyl ester in ether (26 ml) was added. To the precipitate of salts, 3.5 ml H2SO4 (18 N) was added and stirred for 16 hours. Then the organic solution was separated, the salts were washed twice with benzene, dried over sodium sulfate and concentrated in vacuo to give 4-cyano-tetrahydro furane 3-carboxylic acid methyl ester.
3-(Trifluoromethylsulfonyloxy)-2,5-dihydrofuran-4-carboxylic acid methyl ester A solution of <strong>[57595-23-0]tetrahydrofuran-3-one-4-carboxylic acid-methyl ester</strong> (P. Dowd, S.-C. Choi, Tetrahedron 1991, 47, 4847) (2.88 g, 20 mmol) in dichloromethane (200 ml) is mixed at -78 C. with diisopropyl(ethyl)amine (3.96 ml, 23.2 mmol). After 10 minutes, trifluoromethanesulfonic acid anhydride (3.88 ml, 23.2 mmol) is slowly added in drops to it. The batch is warmed to room temperature, stirred for 2 hours and concentrated by evaporation. The residue is purified by column chromatography (SiO2) with ethyl acetate-hexane: 3.62 g (66%) of product. 1H-NMR (CDCl3): delta=3.85 (s, 3H), 4.80 (t, 2H), 4.92 (t, 2H).
(e) 1-(3-Tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile A mixture of 3-tetrahydrofuranylhydrazine hydrochloride (6.2 g, 0.045 mol), sodium methoxide (2.4 g, 0.045 mol) and ethanol (70 ml) was refluxed under argon for 10 minutes. The reaction mixture was cooled to room temperature and 1-ethoxyethylidene malononitrile (6.1 g, 0.045 mol) was added. The reaction mixture was heated to reflux and stirred for 21 hours. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from water to afford 4.7 g (54%) of 1-(3-tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as yellow crystals, m.p. 134-135 C. when dried at 90 C. in high vacuum.
(b) Tetrahydrofuran-3-one A solution of <strong>[57595-23-0]methyl 3-oxo-tetrahydrofuranyl-4-carboxylate</strong> (14.5 g, 0.1 mol) in 10percent H2 SO4 (50 ml) was refluxed for 1 hour. The reaction mixture was cooled and extracted with ether (3*100 ml). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The pale gold residue was distilled to afford 6.8 g (79percent) of tetrahydrofuran-3-one, B.P. 74°-75° C. at 100 mm Hg.
To a suspension of 4-oxo-tetrahydroiuran-3-carboxylic acid methyl ester (prepared according to Dowd, P.; Choi, S-C. Tetrahedron, 1991, 47, 4847-4860; 800 mg, EPO <DP n="60"/>5.55 mmol, leq) in ethanol (20 ml) was added a solution of 2-fluoro-5-chloro- benzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated to 80C overnight. The reaction mixture was cooled to r.t. and the white precipitate was filtered and washed with cold ethyl actetate (2 x 20 ml). The crude residue was partitioned between chloroform and water. The aqueous layer was acidified to pH 4 and the product was extracted with chloroform (3 x 50 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc) to give a white solid 2-(5-chloro-2-fluoro- phenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (440mg, 30%)
With sodium carbonate; In water; at 20 - 80℃; for 25.5h;
To a solution of ethyl imidothiocarbamate hydrobromide (2,59 g) in water (25 mL) were added sodium carbonate (1.48 g) and methyl 4-oxotetrahydro-3-furancarboxylate (1.44 g), then the mixture was stirred for 3.5 hours at room temperature, 18 hours at 70C, then 4 hours at 80C. The reaction mixture was cooled to room temperature, the precipitate was collected, washed with water and diisopropyl ether sequentially to give the title compound (744 mg) having the following physical data. The former water layer was washed with ethyl acetate, extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated. The obtained residue was added by diisopropyl ether, the precipitated solid was collected to give the title compound (139 mg) having the following physical data. TLC: Rf0.65 (ethyl acetate); 1H NMR (CDCl3): delta 1.38 (t, J = 7.36 Hz, 3 H), 3.20 (q, J = 7.36 Hz, 2 H), 4.80 - 4.97 (m, 2 H), 4.98 - 5.15 (m, 2 H), 11.62 - 12.25 (m, 1 H).
Sodium hydride (4 g, 60% w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26% yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60% w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23% yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).
To a solution of DIEA (860 mI_, 4.99 mmol) in dry DCM (20 ml_) cooled to -78C under Argon was added a solution of methyl 4-oxotetrahydrofuran-3- carboxylate (628 mg, 4.63 mmol in 20 ml_ DCM) dropwise. The reaction mixture was stirred -78C for 30 minutes post addition and then treated dropwise with neat trifluoromethanesulfonic anhydride (820 mI_, 4.98 mmol). After stirring the reaction mixture for 2 h 0C, the reaction mixture was quenched by the cautious addition of cold water (11 ml_). The reaction mixture was warmed to ambient temperature and diluted with water and diethyl ether. The aqueous layer was extracted with diethyl ether and the combined organic layers washed with sat. NaHCC>3 and brine, then dried over MgS04. The resulting residue was concentrated in vacuo followed by flash chromatography (Si02, 0-50% DCM/heptane) to yield a pale yellow oil.
Sodium hydride (4 g, 60% w/w in oil dispersion, 100 mmol) was added to a flame-dried flask along with ether (100 mL). To the reaction flask under nitrogen atmosphere, methyl glycolate (7.7 mL, 100 mmol) was added slowly with constant stirring. The reaction mixture was allowed to stir at room temperature for 2 hours under nitrogen atmosphere then solvent was removed in vacuo. To the residue, methyl acrylate (10.8 mL, 120 mmol) in DMSO (50 mL) was added in one portion while the reaction flask was kept immersed in an ice bath. The reaction mixture was allowed to stir at 0 C for 15 minutes then at room temperature for 1 hour. The reaction mixture was then filtered through Celte'3', poured into ice-cold aqueous sulfuric acid solution (150 mL, 2N), and extracted with ether (2 x 200 mL). The organic layer was washed with saturated NaCl solution (500 mL), dried over anhydrous Na2S04, filtered, and solvent was removed in vacuo. The intermediate ketoester was recovered in 26% yield (3.7 g, 25.7 mmol) afterpurificationby column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.3). The ketoester intermediate (3.7g, 25.7 mmol) was added slowly to a solution of sodium hydride (1.4 g, 60% w/w in oil dispersion, 34 mmol) in ether (80 mL) at 0 C with constant stirring under nitrogen atmosphere. After 30 minutes, trifluoromethanesulfonic anhydride (5.3 mL, 31.4 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to stir at 0 C for an additional 1.5 hours then the reaction was poured into water (80 mL) and the layers were separated. The aqueous phase was washed with dichloromethane (2 x 60 mL) and the organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed in vacuo. The 2,5- dihydrofuran ester 13a was recovered in 23% yield (1.6 g, 5.8 mmol) after purification by column chromatography on silica using 25% ethyl acetate/hexanes as the eluent (Rf= 0.45). MS: calc. for C7H7F306S : 257.9 ; Found: GC-MS 7nl5 275 (MH).
With triethylamine;acetic acid; In ethanol; for 2h;Reflux;
To a solution of methyi-4-oxo-tetrahydrofuro-3-carboxylate (1.0 g, 6.94 mmol) in ethanol (16 niL) was added 4-bromobenzylamme (1.621 g5 7.29 mmol) followed by triethylamine (0.919 niL, 6.59 mmol) and acetic acid (0.119 mL, 2.082 mmol). The mixture was refluxed for 2 h. The mixture was concentrated in vacuo, taken up in EtOAc (30 mL) and water (30 mL). The <n="35"/>organic layer was then washed with saturated NaHCC>3 (20 mL). The aqueous layer was then extracted with EtOAc (3 x 40 mL) and the combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SC>4 and concentrated in vacuo to give a brown oil which solidified over time to an oily brown solid, which was taken on crude to the next reaction.
With triethylamine;acetic acid; In ethanol; for 6h;Reflux;
To a solution of metliyl-4-oxo-tetrahydrofuro-3-carboxylate (1.18 g, 8,19 mmol) in ethanol (5 mL), l-(l,3-benzothiazol-2~yl)methanamine hydrochloride (1.73 g, 8.60 ramol), triethylamine (1.20 mL, 8.60 mmol) and acetic acid (47 muL, 0.819 mmol) were added and the reaction mixture was heated to reflux for 6 hr, cooled to ambient temperature and concentrated in vacuo. The resultant residue was partitioned between EtOAc (10 mL) and H2O (5 mL) and the organic layer was washed with KHSO4 (1 X 5 mL), NaHCO3 (1 X 5 mL) brine (1 X 5 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography 10,15% EtOAc/hexanes on SiO2 (40 S+ column) afforded 610 mg of an orange foam: * H NMR (500 MHz, CDCl3) delta 3.73 (s, 3 H), 4.67 (d, 2 H, J- 6.8 Hz), 4.80 (s, 4 H), 7.40 (t, 1 H, J= 7.5Hz), 7.50 (I, 1 H, J= 12 Hz), 7.87 (d, 1 H, J= 8.0 Hz), 7.99 (d, 1 H, J= 8.2 Hz).
General procedure: To a stirred solution of 35b (3.0 g, 13.8 mmol) in AcOH (20 mL) was added ethyl 2-oxocyclopentanecarboxylate (2.37 g, 15.2 mmol) at room temperature and the reaction mixture was allowed to be heated at reflux and stirred for 3 h. The reaction mixture was cooled to room temperature and diluted with Et2O/hexane (1:3). The precipitates were collected by filtration to give 3-(2-methyl-4-methoxyphenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-ol (3.88 g, 91% yield) as an off-white powder, which was used for the next reaction without further purification.
General procedure: To a stirred solution of 35b (3.0 g, 13.8 mmol) in AcOH (20 mL) was added ethyl 2-oxocyclopentanecarboxylate (2.37 g, 15.2 mmol) at room temperature and the reaction mixture was allowed to be heated at reflux and stirred for 3 h. The reaction mixture was cooled to room temperature and diluted with Et2O/hexane (1:3). The precipitates were collected by filtration to give 3-(2-methyl-4-methoxyphenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-ol (3.88 g, 91% yield) as an off-white powder, which was used for the next reaction without further purification.
General procedure: To a solution of <strong>[57595-23-0]methyl 4-oxotetrahydrofuran-3-carboxylate</strong> (9c16a, 1.36 g) in methanol (15 mL) were added 4-chloro-2,5-difluorobenzamidine (815, 1.50 g) and sodium methoxide (420 mg), and the reaction mixture was stirred at room temperature overnight. The mixture was then stirred at 50 C for 9 h and cooled to room temperature. To the mixture were added 1 M hydrochloric acid (10 mL) and water (40 mL) at 5 C, and the reaction mixture was stirred at room temperature for 4 h. The resulting precipitates were collected by filtration, washed with water and dried in vacuo at 50 C to give 10c (756 mg, 68%) as a brown solid: 1H NMR (DMSO-d6) delta 4.85-4.93 (2H, m), 4.93-5.00 (2H, m), 7.82 (1H, dd, J = 6.4, 9.3 Hz), 7,89 (1H, d, J = 6.1, 9.5 Hz), 12.50-13.50 (1H, br); ESI-MS m/z 285, 287 [(M+H)+]
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h;
To a solution of <strong>[57595-23-0]methyl 4-oxotetrahydrofuran-3-carboxylate</strong> (2.60 mL, 18.0 mmol) and benzamidine hydrochloride (3.40 g, 21.7 mmol) in DMF (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.75 mL, 45.1 mmol) at room temperature. The reaction mixture was warmed to 80 C and stirred for 4 h. After cooling to room temperature, sat. NaHCO3 aqueous solution (100 mL) and H2O (100 mL) were added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/CHCl3 = 20% to 100%) to give 2-phenyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (53) (489 mg, 2.28 mmol, 13%) as a colorless amorphous solid. To a solution of 53 (485 mg, 2.26 mmol) in CH2Cl2 (20 mL) were added triethylamine (0.473 mL, 3.39 mmol), 4-dimethylaminopyridine (27.6 mg, 0.226 mmol) and trifluoromethanesulfonic anhydride (0.456 mL, 2.71 mmol). After stirring at room temperature for 15 h, sat. NaHCO3 aqueous solution was added to the reaction mixture and the mixture was extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 10%) to give the title compound (59.8 mg, 0.173 mmol, 8%) as a colorless solid. 1H NMR (CDCl 3) delta: 5.17 (2H, t, J = 2.0 Hz), 5.27 (2H, t, J = 2.0 Hz), 7.49-7.57 (3H, m), 8.41-8.44 (2H, m).
With potassium carbonate; In acetone; at 60℃; for 4h;
General procedure: To a mixture of methyl 4-oxotetrahydrothiophene-3-carboxylate 58a (160 mg, 1 mmol) and potassium carbonate (415 mg, 3 mmol) in acetone (5 mL) is added benzyl bromide (178 muL,1.5 mmol) and the mixture is stirred for 4 hours at 60 C. Water is added, the mixture is extracted with dichloromethane (3x). The combined organic phase is dried with Na2SO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) yields methyl 3-benzyl-4-oxotetrahydrothiophene-3-carboxylate 58b.
methyl 4-((3,4-dimethoxybenzyl)amino)-2,5-dihydrofuran-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 90℃; for 1.5h;
To a solution of (3 ,4-dimethoxyphenyl)methanamine (212 g, 1.27 mol) in anhydrous ethanol (1.1 L) was added dropwise the solution of crude 11 (300 g, assay 55% 1.15 mol) in anhydrous ethanol (1.1 L) over 30 mm using an addition funnel at 90 C (note: slow addition is crucial to good yield). The reaction was subsequently aged at 90 C for 1 h. After the reaction was complete shown by LCMS, the reaction was cooled to ambient temperature and concentrated. The crude residual was purified by trituation with methanol (5 V) to give methyl5 4-((3 ,4-dimethoxybenzyl)amino)-2,5-dihydrofuran-3 -carboxylate (14) as a solid. ?H NMR (CDC13, 400 MHz) : 7.08 (m, 1H), 6.46 (m, 2H), 4.76 (m, 4H), 4.19 (m, 2H), 3.81 (s, 3H), 3.81 (s, 3H), 3.69 (s, 3H), 2.69 (t, 1H). LC/MS (m/z): 294 (M+H).
In ethanol; at 90℃; for 1.5h;
Step B. Methyl 4- ( (3, 4-dimethoxybenzyl) amino) -2, 5-dihydrofuran-3-carboxylate (12)[0227][0228]To a solutio n of (3, 4-dimethoxyphenyl) methanamine (212 g, 1.27 mol) in anhydrous ethanol (1.1 L) was added dropwise the solution of crude 11 (300 g, assay 55 1.15 mol) in anhydrous ethanol (1.1 L) over 30 min using an addition funnel at 90 (note: slow addition is crucial to good yield) . The reaction was subsequently aged at 90 for 1 h. After the reaction was complete shown by LCMS, the reaction was cooled to ambient temperature and concentrated. The crude residual was purified by trituation with methanol (5 V) to give methyl 4- ( (3, 4-dimethoxybenzyl) amino) -2, 5-dihydrofuran-3-carboxylate (12) as a solid.1H NMR (CDCl3, 400 MHz) delta: 7.08 (m, 1H) , 6.46 (m, 2H) , 4.76 (m, 4H) , 4.19 (m, 2H) , 3.81 (s, 3H) , 3.81 (s, 3H) , 3.69 (s, 3H) , 2.69 (t, 1H) . LC/MS (m/z) : 294 (M+H)+.
methyl 4’-((3-((2-(tert-butoxy)-2-oxoethyl)carbamoyl)-4-hydroxy-2-oxofuro[3,4-b]pyridin-1(2H,5H,7H)-yl)methyl)-2-methyl-[1,1’-biphenyl]-4-carboxylate[ No CAS ]
tert-butyl 2-(4-hydroxy-2-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)methyl)-1,2,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxamido)acetate[ No CAS ]
tert-butyl 2-(4-hydroxy-2-oxo-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-6-yl)methyl)-1,2,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxamido)acetate[ No CAS ]
(R)-tert-butyl 3-(tert-butoxy)-2-(4-hydroxy-2-oxo-1-(4-(trifluoromethyl)benzyl)-1,2,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxamido)propanoate[ No CAS ]
methyl 4-((4-(trifluoromethyl)benzyl)amino)-2,5-dihydrofuran-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid; In ethanol; at 90℃; for 5h;
To a solution of methyl 4-oxotetrahydrofuran-3 -carboxylate (11, 50 g, 350 mmol) in anhydrous EtOH (1000 mL) was added (4-(trifluoromethyl) phenyl)methanamine (64 g, 360 mmol), followed by AcQH (60 mL). The reaction mixture was then heated to 90C and stirred for 5 hours when TLC showed that the reaction completed. The reaction mixture was concentrated under reduced pressure to removemost of the solvent. The residue was partitioned between EtOAc (1000 mL) and H20 (1000 mL), and the organic phase was washed with H20 (1000 mL) and brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure to afford methyl 4-((4-(trifluoromethyl)benzyl)amino)-2,5- dihydrofuran-3-carboxylate (12) as a solid, which was used directly in next step without further purification. LC/MS (m/z): 302 (M+H).
tert-butyl 2-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate[ No CAS ]
(E)-tert-butyl 2-(5-((4-(methoxycarbonyl)dihydrofuran-3(2H)-ylidene)amino)-1H-pyrazol-3-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With acetic acid; In ethanol; for 2h;Reflux;
To a solution of intermediate 4 (500 mg, 1.87 mmol) in EtOH (25 mL), methyl 4-oxotetra-hydrofuran-3-carboxylate (0.54 mg, 3.74 mmol, 2 eq.) and AcOH (1.07 mL, 18.7 mmol,10 eq.) were added. The mixture was stirred at reflux during two hours then cooled to roomtemperature. The reaction mixture was evaporated in vacuo and the residue was poured into asaturated solution of NaHCO3. The resulting mixture was extracted with EtOAc (3 x 50 mL).The combined organics were dried over magnesium sulfate and evaporated in the vacuogiving targeted intermediate 33 (700 mg, 100 % pure, 95 % yield).LCMS(M+ 1)=393.
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