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CAS No. : | 488-93-7 | MDL No. : | MFCD00005350 |
Formula : | C5H4O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IHCCAYCGZOLTEU-UHFFFAOYSA-N |
M.W : | 112.08 | Pubchem ID : | 10268 |
Synonyms : |
3-Furoic Acid
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 25.67 |
TPSA : | 50.44 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) : | -6.25 cm/s |
Log Po/w (iLOGP) : | 0.98 |
Log Po/w (XLOGP3) : | 1.03 |
Log Po/w (WLOGP) : | 0.98 |
Log Po/w (MLOGP) : | -0.36 |
Log Po/w (SILICOS-IT) : | 0.69 |
Consensus Log Po/w : | 0.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.58 |
Solubility : | 2.95 mg/ml ; 0.0263 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.68 |
Solubility : | 2.35 mg/ml ; 0.0209 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.92 |
Solubility : | 13.4 mg/ml ; 0.119 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.17 |
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 |
---|---|---|
78% | With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; Reflux | e. To a solution of 3-furoic acid 96 (54.4 g, 485 mmol), triethylamine (105 ml, 753 mmol), tert-butanol (25.2 mL, 786 mmol) in toluene (800 mL) was added dropwise at room temperature over 45 min period diphenyl phosphoryl azide (157.8 mL, 732 mmol). The resulting solution was heated at reflux for 6 h and at room temperature overnight. The reaction was diluted with water (1000 mL) and extracted twice with ethyl acetate (1000 ml). The organic layers were combined washed with water (800 mL), brine (800 mL), decolorized with activated charcoal, dried, filtered and concentrated in vacuo to furnish a brown semisolid. The semisolid was crystallized from dichloromethane (300 mL) and hexanes (600 mL) to furnish tert-butyl furan-3-ylcarbamate 97 (61.5 g, 78percent). 1H NMR (300 MHz, CDC13) δ 7.71 (s, IH), 7.30 - 7.24 (m, IH), 6.43 (s, IH), 6.27 (s, IH), 1.75 - 1.32 (s, 9H). |
76% | Stage #1: for 18 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water at 0℃; for 2 h; |
3-Furoic acid (5.60 g, 1.0 eq) was dissolved in tert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0° C. for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate (6.95 g, 76percent): 1H NMR (CDCl3, 400 MHz) δ 7.71 (bs, 1H), 7.27 (m, 1H), 6.27 (bs, 1H), 6.20 (bs, 1H), 1.50 (s, 9H); MS (Q1) 184 (M)+. |
76% | Stage #1: for 18 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water at 0℃; for 2 h; |
3-Furoic acid (5.6Og, 1.0 eq) was dissolved in fert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0 °C for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate 32 (6.95 g, 76percent) : 1H NMR (CDCl3, 400 MHz) δ 7.71 (bs, IH), 7.27 (m, IH), 6.27 (bs, IH), <n="139"/>6.20 (bs, IH), 1.50 (s, 9H) ; MS (Ql) 184 (M)+. |
76% | Stage #1: for 18 h; Heating / reflux Stage #2: at 0℃; for 2 h; |
3-Furoic acid (5.6Og, 1.0 eq) was dissolved in tert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0 0C for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate 32 (6.95 g, 76percent) : 1H NMR (CDCl3, 400 MHz) δ 7.71 (bs, IH), 7.27 (m, IH), 6.27 (bs, IH), 6.20 (bs, IH), 1.50 (s, 9H) ; MS (Ql) 184 (M)+. |
71% | With diphenyl phosphoryl azide; triethylamine In toluene for 6 h; Heating / reflux | Diphenylphosphoryl azide (78.9 mL) was added dropwise to a solution of 3-furoic acid (Aldrich) (27.2 g) in a mixture of toluene (400 mL), triethylamine (52.5 [ML)] and tert- butanol (35.1 [ML).] The solution was heated to reflux for 6 hours, cooled overnight and water added (500 mL). The mixture was extracted into EtOAc (3 x 500 mL) and the combined organics washed with water [(400 ML), BRINE] (400 mL), decolourised over activated charcoal, dried [(MGS04),] and the solvent removed to give 73 g of a brownish solid. Trituration with 1: 1 [DCM/ISOHEXANE] gave the title compound as a white solid (31.5 g, 71percent) ; [1H] NMR [(CDC13)] [8 1.] 50 (s, 9H), 6.22 (s, br, 1H), 6.27 (s, 1H), 7.26 (d, 1H), 7.69 (s, br, [1H)] ; MS [M/E] [MU 184.] |
70% | at 90℃; for 12 h; | 3-Furoic acid (2.8 g, 25 mmoL), diphenyl azidophosphate (6 ml, 27.5 mmoL) and triethylamine (5 mL, 35 mmoL) were added to tert-butanol (50 mL). The mixture was heated to 90° C. and stirred for 12 hours. After cooled to room temperature, aqueous sodium dicarbonate (2 N, 100 mL) was added. The mixture was filtrated, the filter cake was dissolved in ethyl acetate (100 mL), and washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give white solid 30-h (3.2 g, yield: 70percent). LC-MS (ESI): m/z=184 [M+H]+. |
54% | for 17 h; Heating / reflux | To a solution of 3-furoic acid (5.0 g, 44.61 mmol) in f-butanol (178 mL) were added diphenylphosphoryl azide (10.7 mL, 49.65 mmol) and triethylamine (8.9 mL, 63.85 mmol) and the mixture heated at reflux for 17 h. The resulting dark solution was cooled to RT, concentrated in vacuo to ~ 50 mL, then poured into an aqueous sat. solution OfNaHCO3 at 0 °C and stirred for 2 h. The resulting precipitate was collected by filtration, washed with a little water, then air dried. The resultant tan solid was purified by column chromatography to give the title compound as a white solid (4.4 g, 54 percent). [M + H]+ 184.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; 1,2-dichloro-ethane | ||
With sulfuric acid at 60℃; for 15h; | 1 Furan-3-carboxylic acid hvdrazide (Intermediate compound); A mixture of 3-furoic acid (25 g, 223 mmol), sulfuric acid (2.2 g, 22 mmol) and methanol (250 ml) was stirred at 60°C for 15 h. Hydrazine monohydrate (89.3 g, 1784 mmol) was added and the mixture was stirred at 60°C for 15 h. Methanol and excess of hydrazine was evaporated. The mixture was triturated with dry diethylether, filtered and washed with dry diethylether. Yield 22.7 g. | |
With sulfuric acid at 0 - 20℃; for 12h; |
With sulfuric acid Reflux; | ||
With sulfuric acid for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 350℃; for 0.0666667h; Supercritical conditions; Flow reactor; High pressure; | |
63% | With sulfuric acid for 16h; Reflux; Large scale; | |
43% | With sulfuric acid at 90℃; for 10h; | 3 Take compound IV-1 (1.12 g, 10 mmol)Soluble in ethanol (11.235mL, 0.89M),Concentrated sulfuric acid (522 μL, 9.8 mmol) was added and heated at 90 ° C for 10 h.After allowing the reaction to cool to room temperature,Evaporate the ethanol under reduced pressure,Add water (50mL),Adjust the pH to neutral with saturated sodium bicarbonate solution.Ethyl acetate extraction (20mL x 3),Combine the organic phase,Saturated saline solution (30mL x 2),Dry over anhydrous sodium sulfate.Evaporating the solvent under reduced pressure to give compound IV-2(yellow oil, 614 mg, yield 43%). |
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium aluminium hydride In diethyl ether 1) 10 deg C, 30 min, 2) 25 deg C, 1 h; | |
93% | With lithium aluminium hydride In diethyl ether at 0 - 20℃; for 1h; Schlenk technique; Inert atmosphere; | |
91% | With lithium aluminium hydride In diethyl ether |
91% | With lithium aluminium hydride In diethyl ether for 2h; | |
85% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 12h; | |
83% | With lithium aluminium hydride In tetrahydrofuran for 22h; Heating; | |
80% | With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 24h; | |
77% | With lithium aluminium hydride In diethyl ether for 6h; Ambient temperature; | |
63.1% | With borane-THF In tetrahydrofuran at 0 - 20℃; for 1h; | 69.69A Example 69A: furan-3-ylmethanol To a solution of furan-3-carboxylic acid (50 g, 446 mmol) in tetrahydrofuran(500 mL) was added a solution of borane in tetrahydrofuran (669 mL, 669 mmol) at 0 °C, and the mixture was stirred at 20 °C for 1 hour. One additional vial on 25 g scale and six additional vials on 50 g scale were set up as described above. The reactions conducted in parallel were combined for work up. After cooling to 0 °C, the reaction mixture was quenched with water until gas evolution had ceased. After bulk solvent removal, the resulting crude residue was then partitioned between saturated aqueous NaHCO3 and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (2 × 1000 mL). The combined organic phases were washed with brine (1000 mL), dried Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether: ethyl acetate= 3:1 to give the title compound (230 g, yield 63.1%) as a yellow oil.1HNMR (400 MHz,DMSO-d6) ppm 7.46 - 7.61 (m, 2 H), 4.34 (d, J=5.50 Hz, 2 H), 4.97 (t, J=5.50 Hz, 1 H), 6.44(d, J=0.63 Hz, 1 H). |
63.1% | With borane-THF In tetrahydrofuran at 0 - 20℃; for 1h; | 69A Example 69A: furan-3-ylmethanol To a solution of furan-3-carboxylic acid (50 g, 446 mmol) in tetrahydrofuran(500 mL) was added a solution of borane in tetrahydrofuran (669 mL, 669 mmol) at 0 °C, and the mixture was stirred at 20 °C for 1 hour. One additional vial on 25 g scale and six additional vials on 50 g scale were set up as described above. The reactions conducted in parallel were combined for work up. After cooling to 0 °C, the reaction mixture was quenched with water until gas evolution had ceased. After bulk solvent removal, the resulting crude residue was then partitioned between saturated aqueous NaHCO3 and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (2 × 1000 mL). The combined organic phases were washed with brine (1000 mL), dried Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether: ethyl acetate= 3:1 to give the title compound (230 g, yield 63.1%) as a yellow oil. 1HNMR (400 MHz, DMSO-d6) δ ppm 7.46 - 7.61 (m, 2 H), 4.34 (d, J=5.50 Hz, 2 H), 4.97 (t, J=5.50 Hz, 1 H), 6.44 (d, J=0.63 Hz, 1 H). |
59% | With lithium aluminium hydride In diethyl ether at 0 - 20℃; for 2h; | |
55.7% | With borane-THF In tetrahydrofuran at 20℃; for 2h; | 27.1 Step 1: Synthesis of furan-3-ylmethanol The furan-3-carboxylic acid (25 g, 0.22 mmol, 1.0 eq) was dissolved in tetrahydrofuran (330 mL).A borane-tetrafuran solution (1 mol/L, 330 mL) was slowly added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. TLC showed the reaction was completed, and methanol (40 mL) was slowly added dropwise in an ice bath to quench the reaction. Concentrated under reduced pressure, ethyl acetate (500 mL) was evaporated and evaporated.The crude product was purified by silica gel column chromatography (ethyl ether: ethyl acetate=4:1 v/v)Product (12 g, yield: 55.7%). |
With lithium aluminium hydride; diethyl ether | ||
6.8 g | With lithium aluminium hydride In diethyl ether for 6h; Heating; | |
With lithium aluminium hydride | ||
Multi-step reaction with 3 steps 1: thionyl chloride / 3 h / Inert atmosphere; Reflux 2: Reflux; Inert atmosphere 3: lithium aluminium hydride / diethyl ether / 20 °C / Inert atmosphere | ||
With BH3 In tetrahydrofuran at 0 - 20℃; for 1h; | 270.A Example 270A: furan-3-ylmethanol To a solution of furan-3-carboxylic acid (50 g, 446 mmol) in tetrahydrofuran(500 mL) was added a 1 N solution of borane in tetrahydrofuran (669 mL, 669 mmol) at 0 °C, and the mixture was stirred at 20 °C for 1 hour. One additional vial on 25 g scale and six additional vials on 50 g scale were set up as described above. The reactions conducted in parallel were combined for work up. After cooling to 0 °C, the reaction mixture was quenched with water until gas evolution had ceased. After bulk solvent removal, the resulting crude residue was then partitioned between saturated aqueous NaHCO3 and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (2 1000 mL). The combined organic phases were washed with brine (1000 mL), dried Na2SO4, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether: ethyl acetate= 3:1 to give the title compound (230 g, yield 63.1%). 1HNMR (400 MHz, DMSO-d6) d ppm 7.46 - 7.61 (m, 2 H), 4.34 (d, J=5.50 Hz, 2 H), 4.97 (t, J=5.50 Hz, 1H), 6.44 (d, J=0.63 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride In dichloromethane | |
92% | With thionyl chloride; N,N-dimethyl-formamide for 2h; Ambient temperature; | |
91.5% | With thionyl chloride In benzene for 7h; Heating; |
86% | With oxalyl dichloride In dichloromethane | |
85% | With thionyl chloride for 1.5h; Heating; | |
83% | With thionyl chloride In 1,2-dichloro-ethane for 12h; Heating; | |
81.3% | With thionyl chloride for 24h; Ambient temperature; | |
With thionyl chloride at 120℃; | ||
With thionyl chloride; benzene | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 44h; Ambient temperature; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 16h; Ambient temperature; | ||
With sulfuryl dichloride In benzene for 2h; Heating; | ||
With thionyl chloride for 18h; Ambient temperature; | ||
With 1,3,5-trichloro-2,4,6-triazine | ||
With thionyl chloride In benzene at 80℃; for 3h; | ||
With thionyl chloride for 4h; Heating; | ||
With thionyl chloride In benzene for 2h; Heating; | ||
With thionyl chloride In dichloromethane at 20℃; for 20h; | ||
With thionyl chloride In toluene at 115℃; for 3h; | ||
With thionyl chloride In water | 3 7-Oxabicyclo[2.2.1]hept-5-ene-5-isothiocyanatomethyl-cis-2,3-dicarboxylic Anhydride (ACL-2) STR16 EXAMPLE 3 7-Oxabicyclo[2.2.1]hept-5-ene-5-isothiocyanatomethyl-cis-2,3-dicarboxylic Anhydride (ACL-2) STR16 To 3-furoic acid (7.513 g, 67.02 mmol) was added thionyl chloride (7.5 mL, 102.8 mmol). The mixture was heated gradually to reflux; the reaction vessel was teed to a water aspirator to absorb HCl as it was liberated; the remaining arm of the tee was left open to the atmosphere. After 1 hour at reflux, the reaction mixture was concentrated under reduced pressure (20° C., 20 mm Hg). The crude product was purified by distillation to afford 3-furoyl chloride as a clear, colorless liquid in a yield of 8.796 g, (100 percent of theoretical) having a boiling point of 47°-48° C. at 20 mm Hg; 1H NMR (300 MHz, CDCl3) d 8.21 (s, 1H), 7.50 (s, 1H), 6.78 (s, 1H); 13C NMR (75 MHz, CDCl3) d 160.2, 152.1, 145.3, 124.6, 109.8; IR (neat) 1755 cm-1; MS m/e 130, 95 (base), 67. | |
With thionyl chloride | Reference 2 3-Furoyl chloride (5-1) Reference 2 3-Furoyl chloride (5-1) A mixture of furan-3-carboxylic acid (11.21g, 10.0 mmol) and thionyl chloride (14.5 mL, 20.0 mmol) was stirred at 40 °C for 2 hours 30 minutes. The reaction product was purified by distillation under reduced pressure to give 3-furoyl chloride 5-1 (11.89g, 91.0 %) as colorless crystals (Caution: compound 5-1 is a potent irritant). | |
With thionyl chloride at 20℃; for 12h; | ||
Stage #1: 3-Furoic acid With oxalyl dichloride In dichloromethane at 0℃; Stage #2: In dichloromethane at 20℃; for 10h; | 9 Preparation 9 Preparation 9 3-furoyl chloride 3-furoic acid (25 g, 0.192 mol) was dissolved in DCM (25 ml) and the solution was cooled to 0° C. and oxalyl chloride (39.0 g, 0.307 mol) was added dropwise. DMF (500) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 10 hours. Then, the reaction mixture was concentrated in vacuo at 20-30° C. until the residual volume of the reaction mixture became about 30 ml. The obtained residue was used in the next reaction without further purification | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane | ||
With oxalyl dichloride In dichloromethane at 0 - 20℃; | 9 Preparation 9: 3-furoyl chloride[339] 3-furoic acid (25 g, 0.192 mol) was dissolved in DCM (25 ml) and the solution was cooled to O0C and oxalyl chloride (39.0 g , 0.307 mol) was added dropwise. DMF (5O/i6) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 10 hours. Then, the reaction mixture was concentrated in vacuo at 20-300C until the residual volume of the reaction mixture became about 30 ml. The obtained residue was used in the next reaction without further purification | |
With thionyl chloride In toluene at 70℃; for 2.5h; | 42 Example 42; 5H-Furor3,2-ciϖ,81naphthyridin-4-one (42); 3-Furoic acid (2.5 g, 22.3 mmol), thionyl chloride (7.22 ml, 0.0992 mole) and toluene were combined and heated to 700C for 2.5 h. The mixture was concentrated, and then resuspended in CH2Cl2 (44 mL) and cooled to 0 0C. 2-Amino-3-bromopyridine (5.13 g, 29.6 mmol) and triethylamine (3.07 g, 30.3 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction was quenched with 5% HCl (40 mL), and the product was extracted with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with heptane / EtOAc (7 / 3) to provide furan-3-carboxylic acid (3-bromo-pyridin-2-yl)-(furan-3-carbonyl) amide (1.14 g) as a yellow solid.Furan-3-carboxylic acid (3-bromo-pyridin-2-yl)-(furan-3-carbonyl) amide (180 mg, 0.50 mmol), tristriphenylphosphinepalladium (58 mg, 0.05 mmol), potassium acetate (75 mg, 0.77 mmol) and dimethylacetamide (4 mL) were combined in a 10 ml Microwave tube and heated at 140 0C and 300 W for 30 minutes. The mixture was poured into 1:1 brine: water (15 mL) and extracted with ether (3x10 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with heptane: EtOAc (1:1) to provide 42. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.11 (d) 7.34 (dd) 8.16 (d) 8.33 (s) 8.55 (dd) 12.12 (br. s.) | |
With thionyl chloride at 20℃; for 16h; | ||
With thionyl chloride for 6h; Heating / reflux; | A mixture of 25 g of 3-furoic acid and 65 ml of thionyl chloride was heated to reflux for 6 hours. Then excess thionyl chloride was removed, and the residue was distilled under reduced pressure to give 25 g of 3-furoyl chloride as a colorless oil. | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran for 1h; Inert atmosphere; | ||
With thionyl chloride In dichloromethane for 2h; Cooling with ice; Reflux; | 1 [Reference Example 1] Synthesis of 2-amino-5-(3-furyl)-1,3,4-oxadiazole Thionyl chloride (3 mL) was added to a dichloromethane (10 mL) solution of 3-furancarboxylic acid (2.50 g, 22.3 mmol) under ice cooling, and the mixture was heated to reflux for 2 hours. The solvent was distilled off. After that, the residue was concentrated by the addition of toluene and added to a THF (50 mL) solution of thiosemicarbazide (4.47 g, 49.1 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. To the reaction solution, a saturated aqueous solution of sodium bicarbonate was added. The mixture was subjected to extraction with ethyl acetate and dried over anhydrous sodium sulfate, and then, the solvent was distilled off to obtain 1-(3-furoyl)thiosemicarbazide (3.03 g, 16.4 mmol) (yield: 74%). | |
With thionyl chloride; N,N-dimethyl-formamide In toluene for 16h; | 5.2.1. General procedure for the synthesis of acid chlorides (2a-f, 5a-c) General procedure: Heterocyclic carbolic acids refPreviewPlaceHolder[23], refPreviewPlaceHolder[24] and refPreviewPlaceHolder[25] (1 equiv) were suspended in dry toluene (150 mL) at room temperature. Thionyl chloride (5 equiv) was added dropwise. The reaction mixtures were stirred for 5 min at room temperature and then DMF (3-5 drops) was added. The mixtures were stirred for 16 h and then evaporated to dryness. The residues were used directly in the next step. | |
With oxalyl dichloride In dichloromethane at 20℃; for 12h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With thionyl chloride for 4h; Reflux; | ||
With thionyl chloride for 1h; Reflux; | ||
With thionyl chloride In dichloromethane for 1.5h; Inert atmosphere; Reflux; | ||
With oxalyl dichloride at 20℃; for 12h; | ||
With thionyl chloride at 20℃; for 4h; Inert atmosphere; Reflux; | 5 4.4.5 Synthesis of ethyl 3-furoate, 11 In a two-necked oven dried 50 mL flask, fitted with magnetic stirring and nitrogen atmosphere, 3-furoic acid (2 g, 17 mmol) was placed at room temperature and thionyl chloride (12.9 mL, 177 mmol) was added through the condenser. Then, the mixture was warmed up to reflux, maintaining this temperature for 4 h in order to get complete conversion of 3-furoic acid into 3-furoyl chloride. The excess of thionyl chloride was separated by distillation. Next, ethanol (10.3 mL, 177 mmol) was added to the resulting residue and the solution was warmed up to reflux. After 1 h, as verified by gas chromatography, the acid chloride acid disappeared and converted into ethyl 3-furoate. | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; | General Procedure for amide formation from carboxylic acids General procedure: Oxalyl dichloride (21 mmol, 1.05 equiv) was added to asuspension of the carboxylic acid (20 mmol, 1 equiv) in CH2Cl2(50 mL) at room temperature. A drop of DMF was added and the reaction stirredat room temperature for 1 h (bubbling ceased and the reaction becomes homogeneousduring this period). The volatiles were removed under vacuum, then the oilyresidue was dissolved in CH2Cl2 (50 mL) and cooled in anice-bath. The amine (20 mmol, 1 equiv) and triethylamine (22 mmol, 1.1 equiv)were added in CH2Cl2 (10 mL), and the reaction wasstirred for 30 min, before warming to room temperaure. The solution was washedwith sat. NH4Cl solution and brine, then dried over MgSO4,filtered and concentrated to give the following amides, which were used withoutfurther purification. | |
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | ||
With thionyl chloride for 3h; Reflux; | ||
With thionyl chloride In toluene at 20℃; for 1h; | ||
With thionyl chloride for 3h; Inert atmosphere; Reflux; | 2 Synthesis of N,N-diethyl-3-furamide31 8 In a three-necked oven-dried 100 mL round-bottomed flask fittedwith a condenser, an argon atmosphere, and efficient magneticstirrer, furoic acid 3 (5 g, 44.3 mmol) was placed. Thionyl chloride(12.9 mL, 177 mmol) was then slowly added though the condensertip and a CaCl2 tube was fitted to this end. The reaction mixturewas refluxed for 3 h, observing the release of HCl gas. The excessSOCl2 was removed under atmospheric distillation using a Vigreuxcolumn. In another flask, fitted with an addition funnel, magneticstirrer, and an argon atmosphere, a solution of diethylamine(13.88 mL, 133 mmol) in dry THF (10 mL) was prepared. The furoylchloride 11 obtained was diluted with dry THF (20 mL) and placedin the addition funnel. This solution was added dropwise to theamine solution at 0 C and with vigorous stirring. The reaction mixturewas stirred at room temperature overnight, which led to theformation of a white solid (diethyl ammonium chloride). The crudeproduct was concentrated to dryness in vacuo at room temperatureand the resulting residue diluted with ethyl acetate(100 mL) and washed with water (2 25 mL). The aqueous phasewas acidified with concentrated HCl up to pH = 3 and the resultingsolution was extracted with ethyl acetate (3 25 mL). All organicphases were combined, dried over anhydrous MgSO4, filtered,and concentrated to dryness in vacuo, to give a pure product(5.86 g, Y = 72%), as a colorless oil. IR (film): m = 3060, 2990,2970, 1630 (amide I st.), 1510 (amide II, st.), 1420, 1390, 1370,1320, 1300, 1220, 1160, 1120, 1070, 1020 cm1. 1H NMR(200 MHz, CDCl3): d = 1.21 (6H, t, J = 7.0 Hz, H20), 3.47 (4H, q,J = 7.0 Hz, H10), 6.58 (1H, dd, J1 = 1.8 Hz, J2 = 0.8 Hz, H4), 7.40(1H, t, J = 1.8 Hz, H5), 7.69 (1H, dd, J1 = 1.8 Hz, J2 = 0.8 Hz, H2)ppm. 13C NMR (50 MHz, CDCl3): d = 13.8 (C20), 41.7 (C10),90.2 (C3), 110.2 (C4), 142.6 (C5), 142.7 (C2), 164.1 (C6) ppm. MS[GC-MS(CI), NH3, 70 eV, 150 C]: m/z (%) = 185 (100, M+NH4),168 (79 (M+H+). Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84; N,8.38. Found: C, 64.70; H, 7.90; N, 8.35. GC (50 C, 1 min, 10 C/min, 250 C, 15 min): tR = 13.84 min. TLC (SiO2, hexane/ethylacetate, 50/50): Rf = 0.46 (developed as a white spot on a pinkbackground, with anisaldehyde/sulfuric acid). | |
With thionyl chloride at 70℃; for 4h; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 60℃; for 5h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 0℃; Inert atmosphere; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide for 1h; Reflux; | N-(2-Iodophenyl)-3-furamide (4a) A mixture of furan-3-carboxylic acid (4.01 g, 35.8 mmol), SOCl2 (11.5 mL, 159 mmol), DMF (0.28 mL,3.62 mmol), and CH2Cl2 (35 mL) was heated for 1 h under reflux. After the volatile materials wereremoved in vacuo, a solution of 2-iodoaniline (10.4 g, 47.5 mmol), Et3N (6.76 mL, 48.5 mmol) in CH2Cl2(95 mL) was dropwise added at 0 oC. The mixture was allowed to warm to rt and stirred for 2 h. Aftercooling to 0 oC, the mixture was acidified by a 10% HCl aqueous solution and extracted with CH2Cl2.The organic layer was successively washed with water, a 10% NaOH aqueous solution, and brine. Thesolution was dried over MgSO4 and evaporated to give a residue which was recrystallized from MeOH. Ayellow ocher solid of 4a (10.8 g, 96%) was obtained, mp 94.5-95.5 °C (MeOH) [lit.5a mp 93-94 °C(diisopropyl ether), lit.3c mp 95-97 °C]. 1H-NMR (400 MHz, CDCl3) δ: 6.80 (1H, dd, J = 1.2, 2.0 Hz,4-H), 6.88 (1H, ddd, J = 1.2, 7.6, 8.0 Hz, 4’-H or 5’-H), 7.39 (1H, ddd, J = 1.2, 7.6, 8.0 Hz, 4’-H or 5’-H),7.52 (1H, t, J = 1.6 Hz, 5-H), 7.80 (1H, dd, J = 1.6, 8.0 Hz, 3’-H or 6’-H), 7.89 (1H, s, NH), 8.10 (1H, dd,J = 1.2, 1.6 Hz, 2-H), 8.39 (1H, dd, J = 1.2, 8.4 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 90.2,108.4, 121.9, 123.1, 126.1, 129.6, 138.1, 138.9, 144.4, 145.5, 160.5. IR (KBr) νmax 748, 860, 1015, 1070,1161, 1323, 1433, 1516, 1578, 1659, 2300, 3150, 3317 cm-1. Anal. Calcd for C11H8INO2: C, 42.20; H,2.58; N, 4.47. Found: C, 42.47; H, 2.80; N, 4.41. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With thionyl chloride at 70℃; for 4h; | ||
With phosgene In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; Inert atmosphere; Cooling with ice; | ||
With thionyl chloride at 85℃; for 0.5h; Reflux; | ||
With thionyl chloride; N,N-dimethyl-formamide Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | ||
With thionyl chloride at 60℃; for 4h; Inert atmosphere; | ||
With thionyl chloride for 4h; Reflux; | 1.a Example 1.a After a) Thionyl chloride (65.3mL, 0.9mol) was added dropwise to the 3-carboxylic acid (25.1g, 0.224mol) in a dry 500 ml round-bottomed flask, the reaction mixture was stirred at reflux for 4 hours, cooled to room temperature after spin drying solvent to give compound 1 as a colorless oil, which was used without further purification in the next step. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | Synthesis of different aromatic chain substitutedchloride 6 General procedure: A five or six membered aromatic carboxylic acid 5 wasdissolved in CH2Cl2 with dropping three drop DMF. 1.5times the amount of oxalylchloride was cautiously addedinto the reaction solution at 0 °C. After stirring at ambienttemperature for 3 h, the reaction mixture was concentratedunder reduced pressure to give the corresponding acidchloride intermediate 6. The remaining acid chloride weresynthesized according to the method described above with ayield of 83-92%. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 2h; | 26 EXAMPLE 26 N-((2-Oxo-1,2-dihydroquinolin-4-yl)methyl)-N-phenylfuran-3-carboxamide Oxalyl chloride (86 μL, 1,0 mmol) was added to a solution of furan-3-carboxylic acid (94 mg, 0.84 mmol) and DMF (7 μL, 0.084 mmol) in dry DCM (10 mL) at RT. The resulting mixture was left to stir for 2 h, after which time it was concentrated to dryness under reduced pressure, and redissolved in NMP (2 mL). The resulting solution was added at RT to a separate mixture of 4-((phenylamino)methyl)quinolin-2(1H)-one (100 mg, 0.4 mmol) and DIEA (350 μL, 2.0 mmol) in NMP (3 mL). After 14 h, the reaction mixture was treated with neat propylamine (100 μL, 1.2 mmol), stirred for an additional 30 min at RT, then purified directly via reversed-phase semi-preparative HPLC to afford 40 mg (30%) of N-((2-oxo-1,2-dihydroquinolin-4-yl)methyl)-N-phenylfuran-3-carboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.81 (d, 1H), 7.51 (m, 2H), 7.29-7.38 (m, 4H), 7.22-7.19 (m, 4H), 6.29 (s, 1H), 5.99 (s, 1H), 5.25 (s, 2H). LCMS: 345.5 (M+H)+. | |
With thionyl chloride In toluene for 2h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 3h; Reflux; | ||
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; | 1.2 (2) Synthesis of 2-furoyl chloride Add 2-furancarboxylic acid (0.64 g, 5.7 mmol) and dichloromethane (20 mL) into the reaction flask, slowly add thionyl chloride (1.8 g, 14.3 mmol), 1 drop of DMF, and react at room temperature for 4 hours. The solvent was evaporated under reduced pressure to obtain 0.74 g of yellow oil, which was directly used in the next step. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | Acyl chlorides General procedure: The acid (5 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) and DMF (a few drops) added.Oxalyl chloride (6 mmol, 1.2 equiv.) was added dropwise to the solution, that was cooled in an icewater bath. The resulting mixture was allowed to stir at room temperature for an additional 4 h andthe solvent was evaporated to afford the crude acyl chloride, which was used directly in the nextstep. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogen In acetic acid at 20℃; for 24h; | |
58% | With sodium hydroxide; hydrogen at 20℃; for 78h; | |
With palladium on activated charcoal; acetic acid Hydrogenation; |
With hydrogen In acetic acid | ||
With hydrogen In ethanol for 288h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridinium hydrobromide perbromide; glacial acetic acid at 40℃; for 18h; | |
69% | With pyridinium hydrobromide perbromide In glacial acetic acid | |
60% | With pyridinium hydrobromide perbromide In glacial acetic acid |
60% | With pyridinium hydrobromide perbromide; glacial acetic acid at 35 - 40℃; for 5h; | |
58% | With pyridinium hydrobromide perbromide; glacial acetic acid at 40℃; for 24h; | 19.a (a) Synthesis of 5-bromofuran-3-carboxylic acid (Compound VII-2-1) 3-furoic acid (VII-1-1, 1.04 g, 9.3 mmol) was added to a solution of pyridinium tribromide (2.88 g, 9.0 mmol) in acetic acid (4 mL), and heated at 40 °C for 24 h. After adding satuYield d sodium carbonate solution to the reaction system to neutralize acetic acid, adding appropriate amount of ethyl acetate, washing with water and satuYield d brine successively, the organic layer was dried and concentYield d over anhydrous Na2SO4, and the residue was subjected to column chromatography to obtain a yellow solid. The yield is 58%. |
41% | With NBS In glacial acetic acid for 24h; Ambient temperature; | |
39% | With NBS; glacial acetic acid for 24h; Ambient temperature; | |
21% | With pyridinium tribromide; glacial acetic acid at 20 - 50℃; | 1 Step 1 5-Bromo-furan-3 carboxyhc acid[00359] Furan-3 -carboxyhc acid (Ig, 8 93mmol) is added to a solution of pyϖdmium hydrobromide perbromide (3 02g, 9 46mmol) m acetic acid (5mL) The reaction mixture is stirred at 5O0C for 5 hours, then at room temperature overnight After removing the solvent in vacuo, water is added and a precipitate is formed The solid is collected by filtration and dϖed to yield the title compound (0 364g, 21%) HPLC (254nm) Rt 2 65min (88%) |
15.49% | With pyridinium hydrobromide perbromide; glacial acetic acid at 40℃; for 12h; | I-51a: 5-Bromofuran-3-carboxylic acid To a mixture of pyridinium tribromide (138.39 g, 432.71 mmol) in AcOH (150 ml) was added furan-3-carboxylic acid (50 g, 446.10 mmol). The mixture was stirred at 40°C for 12 h. The mixture was concentrated, diluted with water (500 ml), extracted with EA (400 ml*2), dried with Na2SO4, filtered and concentrated. The residue was purified by Prep. RP LC (flow: 400 ml/min; gradient: from 90% H2O (0.1% FA)/10% ACN to 69% H2O (0.1% FA)/31% ACN in 96 min; 69% H2O (0.1% FA)/31% ACN to 64% H2O (0.1% FA)/36% ACN in 21 min; column: Phenomenex luna C18, 15 μm, 100 Å, I.D.150 mm*H400 mm) to give the title compound (13.5 g, 15.49% yield) as yellow solid.1H NMR (MeOD, 400 MHz): δ ppm 8.14 (1 H), 6.71 (1 H) |
15.49% | With pyridinium hydrobromide perbromide; glacial acetic acid at 40℃; for 12h; | I-51a: 5-Bromofuran-3-carboxylic acid To a mixture of pyridinium tribromide (138.39 g, 432.71 mmol) in AcOH (150 ml) was added furan-3-carboxylic acid (50 g, 446.10 mmol). The mixture was stirred at 40°C for 12 h. The mixture was concentrated, diluted with water (500 ml), extracted with EA (400 ml*2), dried with Na2SO4, filtered and concentrated. The residue was purified by Prep. RP LC (flow: 400 ml/min; gradient: from 90% H2O (0.1% FA)/10% ACN to 69% H2O (0.1% FA)/31% ACN in 96 min; 69% H2O (0.1% FA)/31% ACN to 64% H2O (0.1% FA)/36% ACN in 21 min; column: Phenomenex luna C18, 15 μm, 100 Å, I.D.150 mm*H400 mm) to give the title compound (13.5 g, 15.49% yield) as yellow solid.1H NMR (MeOD, 400 MHz): δ ppm 8.14 (1 H), 6.71 (1 H) |
With chloroform; bromine | ||
With pyridinium hydrobromide perbromide; glacial acetic acid at 40℃; for 16h; | 1.d.i (d) (4- [ (5-Phenyl-furan-3-carbonyl)-amino)-phenyl)-acetic acid (10) (i) To a stirred solution of pyridinium tribromide (14.3g, 44.6mmoles) in acetic acid (20 ml) was added 3-furoic acid (5g, 44.6mmoles). The resulting mixture was heated at 40°C for 16 hours. The acetic acid was evaporated; the residue was dissolved in dichloromethane (50ml), washed with water (3x50ml) and dried (MgS04). The solvent was evaporated and the residue was purified by HPLC (gradient: 20% acetonitrile/80% water containing 0.1% trifluoroacetic acid to 80% acetonitrile/20% water at a rate of 1%/min) to afford 5-Bromo-furan-3-carboxylic acid (7) as a white solid. LC/MS System A; Rt = 2.52mins, m/z (ES-) = 189/191 (M-H for C5H3Br03). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 250℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With quinoline; copper |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; | |
65% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 20℃; for 1h; Inert atmosphere; | |
With lithium diisopropyl amide 1.) THF, -78 deg C, 30 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With diphenyl phosphoryl azide; triethylamine; In toluene; at 20℃;Reflux; | e. To a solution of 3-furoic acid 96 (54.4 g, 485 mmol), triethylamine (105 ml, 753 mmol), tert-butanol (25.2 mL, 786 mmol) in toluene (800 mL) was added dropwise at room temperature over 45 min period diphenyl phosphoryl azide (157.8 mL, 732 mmol). The resulting solution was heated at reflux for 6 h and at room temperature overnight. The reaction was diluted with water (1000 mL) and extracted twice with ethyl acetate (1000 ml). The organic layers were combined washed with water (800 mL), brine (800 mL), decolorized with activated charcoal, dried, filtered and concentrated in vacuo to furnish a brown semisolid. The semisolid was crystallized from dichloromethane (300 mL) and hexanes (600 mL) to furnish tert-butyl furan-3-ylcarbamate 97 (61.5 g, 78%). 1H NMR (300 MHz, CDC13) delta 7.71 (s, IH), 7.30 - 7.24 (m, IH), 6.43 (s, IH), 6.27 (s, IH), 1.75 - 1.32 (s, 9H). |
76% | 3-Furoic acid (5.60 g, 1.0 eq) was dissolved in tert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0 C. for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate (6.95 g, 76%): 1H NMR (CDCl3, 400 MHz) delta 7.71 (bs, 1H), 7.27 (m, 1H), 6.27 (bs, 1H), 6.20 (bs, 1H), 1.50 (s, 9H); MS (Q1) 184 (M)+. | |
76% | 3-Furoic acid (5.6Og, 1.0 eq) was dissolved in fert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0 C for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate 32 (6.95 g, 76%) : 1H NMR (CDCl3, 400 MHz) delta 7.71 (bs, IH), 7.27 (m, IH), 6.27 (bs, IH), <n="139"/>6.20 (bs, IH), 1.50 (s, 9H) ; MS (Ql) 184 (M)+. |
76% | 3-Furoic acid (5.6Og, 1.0 eq) was dissolved in tert-butanol (200 ml) and treated with triethylamine (10 ml, 1.4 eq) and diphenyl phosphoryl azide (12 ml, 1.1 eq). Mixture was heated at reflux for 18 h. Reaction mixture was cooled to room temperature, then concentrated to 50 ml and poured into saturated aq. NaHCO3. Mixture was stirred at 0 0C for 2 h. Solid was collected by filtration and dried under high vacuum. The crude reaction mixture was purified by flash chromatography to yield tert-butyl furan-3-ylcarbamate 32 (6.95 g, 76%) : 1H NMR (CDCl3, 400 MHz) delta 7.71 (bs, IH), 7.27 (m, IH), 6.27 (bs, IH), 6.20 (bs, IH), 1.50 (s, 9H) ; MS (Ql) 184 (M)+. | |
71% | With diphenyl phosphoryl azide; triethylamine; In toluene; for 6h;Heating / reflux; | Diphenylphosphoryl azide (78.9 mL) was added dropwise to a solution of 3-furoic acid (Aldrich) (27.2 g) in a mixture of toluene (400 mL), triethylamine (52.5 [ML)] and tert- butanol (35.1 [ML).] The solution was heated to reflux for 6 hours, cooled overnight and water added (500 mL). The mixture was extracted into EtOAc (3 x 500 mL) and the combined organics washed with water [(400 ML), BRINE] (400 mL), decolourised over activated charcoal, dried [(MGS04),] and the solvent removed to give 73 g of a brownish solid. Trituration with 1: 1 [DCM/ISOHEXANE] gave the title compound as a white solid (31.5 g, 71%) ; [1H] NMR [(CDC13)] [8 1.] 50 (s, 9H), 6.22 (s, br, 1H), 6.27 (s, 1H), 7.26 (d, 1H), 7.69 (s, br, [1H)] ; MS [M/E] [MU 184.] |
70% | With diphenyl phosphoryl azide; triethylamine; at 90℃; for 12h; | 3-Furoic acid (2.8 g, 25 mmoL), diphenyl azidophosphate (6 ml, 27.5 mmoL) and triethylamine (5 mL, 35 mmoL) were added to tert-butanol (50 mL). The mixture was heated to 90 C. and stirred for 12 hours. After cooled to room temperature, aqueous sodium dicarbonate (2 N, 100 mL) was added. The mixture was filtrated, the filter cake was dissolved in ethyl acetate (100 mL), and washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give white solid 30-h (3.2 g, yield: 70%). LC-MS (ESI): m/z=184 [M+H]+. |
54% | With diphenyl phosphoryl azide; triethylamine; for 17h;Heating / reflux; | To a solution of 3-furoic acid (5.0 g, 44.61 mmol) in f-butanol (178 mL) were added diphenylphosphoryl azide (10.7 mL, 49.65 mmol) and triethylamine (8.9 mL, 63.85 mmol) and the mixture heated at reflux for 17 h. The resulting dark solution was cooled to RT, concentrated in vacuo to ~ 50 mL, then poured into an aqueous sat. solution OfNaHCO3 at 0 C and stirred for 2 h. The resulting precipitate was collected by filtration, washed with a little water, then air dried. The resultant tan solid was purified by column chromatography to give the title compound as a white solid (4.4 g, 54 %). [M + H]+ 184.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 3-Furoic acid With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 0.5h; Stage #2: With iodine In tetrahydrofuran; hexane at 20℃; for 2h; | 2-Iodofuran-3-carboxylic acid A solution of furan-3-carboxylic acid (4.41 g, 39.3 mmol) in THF (40 mL) was dropwise added to asolution of nBuLi (55.0 mL, 9.07 mol, 1.65 M in hexane) in THF at -78 oC. The mixture was allowed towarm to rt and stirred for 30 min. After cooling to -78 oC, a solution of I2 (11.0 g, 43.3 mmol) in THF (60mL) was dropwise added to the mixture, then the mixture was warmed to rt and allowed to stand for 2 h.After a 10% HCl aqueous solution was added to acidify the mixture, an extractive work-up with Et2O wascarried out. The organic layer was successively washed with Na2S2O3 and brine, then dried over MgSO4.After evaporation, the resulting residue was subjected to silica gel column chromatography withAcOH/1,1,2,2-tetrachloroethane (1/100) to give a colorless solid of the title compound (5.77 g, 62%), mp168.2-170.0 °C (CHCl3) [lit.10 mp 148-150 °C]. 1H-NMR (400 MHz, CDCl3) δ: 6.79 (1H, d, J = 2.0 Hz,4-H), 7.61 (1H, d, J = 2.0 Hz, 5-H). 13C-NMR (100 MHz, CDCl3) δ: 99.9, 112.9, 123.6, 148.7, 167.9. IR(KBr): νmax 741, 889, 1180, 1312, 1501, 1564, 1690 cm-1. Anal. Calcd for C5H3IO3: C, 25.23; H, 1.27. Found: C, 25.32; H, 1.45. |
62% | Stage #1: 3-Furoic acid With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 0.5h; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran; hexane at -78 - 20℃; for 2h; Inert atmosphere; | |
57% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran; hexane at -80 - -30℃; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran; diethyl ether; hexane at -90 - 20℃; |
With iodine; lithium diisopropyl amide 1.) hexane, THF, -78 deg C, 20 min, 2.) hexane, THF, ether; Multistep reaction; | ||
Stage #1: 3-Furoic acid With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 0.5h; Stage #2: With iodine In tetrahydrofuran at 20℃; | 13.1 Step 1: 2-lodofuran-3-carboxylic acid Step 1: 2-lodofuran-3-carboxylic acid: o a stirring solution of furan-3-carboxylic acid (5 g, 44.6 mmol) in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere at -78 °C was added BuLi (44.6 ml, 1 12 mmol) dropwise. After stirring for 0.5 h, cooling was switched off and the mixture allowed to warm to room temperature. During warming, iodine (12.5 g, 49.1 mmol) as a solution in anhydrous tetrahydrofuran (30 ml) and added dropwise to the stirring mixture. Water was added (100 ml) and the organic solvents were removed in vacuo. The aqueous solution was acidified to ca pH 1 using 2M hydrochloric acid (aq) solution (ca 10-20 ml). The precipitated solid was collected by filtration and dried under vacuum and flowing nitrogen for 16 h to afford the title compound (6.21 g, 59 %) that was used in the next step without further purification. LCMS RT = 0.78 min, M-H" = 236.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 5% 2: 74% | With tert-Amyl alcohol; sodium hydride In tetrahydrofuran at 40℃; for 36h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 74% 2: 5% | With methanol; tert-Amyl alcohol; sodium hydride In tetrahydrofuran at 40℃; for 36h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 25 - 55℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 3h; | 10.b Step b); Acetyl chloride (0.4 ml.) was added dropwise to a solution of compound 14 (0.154 g, 0.334 mmol) in methanol (4 ml.) at 0°C. The reaction mixture was then stirred at rt over night, then concentrated. The residue was redissolved twice in dry DMF (5 ml) and concentrated to dryness, then again dissolved in DMF (6 ml_). 3-Furoic acid (45 mg, 0.401 mmol) and DIEA (221 L, 1.34 mmol) was added to the solution before it was cooled to 0°C and HATU (140 mg, 0.367 mmol) was added. The reaction was stirred for 3 hours at room temperature before the solvent was removed by rotary evaporation. The crude mixture was dissolved in EtOAc (20 ml.) and washed with 10% citric acid (aq) (10 ml.) and NaHCO3 (sat aq) (10 ml_). The organic phase was dried with Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (heptane: ethyl acetate 1 :1 -> 1 :2) to give the product as a transparent oil/solid in 87 % yield (132 mg).LRMS (M+H) 455. NMR (CDCI3, 400 MHz):1.05 (s, 3H), 1.35- 1.52 (m, 4H), 1.56- 1.72 (m, 5H), 1.89 (dd, 1 H, J = 14.6, 3.3), 3.24 (s, 3H), 3.42 (s, 3H), 3.47 (d, 1 H, J = 10.4), 3.70 (d, 1 H, J = 10.0), 3.91 (d, 1 H, J = 10.2), 4.07- 4.13 (m, 1 H), 4.50 (dd, 1 H, J = 10.2, 7.4), 4.58 (dd, 1 H, J = 5.4, 5.4), 4.71 (d, 1 H1 J = 5.5), 4.98 (ddd, 1 H1 J = 8.9, 8.9, 3.4), 6.47 (d, 1 H1 J = 8.3), 6.58 (bs, 1 H), 7.40 (dd, 1 H, J = 1.7, 1.7), 7.89 (bs, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) LDA / 1.) THF, hexane, -78 deg C, 30 min, 2.) THF, hexane, from -78 deg C to RT, 30 min 2: Na, NH3 (liq.) / tetrahydrofuran / 1 h | ||
Multi-step reaction with 2 steps 1: lithium di-isopropylamide (2 equiv.) / tetrahydrofuran; hexane / 0.5 h / -78 °C 2: 0.26 g / tetrahydrofuran; hexane / 0.5 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: boron fluoride ether adduct 2: aq. NaOH solution; potassium permanganate |
Yield | Reaction Conditions | Operation in experiment |
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75% | With N-ethyl-N,N-diisopropylamine; HATU In DMF (N,N-dimethyl-formamide) at 20℃; for 18h; | 55 (3R,3AS,6AR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-1-{4-[3-(3-furoylamino)propoxy]benzyl}-2-hydroxypropylcarbamate (261) A solution of 44 mg (0.068 mmol) of (3R,3AS,6AR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 15 mg (0.14 mmol) of 3-furoic acid, and 36 μL (0.20 mmol) of N,N-diisopropylethylamine in 2 ML of anhydrous DMF was treated with 52 mg (0.14 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and the resulting solution was stirred at RT. After 18 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 97:3 CH2Cl2/MeOH) to afford 38 mg (75%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.88 (s, 1H), 7.38 (s, 1H), 7.29 (d, 1H), 7.10 (m, 3H), 6.84 (d, 1H), 6.76 (d, 2H), 6.56 (s, 1H), 6.34 (br s, 1H), 6.05 (s, 2H), 5.60 (d, 1H), 5.00 (m, 2H), 4.01 (t, 2H), 3.90 (dd, 1H), 3.80 (m, 3H), 3.64 (m, 2H), 3.55 (q, 2H), 3.17-2.63 (m, 8H), 2.03 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 744(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-Furoic acid With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 1.5h; Stage #2: carbon dioxide In tetrahydrofuran; hexanes for 1h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexanes at -10℃; | 9.1 n-Butyllithium (2.5M in hexanes, 196 mL, 491 mmol) was introduced into a dry 3 L 3-necked flask fitted with an addition funnel, argon inlet, and mechanical stirrer. The mixture was diluted with dry THF (500 mL), and cooled to -78 °C. 3-furoic acid (25 g, 223 mmol) was added as solution in THF (500 mL) dropwise. The mixture was stirred for 1.5 h, at which point dry carbon dioxide was bubbled through the reaction mixture for 1 h. After warming gradually to -10 °C, the resultant thick white slurry was treated with aqueous HCl (2 N, 446 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3 x 300 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to afford crude furan-2,3-dicarboxylic acid as an orange solid (44 g) which was used without further purification. 1H NMR (300 MHz, d6-acetone) δ 7.06 (d, J = 1.7, 1), 7.97 (d, J = 1.7, 1), 10.7 (bs, 2H);TLC (CHCl3/MeOH/H2O 6:4:1) Rf = 0.56. | |
Stage #1: 3-Furoic acid; carbon dioxide With n-butyllithium In tetrahydrofuran; hexanes at -78 - -10℃; for 2.5h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexanes; water | 9.1 Step 1 n-Butyllithium (2.5M in hexanes, 196 mL, 491 mmol) was introduced into a dry 3 L 3-necked flask fitted with an addition funnel, argon inlet, and mechanical stirrer. The mixture was diluted with dry THF (500 mL), and cooled to -78° C. 3-furoic acid (25 g, 223 mmol) was added as solution in THF (500 mL) dropwise. The mixture was stirred for 1.5 h, at which point dry carbon dioxide was bubbled through the reaction mixture for 1 h. After warming gradually to -10° C., the resultant thick white slurry was treated with aqueous HCl (2 N, 446 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to afford crude furan-2,3-dicarboxylic acid as an orange solid (44 g) which was used without further purification. 1H NMR (300 MHz, d6-acetone) δ7.06 (d, J=1.7, 1), 7.97 (d, J=1.7, 1), 10.7 (bs, 2H);TLC (CHCl3/MeOH/H2O 6:4:1) Rf=0.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); dichloromethane; at 0 - 20℃; for 24h; | To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0 C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS(M+H, 242). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | A3.a Example A3; a. Preparation of intermediate compound 9; EDCI (0.0062 mol) was added at room temperature to a mixture of (0.0052 mol) (prepared according to the teachings in W02001/030780, of which the content is herein included by reference), 3-furancarboxylic acid (0.0062 mol), HOBT (0.0062 mol) and Et3N (0.0052 mol) in CH2Cl2 (10 ml). The mixture was stirred at room temperature overnight. H20 was added. The mixture was extracted with CH2C12. The organic layer was separated, dried (MgS04), filtered, and the solvent was evaporated. Yield: 1.7 g of intermediate compound 9 (100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | 25 The first step of Scheme 4: To a solution of 5-(4-amino-phenyl)-4-bromo-3-ethoxycarbonylmethoxy-5-phenyl-thiophene-2-carboxylic acid methyl ester (45 mg, 0.1 mmol) in CH2Cl2 was added furan-3-carboxylic acid (2 eq.) and EDCI (3 eq.). The resultant reaction mixture was stirred at room temperature until the disappearance of the starting material as monitored by TLC. The crude reaction mixture was concentrated and directly subjected to column purification on CombiFlash-sq 16× to give 4-bromo-3-ethoxycarbonylmethoxy-5-{4-[(furan-3-carbonyl)-amino]-phenyl]-thiophene-2-carboxylic acid methyl ester (36 mg, 70%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.32 (t, J=7.07 Hz, 3H) 3.88 (s, 3H) 4.30 (q, J=7.07 Hz, 2H) 4.92 (s, 2H) 6.74 (dd, J=1.89, 0.88 Hz, 1H) 7.49 (s, 1H) 7.52 (m, 1H) 7.70 (m, 4H) 8.07 (dd, J=1.52, 0.76 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compounds 41-70 were part of a parallel set prepared in library plate format according to General Procedure L, outlined below. ; L. General Procedure for Plate Preparation-Amide Formation XXI: Resin bound deprotected biarylphenol XVII (prepared from intermediate XII, boronates XIVd and XIVe, following general procedures D-F) was distributed into a 96 well plate, 10 mg of resin (0.013 mmol) per well. To the resin 400 mul of dichloromethane was added, followed by 100 mul of DIEA, followed by 0.13 mmol (10 equiv) of heterocyclic carboxylic acid XXa-XXn was added followed by 61 mg (0.13 mmol, 10 equiv) of PyBrop. The plate was shaken at room temperature for 24 hours, then drained and washed with dichloromethane, methanol/dichloromethane, dimethylformamide, methanol/dichloromethane and dichloromethane. The compounds were cleaved with TFA/dichloromethane (600 mul, 1:1) into a 96 deep well plate and submitted for testing without further purification. (Mass spec results obtained are shown in Table 4). Carboxylic Acids Het-COOH XX: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-Furoic acid; 4-(3-chloro-phenylethynyl)-piperidin-4-ol With benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 0℃; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 4h; | 1 Example: 1 [4-(3-Chloro-phenylethynyl)-4-hydroxy-piperidin-1-yl]-furan-3-yl-ι; A solution of 4-(3-Chloro-phenylethynyl)-piperidin-4-ol (0.707 g, 3 mmol) and furane-3- carboxylic acid (0.403 g, 3.6 mmol) in DMF (12 ml) was treated with Et3N (0.501 ml, 3.6 mmol) and HOBt (0.405 g, 3 mmol), and cooled to 0° C. EDC (0.690 g, 3.6 mmol) was added and the ice bath was removed. After stirring for 4 h, 2M NaHCO3 (100 ml) was added and the mixture was extracted with DCM (2x100 ml). The combined extracts were washed with 0.5 M citric acid (1x100 ml) and brine (1x100 ml) and dried over Na2SO4. Filtration and evaporation of the solvents afforded a yellowish oil (1.03 g). Chromatography on SiO2 EPO (EtOAc/cyclohexanol 1 :1) afforded a colorless oil which was crystallized from Et2O/hexane which led to the title compound as white crystals (0.645 g, 65%). Mp: 93-94°C;MS (LC/MS): 330.3 [M+H]; TLC Rf: 0.49 (EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide; In tetrahydrofuran; THF-ethylbenzene-heptane; | (14) 2-Pivaloyl-3-furoic acid A solution of 3-furoic acid (8.97 g, 0.08 mol) in tetrahydrofuran (200 ml) was cooled to -70 C. and a 2.0M solution of lithium diisopropylamide in THF-ethylbenzene-heptane (80 ml, 0.16 mol) was added dropwise over 3/4 hr at -70 to -20 C. under nitrogen to give a tan suspension. A red solution formed after stirring for 113/4 hours at -20 C. To this solution was added <strong>[64214-60-4]N-methoxy-N-methylpivalamide</strong> (11.67 g, 0.08 mol) in tetrahydrofuran (10 ml) at -40 C. The reaction mixture was left at ambient temperature overnight. Then,it was cooled in ice and neutralized with 6N ethanolic hydrogen chloride (50 ml). The neutralized solution was acidified with 1.5N HCl (150 ml) and was extracted with ether (300 ml). The ether extracts were washed with saturated NaCl, dried over Na2 SO4, filtered and concentrated in vacuo to a brown solid (15.4 g). Chromatography on silica gel using hexane-THF-acetic acid (10-2-0.2) gave a yellow solid (9.8 g), mp 85-89 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 3-Furoic acid; (+)-(1R,3R)-3-amino-1-(3-chloro-phenylethynyl)-cyclohexanol With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; | 1 Examplei : Furan-3-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide; EPO (+)-(1R,3R)-3-Amino-1-(3-chloro-phenylethynyl)-cyclohexanol (115 mg, 0.46 mmol) was dissoived in DMF (5 ml) and treated with furan-3-carboxylic acid ((63 mg, 0.55 mmol) and EDC (108 mg, 0.55 mmol). After stirring for 1.5 h at room temperature, Et3N (0.55 mmol) was added and stirring continued for 18 h. A second batch of EDC (108 mg, 0.55 mmol) was added and stirring continued for 6 h. EtOAc was added and the mixture washed with aqueous sodium bicarbonate and brine. Drying of the organic phase with Na2SO4, filtration and evaporation afforded a crude product (263 mg) which was purified by chromatography on silica gel to afford the title compound as a white solid (105 mg, 66%). MS (LC/MS): 344.2 [M+H]; [α]D = + 95.6° (c=0.5, MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; triethylamine; In chloroform; N,N-dimethyl-formamide; acetonitrile; | EXAMPLE 7 To a stirred solution of 12.5 ml of N,N-dimethylformamide in 7.5 ml of acetonitrile was added slowly a solution of 0.9 ml of oxalyl chloride in 10 ml of acetonitrile at -20 C. and reaction temperature was raised to 20 C. from -15 C. over a period of 30 minutes. To the reaction mixture was slowly added 1.77 g. of furan-3-carboxylic acid at -25 C. and stirring was continued for 16 hours at room temperature. To the reaction mixture were slowly added 1.272 g. of 4-carbamoylimidazolium-5-olate and 5 ml of pyridine at 0 C. and stirring was continued for four hours at room temperature. After 3.8 ml of triethylamine was added to the reaction mixture, separated precipitates were filered off. To the filtrate was added 170 ml of chloroform, then separated crystals were filtered off and dried to give 1.55 g. of 5-carbamoyl-1H-imidazole-4-yl furan-3' -carboxylate. m.p. 173 C. (dec.) Recrystallized was crude material from methanol and water. m.p.: 198 C. (dec.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 25.0℃; for 12.0h; | To a solution of 4-bromo-1 H-pyrrolo[2,3-b]pyridin-3-amine (220 mg, 1.04 mmol)[prepared according to Example 89], 3-furoic acid (128 mg, 1.14 mmol) and diisopropylethyl amine (595 mul_, 3.42 mmol) in DCM (10 mL) at 25 C was added PyBrop (580 mg, 1.25 mmol) in one portion. After 12h, the solution was partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified using column chromatography (silica, 3% MeOH in DCM) affording the title compound (290 mg, 91%) as an orange oil: LC-MS (ES) m/z = 307 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 13: Synthesis of 7-(furan-3-ylcarbonyl)-2,7-diazabicyclo[3.3.0]octane; The following procedures are exemplary of those used to produce various 7- (heteroarylcarbonyl)-2,7-diazabicyclo[3.3.0]octanes. <n="78"/>To a solution of furan-3-carboxylic acid (0.084 g, 0.75 mmol) in anhydrous THF (5 ml.) was added HBTU (0.28 g, 0.75 mmol), followed by triethylamine (0.2 g, 2 mmol). After stirring at ambient temperature for 10 min, the mixture was treated with a solution of tert- butyl 2,7-diazabicyclo[3.3.0]octane-2-carboxylate (commercially available) (0.106 g, 0.500 mmol) in THF (2 ml_). The reaction mixture was stirred for 16 h at ambient temperature. The solvent was removed by rotary evaporation, and the residue was partitioned between ethyl acetate (5 ml.) and saturated sodium bicarbonate (2 ml_). The organic layer was concentrated, and the residue was purified by reverse phase HPLC to give tert-butyl 7- (furan-3-ylcarbonyl)-2,7-diazabicyclo[3.3.0]octane-2-carboxylate. This was dissolved in 1 :1 mixture of trifluoroacetic acid and dichloromethane (1 mL) and the mixture was shaken at ambient temperature for 1 h. The volatiles were removed under reduced pressure, and the residue was dried overnight at high vacuum, to give 0.050 g of 7-(furan-3-ylcarbonyl)-2,7- diazabicyclo[3.3.0]octane as a syrup (0.050 g, 32% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | 105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of <strong>[37993-32-1]1-aminocyclohexanecarboxylic acid methyl ester hydrochloride</strong>, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to obtain 114 g (91%) of the title compound.1H-NMR (CDCl3, delta): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m) 1.62-1.73 (3H, m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s), 6.23 (1H, dd, J=2 Hz, 1 Hz), 7.44 (1H, dd, J=2 Hz, 1 Hz), 7.94 (1H, dd, J=2 Hz, 1 Hz) |
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | REFERENCE EXAMPLE 151-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester 105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of <strong>[37993-32-1]1-aminocyclohexanecarboxylic acid methyl ester hydrochloride</strong>, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to obtain 114 g (91%) of the title compound.1H-NMR (CDCl3, delta): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m), 1.62-1.73 (3H, m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s), 6.23 (1H, dd, J=2 Hz, 1 Hz), 7.44 (1H, dd, J=2 Hz, 1 Hz), 7.94 (1H, dd, J=2 Hz, 1 Hz) |
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | Reference Example 15 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester 105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of <strong>[37993-32-1]1-aminocyclohexanecarboxylic acid methyl ester hydrochloride</strong>, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to obtain 114 g (91%) of the title compound. 1H-NMR (CDCl3, delta): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m), 1.62-1.73 (3H, m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s), 6.23 (1H, dd, J=2Hz, 1Hz), 7.44 (1H, dd, J=2Hz, 1Hz), 7.94 (1H, dd, J=2Hz, 1Hz) |
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | Reference example 15; 1-[(3-Furanylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester [Show Image] 105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of <strong>[37993-32-1]1-aminocyclohexanecarboxylic acid methyl ester hydrochloride</strong>, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to give 114 g (91%) of the title compound. 1H-NMR (CDCl3, delta): 1.34-1.40 (1H, m), 1.43-1.44 (2H, m), 1.62-1.73 (3H, m), 1.90-1.96 (2H, m), 2.10-2.14 (2H, m), 3.73 (3H, s), 5.87 (1H, br-s), 6.23 (1H, dd, J=2Hz, 1Hz), 7.44 (1H, dd, J=2Hz, 1Hz), 7.94 (1H, dd, J=2Hz, 1Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Furoic acid (2.4g, 21. 45mmol) and HATU (8.15g, 21. 45mmol) in DMF (25ml) were stirred at room temperature for 15mins. HOBT (2.9g, 21.45mmol), 3-iodo-4- methylaniline (5. Og, 21. 45mmol) and DIPEA (11. 2ml, 64.35mmol) were added and the reaction stirred at room temperature for 16hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (3: 1). The solvent was evaporated from the product fractions under vacuum to give N- (3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3. 52min, Mu+ 328. NMR: 8H [2H6]-DMSO 9.92, (1H, b), 8.36, (1H, d), 8.23, (1H, d), 7.80, (1H, t), 7.66, (1H, dd), 7.29, (1H, d), 6.98, (1H, d), 2.33, (3H, s). | ||
3-Furoic acid (2.4g) and HATU (8.15g) in DMF (25ml) were stirred at room temperature for 15min. HOBT (2.9g), <strong>[35944-64-0]3-iodo-4-methylaniline</strong> (5. 0g) and DIPEA (11. 2ml) were added and the mixture was stirred at room temp for 16h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (100ml) and aqueous sodium carbonate (10%, 100ml). The aqueous layer was extracted with ethyl acetate (50ml) and the combined organic phases were washed with hydrochloric acid (2N, 75ml), water (75ml) and brine (75ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a silica column and eluted with cyclohexane/ethyl acetate (3: 1) to give the title compound. NMR: 8H [d6-DMSO] 9.92, (1H, b), 8.36, (1H, d), 8.23, (1H, d), 7.80, (1H, t), 7.66, (1H, dd), 7.29, (1H, d), 6.98, (1H, d), 2.33, (3H, s). LCMS: Rt 3.52min, MEt 328. |
Yield | Reaction Conditions | Operation in experiment |
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82% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 0.666667h; Stage #2: With hexachloroethane In tetrahydrofuran at -70 - 20℃; | |
78% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran at -78℃; Stage #2: With hexachloroethane In tetrahydrofuran at -78 - 20℃; | |
72% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 4h; Inert atmosphere; Stage #2: With hexachloroethane In tetrahydrofuran at -78 - 20℃; | 1 Step 1: 2-Chlorofuran-3-carboxylic acid Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed furan-3-carboxylic acid (2.24 g, 19.99 mmol) and THF (100 mL). This was followed by the addition of LDA/THF (2 M, 20 mL) dropwise with stirring at -78oC and the resulting solution was stirred for 4 h at -78oC. Then to the resulting mixture was added hexachloroethane (5.208 g, 22.00 mmol) dropwise with stirring at -78oC. The resulting solution was stirred overnight at RT and then the pH value of the solution was adjusted to 2 with HCl (2 N). The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 2.099 g (72%) of the title compound as a light yellow solid. MS- ESI: 145.0, 147.0 (M-1). |
45% | Stage #1: 3-Furoic acid With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.75h; Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78 - 20℃; | 2-chlorofuran-3-carboxylic acid (14) 1.6M solution of n-butyl-lithium in hexanes (89 mL, 142.4 mmol) at -78 °C was added to a solution of diisopropylamine (12.5 mL, 89.2 mmol) in abs. THF (90 mL). After stirring at -78 °C for 45 minutes, a solution of the furan-3-carboxylic acid 13 (5 g, 44.6 mmol) in abs. THF (30 mL) was added. After stirring for further 45 minutes at -78 °C, hexachloroethane (11.66 g, 49.3 mmol) in abs. THF solution (20 mL) was added. After stirring it at -78 °C for 4 hours, the reaction mixture was allowed to room temperature and stirred overnight. The reaction mixture was quenched with water (200 mL). The aqueous phase was extracted with MTBE (50 ml) twice. Afterwards the water fraction was adjusted to pH = 2 with 2N HCl. The acidified aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic phase was evaporated at reduced pressure, and the crude product was recrystallized from water to give 2-chlorofuran-3-carboxylic acid 14 as pale tan crystals (2.96 g, 45 %). Mp 109.7-115.2°C; 1H NMR (400MHz, CDCl3) δ ppm 10.32 (br s, 1H), 7.34 (d, J = 2.20 Hz, 1H); 6.81 (d, J = 2.20 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ ppm 162.2, 143.5, 140.1, 113.6, 112.4; MS (DUIS-) m/z 145 (M-H) |
2.8 g | Stage #1: 3-Furoic acid With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 40℃; for 0.5h; Stage #2: With hexachloroethane In tetrahydrofuran; hexane at -78℃; for 16h; | 1.A Step A: Preparation of 2-chloro-3-furancarboxylic acid To a solution of diisopropylamine (10.3 g, 102 mmol) in THF (20 mL) was added 2.5M n-BuLi (6.5 g, 102 mmol) in hexane at -78 °C and the reaction mixture was slowly warmed to -40 °C. 3-Furancarboxylic acid (5 g, 41 mmol) in THF (20 mL was then added and the reaction mixture was stirred for 30 minutes. Hexachloroethane (10.60 g, 45.68 mmol) in THF (20 mL) was slowly added at -78 °C and the reaction mixture was stirred for 16 hours. TLC analysis (5% MeOH in DCM) showed completion of the reaction. The reaction mixture was cooled to 0 °C, quenched with IN HCl, and extracted with ethyl acetate (3x). The combined organic layers were washed with brine and dried over Na2S04. The solvent was evaporated under reduced pressure and the obtained crude product was purified by solvent washing to give 2.8 g of the title product as a brown solid. NMR (CDCh, 400 MHz): δ 10.2 (br s, 1H), 7.33 (d, 1H), 6.81 (d, 1H). Mass spec: (M-l) =145. |
Yield | Reaction Conditions | Operation in experiment |
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73% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran Stage #2: 3-Furoic acid In tetrahydrofuran at -78℃; for 1.16667h; Stage #3: 4-fluorobenzaldehyde With hydrogenchloride; sodium hydroxide more than 3 stages; | A.34 (A-34) To a lithium diisopropylamide solution prepared from diisopropylamine(22.0ml, 157 mmol) and n-butyllithium (157 mmol) in tetrahydrofuran(150ml),was added dropwise 3-furancarboxylic acid (8.79 g, 78.5 mmol) in tetrahydrofuran(80ml) at -78°C. The mixture was stirred at the same temperature for 1 hour 10 minutes, to which was added 4-fluorobenzaldehyde (10.7 g, 86.4 mmol) in tetrahydrofuran(30ml).. The temperature was warmed to 0°C for 30 minutes, then water(100 ml) was added to the solution and the organic layer was extracted with 1N sodium hydroxide aqueous solution.The water solution was acidified with concentrated hydrochloric acid, then extracted with ethyl acetate.. The extract was washed, dried and evaporated under reduced pressure to give the residue which was Crystallized from diisopropylether-n-hexane to afford 2-[(4-fluorophenyl)hydroxymethyl]furan-3-carboxylic acid(13.5 g, yield:73%). |
Yield | Reaction Conditions | Operation in experiment |
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67% | Stage #1: 3-Furoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 1h; Stage #2: C30H36F6N4O In dichloromethane at 20℃; | B5 Example B5; Preparation of final compound 11; A mixture of 3-furancarboxylic acid (0.0027 mol), DMAP (0.0027 mol) and Et3N (0.0027 mol) in CH2Cl2, p.a. (100 ml) was stirred at room temperature. Then, EDCI (0.0027 mol) was added and the reaction mixture was stirred at room temperature for 1 hour, giving mixture (I). A mixture of final compound 60 (prepared according to B 1.d) (0.002 mol) dissolved in CH2C12 was added dropwise to mixture (I) and the reaction mixture was stirred overnight at room temperature. The mixture was poured out into NaOH (1 N) and stirred for 15 min. at room temperature. The layers were separated. The aqueous layer was extracted with CH2C12 and the organic layer was dried (MgS04), filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent gradient: CH2Cl2/CH3OH from 100/0 to 90/10). The product fractions were collected and the solvent was evaporated. Yield: 0.914 g of final compound 11 (67 %) |
Yield | Reaction Conditions | Operation in experiment |
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82% | With sulfuric acid In methanol at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
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88% | With trifluorormethanesulfonic acid In dichloromethane at 20℃; for 14h; | 4.2. General procedure for the synthesis of secondary arylamines General procedure: To a mixture of benzyl azide (1 equiv) and aromatic compound (1.2 equiv) in DCM (0.17 mmol/mL) was added TfOH (1.2 equiv) at room temperature. The reaction mixture was monitored by TLC until no further change was observed (see Tables 2and 3 for the reaction times) and the reaction was quenched with satd aq NaHCO3, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified on silica gel to yield the secondary arylamine products. Note: For the synthesis of compounds 6i and 6t, TfOH (1.2 equiv) was added into a solution of benzyl azide (1 equiv) in DCM at room temperature and stirred until the bubbling of N2 gas subsided before the aromatic compound (1.2 equiv) was added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In diethyl ether at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
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79% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 45℃; Inert atmosphere; | 5.3. General procedure B1: amide coupling General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide. Work-up 2 (W2): Water (approximately 2 mL) was added to the reaction mixture and it was transferred to the fridge overnight. The resulting precipitate was filtered and gave the desired carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 45℃; Inert atmosphere; | 5.3. General procedure B1: amide coupling General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 45℃; Inert atmosphere; | 5.3. General procedure B1: amide coupling General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide. Work-up 2 (W2): Water (approximately 2 mL) was added to the reaction mixture and it was transferred to the fridge overnight. The resulting precipitate was filtered and gave the desired carboxamide. |
58% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane for 8.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | General procedure: 5.1.2 General procedure B (for synthesis of compounds 21-31). To the carboxylic acid substrate (50 mg, 1.0 equiv) in DMF (1.5 mL) was added EDC (1.5 equiv) and DMAP (0.1 equiv). The reaction was stirred for 30 min at 23 C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (1.5 equiv) was added and the reaction mixture was stirred for 16 h at 23 C. The reaction was concentrated in vacuo under reduced pressure and the residue was dissolved in CHCl3 (8 mL) and washed successively with saturated aqueous NaHCO3 (5 mL) and H2O (5 mL). The organic layer was separated, dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (0-30% MeOH-CHCl3) to afford the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With trichlorophosphate Reflux; | 4.3. Preparation of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles (4a-g) and (5a-e) General procedure: A mixture of 4-amino-5-(pyridin-3-yl)-4H-[1,2,4]triazole-3-thiol 3 (1 mmol) and substituted aromatic acids (1.1 mmol) inPOCl3 (5 mL) was refluxed for 6-7 h. The reaction mixture was slowly poured into crushed ice with stirring and neutralized with sodium bicarbonate. Solid material was filtered, washed with cold water, dried, and recrystallized from ethanol to afford 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 4a-g and 5a-e [25]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-Furoic acid With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.75h; Inert atmosphere; Stage #2: (1R,2S,5R,SS)-(-)-menthyl p-toluenesulfinate In tetrahydrofuran; diethyl ether at -78 - 20℃; for 1h; Inert atmosphere; | 6 Synthesis of (S)-2-(p-tolylsulfinyl)-3-furoic acid 11 In a 100 mL oven-dried round-bottomed flask, fitted with amagnetic stirrer and under an argon atmosphere, a solution of2.0 M LDA in THF (1.86 mL, 3.72 mmol) and dry tetrahydrofuran(5 mL) were placed. The solution was cooled down to 78 C and3-furoic acid 3 (200 mg, 1.78 mmol) dissolved in dry THF (9 mL)was added dropwise. The reaction mixture was maintained at78 C for 45 min and the formation of the dilithium intermediatetook place without precipitation. This solution was maintained at78 C and (1R,2S,5R)-()-menthyl (SS)-p-toluenesulfinate(275 mg, 0.93 mmol), dissolved in dry THF (10 mL) was addeddropwise after which the reaction mixture was stirred for 1 h, at78 C. Next, the quenching was carried out by the addition ofaqueous 3% (w/w) HCl (10 mL). The reaction mixture was then extractedwith ethyl acetate (3 50 mL). The aqueous acidic phase(pH 10), containingthe product as a sodium carboxylate, was acidified by the dropwiseaddition of concentrated HCl (until pH = 1) and extracted withethyl acetate (3 50 mL). The resulting organic phase was driedover anhydrous MgSO4, filtered, and concentrated to dryness in vacuo,to give a solid residue containing the desired product andunreacted 3-furoic acid. This crude mixture was subjected to aflash column chromatography on silica gel (eluting with mixtureof hexane and ethyl acetate of increasing polarity). The productwas isolated by elution with hexane/ethyl acetate 60:40 as ayellowish solid (209.5 mg, yield = 90%, respect to menthylp-toluenesulfinate, conversion = 100%). Mp = 94-95 C (ethyl/acetatehexane). IR (film): m = 3200-2000 (br, H-O, st), 2927, 1723(CO, st), 1489, 1173, 1024, 1007, 756 cm1. 1H NMR (200 MHz,CDCl3): d = 2.41 (3H, s, H70), 6.88 (1H, d, J = 1.8 Hz, H4), 7.34 (2H,d, J = 8.0 Hz, H30 and H50), 7.53 (1H, d, J = 1.8 Hz, H5), 7.70 (2H, d,J = 8.0 Hz, H20 and H60), 9.90 (1H, br s, O-H) ppm. 13C NMR(50 MHz, CDCl3): d = 21.5 (C70), 112.9 (C4), 121.5 (C3), 125.0 (C30and C50), 130.2 (C20 y C60), 137.3 (C40), 142.8 (C10), 146.0 (C5),154.8 (C2), 163.8 (C6) ppm. MS [GC-MS(CI), NH3, 70 eV, 150 C]:m/z (%) = 268 (100, M+NH4), 251 (37, M+1). Anal. Calcd for: C,57.59; H, 4.03. Found: C, 57.40; H, 4.12. a21D 27:4 (c 0.5, CHCl3).Chiral GC (100 C, 1 min, 5 C/min, 220 C, 20 min): tR = 19.10 min.Ee = 100%. TLC (SiO2, ethyl acetate): Rf = 0.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With chloro[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]copper(I); In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; Sealed tube; | General procedure: In a glovebox, Cu(IPr)Cl catalyst and PMC (62.8 mg, 0.55 mmol,1.1 equiv) were charged to a glass reaction tube. A solution of 3(0.50 mmol) in THF (1.5 mL) was added, the tube was sealed, taken out of the glovebox, and heated at 70 C for 16 h. After cooling tor.t., H2O (2 mL) was added and the reaction mixture was acidified with aqueous HCl (1 M), and saturated with sodium chloride. After extraction with EtOAc (3 × 5 mL), the organic phase was dried overanhydrous sodium sulfate and concentrated under vacuo. The product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 3-Furoic acid With 2,4,6-trimethyl-pyridine; bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-(4-aminobenzamido)-3-cyanopropanamido)benzamido)-3-methoxybenzamido)-3-methoxybenzoate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h; | Compound 20 BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Furan-3-carboxylic acid (3.5 eq, 0.305 mmol, 29 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (72 mg, 92 %). The oil (1 eq, 0.078 mmol, 70 mg) and phenylsilane (8 eq, 0.625 mmol, 0.077 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.039 mmol, 45 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (6 mg, 10 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (dd, J = 8,6 Hz, 1 H), 3.16 (dd, J = 5.4 Hz), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 7.02 (d, J = 1 .3 Hz, 1 H), 7.57 (m, 1 H), 7.82 (m, 6H), 7.97 (m, 5H), 8.05 (d, J = 8.9 Hz, 1 H), 8.43 (s, 1 H), 9.05 (d, J = 7.3 Hz, 1 H), 9.71 (s, 1 H), 10.17 (s, 1 H), 10.58 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H). HR-MS: [M-H]- calculated: 775.1994 [M-H]- found: 775.2000 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 3-Furoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 3-(5-[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one In N,N-dimethyl-formamide at 20℃; for 14h; | 6 Example 6 - Preparation of Compound 4 1784 [0201] The synthesis of Compound 4 followed the procedure of General Procedure 6 1785 following. 1786 General Procedure 6 1788 Compound 2 Compound 4 1789 [0202] To a solution of furan-3-carboxylic acid (0.338 g, 0.00301 moles, 1.2 eq) in 1790 dimethylformamide (5.0 mL) was added EDCI.HCI (0.724 g, 0.00337 moles, 1.5 eq), DIEA 1791 (0.81 lg, 0.00629 moles, 2.5 eq) and finally HOBt (0.074g, 0.00048 moles, 0.5 eq). The 1792 reaction mixture was stirred at room temperature for 30 min, followed by the addition of 1793 compound 2 (0.770 g, 0.00251 moles, 1.0 eq). The mixture was stirred at 14 hours at room 1794 temperature. After checking that the reaction had reached completion by LC-MS, the mixture 1795 was poured into ice cold water under stirring. The product was extracted with ethyl acetate. 1796 The organic phase was dried over sodium sulfate, concentrated under reduced pressure and 1797 purified by column chromatography using neutral silica gel (60-120 mesh), eluting with 15- 1798 25% ethyl acetate in n-hexane as gradient to give pure desired compound 4 (0.45 g, yield: 1799 45%) m/z[M+H]+ 401.84 IH NMR (DMSO-d6, 400 MHz) δ 11.923 (IH, s), 9.024-9.029 1800 (IH, q), 8.274-8.297 (IH, q), 7.888-7.893 (IH, d), 7.833-7.884 (IH, q), 7.500-7.512 (IH, d), 1801 7.085-7.091 (IH, q), 6.965-6.990 (2H, q), 6.313-6.347 (2H, t), 5.771 (IH, s), 4.445-4.560 1802 (IH, d) ppm. |
45% | Stage #1: 3-Furoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 3-(5-[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1,2-dihydropyridin-2-one In N,N-dimethyl-formamide at 20℃; for 14h; | 6 Example 6 - Preparation of Compound 4 Example 6 - Preparation of Compound 4 [ 00213 ] The synthesis of Compound 4 followed the procedure of General Procedure 6 following. General Procedure 6 Compound 2 Compound 4 [ 00214 ] To a solution of furan-3-carboxylic acid (0.338 g, 0.00301 moles, 1.2 eq) in dimethylformamide (5.0 mL) was added EDCI.HC1 (0.724 g, 0.00337 moles, 1.5 eq), DIEA (0.81 lg, 0.00629 moles, 2.5 eq) and finally HOBt (0.074g, 0.00048 moles, 0.5 eq). The reaction mixture was stirred at room temperature for 30 min, followed by the addition of Compound 2 (0.770 g, 0.00251 moles, 1.0 eq). The mixture was stirred at 14 hours at room temperature. After checking that the reaction had reached completion by LC-MS, the mixture was poured into ice cold water under stirring. The product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography using neutral silica gel (60-120 mesh), eluting with 15-25% ethyl acetate in n-hexane as gradient to give pure desired Compound 4 (0.45 g, yield: 45%) m/z[M+H]+ 401.84 1H NMR (DMSO-d6, 400 MHz) δ 11.923 (1H, s), 9.024-9.029 (1H, q), 8.274-8.297 (1H, q), 7.888-7.893 (1H, d), 7.833-7.884 (1H, q), 7.500-7.512 (1H, d), 7.085-7.091 (1H, q), 6.965-6.990 (2H, q), 6.313-6.347 (2H, t), 5.771 (1H, s), 4.445-4.560 (1H, d) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | 4.1.1. Synthesis of compounds 1a-d General procedure: General procedure. To a stirred solution of UA (90.82 mg,0.20 mmol) in CH2Cl2 was added EDCI (46.01 mg, 0.24 mmol),DMAP (29.32 mg, 0.24 mmol), and corresponding acids(0.24 mmol). The reaction mixture was stirred at room temperaturefor 12 h. On completion, the solvent was evaporated and theresidue was poured into water (30 mL) and extracted with AcOEt(30 mL 3). The organic layer was dried over anhydrous Na2SO4and evaporated. Then the crude compounds were purified by a columnchromatography (PE/EA, 6/1, v/v) to afford the desired productsas white solids (1a-d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 3-Furoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5h; | 4.2.13 4.2. Typical procedure for the primary amidation of 3-phenylpropanoic acid 1a with NH4Cl General procedure: To a colorless solution of 75mg (0.50mmol) of 3-phenylpropanoic acid 1a in 10mL of THF were added at 0°C 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) was added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 72mg (96% yield) of 3-phenylpropanamide 2a. 4.2.13 Furan-3-carboxamide 2m 25 mg (45%); colorless powder; mp: 162-164 °C; 1H NMR (400 MHz, MeOD-d4): δ 6.79, 7.56, 8.07 (dd, dd, dd, J = 0.9, 1.9, 1.7, 1.9, 0.9, 1.7 Hz, 1H, 1H, 1H, furanyl); 13C NMR (100 MHz, MeOD-d4): δ 110.0, 123.4, 145.3, 147.1, 167.6; IR (KBr, vmax/cm-1) = 3309 (CONH), 1621 (CON); HRMS (ESI-TOF): Calcd for C5H5NO2Na (M+Na)+: 134.0212, found: 134.0209. |
Multi-step reaction with 2 steps 1: thionyl chloride / 0.5 h / 85 °C / Reflux 2: ammonium hydroxide / dichloromethane / 0.5 h / Cooling with ice | ||
Multi-step reaction with 2 steps 1: thionyl chloride / toluene / 2 h / Reflux 2: ammonium hydroxide / water; dichloromethane / 1 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogenchloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In 1,4-dioxane at 120℃; for 4h; | N,N-Dimethylfuro-3-carboxamide (11) General procedure: A 20 mL Radleys Carousel screw-capped glass tube was charged with carboxylic acid (2 mmol, 1.0 equiv), DMF (1.2 mL), T3P in DMF 50%(1.28 mL, 1.4 g, 1.1 equiv) and HCl (4 M in dioxane, 0.25 mL, 1.0mmol, 0.5 equiv) at r.t. The mixture was heated to 130 °C (ca. 120 °C internal) and stirred until the conversion according to LC-MS or TLCwas ≥95%. The solution was quenched at 10 °C with aq half-saturated Na2CO3 (5 mL; caution: gas evolution) and extracted with i-PrOAc (10mL and 2 × 5 mL or until no product was present in the aqueousphase). Combined organic phases were dried over MgSO4 and concentratedunder reduced pressure. The crude product was purified bychromatography on silica gel as described below. N,N-Dimethylfuro-3-carboxamide (11) The reaction was performed according to the general procedure with3-furoic acid as starting material. After work-up, the crude materialwas absorbed on Celite, concentrated to dryness and purified by chromatographyon silica gel (5 g Isolute SPE column, Flash Si II; heptane-EtOAc, 4:1 to 1:1) to give 11.Yield: 248 mg (89%); off-white solid; mp 68-70 °C (lit.24b 70-71 °C).1H NMR (500 MHz, DMSO-d6): δ = 8.07 (dd, J = 0.9, 1.4 Hz, 1 H), 7.73(m, 1 H), 6.70 (dd, J = 0.8, 1.8 Hz, 1 H), 3.09 (br s, 3 H), 2.95 (br s, 3 H).13C NMR (125 MHz, DMSO-d6): δ = 163.95, 144.49, 143.62, 121.72,111.30, 38.88, 35.72.MS m/z = 140.12 [M + 1]+. |
80% | With tert.-butylhydroperoxide; iron(III) chloride In pyridine; water; toluene at 85℃; for 8h; Inert atmosphere; Sealed tube; | 9 Example 9 :Synthesis of N,N-dimethyl-3-carboxamido furans from 3-furancarboxylic acid and DMF In the reaction flask equipped with a magnetic 20mL was added 3-furan carboxylic acid (0.034g, 0.3mmol),FeCl3 (0.0049 g, 0.03 mmol),TBHP (0.116 g, 0.9 mmol, 70% aqueous solution),DMF (1 mL),Toluene (1 mL),Pyridine (0.118 g, 1.5 mmol),Fill it with argon,Tighten the cap,External temperature 85 ° C closed reaction 8h;Gas chromatography monitoring;After the reaction is completed,Rotary evaporation to remove the solvent,After column chromatography (ethyl acetate: petroleum ether = 4:1), an oily liquid was obtained.Yield 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 3-Furoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; Stage #2: 3,5-dinitrobenzyl alcohol With pyridine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 47h; | 6 Synthesis of 3,5-amino benzyl furan-3-carboxylate (3-DABFr) In 500mL four-necked flask 3-furan carboxylic acid 8.2g, and the dichloromethane 240mL added, and the mixture was cooled from room temperature to 0 ° C. Then, dichloride Okirariru 6.4 mL, and DMF0.5g added and stirred at room temperature for 2 hours. After stirring, 3,5-di-nitrobenzyl alcohol 15.0 g, and the pyridine 9.7mL was added, followed by stirring for 47 hours at room temperature. After completion of the reaction, the mixture was stirred for 1 hour adding pure water 50 mL. The organic layer was then extracted by adding ethyl acetate, the organic layer was washed with 1N hydrochloric acid, a saturated sodium bicarbonate solution and saturated brine. The organic layer over anhydrous magnesium sulfate and dehydrated and dried, after filtration, was evaporated using a rotary evaporator. It performs residue recrystallized from ethyl acetate to give the dinitro compound of 16.8g (78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere; | 4.1.5 General procedure for the synthesis of 9, 14, 29, 30, 32 and 34 General procedure: To a solution of 14-amino-tetrandrine M2 (100mg, 0.16mmol) in CH2Cl2 (3mL) under the protection of argon atmosphere was added carboxylic acid (0.16mmol, 1.0 eq), EDC·HCl (0.19mmol, 1.2 eq) and DMAP (0.03mmol, 0.2 eq) and stirred at room temperature for 3-4h. After the reaction was completed, the mixture was poured into a saturated aqueous solution of NaHCO3 and extracted by CH2Cl2 (repeated three times). The combined organic phase was washed by brine and dried over anhydrous MgSO4 before vacuum suction filtration. The removing of the solvent in vacuo afforded the crude product, which was chromatographied on silica gel (CH2Cl2/MeOH, 50/1 v/v, 0.1% TEA) to provide the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 12h; | 1-53 Intermediate Compound 53’: 4-hydroxybutylfuran-3-carboxylate To a stirred solution of butane-1,4-diol (540 mg, 6 mmol) in DCM (10 mL) was added furan-3-carboxylic acid (224 mg, 2 mmol), DCC (453 mg, 2.2 mmol) and DMAP (24 mg). The reaction was stirred at 25 °C for 12 h. After that, the reaction mixture was diluted with saturated aqueous NH4C1 (10 mL) and stirred for 5 mm. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (270 mg, 73%) as a pale yellow oil. ‘H NMR was performed at 400MHz with CDC13 as solvent to characterize the titled compound, results are as follows: = 8.00 (s, 1 H), 7.42 (s, 1 H), 6.73 (s, 1 H), 4.28 (t, J= 6.4 Hz, 2 H), 3.70 (t, J= 6.4 Hz, 2 H), 1.83-1.67 (m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.9% | Stage #1: 3-Furoic acid With sulfuric acid In methanol at 60℃; for 3h; Stage #2: With hydrazine hydrate In ethanol at 100℃; for 5h; | 62.1 [Step 1]Furan-3-carbohydraz ide To a solution of furan-3-carboxylic acid (10.5 g,89.2 mmol) in methanol (100 mL), sulfuric acid (0.500 mL, 8.92 mmol) was added, and the mixture was stirred at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethanol (70 mL) . Hydrazine monohydrate (21.5 mL, 446 mmol) was added thereto, and the mixture was stirred at 100°C for 5 hours. The reaction solution was concentrated under reduced pressure, and thedeposited solid was collected by filtration usingdiisopropyl ether. The obtained solid was dried under reduced pressure at 50°C to obtain the title compound (5.95 g, 47.2 mmol, 52.9%) as a yellow solid.1H-NMR (500 MHz, CDC13) δ (ppm) : 4.06 (2H, s, NH2), 6.62 (1H, s), 7.21 (1H, s, NH), 7.46 (1H, s), 7.96 (1H, s). MS (ESI) : m/z 127 [M+H]+. |
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / Reflux 2: hydrazine hydrate / methanol / 16 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | Synthesis of N-(1-(4-(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl)-1-oxo-3-phenyl propan-2-ylDerivatives 16a-r: General procedure: General Procedure: To a 25 mL RBFwas charged Compound14 (0.200 gm,0.452 mmol), carboxylic acid15 (0.474 mmol), TBTU (0.189 gm,0.587 mmol), DMF (2.0 mL, 10 Vol) and DIPEA (0.24 mL, 1.356 mmol) at RT undernitrogen atmosphere. The reaction was stirred for 12 hr at RT then monitored byTLC, SM was absent. The reaction was diluted with water (20 mL) and extractedwith EtOAc (20 mL x 2) then dried with Na2SO4. Thesolution was distilled under vacuum at 40 °C and dried to get crude product.The crude product was purified by Column chromatography to obtained product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 3-Furoic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.166667h; Stage #2: 4-[(2S',6S')-6'-(4-((6-aminohexyl)oxy)butyl)tetrahydropyran-2-yl]-1-[(2S'',6S'')-6''-(4-hydroxybutyltetrahydropyran-2-yl)methyl]-1H-1,2,3-triazole In dichloromethane at 20℃; | 4.2.10 4.1.1. General procedure for amide coupling General procedure: The appropriate carboxylic acid (34.2 lmol, 2 eq), EDCIHCl(5.30 mg, 34.2 lmol, 2 eq) and DMAP (17.1 lmol, 1 eq) were combinedin CH2Cl2 (2 mL) and stirred at RT for 10 min. Amine 15(10.0 mg, 17.1 lmol, 1 eq) was added and the resulting mixturestirred at RT overnight. Reaction was, quenched by the additionof saturated aqueous NH4Cl solution (5 mL), extracted with EtOAc(3 5 mL) and the combined organic layers washed with 0.1 Maqueous KOH solution, brine, dried (MgSO4), filtered and concentratedin vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; | (3,4-Dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)(furan-3-yl)methanone (6m) To a solution of compound 5 (0.120 g, 0.69 mmol) in DCM(5 ml), furan-3-carboxylic acid (0.094 g, 0.84 mmol), HOBt(0.113 g, 0.84 mmol), EDCI (0.2 g, 1.04 mmol) and Et3N(0.48 ml, 3.44 mmol) were added and the mixture wasstirred overnight at room temperature. The mixture was thenpartitioned between DCM and saturated NaHCO3 aqueoussolution and the organic layer was washed with brine, driedover Na2SO4, filtered, and evaporated in vacuo. The cruderesidue was further purified by flash chromatography usingsilica gel and eluting by a mixture of DCM/methanol (98:2)to afford the required amides (6m) as a yellowish whitesolid. Yield: 92%. 1H-NMR (400 MHz, DMSO-d6): δ 2.81(br. s., 2H) 3.34 (s, 2H) 4.80 (br. s., 2H) 6.72-6.77 (m, 1H,Ar-H) 6.98 (t, J = 7.34 Hz, 1H, Ar-H) 7.06 (t, J = 7.34,Hz, 1H, Ar-H) 7.32 (d, J = 7.58 Hz, 1H, Ar-H) 7.41 (d, J= 7.58 Hz, 1H, Ar-H) 7.80 (s, 1H, Ar-H) 8.14 (s, 1H,Ar-H). 13C-NMR (400 MHz, DMSO-d6): δ 22.24, 40.15,55.36, 110.78, 111.56, 118.02, 119.05, 121.35 126.98,131.25, 136.49, 144.06, 164.05. MS (EI+) m/z: 266 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-Furoic acid With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: p-toluamidoxime In dimethyl sulfoxide at 20℃; for 18h; | General procedure for the synthesis of 1,2,4-oxadiazoles 4a-w General procedure: To a solution of carboxylic acid 1 (1.1 mmol) in dry DMSO (0.5-1 mL) CDI (195 mg, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, then amidoxime 2 (1.0 mmol) was added. The reaction mixture was stirred at room temperature for another 18 h, then to the reaction mixture powdered NaOH (1.2 mmol) was added rapidly. The reaction mixture was stirred at room temperature for 2 h. Then the reaction mixture was diluted with cold water (30 mL). The resulting precipitate was filtered off, washed with cooled water (25 mL) and dried in air at 50 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Stage #1: 3-Furoic acid With 4-methyl-morpholine In tetrahydrofuran at -20℃; Inert atmosphere; Stage #2: o-trifluoromethylbenzylamine With isobutyl chloroformate In tetrahydrofuran at -15 - 20℃; for 1.5h; Inert atmosphere; | General procedure for synthesis of amides General procedure: The compounds 5-13 were synthesized using the mixed anhydrides method (21) of peptide synthesis. The suitable acid (10 mmol) was dissolved in dry tetrahydrofuran (THF) or a mixture of dimethylformamide (DMF)/tetrahydrofuran (30 mL). Next, N-methylmorpholine (NMM) (10 mmol, 1.1 mL) was added and the mixture was stirred under nitrogen and chilled to -20°C. Isobutyl chloroformate (IBCF) (10 mmol, 1.3 mL) was added dropwise to keep the temperature below -15°C. Then the suitable amine: 2- or 4-fluorobenzylamine; 2- trifluoromethoxybenzylamine; 2-trifluoromethylbenzylamine, 4-bromobenzylamine or 1-naphthylmethylamine (10 mmol) in THF was added in small portions and the reaction mixture was stirred at -15°C for 30 min. and at room temperature for 1 h. The solution was concentrated in vacuo and the residue was dissolved in CHCl3 (40 mL). This solution was washed with 20 mL portions of 1 M HCl, saturated NaHCO3 solution and saturated NaCl solution, then dried with anhydrous MgSO4, filtered and concentrated in vacuo. The obtained compounds were purified as follows: 5, 6, 8, 11, 12 and 13 by crystallization from ethyl acetate/hexane, 10 by crystallization from ethyl acetate and 7, 9 by column chromatography in chloroform as eluent and then by crystallization from ethyl acetate/hexane. All stages of the synthesis were controlled by the thin-layer chromatography. The general procedure for the synthesis of the obtained compounds is shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 3h; Inert atmosphere; | 1 Step 1 : Furan-3-carboxylic acid (R)-l-phenyl-ethyl ester To a solution of 3-furancarboxylic acid (2.00 g; 17.84 mmol) in 40 ml dry dichloromethane are added (R)-l -phenyl-ethanol (2.64 ml; 21 .41 mmol), 4- dimethylamino-pyridine (2.18 g; 17.85 mmol) and (3-dimethylamino-propyl)- ethyl-carbodiimide hydrochloride (3.84 g; 19.63 mmol) under argon- atmosphere at 0°C. The clear reaction solution is stirred without further cooling for 3h. The reaction solution is quenched with sat. NH4CI and extracted with dichloromethane. The organic layer is washed 3x with sat. NaHCO3 solution and brine, dried over Na2SO4, and filtrated. After evaporation of the solvent the reaction mixture is purified by flash chromatography (silica gel; EE/heptane gradient; 0-30 % EE) to obtain furan-3-carboxylic acid (R)-l -phenyl-ethyl ester (3.55 g; yield 90%; yellow oil). LCMS Method A: (M+H) not detected; Rt 2.46 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In benzene; at 40℃; for 4h; | A freshly prepared solution of titanocene dichloride (0.25 g, 1.004mmol) in anhydrousbenzene (15mL) was added to a stirred solution of furan-3-carboxylic acid (0.225 g,1.99mmol) in anhydrous benzene (15mL). Subsequently, a benzene solution (10mL) ofNEt3 (0.282mL, 2.008mmol) was added dropwise where upon the blood-red solutionturned bright-orange along with precipitation of Et3NHCl. The reaction mixture wasslowly heated to 40 C and stirring were continued for additional 4 h. The orange solutionwas filtered through a frit covered with pre-dried neutral silica (1 cm layer, mesh size100-200) and eluted with anhydrous benzene (30.5mL). The clear filtrate was concentratedusing a rotary evaporator to around 2mL and precipitated with an excess ofanhydrous hexane. The orange solid was collected on a frit, washed with hexane(25mL), dried, and recrystallized from anhydrous benzene at ambient temperature toafford orange crystals, which were isolated by filtration. Yield: 0.35 g, 60%. m. p.:110-112 C (dec.). IR absorption (cm2-1): 1628 m(OCO)asym, 1562, 1504, 1396 m(OCO)sym,1338, 1314, 1194, 1182, 1150, 1006, 837, 779, 766, 559. 1H NMR (CDCl3): 8.05 (s, 2H, H-2),7.39 (urd, 2H, H-5), 6.71 (urd, 2H, H-4), 6.52 (s, 10H, C5H5), ppm. 13C{1H} NMR (CDCl3):168.9 (COO), 149.1 (C-5), 144.0 (C-2), 120.2 (C5H5), 118.7 (C-3), 109.8 (C-4) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 3-Furoic acid With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 1.5h; Inert atmosphere; Schlenk technique; Stage #2: methyl iodide In N,N-dimethyl-formamide at 90℃; for 12h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 3-Furoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Stage #2: N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide In dichloromethane at 20℃; | 27 Example 27 - Synthesis of N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-2-(l-(furan-3-carbonyl)piperidin-3-yl)acetamide (196) A solution of 3-furoic acid (18 mg, 0.161 mmol) and DIEA (51 pL, 0.294 mmol) in dry DCM (4 mL) was treated with TBTU (61 mg, 0.191 mmol) and the solution was stirred for 1 hour at room temperature. N-(6-acetylbenzo[rf][1,3]dioxol-5-yl)-2-(piperidin-3-yl)acetamide HC1 salt (Example 24a) (50 mg, 0.147 mmol) was then added and the mixture stirred overnight at room temperature. The solvent was removed under vacuum and the residue purified by silica gel chromatography using 0-50% EtOAc in hexanes as eluent to afford the title compound as a white powder (66.5 mg, quantitative yield). MS 399 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrabutylammomium bromide; toluene-4-sulfonic acid In acetonitrile for 7.5h; Electrolysis; Green chemistry; | |
36% | With dihydrogen peroxide; potassium iodide In ethyl acetate at 20℃; for 5.5h; | 11 Example 1The preparation method of the N-acetyl derivative of the compound of formula (3a) includes the following steps: General procedure: Add N-acetyl indole 3-one (0.2mmol, 35mg), benzoic acid (0.6mmol, 73.2mg) to a 10mL single-necked bottle, and then add the oxidant H2O2 (1.5 equivalents, 30ul), KI (5mol%, 1.66 mg), 1 mL of ethyl acetate, reaction at room temperature for 5 h, the reaction is completed, silica gel column chromatography (petroleum ether: ethyl acetate 3: 1), the obtained crude product is added to a saturated sodium carbonate solution, extracted with ethyl acetate, and washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid. NMR and GC-MS confirmed that it was N-acetyl 3-oxoindole derivative 3a. Yield: 85%; |
30% | With dihydrogen peroxide; potassium iodide In water; ethyl acetate at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 6h; | 3.3. General Synthetic Procedures for Target Compounds 1-20 General procedure: Intermediate d (10 mmol), EDCI (10 mmol), DMAP (0.1 mmol), and aromatic acid (10 mmol)were dissolved in DCM (CH2Cl2, 30 mL). The mixture was stirred at room temperature for 6 h.The target compounds 1-10 were purified via column chromatography. Similarly, the intermediateb, e, f, and target compounds 11-20 were synthesized by using the same methods. The spectrogram oftarget compounds 1-20 are presented as Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; | Step 3 General procedure: Unless specified, the unprotected urea (1 equiv.) from step 2, EDCI (1.5 equiv.), DMAP (1.5 equiv.) and corresponding carboxylic acid (1.5 equiv.) was dissolved in CH2Cl2 (8.3 mM, unprotected urea) and was stirred overnight (12h) at rt. The reaction was quenched by addition of HCl solution (1M). The organic layer was collected and the aqueous layer was extracted 4 times with EtOAc (EtOAc: Aqueous layer/ 1:1(v:v)). The combined organic layer was dried over anhydrous magnesium sulfate and was concentrated in vacuo and further purified by flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; | Step 3 General procedure: Unless specified, the unprotected urea (1 equiv.) from step 2, EDCI (1.5 equiv.), DMAP (1.5 equiv.) and corresponding carboxylic acid (1.5 equiv.) was dissolved in CH2Cl2 (8.3 mM, unprotected urea) and was stirred overnight (12h) at rt. The reaction was quenched by addition of HCl solution (1M). The organic layer was collected and the aqueous layer was extracted 4 times with EtOAc (EtOAc: Aqueous layer/ 1:1(v:v)). The combined organic layer was dried over anhydrous magnesium sulfate and was concentrated in vacuo and further purified by flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With palladium(II) trimethylacetate In toluene at 110℃; for 4h; Sealed tube; | 12 Intermediate compound I: 1-(2-((tert-butoxycarbonyl)amino)-5-methoxyphenyl)-3-oxo-3-(quinolin-8-ylamino)propylfuran-3-carboxylate Preparation Combine 0.1mmol 3-(3-methoxyphenyl)-N-(quinolin-8-yl) propionamide, 0.01mmol palladium pivalate, 0.2mmol di-tert-butyl azodicarboxylate, 0.15mmol3-furan carboxylic acid and 1 mL of anhydrous toluene were added to the reaction flask, sealed and heated to 110° C. to react for 4 hours, cooled to room temperature, and purified to obtain Intermediate (I) with a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 65% 2: 7% 3: 7% | With aluminum (III) chloride; triethylamine In dichloromethane at 20℃; for 48h; | General experimental methods for AlCl3-catalyzedCannizzaro/Tishchenko reactions General procedure: A mixture of AlCl3(0.5 mmol), the aldehyde (10 mmol),and triethylamine (5 mmol) was added to 2 cm3of driedCH2Cl2and stirred for 2 days at room temperature underargon atmosphere until the aldehyde was completelyconsumed. The reaction progress was probed by TLCand GC/MS (Agilent 6890 (GC)/5972A (MS)). The reactionmixture was then filtered through Whatman filterpaper (grade 2), and treated with sodium bicarbonatesolution, followed by isolating the organic phase via aseparatory funnel. The aqueous phase washed severaltimes with CH2Cl2to make sure that all organic materialsextracted. Then, the organic phase was dried usingsodium sulfate and subsequently analyzed by GC/MSand 1H NMR, and validated using melting or boilingpoint of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In dichloromethane at 20℃; for 24h; Inert atmosphere; | 13 Example 13 First weigh compound M13 (26.9mg, 0.24mmol), K2CO3 (27.6mg, 0.20mmol) and compound A01 (82.4mg, 0.20mmol) into the reaction tube,Air was evacuated through a vacuum line three times, DCM (2.0 mL) was added under a nitrogen atmosphere, and the reaction was carried out at room temperature for 24 h.After the reaction was completed, the solvent was removed by rotary evaporation, the sample was dry loaded, and column chromatography (300-400 mesh chromatography silica gel) (petroleum ether-ethyl acetate = 9:1) to obtain the product P13 was 31.6 mg, and the yield was 72%. |
72% | With potassium carbonate In dichloromethane at 20℃; for 24h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With histidine tagged carboxyl methyltransferase from Aspergillus fumigatus; histidine tagged S-adenosylhomocysteine nucleosidase In aq. phosphate buffer at 25℃; for 16h; Enzymatic reaction; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
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50% | Stage #1: 4-((E)-3,5-dimethoxy-2-((E)-2-nitrovinyl)styryl)aniline With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 25℃; for 0.5h; Stage #2: furan-3-carboxylic acid In dichloromethane at 25℃; for 10h; | General procedure: Compound 1e (120 mg, 0.368 mmol) and DIPEA (95 mg,0.735 mmol) was dissolved CH2Cl2 (8 mL), then HATU (182 mg,0.478 mmol) was added into the solution. After the mixture wasstirred at 25 C for 30 min, tertiary carboxylic acid (50 mg,0.478 mmol) was added into the mixture, and then it was stirred at25 C for 10 h. After the reaction was completed, the reaction wasadded H2O, then extracted with DCM (45 mL 2). The combinedorganic layer was washed with saturated brine solution, dried overanhydrous Na2SO4, and concentrated to give the yellow solid, thenpurified by column chromatography (gradient elution of PE/DCM10/90 v/v) to obtain compound 1. Compounds 2e31 were obtainedaccording to the similar procedures. |
50% | Stage #1: 4-((E)-3,5-dimethoxy-2-((E)-2-nitrovinyl)styryl)aniline With N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate In dichloromethane at 25℃; for 0.5h; Stage #2: furan-3-carboxylic acid In dichloromethane at 25℃; for 10h; | General procedure: Compound 1e (120 mg, 0.368 mmol) and DIPEA (95 mg,0.735 mmol) was dissolved CH2Cl2 (8 mL), then HATU (182 mg,0.478 mmol) was added into the solution. After the mixture wasstirred at 25 C for 30 min, tertiary carboxylic acid (50 mg,0.478 mmol) was added into the mixture, and then it was stirred at25 C for 10 h. After the reaction was completed, the reaction wasadded H2O, then extracted with DCM (45 mL 2). The combinedorganic layer was washed with saturated brine solution, dried overanhydrous Na2SO4, and concentrated to give the yellow solid, thenpurified by column chromatography (gradient elution of PE/DCM10/90 v/v) to obtain compound 1. Compounds 2e31 were obtainedaccording to the similar procedures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 3-Furoic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: 5-(1H-benzo[d]imidazol-2-yl)-1-(4-methoxybenzyl)-1H-pyrazol-3-amine In N,N-dimethyl-formamide at 23℃; for 18h; | B12.1 Step 1: N-[5-(lH-benzimidazol-2-yl)-l-[(4-methoxyphenyl)methyl]-pyrazol-3-yl]furan-3- carboxamide. 3-Furoic acid (18.4 mg, 0.164 mmol) and HATU (65.5 mg, 0.172 mmol) were dissolved in DMF (1.50 mL) at 0 °C. DIEA (80.4 μL , 0.470 mmol) was added, and the mixture was stirred at 0 °C for 5 min. 5-(lH-benzimidazol-2-yl)-l-[(4- methoxyphenyl)methyl]pyrazol-3-amine (J-l) (50 mg, 0.157 mmol) was added. The mixture was warmed to 23 °C and stirred for 18 h. Water (25 mL) was added. The mixture was filtered, and the solid was washed with water, and dissolved in 9:1 DCM:MeOH (20 mL). The organic phase was dried (MgSO4), filtered, and concentrated to provide the title compound as a solid (58.6 mg, 91%). 1H NMR (400 MHz, DMSO) δ 13.14 (s, 1H), 10.87 (s, 1H), 8.46 (dd, J= 1.5, 0.8 Hz, 1H), 7.78 (t, J= 1.7 Hz, 1H), 7.75 - 7.71 (m, 1H), 7.57 - 7.53 (m, 1H), 7.51 (s, 1H), 7.31 - 7.27 (m, 1H), 7.26 - 7.21 (m, J= 8.4, 4.9, 2.0 Hz, 3H), 7.06 (dd, J= 1.9, 0.8 Hz, 1H), 6.88 - 6.84 (m, 2H), 6.03 (s, 2H), 3.69 (s, 3H). m/z (ES+), [M+H]+ 413.9. HPLC (A05) tR = 2.44 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 4-dimethylaminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 25℃; | 14 Example 14 Take furan-3-carboxylic acid (1.20mmol) and dehydroabietylamine (1.0mmol) in a single-necked flask, add dichloromethane (10mL) to dissolve, add catalyst 4-dimethylaminopyridine (0.20mmol) and condensing agent under stirring EDCI (1.20 mmol), after the addition, reacted at 25°C for 6-10 h, detected by TLC, the reaction was completed, the organic layer was washed with saturated sodium bicarbonate solution, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, reduced Pressure concentrated to remove dichloromethane to obtain crude product, which was purified by silica gel column chromatography (eluent dichloromethane) and dried to obtain target compound I-14. Yield 81%, white solid, mp 129-130 ° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.1% | Stage #1: furan-3-carboxylic acid With thionyl chloride at 70℃; for 4h; Reflux; Stage #2: 4-amino-7-hydroxycoumarin In propan-2-one at 56℃; for 24h; | Procedure iii: General procedure: Note that the synthesis of compound 3e is taken as an example here.Dibromohexanoic acid (602.5 mg, 3 mmol) and thionyl chloride (0.6 mL, 7.8 mmol) wereadded to a 25 mL round-bottomed flask fitted with a stirring bar and a condenser connectingwith a gas absorber for SO2. When the mixture was heated to 70 C, it turned brown. Themixture was reuxed for 4 h, then the thionyl chloride was removed under reducedpressure. After adding 7-hydroxy-4-amino coumarin (51.7 mg, 0.3 mmol) and acetone(4 mL), the solution was heated to 56 C. The reaction was stopped after 24 h. |
Tags: 488-93-7 synthesis path| 488-93-7 SDS| 488-93-7 COA| 488-93-7 purity| 488-93-7 application| 488-93-7 NMR| 488-93-7 COA| 488-93-7 structure
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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