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CAS No. : | 5006-22-4 | MDL No. : | MFCD00001319 |
Formula : | C5H7ClO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 118.56 | Pubchem ID : | - |
Synonyms : |
|
Signal Word: | Danger | Class: | 8,3 |
Precautionary Statements: | P210-P233-P240-P241-P242-P243-P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P363-P370+P378-P403+P235-P405-P501 | UN#: | 2920 |
Hazard Statements: | H225-H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
71.77% | With ammonia In dichloromethane; water at -20 - 20℃; | A solution of cyclobutyl carbonyl chloride (5 g, 42.37 mmol) in dichloromethane (20 mL) was treated with aqueous ammonia solution (20 mL) at -20 °C.The resulting reaction mixture was stirred overnight at room temperature. Volatiles were removed under vacuum. The precipitated solid was filtered and dried under vacuum to afford the cyclobutane carboxamide (3 g, 71 .77percent).1H NMR (400 MHz, DMSO-c/6): δ 7.02 - 7.16 (m, 1 H), 6.65 (br. s., 1 H), 2.95 (quind, J=8.43, 8.43, 8.43, 8.43, 0.85 Hz, 1 H), 1 .61 - 2.18 (m, 6H). |
71.77% | With ammonia In dichloromethane; water at -20 - 20℃; | A solution of cyclobutyl carbonyl chloride (5 g, 42.37 mmol) in dichloromethane (20 mL) was treated with aqueous ammonia solution (20 mL) at -20° C. The resulting reaction mixture was stirred overnight at room temperature. Volatiles were removed under vacuum. The precipitated solid was filtered and dried under vacuum to afford the cyclobutane carboxamide (3 g, 71.77percent). 1H NMR (400 MHz, DMSO-d6): δ 7.02-7.16 (m, 1H), 6.65 (br. s., 1H), 2.95 (quind, J=8.43, 8.43, 8.43, 8.43, 0.85 Hz, 1H), 1.61-2.18 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: With triethylamine; magnesium chloride In acetonitrile at 10 - 20℃; for 2.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 19 h; Stage #3: With hydrogenchloride In water; ethyl acetate |
The ethyl 3-cyclobutyl-3-oxopropanoate used as starting material was prepared as follows: To a suspension of potassium 3-ethoxy-3-oxopropanoate (60.3 g, 354.25 mmol) in acetonitrile (600 mL) under argon at 10 °C was added triethylamine (75 mL, 540 mmol) then magnesium chloride (40.2 g, 421.72 mmol) keeping the temperature below 25 °C. The thick white suspension was stirred for 2.5 hours under argon at room temperature.Cyclobutanecarbonyl chloride (19.25 mL, 167 mmol) was added slowly (over 1 hour) to the re-cooled mixture at 0-5 °C. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The solvent was then evaporated. The white residue was taken up in EtOAc (700 mL) and 2M HC1 (about 400 mL) was added until it was all in solution (pH of aqueous = 5). The organic layer was separated then washed with 2M. HC1 (200 mL), sat. NaHC03 (2 x 200 mL, saturated aqueous solution) and the organic layer was dried (MgS04), filtered and evaporated to afford ethyl 3-cyclobutyl-3-oxopropanoate(28.0 g, 98 percent) as pale yellow oil.1H NMR (400.132 MHz, CDC13) δ 1.28 (3H, t), 1.80-1.89 (1H, m), 1.91-2.05 (1H, m), 2.12-2.34 (4H, m), 3.39 (2H, s), 3.34-3.42 (1H, m), 4.19 (2H, q). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With [2,2]bipyridinyl; n-butyllithium In tetrahydrofuran; hexanes at -55 - 20℃; | 9a) Ethyl 3-cyclobutyl-3-oxopropanoate To a solution of monoethyl malonate (12.0 mL, 101 mmol) and a few milligrams of 2,2'-bipyridyl in tetrahydrofuran (250 mL) at approximately -55° C. was added in a dropwise fashion butyl lithium (2.5 M in hexanes, 81.0 mL, 202 mmol). Then cyclobutanecarbonyl chloride (6.00 mL, 50.6 mmol) was added dropwise. The flask was removed from the cold bath and the mixture was allowed to stir while warming to ambient temperature. The mixture was poured into 1 N aqueous hydrochloric acid and extracted twice with ether. The combined organic layers were dried over magnesium sulfate, washed twice with saturated sodium bicarbonate, dried again over magnesium sulfate, concentrated and purified by chromatography (silica gel, 7.5percent ethyl acetate in hexanes) to afford ethyl 3-cyclobutyl-3-oxopropanoate (6.69 g, 78percent). 1H-NMR (400 MHz, DMSO-d6) δ 4.06 (q, J=7 Hz, 2H), 3.49 (s, 2H), 3.38-3.32 (m, 1H), 2.11-2.05 (m, 4H), 1.90-1.85 (m, 1H), 1.87-1.66 (m, 1H) 1.15 (t, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride In toluene Heating; | |
48.9% | With thionyl chloride at 0 - 90℃; for 1.5h; Large scale; | R2 Example R2. Synthesis of cyclobutanecarbonyl chloride r-2 The cyclobutanecarboxylic acid (950 g, 9.49 mol, 905 ml_) was cooled to 0°C, and then SOCI2 (2.00 L) was added dropwise with stirring. Thereafter, the mixture was stirred at 90°C for 1.5 h. The reaction mixture was distilled in vacuum (80°C, 20 mmHg) to give compound r-2 (1.10 kg, 48.9% yield) as a colorless liquid. |
With phosphorus trichloride |
With thionyl chloride | ||
With thionyl chloride | ||
With thionyl chloride In benzene | ||
With thionyl chloride for 1h; Heating; | ||
With thionyl chloride In dichloromethane at 20℃; | ||
In thionyl chloride | 1 1-Cyclobutyl-1-hydroxy-3-(4-phenyl-1-piperazinyl)-1-phenyl-2-propanone EXAMPLE 1 1-Cyclobutyl-1-hydroxy-3-(4-phenyl-1-piperazinyl)-1-phenyl-2-propanone In a 5-L round bottomed flask equipped with an overhead stirrer and a pressure equalizing addition funnel was placed 1460 mL (20.0 mole) of thionyl chloride. To this solution was added dropwise over a 4 hour period cyclobutanecarboxylic acid (1910 mL, 20 mole). During the addition the reaction vessel was cooled in an ice-salt bath. The mixture was stirred overnight at room temperature and then brought to reflux for 5 hours. The mixture was distilled under atmospheric pressure to give 2260.2 g of cyclobutanecarbonyl chloride, bp 130°-135° C. | |
In thionyl chloride | 1 1-Cyclobutyl-1-hydroxy-3-(4-phenyl-1-piperazinyl)-1-phenyl-2-propanone Example 1 1-Cyclobutyl-1-hydroxy-3-(4-phenyl-1-piperazinyl)-1-phenyl-2-propanone In a 5-L round bottomed flask equipped with an overhead stirrer and a pressure equalizing addition funnel was placed 1460 mL (20.0 mole) of thionyl chloride. To this solution was added dropwise over a 4 hour period cyclobutanecarboxylic acid (1910 mL, 20 mole). During the addition, the reaction vessel was cooled in an ice-salt bath. The mixture was stirred overnight at room temperature and then brought to reflux for 5 hours. The mixture was distilled under atmospheric pressure to give 2260.2 g of cyclobutanecarbonyl chloride, bp 130 - 135 °C. | |
With oxalyl dichloride In N,N-dimethyl-formamide for 1.5h; Reflux; | Cyclobutanecarboxylic acid (10.0 g) was cooled to 0C, and then thionyl chloride (20 ml.) was added dropwise with stirring. Then the mixture was refluxed for 1.5 hours. The product was distilled to give 10 g of forerun and 9.5 g of the desired cyclobutanecarbonyl chloride (32 °C/20mmHg) as a colorless liquid. Reference: b.p. 130-140 0C (760mmHg) | |
With oxalyl dichloride In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | ||
With thionyl chloride at 0℃; for 1.5h; Reflux; | A Step A: Cyclobutanecarboxylic acid (50.0 g, 499 mmol) was cooled to 0 0 C, then thionyl chloride (100 ml) was added dropwise with stirring. Then the reaction mixture was refluxed for 1.5 hours. The product was separated by distillation to give cyclobutanecarbonyl chloride. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; | 37 To a 0 °C solution of cyclobutane carboxylic acid (7.50 g, 74.9 mmol) in DCM (100 mL) was added oxalyl chloride (12.00 g, 95 mmol) followed by catalytic amount of DMF. The resultant mixture was stirred at T for 1 h. The solvent from the reaction mixture was completely evaporated to a light coloured viscous mass. In a different RB flask, a suspension of semicarbazide hydrochloride (9.00 g, 81 mmol) in DCM (100 mL) was treated with triethylamine (18.00 g, 178 mmol) and stirred at -10 °C for 30 minutes. To the reaction mixture was added the acid chloride dissolved in DCM (20 mL) at the same temp and the resultant mixture was stirred at RT over night. The solvent from the reaction mixture was completely removed and the residue was stirred in MeCN (100 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and was treated with sodium hydroxide (7.50 g, 188 mmol) and water (20 mL). The resulting reaction mixture was heated at 100 °C for 3 h, cooled to RT, and acidified with cone, sulfuric acid. The solids were collected, washed sparingly with cold water, and dried to provide 3-cy clobutyl-lH- 1,2,4- triazol-5(4H)-one, (6.40 g, 61.4 % yield) as white solid. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | ||
With pyridine; oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere; | ||
With thionyl chloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 24℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1.5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide for 2h; | ||
With thionyl chloride In dichloromethane for 6h; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 40℃; for 10h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 35℃; for 1.5h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 2h; Inert atmosphere; | 1 Step 1 - Synthesis of Intermediate Y.2, cyclobutanecarbonyl chloride. A solution of cyclobutanecarboxylic acid (2.00 g, 20.0 mmol) in DCM (40 mL) was cooled to 0 °C and (COCl)2 (3.50 mL, 40.0 mmol) was added dropwise. After the addition was complete, DMF (0.2 mL) was added, and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was then concentrated to afford cyclobutanecarbonyl chloride, which was used directly in the next reaction without further purification. | |
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. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminium trichloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.77% | With ammonia; In dichloromethane; water; at -20 - 20℃; | A solution of cyclobutyl carbonyl chloride (5 g, 42.37 mmol) in dichloromethane (20 mL) was treated with aqueous ammonia solution (20 mL) at -20 C.The resulting reaction mixture was stirred overnight at room temperature. Volatiles were removed under vacuum. The precipitated solid was filtered and dried under vacuum to afford the cyclobutane carboxamide (3 g, 71 .77%).1H NMR (400 MHz, DMSO-c/6): delta 7.02 - 7.16 (m, 1 H), 6.65 (br. s., 1 H), 2.95 (quind, J=8.43, 8.43, 8.43, 8.43, 0.85 Hz, 1 H), 1 .61 - 2.18 (m, 6H). |
71.77% | With ammonia; In dichloromethane; water; at -20 - 20℃; | A solution of cyclobutyl carbonyl chloride (5 g, 42.37 mmol) in dichloromethane (20 mL) was treated with aqueous ammonia solution (20 mL) at -20 C. The resulting reaction mixture was stirred overnight at room temperature. Volatiles were removed under vacuum. The precipitated solid was filtered and dried under vacuum to afford the cyclobutane carboxamide (3 g, 71.77%). 1H NMR (400 MHz, DMSO-d6): delta 7.02-7.16 (m, 1H), 6.65 (br. s., 1H), 2.95 (quind, J=8.43, 8.43, 8.43, 8.43, 0.85 Hz, 1H), 1.61-2.18 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium on activated charcoal; In 1-methyl-pyrrolidin-2-one; at 20℃; under 2068.65 Torr; for 2h; | Example 4: Preparation of Nalbuphine from Noroxymorphone; Cyclobutane carbonyl chloride (1.44ml, 25.2mmol) was hydrogenated for 2 hours in JV-methylpyrrolidinone (30ml) at 40 psi and room temperature in the presence of palladium on charcoal catalyst. The crude solution of cyclobutane carboxaldehyde was filtered through a bed of celite. To 15ml of the above filtered solution, noroxymorphone (2.78g, 7.96mmol) was added followed by platinum on carbon catalyst and the mixture hydrogenated at 50C and 40psi. After 2 hours the catalyst was filtered off and sodium borohydride (3g) added portionwise. HPLC analysis of the crude reaction mixture and comparison against a known sample of nalbuphine confirmed the formation of nalbuphine. | |
palladium; In tetrahydrofuran; | EXAMPLE 3 10 parts of cyclobutylcarboxylic acid chloride in tetrahydrofuran is hydrogenated over 10% palladium on carbon catalyst, to provide cyclobutylcarboxaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine In N,N-dimethyl-formamide at 20℃; for 1h; | Step-a: N'-phenylcvclobutanecarbohydrazide: Step-a: N'-phenylcvclobutanecarbohydrazide: Cyclobutanecarbonyl chloride (21.92 g, 184 mmol) was added dropwise at RT to phenyl hydrazine (20 g, 184 mmol) and pyridine (20 mL, 257 mmol) in 30 mL DMF. The mixture was stirred for 1 h at RT and poured into 200 mL of aq.1M HC1 solution. The precipitated solid was filtered, washed with 50 mL water and dried. The solid was washed with 20 mL of diethyl ether and dried under reduced pressure (32 g, 91%). 'H-NMR (400 MHz, DMSO- 6) δ 9.45 (s, 1H), 7.64 (d, 1H), 7.14 (m, 2H), 6.68 (m, 3H), 3.1 (m, 1H), 2.10 (m, 4H), 1.86 (m, 1H), 1.81 (m, 1H); LC-MS: 191.1 [M+H]+. |
72% | With pyridine In N,N-dimethyl-formamide Ambient temperature; | |
52% | With pyridine In N,N-dimethyl-formamide at 20℃; for 1h; | 30.1 Step 1 Cyclobutanecarboxylic acid N'-phenylhydrazide 3.54 mL (31.0 mmol) cyclobutanecarboxylic acid chloride were added dropwise at RT to 3.00 mL (30.2 mmol) phenylhydrazine and 4.75 mL (60.0 mmol) pyridine in 30 mL DMF. The mixture was stirred for 1 h at RT and poured onto 200 mL of a 1M hydrochloric acid solution. The precipitated solid was suction filtered, washed with 50 mL water and dried i. vac. The product was extracted with 50 mL ether and suction filtered. The solid was washed with 20 mL ether and dried in the air. Yield: 3.00 g (52% of theory) ESI-MS: m/z=191 (M+H)+ |
With pyridine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With aluminium trichloride In dichloromethane at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane for 4h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine In dichloromethane at 50℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In dichloromethane at 20℃; for 0.166667h; | 12 Example 12: λ/-(1-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin- 4-yl)-/V-methylcyclobutanecarboxamideTo a solution of 1-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1A7-pyrazol-1-yl]acetyl}-λ/- methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 ml_) at room temperature was added triethylamine (56 μl_, 0.40 mmol) followed by cyclobutanecarbonyl chloride (42 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2 - 8% MeOH/DCM to yield the title compound as a white solid, 154 mg, 85%; 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz), 7.66 (2 H, d, J=6.06 Hz), 7.30 (2 H, dd, J=8λ6, 5.68 Hz), 7.15 (2 H, t, J=8.97 Hz), 6.52 (1 H, s), 5.08 - 5.33 (2 H, m), 4.42 - 4.57 (0.5 H, m), 4.38 (1 H, d, J=13.39 Hz), 3.95 (3 H, s), 3.64 - 3.79 (0.5 H, m), 3.36 - 3.48 (0.5 H, m), 3.24 - 3.34 (0.5 H, m), 3.03 - 3.20 (1 H, m), 2.55 - 2.76 (4 H, m), 2.01 - 2.28 (4 H, m), 1.39 - 1.99 (6 H, m); m/z (APCI+) for C28H32N5O2F 490.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With [2,2]bipyridinyl; n-butyllithium; In tetrahydrofuran; hexanes; at -55 - 20℃; | 9a) Ethyl 3-cyclobutyl-3-oxopropanoate To a solution of monoethyl malonate (12.0 mL, 101 mmol) and a few milligrams of 2,2'-bipyridyl in tetrahydrofuran (250 mL) at approximately -55 C. was added in a dropwise fashion butyl lithium (2.5 M in hexanes, 81.0 mL, 202 mmol). Then cyclobutanecarbonyl chloride (6.00 mL, 50.6 mmol) was added dropwise. The flask was removed from the cold bath and the mixture was allowed to stir while warming to ambient temperature. The mixture was poured into 1 N aqueous hydrochloric acid and extracted twice with ether. The combined organic layers were dried over magnesium sulfate, washed twice with saturated sodium bicarbonate, dried again over magnesium sulfate, concentrated and purified by chromatography (silica gel, 7.5% ethyl acetate in hexanes) to afford ethyl 3-cyclobutyl-3-oxopropanoate (6.69 g, 78%). 1H-NMR (400 MHz, DMSO-d6) delta 4.06 (q, J=7 Hz, 2H), 3.49 (s, 2H), 3.38-3.32 (m, 1H), 2.11-2.05 (m, 4H), 1.90-1.85 (m, 1H), 1.87-1.66 (m, 1H) 1.15 (t, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Example 44 Synthesis of l-[l-(4-chlorophenyl)-5-cyclobutyl-pyrazol-4-yl]-3-[2-methyl-4- (trifluoromethyl)imidazol-l-yl]pyrrolidin-2-one [0216] a) Pyridine (20.46 mL, 253 mmol) was added to a solution of cyclobutanecarboxylic acid chloride (10.0 g, 84.3 mmol) and isopropylidene malonate (12.16 g, 84.3 mmol) in (( (100 mL) at 0 C and the mixture was stirred at room temperature for 1.5 h. Methanol (100 mL) was then added and the resulting mixture was stirred at reflux for 3 h, cooled to room temperature, and partitioned between aqueous HCl (1 M, 200 mL) and EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 20% EtOAc/hexanes gradient elution) to give methyl 3-cyclobutyl-3-oxo-propanoate (11.6 g, 88% yield). [0217] b) A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (5.8 g, 37.2 mmol) and N,N-dimethylformamide dimethyl acetal (25 g, 210 mmol) was stirred at 100 C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo to give an oily residue that was directly carried to the next step. [0218] c) A mixture of the intermediate (~ 37.2 mmol) obtained in step b, 4- chlorophenylhydrazine hydrochloride (6.67 g, 37.2 mmol) and K2CO3 (10.3 g, 74.4 mmol) in DMF (50 mL) was stirred at 100 C for 1 h. After cooling to room temperature the mixture was diluted with aqueous HCl (200 mL) and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 10% EtOAc/CH2Cl2 gradient elution) to give methyl 1- (4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 76% yield). [0219] d) A mixture of methyl l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 28.5 mmol) and lithium hydroxide monohydrate (3.6 g, 85.6 mmol) in MeOH (25 mL), THF (25 mL) and FLO (12 mL) was stirred at 80 C for 1 h. After cooling to room temperature the mixture was acidified with 1 M aqueous HCl and extracted with EtOAc (400 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (6.92 g, 87% yield). [0220] e) To a mixture of l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (4.0 g, 14.4 mmol) in CH2CI2 (100 mL) was added oxalyl chloride (3.78 mL, 43.4 mmol) and DMF (0.06 mL). After 2 h at room temperature, the reaction mixture was concentrated in vacuo, re-dissolved in 40 mL of acetone, and added to a 0 C solution of a 3 (3.75 g, 57.8 mmol) in H2O (40 mL). Brine (150 mL) and EtOAc (350 mL) were then added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was stirred in 100 mL of toluene at 95 C for 1 h, cooled to room temperature, and then treated with 150 mL of 6 M aqueous HCl at 1 10 C for 1 h. After cooling to room temperature, the mixture was basified with dilute NH4OH and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2 gradient elution) to yield l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (2.9 g, 81% yield). [0221] f) A mixture of l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (0.080 g, 0.32 mmol) and 3-[2-methyl-4-(trifluoromethyl)imidazol-l-yl]tetrahydrofuran-2-one (0.080 g, 0.34 mmol) in 1,2-dichloroethane (2 mL) was treated with MesAl (0.32 mL, 0.64 mmol, 2 M/toluene) at room temperature for 1.5 h. The reaction mixture was then quenched with saturated aqueous aHC03 solution and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the desired alcohol intermediate. [0222] g) A 0 C solution of the alcohol intermediate (-0.32 mmol) obtained in step f and Et3 (0.067 mL, 0.48 mmol) in CH2C12 (1.5 mL) was treated with methanesulfonyl chloride (0.027 mL, 0.35 mmol) for 10 min. The mixture was then basified with saturated aqueous aHC03 solution and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the desired mesylate. [0223] h) A mixture of the mesylate (~ 0.032 mmol) obtained in step g and Ets (0.15 mL, 1.07 mmol in 1,2-dichloroethane (3 mL) was stirred at 75 C for 3 h. After cooling to room temperature the reaction mixture was directly purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2), followed by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent) to afford the titled compound (0.060 g, 40% yield, free form). XH NMR (400 MHz, CDCI3) δ 7.57 (s, 1 H), 7.43 (m, 2 H), 7.36 (m, 2 H), 7.23 (d, J= 1.2 Hz, 1 H), 4.95 (dd, J= 9.2, 8.4 Hz, 1 H), 3.86 (m, 2 H), 3.71 (m, 1 H), 2.84 (m, 1 H), 2.50 (s, 3 H), 2.36 (m, 1 H), 1.99 (m, 6 H); MS: (ES) m/z calculated for C22H21C1F3 50 [M + H]+... | |
88% | Pyridine (20.46 mL, 253 mmol) was added to a solution of cyclobutanecarboxylic acid chloride (10.0 g, 84.3 mmol) and isopropylidene malonate (12.16 g, 84.3 mmol) in CH2Cl2 (100 mL) at 0 C. and the mixture was stirred at room temperature for 1.5 h. Methanol (100 mL) was then added and the resulting mixture was stirred at reflux for 3 h, cooled to room temperature and partitioned between aqueous HCl (1 M, 200 mL) and EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0-20% EtOAc/hexanes gradient elution) to give methyl 3-cyclobutyl-3-oxo-propanoate (11.6 g, 88% yield). | |
a.1.1 : Methyl^-cyclobutanoyl-acetate; 22 g of meldrum's acid (2,2-dimethyl-1 ,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 gMS (ESI) m/z: 157.1 [M+H]+1H-NMR (CDCI3): δ [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1 H), 2.2-2.4 (m, 2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1 H). |
2, 2-dimethyl-l, 3-dioxane-4, 6-dione (54.2 g, 376 mmol) was dissolved in CHCI3 (400 mL), then pyridine (50.6 mL, 625 mmol, 1.83 eq) was added to the mixture. A solution of cyclobutanecarbonyl chloride (40.5 g, 342 mmol) in CHCI3 (160 mL) was added dropwise to the reaction at a temperature of between 5-10 0 C while cooling in an ice-bath. Then the reaction mixture was stirred at 0 0 C for 1 hour, and at room temperature for 1 hour. The reaction mixture was then cooled to 0 0 C, and IN aqueous HC1 (400 mL) was added. Then the reaction mixture was extracted with CHCI3 (300 mL x 3). The combined organic layers were washed with water, and dried over anhydrous Na2SC"4, followed by concentration under reduced pressure. Then MeOH (400 ml) was added to the residue and the solution was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting residue was distilled to give methyl 3-cyclobutyl-3-oxopropanoate. 1H NMR (400 MHz, CDC13) £3.68 (s, 3H), 3.36 (s, 2H), 2.27-2.10 (m, 4H), 1.99-1.75 (m, 2H), 1.25-1.19 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: lithium aluminum hydride / diethyl ether / 2 h / Heating 2: pyridine 3: 82 percent / dimethylsulfoxide / 1.5 h / 130 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (i) PhLi, Et2O, (ii) /BRN= 956624/, benzene 2: benzene 3: FeCl3 / aq. HCl 4: aq. NaOH / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h; | 3-fluoro-4-[piperazinyl-4-yl]phenyl]-2-oxazolidin-5-yl]methyl]]acetamide (200 mg, 0.47 mmol) (obtained according to the procedure described in preparation 9) was reacted with cyclobutane carbonyl chloride (49 mkl, 0.6 mmol) and K2CO3 (190 mg, 1.4 mmol) in DMF (10 ml) at the ambient temperature for 12 hrs. The product was purified through a silica gel column using 10 % MeOH in EtOAc to obtain the title compound (150 mg, yield 72 %). 1H-NMR (CDCl3): delta 0.8 (3H, m), 1.3 (3H, m), 2.0 (3H, s), 2.9 (4H, m), 3.8 (3H, m), 4.0 (2H, m), 4.1 (2H, m), 4.4 (1H, m), 4.5 (2H, m), 6.9-7. 5 (3H, m, aromatic). Mass: M+I= 419 |
Yield | Reaction Conditions | Operation in experiment |
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100% | With triethylamine In dichloromethane at 0 - 20℃; for 14h; | 19.a a) Cyclobutane carbonyl chloride (5 ml, 43.8 mmol) was slowly added to a solution of ethyl glycinate (5.86 g, 42 mmol) in dichloromethane (100 ml) and triethylamine (14.6 ml, 105 mmol) at 0 C. The mixture was then stirred at ambient temperature for 14 hours. The reaction mixture was washed with a dilute hydrochloric acid (1.0 N), the organic phase was separated, dried and evaporated in vacuo to give a yellow solid. Recrystallisation from dichloromethane/petroleum ether yielded ethyl N- (cyclobutylcarbonyl) glycinate as a white solid (7.78 g, 100 % yield): 'H-NMR (DMSO d6): 8.08 (t, 1H), 4.09 (q, 2H), 3.79 (s, 2H), 3.07 (M, 1H), 2.00-2. 18 (m, 4H), 1.89 (M, 1H), 1.78 (M, 1H), 1.20 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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91% | With aluminum (III) chloride In 1,2-dichloro-ethane at -10 - 10℃; for 0.75h; | 3.a Example 3; 1-cyclobutylmethyl-4-methylsulfanyl-benzene; a) cyclobutyl-(4-methylsulfanyl-phenyl)-methanone Cyclobutane carboxylic acid chloride (4.50g, 38 MMOL) DISSOLVED in DICHLOROETHANE (10 MI) was added dropwise to a COLD (-10°C) suspension OF AICI3 (4. 81g, 38 MMOL) in DICHLOROETHANE (20 ML). To this solution was added METHYLSULFANYL-BENZENE (4.49g, 36 MMOL) at such a rate that the temperature did not exceed 10°C. After the mixture was stirred for 45 min in an ice bath, it was poured on water and extracted with DICHLOROETHANE. The organic phase was separated, washed with water and brine, dried (MGS04) and concentrated in vacuo to yield a crystalline solid (6.78g, 91%). 1H-NMR (CDCl3, 400MHZ) : 7.81-7. 79 (m, J = 6.8 Hz, 2H), 7.27-7. 24 (m, J = 6.8 Hz, 2H), 3.95 (QUINT. , J = 8.5 HZ, 1 H), 2.51 (S, 3H), 2.47-2. 23 (M, 4H), 2.13-2. 03 (M, 1 H), 1.95-1. 86 (m, H) ppm. GC/MS (El) : 206 (M+, 18), 178 (2), 151 (100), 123 (7), 108 (8), 79 (5), 45 (6) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine In tetrahydrofuran at 20℃; for 24h; | 6 Cyclobutanoyl chloride (19 ML, 17.03 mmol) was added to a suspension of 3-AMINO-1- ETHOXYCARBONYL-5- [ (2-CHLORO) PYRIMIDIN-4-YL]-4, 6-DIHYDROPYRROLO [3,4-c] pyrazole dihydrochloride (3.5 g, 11.35 mmol) in dry THF (220 ml) and dry pyridine (75 ml). The mixture was stirred at room temperature for 24 hours. The solvents were evaporated and the residue was taken up in hot water (75 ml), stirred for about 30 minutes, filtered, washed with diethyl ether and dried under vacuum at 30°C. The title compound was obtained as a beige powder (4.2 g, 95%). 1H-NMR (400MHZ, DMSO-86) ppm: 10.94 (s 1H), 8.15 (d, 2H), 6.67 (d, 1H), 4.87- 4.58 (M, 4 H), 4. 42 (q, 2H), 3.34 (m, lH), 2. 43-1. 71 (M, 6H), 1.37 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine In tert-butylmethyl ether at 0 - 20℃; for 2h; | 1 2-[(Cyclobutylcarbonyl)thio]benzoic acid REFERENCE EXAMPLE 1 2-[(Cyclobutylcarbonyl)thio]benzoic acid Thiosalicylic acid (6.17 g, 40 mmol) was suspended in tert-butylmethyl ether (100 ml) at room temperature. While stirring under ice cooling, pyridine (7.91 g, 100 mmol) and then cyclobutanecarbonyl chloride (5.00 g, 42 mmol) were dropwise added to the suspension. After the reaction mixture was stirred for 2 hours, the mixture was diluted with water and 6N hydrochloric acid was added thereto to make its liquid property acidic. The mixture was extracted (100 ml x 3) with tert-butylmethyl ether-tetrahydrofuran (3:1, v/v). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give the title compound (9.11 g, 96%). A part (1.0 g) of the compound was recrystallized from ethyl acetate-hexane to give colorless crystals (0.81 g). Melting point: 92.6-95.5°C IR (KBr): 2988, 2946, 1701, 1586, 1474, 1437, 1406, 1298, 1265, 1144, 1109, 1053, 959, 816, 748 cm-1. 1H-NMR (CDCl3) δ:1.83-2.58 (6H, m), 3.40-3.60 (1H, m), 7.33-7.64 (3H, m), 8.09 (1H, d, J=7.2 Hz). Elemental analysis: as C12H12O3S Calcd.: C, 61.00; H, 5.12. Found: C, 60.88; H, 5.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In dichloromethane at 20℃; for 18h; | 27 Preparation 27 tert-Butyl (3S)-3-[(cyclobutylcarbonyl)amino]pyrrolidine-1-carboxylate Cyclobutanecarbonylchloride (9 g, 76 mmol) was added to a solution of triethylamine (12.5 ml, 89.7 mmol) and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (12.87 g, 69 mmol) in dichloromethane (385 ml) at room temperature under nitrogen. After stirring for 18 hours at room temperature, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the title product as a light brown glass, (17.4 g, 94%) 1HNMR(400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.75-2.00 (m, 3H), 2.07-2.30 (m, 5H), 2.95 (m, 1H), 3.15 (m, 1H), 3.40 (m, 2H), 3.60 (m, 1H), 4.44 (m, 1H), 5.40 (brs, 1H) |
94% | With triethylamine In dichloromethane at 20℃; for 18h; | 7 Cyclobutanecarbonylchloride (9g, 76mmol) was added to a solution of triethylamine (12.5ml, 89.7 mmol), and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (12.87g, 69mmol), in dichloromethane (385ml), at room temperature, under nitrogen. After stirring for 18 hours at room temperature, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the title product as a light brown glass, (17.4g, 94%).1HNMR(400MHz, CDCI3) δ: 1.45 (s, 9H), 1.75-2.00 (m, 3H), 2.07-2.30 (m, 5H)1 2.95 (m, 1 H), 3.15 (m, 1 H), 3.40 (m, 2H), 3.60 (m, 1 H), 4.44 (m, 1 H), 5.40 (brs, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N-methyl-acetamide; N,N-dimethyl-formamide; | [3,2-e:2',3'-g]isoquinoline-1,8abeta(9H)-diol, monohydrochloride (compound 15) 6,7,8,14bbeta-Tetrahydro-4,8(R,alpha)-methano-4bS* -5H-bisbenzofuro[3,2-e:2',3'-g]isoquinoline-1,8abeta(9H)-diol (260 mg, 0.720 mmol) was slurried in dimethylformamide (DMF, 3 mL). Triethylamine (218 mg, 2.16 mmol) was added, followed by a solution of cyclobutanecarbonyl chloride (213 mg, 1.80 mmol) in DMF (2 mL). After stirring for 4 h, the mixture was poured into 1 N aq HCl (25 mL) and the mixture was extracted with ethyl acetate (2*25 mL). The combined organic extracts were washed with 1 N aq NH4 OH, then the solvent was evaporated in vacuo to give the intermediate cyclobutyl amide as an oily residue. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 0 - 20℃; | I.Intermediates:; a. Preparation of 4-r4-(3-chloro-propvD-piperazin-1 -yll-pyrimidines; a. 1 2-terf-Butyl-4-r4-(3-chloro-propyl)-piperazin-1 -vll-6-cvclobutvl-pyrimidine; a.1.1: Methvl-2-cyclobutanoyl-acetate; 22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 gMS (ESI) m/z: 157.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1H), 2.2-2.4 (m,2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | In benzene | 24 2-(4'-Cyclobutamidophenyl)benzothiazole (KF497) Example 24 2-(4'-Cyclobutamidophenyl)benzothiazole (KF497) This is an example of a cyclic amide derivative. To a solution of 2-(4'-aminophenyl)benzothiazole (0.8 g, 3.54 mmol) in benzene (40 ml) at 80° C. was added dropwise cyclobutanecarbonyl chloride (1.1 ml, 9.64 mmol). A yellow solid formed, and the mixture was stirred at 80° C. for 30 minutes. The solid was filtered, washed with benzene and diethyl ether to give a yellow powder (1.18 g, 96.9%), which is a 2-(4'-cyclobutylacetamidophenyl)benzothiazole hydrochloride, m.p. 247-248° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-Chloro-3-nitroaniline; Cyclobutanecarbonyl chloride With pyridine In dichloromethane at 0 - 20℃; for 1h; Stage #2: With potassium carbonate In methanol; water Stage #3: With hydrogen In methanol for 18h; | 138.a; 139.a Cyclobutylcarbonyl chloride (3.64 ml_, 31.9 mmol) was added dropwise to an ice-cooled, stirred solution of 4-chloro-3-nitroani.ine (5.00 g, 29.0 mmol) and pyridine (3.5 mL, 43.2 mmol) in dichloromethane (30 mL) under argon. The mixture was allowed to warm to room temperature and stirred 1 h, then the solevent removed under reduced pressure. 0.5 M aqueous potassium carbonate (10 mL) and methanol(30 mL) was added and the mixture stirred 0.5 h, then diluted with water (200 mL) and extracted with ethyl acetate. The extracts were washed (1 M aq HCI, water, brine), dried (MgSO4) and evaporated to dryness under reduced pressure. A solution of the crude amide in methanol (150 mL) was stirred with Raney nickel (~ 0.5 g) under 1 atm of hydrogen for 18 h. After removal of the hydrogen, the mixture was filtered through a PTFE micropore filter, then evaporated under reduced pressure to give the title compound (6.52 g, 100%) as an oil. 1 H NMR (400MHz, DMSOd6) δ 1.80 (m, 1 H), 1.92 (m, 1 H), 2.03-2.11 (m, 2H), 2.14-2.24 (m, 2H), 3.18 (m, 1 H), 5.32 (s, 2H), 6.73 (dd, J = 8.6, 2.5 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 2.5 Hz, 1 H), 9.56 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-Chloro-3-nitroaniline; Cyclobutanecarbonyl chloride With pyridine In dichloromethane at 0 - 20℃; for 1h; Stage #2: With potassium carbonate In methanol; water for 0.5h; | 5.a Cyclobutylcarbonyl chloride (3.64 ml_, 31.9 mmol) was added dropwise to an ice-cooled, stirred solution of 4-chloro-3-nitroaniline (5.00 g, 29.0 mmol) and pyridine (3.5 ml_, 43.2 mmol) in dichloromethane (30 ml_) under argon. The mixture was allowed to warm to room temperature and stirred 1 h, then the solevent removed under reduced pressure. 0.5 M aqueous potassium carbonate (10 ml_) and methanol (30 ml_) was added and the mixture stirred 0.5 h, then diluted with water (200 mL) and extracted with ethyl acetate. The extracts were washed (1 M aq HCI, water, brine), dried (MgSO4) and evaporated to dryness under reduced pressure.A solution of the crude amide in methanol (150 mL) was stirred with Raney EPO nickel (~ 0.5 g) under 1 atm of hydrogen for 18 h. After removal of the hydrogen, the mixture was filtered through a PTFE micropore filter, then evaporated under reduced pressure to give the title compound (6.52 g, 100%) as an oil. 1 H NMR(400MHz, DMSOd6) δ 1.80 (m, 1 H), 1.92 (m, 1 H), 2.03-2.11 (m, 2H), 2.14-2.24 (m, 2H), 3.18 (m, 1 H), 5.32 (s, 2H), 6.73 (dd, J = 8.6, 2.5 Hz, 1 H), 7.05 (d, J = 8.6Hz, 1 H), 7.20 (d, J = 2.5 Hz, 1 H), 9.56 (s, 1 H). |
With pyridine In dichloromethane at 0 - 20℃; for 1h; | 47.a Λ/-(3-Amino-4-chlorophenyl)cyclobutanecarboxamide. Cyclobutylcarbonyl chloride (3.64 ml_, 31.9 mmol) was added dropwise to an ice-cooled, stirred solution of 4-chloro-3-nitroaniline (5.00 g, 29.0 mmol) and pyridine (3.5 ml_, 43.2 mmol) in dichloromethane (30 mL) under argon. The mixture was allowed to warm to room temperature and stirred 1 h, then the solevent removed under reduced pressure. 0.5 M aqueous potassium carbonate (10 mL) and methanol(30 mL) was added and the mixture stirred 0.5 h, then diluted with water (200 mL) and extracted with ethyl acetate. The extracts were washed (1 M aq HCI, water, brine), dried (MgSO4) and evaporated to dryness under reduced pressure. A solution of the crude amide in methanol (150 mL) was stirred with Raney nickel (~ 0.5 g) under 1 atm of hydrogen for 18 h. After removal of the hydrogen, the mixture was filtered through a PTFE micropore filter, then evaporated under reduced pressure to give the title compound (6.52 g, 100%) as an oil. 1 H NMR (400MHz, DMSOd6) δ 1.80 (m, 1 H), 1.92 (m, 1 H), 2.03-2.11 (m, 2H), 2.14-2.24 (m, 2H), 3.18 (m, 1 H), 5.32 (s, 2H), 6.73 (dd, J = 8.6, 2.5 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 1 H), 7.20 (d, J = 2.5 Hz, 1 H), 9.56 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 18 - 25℃; for 0.5h; | Method 73; N-(5-Methyl- 1 ,2-oxazol-4-yl)cyclobutanecarboxamide; Cyclobutyl carbonyl chloride (26.7 ml) was added dropwise to a stirred solution of 5- methyl-l,2-oxazol-4-amine hydrochloride (30g) and TEA (80 ml) in DCM (450 ml) at EPO <DP n="131"/>ambient temperature. The reaction mixture was stirred for 30 min then washed with water (150 ml), 10% aq. citric acid (2 x 100 ml), sat. aq. NaHCO3 (2 x 100 ml). The aqueous layers were re-extracted with DCM (2 x 100 ml), the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ether (250 ml), filtered and dried to give the title compound as a beige solid (35.3 g). NMR (300.072 MHz, CDCl3) 8.52 (s, IH), 6.60 (br.s, IH), 3.14 (quintet, IH), 2.45-2.16 (m, 5H), 2.11-1.84 (m, 2H); m/z 181. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; triethylamine In 1,2-dichloro-ethane at 20℃; | 10 To a 0.075 M 1,2-dicholoroethane solution of l-(4)4'-dichlorobenzhydryl)piperazine (450 μL, 33.8 μmol), triethylamine (1.2 eq, 4 mg, 40.5 μmol), and DMAP (10 mol%, 0.4 mg, 3.4 μmol) was added 300 μL of a 0.125 M solution of cyclobutanecarbonyl chloride (37.5 μmol) in 1,2-dichloroethane. The mixture was stirred overnight at room temperature, then EPO filtered on hydromatrix-filled filter pre-treated with 500 μL of 2N NaOH solution. The hydromatrix was washed with 500 μL of dichloromethane and evaporated to dryness in the Genevac. Estimated yield from combichem plate: 11.8 mg (88%). 1H NMR (SOO MHZ, DMSO-de) 50.87 (m, IH), 1.30 (m, IH), 1.46 (m, IH), 1.71 (m, IH), 1.85 (m, IH), 2.04 (d, J= 9.0 Hz, IH), 2.11 (m, IH), 2.23 (s, 4H), 3.30 (s, br, 2H), 3,45 (s, br, 2H), 4.41 (s, IH), 7.38 (d, /= 8.5 Hz, 4H), 7.43 (d, /= 8.5 Hz, 4H); +ES MS (M+l) 402.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: [(3-methoxyphenyl)phenylamino]acetonitrile With ammonia; hydrogen In tetrahydrofuran; ethanol at 60℃; for 6h; Stage #2: Cyclobutanecarbonyl chloride With triethylamine In tetrahydrofuran at 20℃; for 1h; Further stages.; | |
Stage #1: [(3-methoxyphenyl)phenylamino]acetonitrile With ammonia; hydrogen In ethanol Stage #2: Cyclobutanecarbonyl chloride With triethylamine | General procedure: [00123] The (aminoalkyl)-amido derivatives (5a-p) were prepared by /V-cyanoalkylation of the corresponding secondary amines (3a-k, 3p) with bromoacetonitrile or bromoproprionitrile in the presence of sodium hydride, followed by reduction of the intermediate nitriles (4a-m, 4p) and /V-acylation of the crude Λ/,/V-disubstituted diamines with anhydrides, acid chloride or isocyanates (Scheme 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 16h; | 9(d).1 Synthesis 9(d)epimerChemical Formula C21H27NO4 Chemical Formula C26H31NO6Exact Mass 357 2 Exact Mass 453 2 Molecular Weight 357 4 Molecular Weight 453 5Nalbuphine 3,N-DCBC-6a-Noroxymorphol Step 1: Synthesis of 3, N-DCBC-Noroxymorphone from Noroxymophone[0092] Into a dried flask was added noroxymorphone (7.70 g, 26.8 mmol), tetrahydrofuran(anhydrous, 35 mL), then triethylamine (5.70 g, 56.3 mmol, 7.9 mL). The mixture was cooled to 5°C (ice/hbO) then cyclobutanecarbonyl chloride (6.36 g, 53.6 mmol, 6.11 mL) was added dropwise. After the addition was complete, the reaction was warmed to room temperature and stirred for 16 hours. HPLC analysis indicated the reaction was complete. The reaction was filtered rinsing the solid with 10 mL of tetrahydrofuran. The filtrate was evaporated under reduced pressure producing a thick oil. The oil was dissolved in CHCb (100 mL). The chloroform solution was then washed with 5% HCI/H2O (2 x 25 mL), dried over anhydrous MgSCM (5 g), filtered and evaporated to dryness producing the product (12.05 g, 99% yield). |
12.5 g | With triethylamine In tetrahydrofuran at 15℃; for 1.5h; | 31 Example 31. Acylation of noroxymorphone to N,0- bis(cyclobutanecarbonyl)noroxymorphone Noroxymorphone (10 g, 10%> of water. 0.031 mol) was suspended in THF (90 mL) at rt. The suspension was cooled at 15 °C and triethylamine (9.8 g, 0.97 mol) was added dropwise and the reaction was stirred for about 5 minutes. Cyclobutanecarbonyl chloride (9.9 g, 0.835 mol) was added at 15 °C in 30 minutes and the suspension was stirred during 1 hour. Salts were filtered and washed with THF and the filtrate was evaporated giving an oil which was dissolved in dichloromethane (100 mL) and washed with 5% aqueous sodium bicarbonate. The organic layer was dried over sulphate and the solvent was evaporated affording a sticky solid that was triturated with isopropyl ether (100 mL). The solid was filtered and washed with ether. (0310) After drying (50°C in vacuo), 12.5 g of N,03-bis(cyclobutanecarbonyl)noroxymorphone was obtained (as white fine solid). HPLC purity: >98. Yield: 87% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; at 0 - 20℃;Inert atmosphere; | To a stirred solution of N-(3-Aminopropyl)-N-methylcarbamic acid tert-butylester (600 mg, 3.19 mmol) under nitrogen at 0 0C was added N,N-diisopropylethylamine (610 mul, 3.51 mmol), followed by a dropwise addition of cyclobutanecarbonyl chloride (366 mul, 3.19 mmol). The reaction mixture was stirred at 0 0C for 1 hour, then allowed to warm up to room temperature and stirring continued overnight. The solution was diluted with DCM and washed successively with saturated aqueous NaHCO3, IM HCl (aq), water and brine, and the organic phase was dried (MgSO4) and concentrated. Purification by column chromatography on Biotage SP4 (ethyl acetate/methanol gradient) gave a colourless oil (281 mg, 49%) which was used in Step 2 without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In dichloromethane at 20℃; Cooling with ice; | 11.1 A solution of cyclobutanecarbonyl chloride (6.7 ml, 58.6 mmol) in DCM (20 ml) was added slowly to a stirred solution of (3-amino-propyl)-carbamic acid tert-butyl ester (10.0 g, 57.5 mmol) and TEA (12.0 ml, 86.2 mmol) in DCM (180 ml) with ice cooling. The RM was then stirred at rt for 2 hours. After this time the mixture was washed with 10% aqueous citric acid and water. The organic phase was separated, dried and concentrated to provide a white solid (14.3 g, 97 %). 1H NMR (400 MHz, DMSCW6) δ ppm 1.37 (9 H, m), 1.40 - 1.55 (2 H, m), 1.62 - 2.30 (6 H, m), 2.75 - 3.12 (5 H, m), 6.78 (1 H, t, /=5.50 Hz), 7.61 (1 H, t, /=5.50 Hz) |
76% | With sodium hydrogencarbonate In ethyl acetate at 15 - 25℃; for 18h; | Intermediate FI : N-(3-aminopropyl)cyclobutanecarboxamide hydrochloride salt. A solution of tert-butyl (3-aminopropyl)carbamate (5.0 g, 29 mmol) in EtOAc (100 mL) was treated with sat’d NaHCCL (aq) (100 mL) and the biphasic mixture was treated drop-wise with cyclobutanecarbonyl chloride (3.6 mL, 32 mmol) and stirred at rt for 18 h. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organics were dried over anhydrous Na2S04 and concentrated to afford tert-butyl (3- (cyclobutanecarboxamido)propyl)carbamate (5.6 g, 76 % yield) as a white solid. 'H NMR (DMSO- e, 500 MHz): d 7.57 (s, 1H), 6.73 (s, 1H), 2.85-3.00 (m, 5H), 2.04-2.12 (m, 2H), 1.97 (m, 2H), 1.86 (m, 1H), 1.69-1.76 (m, 1H), 1.47 (m, 1H), 1.36 (s, 9H); MS (ESI) m/z: 279.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | Stage #1: 6(5H)-phenanthridinone With sodium hydride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: Cyclobutanecarbonyl chloride In tetrahydrofuran at 20℃; for 1h; | 1 General Procedure 1 (GP 1). Synthesis of 5-acyl-SH phenanthridine-6-ones. ; 5H-Phenanthridin-6-one (1.0 mmol) was dissolved in dry tetrahydrofuran (5 mL) in an argon atmosphere, and a few drops of dry dimethylformamide were added. Sodium hydride (1.1 mmol) was added in portions and the mixture was stiired for 20 min at r.t.. A solution of the appropriate carboxylic acid chloride (1.0 mmol) in dry tetrahydrofuran was added slowly and the mixture was allowed to stir for 1 h at r.t.. The crude product was purified by silica gel chromatography using a petroleum ether - ethyl acetate gradient. ; Example 1: 5-Cyclobutanecarbonyl-5H-phenanthridin-6-one was prepared from 5H- phenanthridin-6-one and cyclobutanecarboxylic acid chloride according to GP 1. Yield, 2 %. (at)H-NMR (CD30D): No. = 1.95-2.09 (m, 1 H), 2.11-2.26 (m, 1 H), 2.36-2.55 (m, 4 H), 3.64 (squint, J= 8.5 Hz, 1 H), 7.32 ("t", J= 7.5 Hz, 1 H), 7.37 ("t", J= 7.7 Hz, 1 H), 7.47 ("t", J= 7.5 Hz, 1 H), 7.53 ("t", J= 7.5 Hz, 1 H), 7.70 (d, J= 7.5 Hz, 1 H), 7.74 (d, J= 7.5 Hz, 1 H), 7.90 (d, J= 7.5 Hz, 1 H), 8.22 (d, J= 7.7 Hz, 1 H) ; (+) -ESI-MS: m/z = 278 [M+H]+, 196 [5H-phenauNridin-6-one+mL |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In tetrahydrofuran at 20℃; for 3h; | F1.4 Stage 4: N-(4-[5-(3,5-di-tert-butylphenyl)-1,2,4-oxadiazol-3-yl]methyl}phenyl)cyclobutanecarboxamide Triethylamine (42 μL, 2 eq) and cyclobutane carbonyl chloride (27 mg, 1.5 eq) are successively added to a solution of 4-[5-(3,5-di-tert-butylphenyl)-1,2,4-oxadiazol-3-yl]methyl}phenyl)amine (55 mg) in THF (0.8 mL). The mixture is stirred for 3 hours at ambient temperature then concentrated under reduced pressure. Dichloromethane and water are added to the residue. After decantation and extraction, the organic phases are combined, washed twice with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. The solid obtained is purified by flash chromatography on silica gel (eluent: 100% heptane to heptane/ethyl acetate 6:4) in order to produce the expected compound in the form of a white solid (56 mg, 85% yield). MS/LC: calculated MM=445.6; m/z=446.3 (MH+) NMR (1H, 400 MHz, DMSO-d6): 1.32 (s, 18H), 1.80 (m, 1H), 1.92 (m, 1H), 2.09 (m, 2H), 2.20 (m, 2H), 3.19 (m, 1H), 4.10 (s, 2H), 7.23 (AB, 2H), 7.55 (AB, 2H), 7.72 (s, 1H), 7.85 (s, 2H), 9.68 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | The ethyl 3-cyclobutyl-3-oxopropanoate used as starting material was prepared as follows: To a suspension of potassium 3-ethoxy-3-oxopropanoate (60.3 g, 354.25 mmol) in acetonitrile (600 mL) under argon at 10 C was added triethylamine (75 mL, 540 mmol) then magnesium chloride (40.2 g, 421.72 mmol) keeping the temperature below 25 C. The thick white suspension was stirred for 2.5 hours under argon at room temperature.Cyclobutanecarbonyl chloride (19.25 mL, 167 mmol) was added slowly (over 1 hour) to the re-cooled mixture at 0-5 C. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The solvent was then evaporated. The white residue was taken up in EtOAc (700 mL) and 2M HC1 (about 400 mL) was added until it was all in solution (pH of aqueous = 5). The organic layer was separated then washed with 2M. HC1 (200 mL), sat. NaHC03 (2 x 200 mL, saturated aqueous solution) and the organic layer was dried (MgS04), filtered and evaporated to afford ethyl 3-cyclobutyl-3-oxopropanoate(28.0 g, 98 %) as pale yellow oil.1H NMR (400.132 MHz, CDC13) delta 1.28 (3H, t), 1.80-1.89 (1H, m), 1.91-2.05 (1H, m), 2.12-2.34 (4H, m), 3.39 (2H, s), 3.34-3.42 (1H, m), 4.19 (2H, q). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With aluminum (III) chloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | General procedure: To a solution of compound 1 (20.5 mmol) in 60 mL of a mixture of dichloromethane-DMF at 0 C, was added the aluminum chloride (61.6 mmol) and the mixture was allowed to stir for 5 min while keeping the temperature at 0 C. The desired acyl chloride (26.7 mmol) was added dropwise cautiously and the mixture stirred for 1 h at room temperature. The reaction mixture was then hydrolyzed with ice-water (100 mL) and the two phases were separated. The organic phase was washed with water, dried (MgSO4), filtered and evaporated under reduced pressure to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With aluminum (III) chloride In dichloromethane at 20℃; | 16 Cyclobutyl(4-hydroxyphenyl)methanone Reference Example 16 Cyclobutyl(4-hydroxyphenyl)methanone Aluminum chloride (1.59 g, 11.9 mmol) was added to a dichloromethane (10 mL) solution of phenol (1.03 g, 10.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 45 minutes. Cyclobutanecarboxylic acid chloride (1.33 mL, 11.7 mmol) was added dropwise to the obtained reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4 hours. Further, aluminum chloride (1.58 g, 11.8 mmol) was added at room temperature, and the mixture was stirred. The aluminum chloride was confirmed to be dissolved thoroughly, and then the mixture was stood still overnight. The reaction mixture was added to hydrochloric acid under ice cooling, and the mixture was subjected to extraction once with ethyl acetate. The organic layer thus obtained was washed with brine twice, and then was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10->80:20, v/v) to give the title compound (993 mg, yield: 51%). 1H-NMR (400 MHz, CDCl3) δ ppm: 7.84 (2H, dt, J=9, 2 Hz), 6.87 (2H, dt, J=9, 2 Hz), 5.64 (1H, brs), 4.00-3.91 (1H, m), 2.44-2.39 (2H, m), 2.30-2.26 (2H, m), 2.13-2.02 (1H, m), 1.95-1.85 (1H, m). |
With aluminum (III) chloride In dichloromethane | ||
Stage #1: phenol With aluminum (III) chloride In dichloromethane Stage #2: Cyclobutanecarbonyl chloride In dichloromethane | General procedure: Aluminium chloride (4.5g, 33.8mmol) was added to a solutionof phenol (1.5g, 16.0mmol) in anhydrous dichloromethane(DCM) (15mL). The slurry was left to stir for 1hbefore acetyl chloride (1.3mL, 17.6mmol) was added in adropwise manner. The solution was left to stir for a further14h. The reaction was quenched using an ice-cold solution ofaqueous hydrochloric acid (HCl, 1M) (30mL) and extractedinto diethyl ether (DEE) (2x50mL). The combined organiclayer was extracted into sodium hydroxide (NaOH, 2M)(2x50mL) and then acidified to pH 2 using aqueous HCl(1M, 40mL). The product was extracted into DEE(2x50mL), the organic layer was washed with water(2x50mL) and dried over anhydrous magnesium sulfate(MgSO4). The solvent was removed under vacuum to give abrown solid. Column chromatography of the crude solidgave 5a as a white solid (1.6g, 73.5% yield); m.p.=109.4-110.3oC (lit. m.p.=110.2-110.4oC [12]); Rf: 0.35[DEE/petroleum spirit (40-60oC) (50:50)]. (max) (Film) cm-1:3315.6 (OH), 1661.6 (C=O), 1605.3 (Ar C=C); H(d6-Acetone): 9.20 (1H, s, OH), 7.89 (2H, dd, J=8.9Hz, Ph-H),6.91 (2H, dd, J=8.9Hz, Ph-H), 2.48 (3H, s, CH3); c(d6-Acetone): 196.36 (C=O), 162.63 (C-O), 131.57, 130.51,115.97 (Ar-C), 26.34 (CH3); GC: tR=5.6min; LRMS (m/z):136 (M+, 41%), 121 (M+-CH3, 100%), 93 (M+-C2H3O, 28%);HRMS (ES): found 137.05971 C8H9O2 requires 137.15586;Elemental analysis: found C 70.42%, H 5.88% C8H8O2 requiresC 70.58%, H 5.92%.Fig. (2). To show the theoretically derived TS for the oxidation ofthe C(17)-OH to the C(17)=O catalysed by 17-HSD3 [6].RR1OFig. (3). Proposed pharmacophore for the inhibition of type 1 and 3of the 17-HSD family of enzymes (R=hydrogen bonding group,e.g. OH; R1=alkyl or cycloalkyl moiety). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; | Rigid esters can also be prepared from activated acids. To a solution of <strong>[38748-32-2]triptolide</strong> in methylene chloride with a slight molar excess of triethylamine, add cyclobutane carbonylchloride (Aldrich, 95706). Concentrate the reaction and filter off the resulting triethylamine hydrochloride. Wash the remaining solution is with dilute sodium bicarbonate. Concentrate and purify to obtain the 14-cycolbutane carbonylester indicated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a stirred solution of compound 16 (500 mg, 2.7 mmol) in DCM (50 mL), cyclohexanecarbonyl chloride (532 L, 4.0 mmol) was added at 0 C. The mixture was stirred at room temperature overnight. The reaction was quenched with NaHCO3 (aq.), extracted with DCM (50 mL × 3). The organic phases were then processed in the usual way and chromatographed (1:1 petroleum ether/ EtOAc) to afforded compound 19 (350 mg, 43%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 2h; Inert atmosphere; | 22 Example 22 Example 223-((5-Chlorobenzo[d]thiazol-2-yl)methoxy)-2,6-difluorobenzamide (25.1 mg) and a stir bar were placed under vacuum in a 2-dram vial. The vial was then filled with N2 (g). 3-((5- chlorobenzo[d]thiazol-2-yl)methoxy)-2,6-difluorobenzamide was dissolved in anhydrous THF (4.0 mL) and the resulting solution was stirred under N2 (g) while at room temperature. Cyclobutanecarbonyl chloride (8.1 1iL, 1.0 eq., Sigma-Aldrich Co.) was added dropwise via syringe, followed by addition of sodium hydride (60% in oil dispersion) (14.3 mg, 5.0 eq.). The reaction was heated at 50 °C for 2 hours. After cooling to room temperature, the reaction was concentrated to a residue and then dissolved in EtOAc / H20. After shaking, the aqueous phase was separated and then extracted with EtOAc. The combined EtOAc phases were dried over Na2SO4, filtered, and concentrated to a solid. Chromatography with solvent gradient 0> 30% EtOAc / hexanes isolated the product as a solid (22.9 mg, 74% yield). ‘H NMR (400 MHz) (CD3OD) ö: (d, J 8.5 Hz, 111), 7.906 (d, J= 2.1 Hz, 1H), 7.37 (dd, J= 8.5 Hz, J- 2.1 Hz, 1H), 7.28 (ddd, J= 9.2 Hz, J 9.2 Hz, J= 5.1 Hz, 1H), 6.91 (ddd, J= 9.2 Hz, J= 9.2 Hz, J = 2 Hz, IH), 5.50 (s, 2H), 3.38 (m, 1H), 2.18 (m, 4H), 1.92 (m, 1H), 1.79 (m, 1H). MS: m/e 437 (M+1). |
74% | With sodium hydride In tetrahydrofuran; mineral oil at 50℃; for 2h; Inert atmosphere; | 22 3-((5-Chlorobenzo[d]thiazol-2-yl)methoxy)-2,6-difluorobenzamide (25.1 mg) and a stir bar were placed under vacuum in a 2-dram vial. The vial was then filled with N2 (g). 3-((5-chlorobenzo[d]thiazol-2-yl)methoxy)-2,6-difluorobenzamide was dissolved in anhydrous THF (4.0 mL) and the resulting solution was stirred under N2 (g) while at room temperature. Cyclobutanecarbonyl chloride (8.1 μL, 1.0 eq., Sigma-Aldrich Co.) was added dropwise via syringe, followed by addition of sodium hydride (60% in oil dispersion) (14.3 mg, 5.0 eq.). The reaction was heated at 50° C. for 2 hours. After cooling to room temperature, the reaction was concentrated to a residue and then dissolved in EtOAc/H2O. After shaking, the aqueous phase was separated and then extracted with EtOAc. The combined EtOAc phases were dried over Na2SO4, filtered, and concentrated to a solid. Chromatography with solvent gradient 0>30% EtOAc/hexanes isolated the product as a solid (22.9 mg, 74% yield). 1H NMR (400 MHz) (CD3OD) δ: (d, J=8.5 Hz, 1H), 7.906 (d, J=2.1 Hz, 1H), 7.37 (dd, J=8.5 Hz, J=2.1 Hz, 1H), 7.28 (ddd, J=9.2 Hz, J=9.2 Hz, J=5.1 Hz, 1H), 6.91 (ddd, J=9.2 Hz, J=9.2 Hz, J=2 Hz, 1H), 5.50 (s, 2H), 3.38 (m, 1H), 2.18 (m, 4H), 1.92 (m, 1H), 1.79 (m, 1H). MS: m/e=437 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 20℃; | 3I.1 6-Fluoropyridin-3-amine (600 mg, 5.35 mmol) was dissolved in dichloromethane (20 mL), triethylamine (1.49 mL, 10.7 mmol) and cyclobutanecarbonyl chloride (0.67 mL, 5.89 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added diisopropyl ether and the precipitated crystals were collected by suction filtration to give N-(6-fluoropyridin-3-yl)cyclobutanecarboxamide (899 mg, 86%). ESIMS m/z: 195 (M + H)+; 1H NMR (270 MHz, CDCl3, δ): 1.85-2.10 (m, 2H), 2.10-2.49 (m, 4H), 3.08-3.30 (m, 1H), 6.77-7.01 (m, 1H), 7.56 (br s, 1H), 8.17-8.35 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In dichloromethane at 20℃; for 0.5h; | 144.2 Step 2N-{2-14-(cyclobutylcarbonyl)piperazin-1-ylj-4-13-methyl-4-(tetrahydro-2H-pyran-4-yloxy)-1H-indazol-6-ylj phenyl} acetamide Step 2N-{2-14-(cyclobutylcarbonyl)piperazin-1-ylj-4-13-methyl-4-(tetrahydro-2H-pyran-4-yloxy)-1H-indazol-6-ylj phenyl} acetamideA solution of cyclobutanecarbonyl chloride (20.97 mg, 0.177 mmol) in CH2C12 (0.2 mL) wasadded to a solution of N- {4-[3 -methyl-4-(tetrahydro-2H-pyran-4-yloxy)- 1H-indazol-6-yl] -2-(piperazin-1-yl)phenyl}acetamide (53 mg, Step 1) and triethylamine (50 mg) in CH2C12 (1.5mL), and the mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) wasadded, and the solution stirred at room temperature for 4 hours. The mixture wasconcentrated, and the residue was purified by flash chromatography (silica gel eluted withethyl acetate-ethanol (100:0 - 97:3) to provide the titled compound (54 mg, 86%). ‘H NMR(300 MHz, DMSO-d6) 5 ppm 1.66 - 1.83 (m, 3H), 1.84 - 1.97 (m, 1H), 2.00 - 2.29 (m, 7H),2.15 (s, 3H), 2.59 (s, 3H), 2.81 - 2.90 (m, 4H), 3.50 - 3.65 (m, 4H), 3.65 - 3.73 (m, 2H), 3.80- 3.92 (m, 2H), 4.94 (tt, J = 7.2, 3.3 Hz, 1H), 6.72 (s, 1H), 7.12 (s, 1H), 7.32 - 7.42 (m, 1H),7.37 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 8.96 (s, 1H), 12.52 (s, 1H); MS (ESI) m/z 532 (M+H). |
86% | With triethylamine In dichloromethane at 20℃; for 0.5h; | 144.2 Step 2 N-{2-[4-(cyclobutylcarbonyl)piperazin-1-yl]-4-[3-methyl-4-(tetrahydro-2H-pyran-4-yloxy)-1H-indazol-6-yl]phenyl}acetamide Step 2 N-{2-[4-(cyclobutylcarbonyl)piperazin-1-yl]-4-[3-methyl-4-(tetrahydro-2H-pyran-4-yloxy)-1H-indazol-6-yl]phenyl}acetamide A solution of cyclobutanecarbonyl chloride (20.97 mg, 0.177 mmol) in CH2Cl2 (0.2 mL) was added to a solution of N-{4-[3-methyl-4-(tetrahydro-2H-pyran-4-yloxy)-1H-indazol-6-yl]-2-(piperazin-1-yl)phenyl}acetamide (53 mg, Step 1) and triethylamine (50 mg) in CH2Cl2 (1.5 mL), and the mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added, and the solution stirred at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel eluted with ethyl acetate-ethanol (100:0-97:3) to provide the titled compound (54 mg, 86%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66-1.83 (m, 3H), 1.84-1.97 (m, 1H), 2.00-2.29 (m, 7H), 2.15 (s, 3H), 2.59 (s, 3H), 2.81-2.90 (m, 4H), 3.50-3.65 (m, 4H), 3.65-3.73 (m, 2H), 3.80-3.92 (m, 2H), 4.94 (tt, J=7.2, 3.3 Hz, 1H), 6.72 (s, 1H), 7.12 (s, 1H), 7.32-7.42 (m, 1H), 7.37 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 8.96 (s, 1H), 12.52 (s, 1H); MS (ESI) m/z 532 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triethylamine In dichloromethane at 20℃; for 16h; | B.2.3 Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N- methylcyclobutanecarboxamide Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N- methylcyclobutanecarboxamide To a solution of {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutanecarbonyl chloride (188 mg, 1.60 mmol) in DCM (10 mL) at rt was added triethyl amine (0.41 mL, 2.92 mmol). The reaction mixture was left to stir at rt for 16 h, then concetrated in vacuo. The residue was purified using a Teledyne ISCO Chromatography [0 100% EtOAc/Heptanes] to afford N-{3-[(5-bromo-2-chloropyrimidin- 4-yl)amino]propyl}-N-methylcyclobutane carboxamide (268 mg, 56%). LC-MS (ES+): m/z = 363.04/365.04 [MH+], tR = 2.18 min. |
56% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.3 Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide To a solution of {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutanecarbonyl chloride (188 mg, 1.60 mmol) in DCM (10 mL) at rt was added triethyl amine (0.41 mL, 2.92 mmol). The reaction mixture was left to stir at rt for 16 h, then concentrated in vacuo. The residue was purified using a Teledyne ISCO Chromatography [0→100% EtOAc/Heptanes] to afford N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutane carboxamide (268 mg, 56%). LC-MS (ES+): m/z=363.04/365.04 [MH+], tR=2.18 min. |
56% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.B.2.3 Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N- methylcyclobutanecarboxamide To a solution of {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutanecarbonyl chloride (188 mg, 1.60 mmol) in DCM (10 mL) at rt was added triethyl amine (0.41 mL, 2.92 mmol). The reaction mixture was left to stir at rt for 16 h, then concetrated in vacuo. The residue was purified using a Teledyne ISCO Chromatography [0 ^ 100% EtOAc/Heptanes] to afford N-{3-[(5-bromo-2-chloropyrimidin- 4-yl)amino]propyl}-N-methylcyclobutane carboxamide (268 mg, 56%). LC-MS (ES+): m/z = 363.04/365.04 [MH+], tR = 2.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: methyl 2-(4-methoxyphenyl)-5-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: Cyclobutanecarbonyl chloride In dichloromethane at 0 - 20℃; for 2h; | No. I.6-4: Methyl 5-[(cyclobutylcarbonyl)oxy]-2-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-4-carboxylate No. I.6-4: Methyl 5-[(cyclobutylcarbonyl)oxy]-2-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-4-carboxylate Methyl 2-(4-methoxyphenyl)-5-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate (150 mg, 0.49 mmol) was dissolved in abs. dichloromethane (5 ml) under argon in a baked-out round-bottom flask. This was followed by the addition of triethylamine (0.08 ml, 0.59 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After cooling to 0° C., cyclobutanecarbonyl chloride (0.06 ml, 0.49 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then admixed with water. After thorough repeated extraction of the aqueous phase with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetate/n-heptane gradient) of the remaining residue gave methyl 5-[(cyclobutylcarbonyl)oxy]-2-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-4-carboxylate (190 mg, 99% of theory) in the form of a colorless solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 7.32 (d, 2H), 6.96 (d, 1H), 6.90 (d, 2H), 6.87 (d, 1H), 5.75 (t, 1H), 3.88 (dd, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.47 (dd, 1H), 3.25 (m, 1H), 2.49 (m, 2H), 2.34 (m, 2H), 2.04 (m, 2H). |
99% | Stage #1: methyl 2-(4-methoxyphenyl)-5-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: Cyclobutanecarbonyl chloride In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With triethylamine; In toluene; at 0 - 20℃; | General procedure: To a stirred and cooled solution of <strong>[2770-11-8]2-(4-chlorophenoxy)aniline</strong> (330 mg, 1.50 mmol) and triethylamine (230 muL, 1.65 mmol) in toluene (5 mL), the appropriate acid chloride (pivaloyl chloride, 2,2-dimethylbutyryl chloride, 3-methylbutyryl chloride, propyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, methyl succinyl chloride, 4-methoxybenzoyl chloride) (1.65 mmol) was added. Subsequently the reaction mixture was allowed to warm to room temperature. The progress of the reaction was monitored by TLC. After 2-9 h the reaction mixture was extracted with a saturated sodium hydrogen carbonate solution, with a hydrogen chloride solution (10%), with brine and finally with water. Afterwards the organic solution was dried over sodium sulfate and evaporated under reduced pressure. The residue was further purified by recrystallization or column chromatography over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In toluene at 0 - 20℃; | General Procedure for the Synthesis of Compounds 11-18 General procedure: To a stirred and cooled solution of 2-(4-methoxyphenoxy)aniline hydrochloride (1.50 mmol) and triethylamine (4.00 mmol) in toluene (5-8 mL), the appropriate acid chloride (pivaloyl chloride, 2,2-dimethylbutyryl chloride, 3-methylbutyryl chloride, propyl chloride, cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride, methyl succinyl chloride, 4-methoxybenzoyl chloride) (1.65 mmol) was added. Thereafter the reaction mixture was allowed to warm to room temperature. The progress of the reaction was monitored by TLC. After 4-24 h an aqueous work-up was performed similar to that of compounds 1-8. The resulting residue was further purified by recrystallization or column chromatography over silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 1h; | (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclobutanecarboxamido)propanoic acid Cyclobutanecarbonyl chloride (72.7 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were dropped at the same time to a stirred solution of <strong>[181954-34-7](S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid</strong> (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0 C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL*1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (156 mg, 61%). Analysis LCMS Condition A: Retention time=0.94 min; ESI-MS(+) m/z 409.1 (M+H) 1H NMR (400 MHz, methanol-d4) delta 7.80 (d, J=7.5 Hz, 2H), 7.67 (br s, 2H), 7.44-7.35 (m, 2H), 7.35-7.27 (m, 2H), 4.37-4.31 (m, 2H), 4.23 (s, 1H), 3.55-3.48 (m, 1H), 3.14 (s, 2H), 2.31-2.08 (m, 7H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 1h; | (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclobutanecarboxamido)butanoic acid Cyclobutanecarbonyl chloride (69.7 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of <strong>[161420-87-7](S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid</strong> (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0 C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL*1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (92.6 mg, 37%). Analysis LCMS Condition A: Retention time=0.94 min; ESI-MS(+) m/z 423.1 (M+H) 1H NMR (400 MHz, methanol-d4) delta 7.80 (d, J=7.5 Hz, 2H), 7.72-7.65 (m, 2H), 7.43-7.36 (m, 2H), 7.35-7.28 (m, 2H), 4.41-4.32 (m, 2H), 4.28-4.15 (m, 2H), 3.20 (d, J=7.0 Hz, 1H), 3.08 (s, 1H), 2.31-2.04 (m, 6H), 1.97 (d, J=9.9 Hz, 1H), 1.84 (d, J=7.3 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 7.0h; | Under the argon 2-chloro-6-trifluoromethyl-nicotinic acid (3000 mg, 13 . 30mmol) is added to the 24% of an aqueous ammonia solution (5 ml) in, then adding cuprous chloride (I) (1580 mg, 15 . 96mmol). The resulting reaction mixture in the pressure vessel 100 C temperature and at about 5 of the increased stirring under the pressure of 15 hours. After the cooling to room temperature, the pressure is dropped to standard pressure, the ethyl acetate and dilute hydrochloric acid (2N) in added to the reaction mixture. The aqueous phase is extracted repeatedly with ethyl acetate, the combined organic phase is then dried by using magnesium sulphate, filtered and concentrated under reduced pressure. The crude product purification column chromatographying (ethyl acetate/n-heptane gradient) to obtain colorless solid <strong>[890302-02-0]2-amino-6-trifluoromethyl-nicotinic acid</strong> (1640 mg, theoretical value of 58%). The <strong>[890302-02-0]2-amino-6-trifluoromethyl-nicotinic acid</strong> (500 mg, 2 . 43mmol) dissolved in anhydrous tetrahydrofuran (8 ml) in, then adding triethylamine (369 mg, 3 . 64mmol). Thereafter, the reaction solution is cooled to under the argon 0 C, and slowly dropping cyclobutyl formyl chloride (316 mg, 2 . 69mmol). The resulting reaction mixture is stirred at room temperature for 7 hours, then adding distilled water and methylene chloride. Repeated extraction of the aqueous phase with methylene chloride, then the combined organic phase dried with magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the crude product with preparative HPLC (acetonitrile/water/trifluoroacetic acid gradient) to obtain colorless solid 2 - [(cyclobutyl-carbonyl) amino] - 6 - (trifluoromethyl) nicotinamide (197 mg, of the theoretical value 28%). The 2 - [(cyclobutyl-carbonyl) amino] - 6 - (trifluoromethyl) nicotinamide (197 mg, 0 . 68mmol) dissolved in second grade acid anhydride (5 ml) in, and the argon gas under stirring under the reflow conditions for 5 hours. After the cooling to room temperature, adding concentrated ammonia solution (10 ml), and the reaction mixture is stirred at room temperature for 6 hours. Filtering and drying precipitated solid. The crude product with preparative HPLC purification to obtain strawcoloured solid 2-cyclobutyl-7 - (trifluoromethyl) pyrido [2,3-d] pyrimidine -4 (3H)-one (55 mg, theoretical value of 30%). 1 HNMR (400MHz, CDCl 3 delta, PPM) 8.79 (d, 1H), 7.78 (d, 1H), 7.28 (br.s, 1H, NH), 3.62 (quint, 1H), 2.64 (m, 2H), 2.48 (m, 2H), 2.18 (m, 1H), 2.02 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium diacetate; silver carbonate In o-xylene for 36h; Inert atmosphere; regioselective reaction; | General procedure for the multicomponent reaction comprising one-pot installation of bidentate directing group and Pd(II)-catalyzed direct β-arylation of C(sp3)-H bond of General procedure: A mixture of 8-aminoquinoline (0.4mmol), an appropriate carbonyl chloride (0.4mmol), an appropriate aryl iodide (0.16-0.24mmol, 4-6 equiv), Pd(OAc)2 (10mol %) and Ag2CO3 (0.6-0.8mmol, 1.5-2 equiv) was heated in o-xylene (2mL) at 110 °C for an appropriate reaction period (12-36 h). Then, reaction mixture was cooled to rt and the solvent evaporated in vacuo to give the crude product, which was purified by chromatography to give the corresponding C-H arylated products (see the respective Tables 1-4/Scheme 2 for the specific entries and reaction conditions). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-Amino-2,1,3-benzothiadiazole; Cyclobutanecarbonyl chloride With triethylamine Inert atmosphere; Stage #2: Cyclobutanecarbonyl chloride In dichloromethane at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In a 100 mL round-bottomed flask, 500 mg of <strong>[100846-24-0]5-(trifluoromethyl)indole</strong> (2.7 mmol; 1 eq) were dissolved in 5 mL of diethyl ether. 1 mL of a 3 M solution of methyl magnesium bromide in diethyl ether (2.97 mmol; 1.1 eq) was added and the reaction medium was stirred for 15 min at RT. 2.7 mL of a 1 M solution of ZnCl2 in diethyl ether (2.7 mmol; 1 eq) were added and the reaction medium was stirred at RT for 30 min. 0.31 mL of cyclobutanecarboxylic acid chloride (2.7 mmol; 1 eq) were added and the reaction medium was stirred at RT for 30 min. The reaction was stirred by adding a saturated NH4Cl solution and then the medium was extracted 3 times with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica usin a cyclohexane/20% to 50% ethyl acetate eluent, to give 325 mg of the title compound in the form of an orange solid. Yld: 45%. 1H NMR (300 MHz, CHCl3-d) deltappm 1.89-2.03 (m, 2H) 2.21-2.35 (m, 2H) 2.43-2.58 (m, 2H) 3.81-3.95 (m, 1H) 7.46-7.56 (m, 2H) 7.85 (d, J=3.0 Hz, 1H) 8.69 (brs. 1H) 8.76-8.80 (m, 1H). LC-MS: m/z (M+H)+: 268. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
83% | With triethylamine In tetrahydrofuran at 20℃; for 2h; | tert-Butyl 4-(cyclobutylcarbonyl)piperazine-1-carboxylate (16a) To a solution of 15 (4.47 g, 24 mmol) THF (50 mL) was added Et3N (4.2 mL) and cyclobutanecarbonyl chloride (2.37 g, 20 mmol), and the resulting mixture was stirred at room temperature for 2 h. The mixture was poured into water, and extracted with AcOEt. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from hexane to give 16a (4.45 g, 83%) as a colorless crystal. 1H NMR (300 MHz, CDCl3) δ: 1.47 (9H, s), 1.79-2.05 (2H, m), 2.08-2.24 (2H, m), 2.26-2.46 (2H, m), 3.18-3.34 (3H, m), 3.35-3.47 (4H, m), 3.51-3.65 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 20℃; for 2h; | 5.A (A) N- (2- ( (5-methoxy-2- nitrophenyl) amino) ethyl) cyclobutanecarboxamide In a lOOml reactor with magnetic stirring, N1’(5 methoxy2nitronhenyl)ethane-4,2-diamine (Ig, 4.73xmnol), dichioromethane (SOmi) and trietixylamine (0.67m1, 4.SOmmol) were added. The reaction medium was kept under stirring anda solution of cyclooutanecarhony.1 chorde (0 . 54m1 ,4. 73mmol) in aichloromethane (10m1.) was slowly added through an addition funnel. The reaction medium was kept under stirring at room temperature for 2 hours. After the completion of the reaction, 10% aqueous hydrochloric acid solution (lOml) was added, The dichloromethane was separated and the aqueous phase was extracted with dichioromethane (2x20m1) The organic phase was washed with 5% aqueous bicarbonate solution (lOOmI) and saturated sodium chloride solution (lOOml) . The organic extract was separated, dried with anhydrous magnesium sulfa..t e and roto evaporated, yielding a ye1ow solid product which was useddirectly in the next step. (m=1.25 g. Yield: 90%) |
In ethanol at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48h; | To an ice-cooled solution of <strong>[2734-70-5]2,6-dimethoxyaniline</strong> (Amfinecom Inc., 2.0 g, 13.1 mmol) in DCM (65 mL) was added N,N-diisopropylethylamine (6.8 mL, 39.2 mmol) followed by cyclobutanecarbonyl chloride (Sigma-Aldrich, 1.56 mL, 13.7 mmol) slowly via syringe. The resulting solution was warmed to RT and stirred for 48 h, then was partitioned between water and DCM (2X). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to provide Example 1.01 (2.92 g, 95% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.3% | With triethylamine; In dichloromethane; at 20℃; for 1.0h;Cooling; | General procedure: TEA (1.4 g, 14.0 mmol) and 3b (1.0 g, 2.79 mmol) was dissolved in anhydrousCH2Cl2 (8 mL) and cyclopropanecarbonyl chloride (0.29 g, 2.79 mmol) was addeddropwise at -0 C and then allowed to react at room temperature for one hour. Themixture was washed with H2O and dried over anhydrous Na2SO4. After filtered,evaporation and purification by column chromatography using petroleumether/EtOAc (2:1) as eluent to give a glassy solid 0.43 g (39.7% yield). 1H NMR (400MHz, CDCl3) delta 0.73-0.79 (m, 2H), 0.84 (s, 3H), 0.90 (dd, J1 = 3.0 Hz, J2 = 6.5 Hz,6H), 0.93-0.98 (m, 2H), 1.24 (d, J = 10.6 Hz, 2H), 1.28 (s, 3H), 1.39 (s, 3H),1.41-1.44 (m, 1H), 1.46-1.51 (m, 1H), 1.61 (dt, J1 = 6.7 Hz, J2 = 12.9 Hz, 1H),1.79-1.85 (m, 1H), 1.89 (td, J1 = 2.9 Hz, J2 = 5.6 Hz, 1H), 2.02 (t, J = 5.6 Hz, 1H),2.14-2.21 (m, 1H), 2.28-2.37 (m, 1H), 3.16 (dd, J1 = 7.1 Hz, J2 = 13.1 Hz, 1H),3.90-4.01 (m, 2H), 4.28 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 6.66 (s, 1H), 6.85 (s, 1H).MS (ESI) m/z 391.5 [M+H]+.Compounds 4g-4v were prepared from the corresponding carboxylic acids andboric acid ester hydrochloride following the similar procedure described for thesynthesis of 4f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With pyridine; at 30 - 65℃; | General procedure: A weighed portion of 1 (2.56 g, 0.01 mol) was dissolved in Py (50 mL), treated with the appropriate carboxylic acid chloride (2-5, 0.01-0.03 mol), stirred vigorously, and heated (30-65C). The course of the reaction and purity of isolated derivatives were monitored using TLC. When the reaction was finished (3-10 h), a part of the solvent was removed. The resulting concentrated solution was worked up with H2O and acidified by HCl to pH 4. The resulting precipitate was filtered off and dried. The products were isolated by column chromatography over silica gel with elution by hexane with a gradual switch to hexane-EtOAc mixtures (gradient from 100:1 to 1:5). Recrystallization used hexane-EtOAc (1:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane at 20℃; for 2h; | 4 Preparation of compound 4: According to the method of Example 1: Dissolve 50 mg, 0.14 mmol of 1", 2"-dihydroxanthohumol C in 2 mL of dichloromethane, add 0.05 mL of triethylamine, 0.36 mmol, Add cyclobutyryl chloride 20mg, 0.17mmol, stir at room temperature for 2h, quench with saturated sodium bicarbonate solution, extract with dichloromethane, separate the layers, wash the organic phase with saturated brine, then dry with anhydrous sodium sulfate, concentrate and then It is eluted with a 200-300 mesh gradient on a silica gel column, and the eluent is petroleum ether and ethyl acetate at a volume ratio of 5:1, and the light yellow solid compound 4(E)-4-(3-(5-hydroxy-7) -Methoxy-2,2-dimethylbenzopyran-6-yl)-3-oxoprop-1-en-1-yl)phenylcyclobutane carboxylate 78%; |
78% | With triethylamine In dichloromethane at 20℃; | 2.1 General procedure for preparation of compounds (5a-5k) General procedure: The solution of 1″,2″-dihydroxanthohumol C (0.14 mmol), triethylamine (0.16 mmol) andcorresponding acyl chloride (0.14 mmol) in CH2Cl2 was stirred at 20 for 1-4 h and then treatedwith an excess of saturated aqueous NaHCO3, The mixture was extracted with CH2Cl2, and thecombined organic layers were washed with water, dried over Na2SO4, and evaporated underreduced pressure. The obtained residue was purified by silica gel chromatography with petroleumether/ethyl acetate to give 5a-5k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: tert-butyl 4-((4-(4-chlorophenoxy)phenyl)glycyl)piperidine-1-carboxylate With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: Cyclobutanecarbonyl chloride In dichloromethane at 20℃; for 0.5h; | General synthesis of intermediate m31-m38 General procedure: To a solution of m2 (2.0 g, 4.49 mmol) in 30 mL anhydrous DCM was added TEA (0.91 g, 8.99 mmol) at 0 . The mixture was stirred for 0.5 h before the addition of different substituted acylchlorides (4.94 mmol). After the mixture was stirred for 0.5 h at room temperature, the solvent was extracted with water and DCM, the combined organic layer was washed with brine, dried over with anhydrous Na2SO4, and concentrated in vacuo. Purified of the residue via flash column chromatography on silica gel afforded m31-m38. |
65% | Stage #1: tert-butyl 4-((4-(4-chlorophenoxy)phenyl)glycyl)piperidine-1-carboxylate With triethylamine In dichloromethane at 0℃; for 0.5h; Stage #2: Cyclobutanecarbonyl chloride In dichloromethane at 20℃; for 0.5h; | General synthesis of intermediate m31-m38 General procedure: To a solution of m2 (2.0 g, 4.49 mmol) in 30 mL anhydrous DCM was added TEA (0.91 g, 8.99 mmol) at 0 . The mixture was stirred for 0.5 h before the addition of different substituted acylchlorides (4.94 mmol). After the mixture was stirred for 0.5 h at room temperature, the solvent was extracted with water and DCM, the combined organic layer was washed with brine, dried over with anhydrous Na2SO4, and concentrated in vacuo. Purified of the residue via flash column chromatography on silica gel afforded m31-m38. |
Tags: 5006-22-4 synthesis path| 5006-22-4 SDS| 5006-22-4 COA| 5006-22-4 purity| 5006-22-4 application| 5006-22-4 NMR| 5006-22-4 COA| 5006-22-4 structure
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H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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