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CAS No. : | 5006-22-4 |
Formula : | C5H7ClO |
M.W : | 118.56 |
SMILES Code : | O=C(Cl)C1CCC1 |
MDL No. : | MFCD00001319 |
GHS Pictogram: | ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H314 |
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 |
Class: | 8(3) |
UN#: | 2920 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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 |
---|---|---|
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 |
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
A731297 [76730-63-7]
3-(Cyclobutylmethyl)cyclobutanecarbonyl chloride
Similarity: 1.00
A575122 [143610-57-5]
Trans-3-butylcyclobutanecarbonyl chloride
Similarity: 1.00
A255504 [N/A]
2-Ethylpentanedioyl dichloride
Similarity: 0.96
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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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