Preparation of boron trifluoride tetrahydrofuran and its application background and overview in organic synthesis
Boron trifluoride tetrahydrofuran refers to boron trifluoride tetrahydrofuran complex.
Preparation of boron trifluoride tetrahydrofuran and its application in organic synthesis
The current production technology in Japan and the United States is to react liquid boron trifluoride and tetrahydrofuran, and dry it with a magnesium drum to obtain flaky boron trifluoride tetrahydrofuran. This reaction is an exothermic reaction, and the reaction temperature is difficult to control, and Product drying costs are high.
CN201210424080.4 provides a production process for boron trifluoride tetrahydrofuran. Slowly drop tetrahydrofuran into the caustic soda kettle, absorb water to generate tetrahydrofuran vapor, introduce tetrahydrofuran vapor into the complexing device, and at the same time introduce boron trifluoride gas for complexation reaction. The mass ratio of tetrahydrofuran to boron trifluoride gas is: The reaction is carried out at 1:2, the temperature is controlled between 30°, and the reaction time is 2 hours; after drying, boron trifluoride tetrahydrofuran is obtained. This process is produced by complexing reaction between tetrahydrofuran steam and boron trifluoride gas. It has low cost and the reaction temperature can be easily controlled at normal temperature or slightly higher.
Preparation of boron trifluoride tetrahydrofuran and its application in organic synthesis [2]
Preparation of boron trifluoride tetrahydrofuran and its application in organic synthesis 1. Used to synthesize a diarylmethane derivative
Diarylmethane is an important structural unit of biologically active natural products, drugs and pesticides, and has high application value. For example, berobate has the parent structure of diarylmethane, has a strong blood-lipid-lowering effect, and can be used for clinical hyperlipidemia. In industry, diarylmethane and its derivatives can also be used as synthetic precursors for aromatics, spices, polycarbonate resins, dyes, etc., and have good market application prospects.
CN201310043956.5 provides a synthesis method of diarylmethane derivatives. The specific steps are as follows: (1) Benzyl alcohol is used as the benzylation reagent, boron trifluoride and tetrahydrofuran are used as the reaction reagent, and toluene is used as the raw material and also serves as the reaction reagent. Solvent, according to the ratio of benzyl alcohol millimole: boron trifluoride tetrahydrofuran millimole: toluene ml ratio is 1:1:2, add benzyl alcohol (108.1 mg, 1.0 mmol) and toluene (2.0 mL) to the reactor in sequence. , while stirring, add boron trifluoride tetrahydrofuran (110 μL, 1.0 mmol), complete the addition, raise the temperature to 80°C, and continue stirring to carry out benzylation of toluene for 2 hours. (2) After step (1) is completed, cool the benzyltoluene reaction solution prepared in step (1) naturally in the air, flush the condensation system of the reactor with methylene chloride, and merge the washing liquid into the reactor The reaction solution; then concentrate the mixed solution in the reactor by rotary evaporation, and collect the concentrated solution; purify the concentrated solution with silica gel column chromatography, elute with the eluent, and concentrate the effluent from the silica gel column chromatography by rotary evaporation , and drained to obtain colorless and transparent liquid benzyltoluene (129.4 mg, yield 71%, 1-benzyl-2-methylbenzene:1-benzyl-4-methylbenzene=40:60). The eluent was petroleum ether. The method of the invention can be widely used in the industrial production of diarylmethane derivatives. Diarylmethane derivatives can be used as synthetic precursors for drugs, pesticides, aromatics, spices, polycarbonate resins, dyes, etc., and have good market application prospects.
Preparation of boron trifluoride tetrahydrofuran and its application in organic synthesis 2. Synthesis of formononetin
CN201010570613.0 provides a method for synthesizing formononetin using boron trifluoride and tetrahydrofuran.
1) Add p-methoxyphenylacetic acid and resorcinol as raw materials into the container, then add boron trifluoride-tetrahydrofuran solution, and then raise the temperature of the mixture to 40-50°C, and Stir the reaction at this temperature for 3-5 hours;
2) Lower the temperature of the reaction solution after the above reaction to room temperature, add water, continue to stir the reaction for 5-10 hours, stop stirring, filter, and recrystallize the obtained filtrate with a water-methanol mixed solvent, filter, and obtain the intermediate Body;
3) Mix the above intermediate and boron trifluoride-tetrahydrofuran solution in a container, and then add N,N-dimethylformamide dropwise at a temperature of 13°C to obtain solution A;
4) At a temperature of 13°C, add phosphorus oxychloride dropwise into a container containing N,N-dimethylformamide. After the addition is completed, raise the temperature of the mixture to 55°C. React for 20 minutes to obtain solution B;
5) Use ice water to cool the container containing solution A to below 5°C, and then add solution B dropwise to solution A. During the dripping process, control the temperature below 20°C. After the dropwise addition is completed, continue reaction 3 hours, when the test results show that the raw material content is less than 5%, add the resulting reaction liquid dropwise to the 37% hydrochloric acid solution at 85°C. After the dropwise addition is completed, reflux for 1 hour, and then cool, filter, and wash the precipitated solid to obtain Crude product;
6) Recrystallize the above crude product with a water-methanol mixed solvent to obtain the product formononetin, with a content (HPLC) greater than 99.0% and a total yield greater than 80%.
The synthesis method of formononetin provided by the present invention is to use boron trifluoride-tetrahydrofuran as the solvent in the first step of the condensation reaction instead of boron trifluoride-ether in the prior art. The boiling point and safety are much higher than ether, thus making industrial mass production possible; in the first step of product purification, a water-methanol mixed solvent is used to replace the pure methanol or pure ethanol solvent in the existing technology, which can significantlySignificantly reduces production costs without changing the effect.
In addition, the final step of product purification also uses a water-methanol mixed solvent to replace the pure methanol or pure ethanol solvent in the existing technology, which will further reduce the total cost. In addition, this synthesis method also has the advantages of simple operation, convenience, and high safety.
Preparation of boron trifluoride tetrahydrofuran and its application in organic synthesis 3. Used to synthesize a palonosetron hydrochloride compound
Palonosetron Hydrochloride is a new generation of selective 5-HT3 receptor antagonist developed by the Swiss company Helsinn. Its chemical name is: Palosetron Hydrochloride Compound, July 2003 On March 25, the product was approved by the U.S. Food and Drug Administration (FDA) for clinical use in the treatment of acute and delayed nausea and vomiting caused by emetogenic chemotherapy with moderate or highly pure calcium carbonate. Preparation of palonosetron hydrochloride:
Dissolve 27.0g (100mmol) (S)-N-(((S)-1,2,3,4-tetralin-1-yl)methyl)-3-aminoquinine in 270mL toluene , slowly add a toluene solution containing 7.3g (24.75mmol) triphosgene dropwise. After the dripping is completed, the temperature is raised to reflux for 1 hour, and a toluene solution containing 2.5g (8.42 mmol) triphosgene is added dropwise under reflux, and the reflux reaction is continued for 2 hours. After the reaction is completed, 56.5g (mmol) boron trifluoride tetrahydrofuran solution is added dropwise, and the reaction is refluxed for 2 hours. After the reaction is completed, add 150 mL of 1 mol/L dilute hydrochloric acid and reflux for 1 hour. Lower to room temperature, let stand for liquid separation, extract the toluene layer with 100 mL of dilute hydrochloric acid of tri-tert-butylphosphine tetrafluoroborate, combine the water layers, adjust the pH to 11-12 with 40% sodium hydroxide solution, extract with ethyl acetate, and combine The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and concentrated to dryness under reduced pressure to obtain 22.8g of pale yellow palonosetron free base oil. Add 450 mL of absolute ethanol to the palonosetron free base oil, stir and dissolve, add dropwise hydrogen chloride ethanol solution to adjust the pH to 2-4, cool to 10°C, incubate and crystallize for 2 hours, filter, and dry the filter cake in a vacuum at 50°C. 21.6g of palonosetron hydrochloride was obtained, with a total yield of about 65%.
