Method for preparing desflurane by using microchannel continuous flow technology

Abstract

The invention discloses a method for preparing desflurane by using a micro-channel continuous flow technology, which is characterized in that in a micro-channel reactor, isoflurane is taken as a reactant and reacts with a complex formed by hydrogen fluoride and diazine with a catalytic action to prepare desflurane. Different from the traditional kettle reaction, the method disclosed by the invention adopts a micro-channel continuous flow technology to directly obtain the target product desflurane by a one-step method, so that the synthesis path is greatly simplified, and the reaction efficiency is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of fluorine chemical synthesis, and specifically relates to a method for synthesizing 2-(fluoromethoxy)-1,1,1,2-tetrafluoroethane (desflurane) by utilizing microchannel continuous flow technology. Background Art

[0002] Desflurane ( Desflurane is a volatile inhalation anesthetic primarily used for the induction and maintenance of general anesthesia. It inhibits the central nervous system, producing a sedative and anesthetic effect, temporarily rendering the patient unconscious, thereby alleviating pain, anxiety, and other stress reactions associated with surgery. It is a colorless, transparent liquid with a distinctive odor. Desflurane primarily acts on GABA (gamma-aminobutyric acid) receptors in the central nervous system, increasing the frequency of GABA-mediated chloride channel opening, leading to postsynaptic membrane hyperpolarization, thereby inhibiting neuronal excitability and producing an anesthetic effect. Desflurane has a low blood / gas partition coefficient, allowing for rapid alveolar absorption into the bloodstream, rapid onset of action, and rapid recovery. It is also relatively controllable, making the depth of anesthesia easily adjustable. It also exhibits excellent muscle relaxant properties, eliminating the need for additional muscle relaxants. It also exhibits strong analgesic effects and a robust anesthetic effect. It also has very low hepatotoxicity and renal toxicity, minimizing effects on vital organs. Therefore, this agent is widely used internationally.

[0003] It can be found from the existing reported literature that the common synthetic raw materials for the preparation of desflurane include 2-chloro-2-(chlorofluoromethoxy)-1,1,1-trifluoroethane, dichloromethoxy-1,1,1,2-tetrafluoroethane and isoflurane. Among them, the most mainstream and efficient method is to use isoflurane as a raw material to obtain desflurane through HF fluorination reaction.

[0004] Patent WO 2006076324A3, published in 2006, discloses a method for synthesizing fluorinated ethers. In the presence of chromium trioxide (Cr2O3) as a catalyst, isoflurane is bubbled with HF at 175°C to produce desflurane. After purification, the yield of the target product, desflurane, is 75.3%. While the use of Cr2O3 as a catalyst in this patent increases the reaction rate, the catalyst's activity is susceptible to reaction conditions, and the catalyst surface is easily passivated by HF after the reaction, resulting in reduced reuse efficiency. Furthermore, unreacted HF must be recovered through a complex recycling system, increasing equipment investment and energy consumption, resulting in a recovery rate of only 75.3%.

[0005] Patent US 5283372A reports a method for fluorinating isoflurane using bromine trifluoride (BrF3). Specifically, BrF3 is added dropwise to a mixture of isoflurane and bromine water at -18°C. The BrF3 used in this method is less toxic than the traditional SF4, but the yield is low, limiting its industrial scalability. Furthermore, the reaction requires low temperatures (-18°C), which increases the difficulty, cost, and complexity of industrial scale-up.

[0006] Patent CN 102617298A discloses a method for synthesizing desflurane. Potassium fluoride is used as a fluorination agent to react with isoflurane to produce desflurane. The reaction temperature is 220-230°C, the volume ratio (V / V) of alcohol ether to isoflurane is 2.16:1, and the reaction time is 12 hours. However, the yield is only 43.8%. Furthermore, due to the solubility of potassium fluoride in the solvent system, the reaction time is as long as 12 hours, limiting production efficiency.

[0007] As can be seen from the above, all existing methods for synthesizing Desflurane using isoflurane as a raw material have problems such as low safety, low yield, and poor reaction efficiency. Therefore, it is particularly important to find a new and efficient method for synthesizing Desflurane. Summary of the Invention

[0008] The present invention provides a method for preparing Desflurane using microchannel continuous flow technology, which realizes a one-step process for directly obtaining the target product Desflurane, greatly simplifies the synthesis path, and improves the reaction efficiency.

[0009] To achieve the above object, the present invention adopts the following technical solutions: A method for preparing desflurane using microchannel continuous flow technology comprises reacting isoflurane with a complex formed by hydrogen fluoride and a catalytic diazine in a microchannel reactor to prepare desflurane. The reaction formula is as follows: .

[0010] Wherein, the diazine includes any one of pyrazine, pyrimidine and pyridazine.

[0011] Specifically, it includes the following steps: 1) mixing diazine and HF to form an HF-diazine complex; 2) the HF-diazine complex obtained in step 1) and isoflurane are flowed into a premixing chamber for mixing; 3) The mixture obtained in step 2) is fed into a microchannel reactor for reaction, and the resulting effluent is extracted and purified to obtain Desflurane.

[0012] Furthermore, the molar ratio of HF to diazine used in step 1) is 2:1.

[0013] Furthermore, in step 2), the flow rate ratio of HF-diazine complex to isoflurane is 22:10.

[0014] Furthermore, the temperature of the premixing chamber in step 2) is 10°C.

[0015] Furthermore, the reaction temperature in step 3) is 15° C. and the reaction time is 7 minutes.

[0016] Furthermore, the extraction in step 3) uses a cold NaOH solution with a mass concentration of 5%.

[0017] Furthermore, the purification method in step 3) is distillation.

[0018] The advantages of the present invention are as follows: First, the use of a six-membered diazaaromatic ring compound complexed with HF as a reaction medium can omit the amount of pyridine used in traditional schemes and improve the sustained release efficiency of HF, thereby increasing the reaction yield; Second, the use of microchannel continuous flow technology can reduce storage volume and reduce the risk of explosion or leakage.

[0019] Third, the use of microchannel continuous flow technology can alleviate thermal runaway, and the efficient heat dissipation efficiency in the microchannel can prevent dangerous temperature surges during exothermic reactions.

[0020] Fourth, microchannel reactors can precisely regulate temperature, and their high surface area to volume ratio facilitates rapid heat transfer, ensuring uniform temperature distribution and minimizing side reactions.

[0021] Fifth, the microchannel reactor has adjustable residence time, and its flow rate can be adjusted to optimize reaction kinetics, thereby improving yield and selectivity.

[0022] Sixth, product quality consistency, laminar flow and efficient micro-mixing reduce variability, thereby reducing the production of side reactions and improving reproducibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The desflurane prepared in Example 1 1 H-NMR spectrum.

[0024] Figure 2 The desflurane prepared in Example 1 19 F-NMR spectrum.

[0025] Figure 3 This is the LC spectrum of Desflurane prepared in Example 1. DETAILED DESCRIPTION

[0026] In order to make the contents of the present invention easier to understand, the technical solutions of the present invention are further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0027] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0028] Example 1 Pyrazine and HF were mixed in a molar ratio of 1:2 to form an HF-pyrazine complex. The premixing chamber temperature was then adjusted to 10°C, and isoflurane (184 g, 1 mol) was introduced at a rate of 10 mL / min. Simultaneously, the HF-pyrazine complex (90 g, 0.75 mol) was introduced at a rate of 22 mL / min. The microchannel reactor plate temperature was adjusted to 15°C. The mixture in the premixing chamber was then pumped into the microchannel reactor plate via a delivery pump. The mixture remained there for 7 minutes before flowing directly into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (136 g, 81% yield). This crude product was then distilled in a rectification column to obtain the purified product (99.99% purity as determined by liquid chromatography).

[0029] Example 2 Pyrimidine and HF were mixed in a molar ratio of 1:2 to form an HF-pyrimidine complex. The premixing chamber temperature was then adjusted to 10°C, and isoflurane (184 g, 1 mol) was introduced at a rate of 10 mL / min. Simultaneously, the HF-pyrimidine complex (90 g, 0.75 mol) was introduced at a rate of 22 mL / min. The microchannel reactor plate temperature was adjusted to 15°C. The mixture in the premixing chamber was then pumped into the microchannel reactor plate via a delivery pump. The mixture remained there for 10 minutes before flowing directly into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (128 g, 76% yield). This crude product was then distilled in a rectification column to obtain a purified product (99.99% purity as determined by liquid chromatography).

[0030] Example 3 Pyridazine and HF were mixed in a molar ratio of 1:2 to form an HF-pyridazine complex. The premixing chamber temperature was then adjusted to 10°C, and isoflurane (184 g, 1 mol) was introduced at a flow rate of 10 mL / min. Simultaneously, the HF-pyridazine complex (90 g, 0.75 mol) was introduced at a flow rate of 22 mL / min. The microchannel reactor plate temperature was adjusted to 15°C. The mixture in the premixing chamber was then pumped into the microchannel reactor plate via a delivery pump. The mixture remained there for 10 minutes before flowing directly into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (121 g, 72% yield). This crude product was then distilled in a rectification column to obtain a purified product (99.99% purity as determined by liquid chromatography).

[0031] Comparative Example 1 The temperature of the premixing chamber was adjusted to 10°C, and isoflurane (184 g, 1 mol) was introduced into the premixing chamber at a flow rate of 10 mL / min. Simultaneously, HF (30.02 g, 1.5 mol) was introduced into the premixing chamber at a flow rate of 22 mL / min. The temperature of the microchannel reactor's plate was adjusted to 15°C. The mixture obtained in the premixing chamber was then pumped into the microchannel reactor's plate via a delivery pump. The mixture was allowed to remain there for 10 minutes before flowing directly into a 5% sodium hydroxide solution at 0°C. After separation, the resulting organic layer was washed three times with a 5% sodium hydroxide solution to obtain a crude product (2 g, yield <2%). However, the crude product was too small to be distilled to obtain the pure product.

[0032] Comparative Example 2 Pyrazine and HF were mixed in a 1:2 molar ratio to form an HF-pyrazine complex. Isoflurane (184 g, 1 mol) was placed in a reactor and the HF-pyrazine complex (90 g, 0.75 mol) was added. The system temperature was set to 10°C and allowed to react for 1 hour. The temperature was then raised to 15°C and the reaction continued for 12 hours. After the reaction ceased, the reaction solution was poured into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (31.92 g, 19% yield). The crude product was then distilled in a rectification column to obtain the pure product (the sample purity was 99.99% as determined by liquid chromatography).

[0033] Comparative Example 3 Pyridine and HF were mixed in a molar ratio of 1:2 to form an HF-pyridine complex. The premixing chamber temperature was then adjusted to 10°C, and isoflurane (184 g, 1 mol) was introduced into the premixing chamber at a rate of 10 mL / min. Simultaneously, the HF-pyridine complex (171 g, 1.5 mol) was introduced into the premixing chamber at a rate of 22 mL / min. The microchannel reactor plate temperature was adjusted to 15°C. The mixture in the premixing chamber was then pumped into the microchannel reactor plate via a delivery pump. The mixture remained there for 10 minutes before flowing directly into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (97 g, 58% yield). This crude product was then distilled in a rectification column to obtain a purified product (99.99% purity as determined by liquid chromatography).

[0034] Comparative Example 4 Pyrazine and HF were mixed in a molar ratio of 1:2 to form an HF-pyrazine complex. The premixing chamber temperature was then adjusted to 15°C, and isoflurane (184 g, 1 mol) was introduced into the premixing chamber at a flow rate of 10 mL / min. Simultaneously, the HF-pyrazine complex (90 g, 0.75 mol) was introduced into the premixing chamber at a flow rate of 22 mL / min. The microchannel reactor plate temperature was adjusted to 15°C. The mixture in the premixing chamber was then pumped into the microchannel reactor plate via a delivery pump. The mixture remained there for 7 minutes before flowing directly into a 0°C 5% sodium hydroxide solution. After separation, the organic layer was washed three times with 5% sodium hydroxide solution to obtain a crude product (82 g, 49% yield). This crude product was then distilled in a rectification column to obtain the purified product (99.99% purity as determined by liquid chromatography).

[0035] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for preparing desflurane using microchannel continuous flow technology, characterized in that: The following steps are involved: 1) mixing diazine and HF to form an HF-diazine complex; 2) the HF-diazine complex obtained in step 1) and isoflurane are flowed into a premixing chamber for mixing; 3) The mixture obtained in step 2) is fed into a microchannel reactor for reaction, and the resulting effluent is extracted and purified to obtain Desflurane.

2. The method according to claim 1, characterized in that The diazine in step 1) includes any one of pyrazine, pyrimidine and pyridazine.

3. The method according to claim 1, characterized in that The molar ratio of HF to diazine used in step 1) is 2:

1.

4. The method according to claim 1, wherein The flow rate ratio of HF-diazine complex to isoflurane in step 2) is 22:

10.

5. The method according to claim 1, wherein The temperature of the premixing chamber in step 2) is 10°C.

6. The method according to claim 1, characterized in that The reaction temperature in step 3) is 15°C and the reaction time is 7 minutes.

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