Preparation method and packaging method of isoflurane

Abstract

The invention provides a preparation method and a packaging method of isoflurane, and belongs to the technical field of halogen-containing acyclic compounds. Trifluoroethanol and monochlorodifluoromethane are used as initial raw materials, a selective fluorine reagent and a NaCl solid are added, the trifluoroethanol and the monochlorodifluoromethane are etherified, under the action of the selective fluorine reagent, the obtained etherified intermediate and NaCl are chlorinated, the reaction temperature of etherification and chlorination is 60-120 DEG C, one-pot method isoflurane preparation without taking the intermediate is carried out, and the isoflurane preparation process is simplified. The preparation method is simple in steps and simple in subsequent treatment, and a high-purity product can be obtained.

Description

Technical Field

[0001] The present application relates to a preparation method and a packaging method of isoflurane, and belongs to the technical field of halogen-containing acyclic compounds. Background Art

[0002] Isoflurane is an important drug in modern anesthesiology. It belongs to the class of halogenated hydrocarbon anesthetics and is commonly used as an inhaled anesthetic. Its safety and effectiveness make it widely used in medical treatment. Compared with other anesthetics, isoflurane has a better anesthetic effect and can quickly induce anesthesia and maintain anesthesia. Its anesthetic effect is mainly achieved by inhibiting nerve conduction in the central nervous system. The pharmacological effect of isoflurane is relatively mild and can better maintain a stable state during anesthesia. Isoflurane can reduce peripheral vascular resistance during anesthesia, leading to a decrease in blood pressure, but will not cause severe cardiac depression. In general, isoflurane is a relatively safe and stable volatile anesthetic. Due to its mild pharmacological effect and adjustability, it has become one of the important drugs in modern anesthesia.

[0003] There are many existing isoflurane preparation processes, such as: US3535425 (1970) uses trifluoroethanol and dimethyl sulfate to react under alkaline conditions to obtain the corresponding methyl ether, which is then chlorinated and fluorinated to obtain the ether, and then chlorinated under light to obtain isoflurane, but the reaction process is demanding, not only the reaction temperature must be controlled above 150°C, but also a certain negative pressure and other conditions must be met; US4855511 (1988) uses acetoacetic acid as the starting material, and reacts with thionyl chloride or phosphorus pentachloride to generate acyl chloride, which is then chlorinated and fluorinated to generate isoflurane. The dimethyl sulfate introduced is a highly toxic substance, and a large number of by-products will be produced during the chlorination process. Hydrogen fluoride is highly corrosive and toxic, and the environmental pollution is serious. CN 101830781 A uses (2,2,2-trifluoroethyl)-difluoromethyl ether (etherate) as a starting material. During the chlorination process, an appropriate amount of water is first added to the etherate, and an appropriate amount of chlorine is introduced under stirring and at a suitable temperature for chlorination to obtain a mixture of isoflurane, a small amount of impurities and unreacted etherate. CN 118221498 A uses 1,1,1-trifluoro-2,2-dichloroethane as a starting material to obtain an intermediate, and difluorochloromethane is introduced under the action of a base to finally obtain isoflurane. Although the introduction of toxic gases such as chlorine is avoided, the reaction process needs to be carried out under a higher pressure. Kazutaka et al. prepared isoflurane using NCS as a raw material under light, but the method is costly and the light conditions make it difficult to achieve industrial production. Summary of the invention

[0004] In view of this, the present application provides a method for preparing isoflurane, which has mild reaction conditions and can achieve a low temperature reaction not exceeding 120°C. Etherification and chlorination can be carried out simultaneously in one reactor, and there is no need to remove the intermediate for purification or other treatments. It is easy to scale up production, and solves the problems of the prior art such as high toxicity of raw materials, low yield, large interference of by-products on subsequent treatments, and many purification steps required.

[0005] Specifically, the present application is implemented through the following scheme: A method for preparing isoflurane, which comprises taking trifluoroethanol and difluorochloromethane as starting materials, adding a selective fluorine reagent and NaCl solid, etherifying the trifluoroethanol and difluorochloromethane, chlorinating the obtained etherified intermediate with NaCl under the action of the selective fluorine reagent, wherein the reaction temperatures of the etherification and chlorination are both 60-120° C., and preparing isoflurane in one pot without taking the intermediate. The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:0.75~2:0.65~1.5. The selective fluorine reagent of the reaction is octane di(tetrafluoroborate) salt, N-fluorobisbenzenesulfonamide (NFSI); its structural formula is as follows: .

[0006] The reaction equation for the one-pot isoflurane preparation process is expressed as follows: .

[0007] The above reaction conditions are mild, the damage to equipment is low, the process is simple, and it is green and environmentally friendly.

[0008] Further, as a preference: The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:1.0~1.5:1.2~1.3.

[0009] The reaction temperature is 60~90°C, preferably 80~90°C.

[0010] The amount of the selective fluorine reagent is 5-10% of the molar amount of trifluoroethanol.

[0011] In the one-pot isoflurane preparation process, a reaction solvent is also added, and the reaction solvent is any one of water (H2O), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dioxane (1,4-dioxane), and acetonitrile.

[0012] In the one-pot isoflurane preparation process, a base is also added, and the base is one or a mixture of KOH, NaOH, and triethylamine. More preferably, the amount of the base is 0.5 to 1.5 times the molar amount of trifluoroethanol, and 1.2 to 1.5 times.

[0013] After the chlorination reaction is completed, the crude product is filtered through a Buchner funnel, and then distilled in sequence to obtain refined isoflurane (48-49°C fraction).

[0014] Also provided is a method for encapsulating isoflurane prepared by the above method, the steps being as follows: Step 1: After cleaning the medicinal glass bottle, use compressed air to blow out the water on the surface of the medicinal glass bottle, place the medicinal glass bottle in a hot air circulation oven, and set the temperature of the hot air circulation oven to 60±5℃, and the drying time to 60~70 min; Step 2: Connect a delivery pipe to the isoflurane raw material barrel, use a peristaltic pump to quantitatively extract isoflurane into a liquid storage tank, and then send it to a transfer tank through the liquid storage tank. Step 3: Place the medicinal glass bottles dried in step 1 to the bottle sorting station, turn on the turntable for bottle sorting, rotate the medicinal glass bottles to the conveying port of the filling machine, and make the medicinal glass bottles enter the limiting channel; pour the bottleneck sleeve into the ring sorting plate, and complete the ring sorting after the bottleneck sleeve fills the guide ring track; pour the aluminum caps into the oscillator, and complete the cap sorting after the aluminum caps fill the track. Step 4: Open the transfer tank valve, turn on the power, set the filling parameters, start the filling conveyor, manually place 5 empty medicinal glass bottles for position limiting, adjust the filling machine parameters, and switch to automatic operation after the filling volume stabilizes, and then start filling; The filling process includes filling, ring pressing, and capping in sequence, and the capping is completed and then transferred to the outsourcing room via a conveyor belt. Before and after filling, take two empty bottles for torque test. The value is qualified if it is between 0.7 and 1.7 N×m. Step 5. Connect the main power of the clarity tester, turn on the light inspection light, sample the products on the filling line every 30±5 minutes, and take 6 bottles each time to send them to the central control room for light inspection and record. The qualified standards are: the glass bottle has a clean appearance, without color spots, sand spots, cracks, or flaws; the aluminum cap is not loose, not crooked, and there is no breakage at the connecting points of the aluminum cap. The shape is regular and clean, there is no leakage, and there are no other poor appearance phenomena; the product in the bottle is clear and transparent, without glass chips, metal chips, fibers or lumps with a length or particle size exceeding 2 mm, and other obviously visible foreign matter.

[0015] In the above process, the corresponding device for assembling the bottleneck sleeve with the clean medicinal glass bottle mainly includes a transmission mechanism, a turntable, a ring adding mechanism, a ring pressing mechanism, a ring pressing bracket, a connector, etc.

[0016] The transmission mechanism includes two limiting channels and a conveyor belt. The turntable is located between the two limiting channels. The medicinal glass bottles pass through the turntable and the pressure ring mechanism in sequence. Multiple medicinal glass bottles can be placed in the limiting channels. The conveyor belt is driven by a motor. The limiting channels are respectively installed on the conveyor belt. The width of the conveyor belt is adapted to the width of the medicinal glass bottles. The two limiting channels are arc-shaped near the turntable, which is convenient for the medicinal glass bottles to enter the turntable mechanism.

[0017] The turntable is driven by a motor, and there are multiple bayonet holes evenly distributed on the outside of the turntable. A panel is fixedly connected to the frame along the outside of the turntable. The medicinal glass bottles are clamped on the inside of the panel and the outside of the bayonet holes. The turntable is rotated by the motor, and the bayonet holes and the panel can clamp the medicinal glass bottles transmitted by the transmission mechanism.

[0018] The ring adding mechanism includes a ring sorting disc and a ring guide. The ring sorting disc is arranged on one side of the rotating disc, and the outer side of the ring sorting disc is fixedly connected with the ring guide. The other end of the ring guide is connected to the ring pressing mechanism. Multiple bottleneck sleeves are placed in the ring sorting disc, and the bottleneck sleeves in the ring sorting disc can slide into the ring pressing mechanism along the ring guide.

[0019] The pressing ring mechanism includes a pressing ring bracket, a fixing ring sleeve, a pre-pressor, a clamp, a compactor, etc.

[0020] The pressure ring bracket is fixedly connected to the frame and is located just above the junction of the turntable and the enclosure. A fixed ring disc is slidably connected to the pressure ring bracket. A connector for clamping the bottle neck sleeve is provided on the fixed ring disc, and a pre-compressor is provided above the connector. The fixed ring disc slides through cylinder 1. With this solution, the connector can support the bottle neck sleeve on the fixed ring disc, and the pre-compressor can push the bottle neck sleeve on the fixed ring disc onto the medicinal glass bottle, preliminarily fixing the bottle neck sleeve on the medicinal glass bottle.

[0021] The fixing ring plate is provided with a slot, which cooperates with the guide ring and the bottle neck sleeve. When the bottle neck sleeve needs to be clamped, the slot is located at the end of the guide ring, and when the bottle neck sleeve needs to be installed, the slot is located above the clamping port. With this solution, the fixing ring plate can drive the bottle neck sleeve to move from the end of the guide ring to the top of the medicinal glass bottle.

[0022] The two side walls opposite to the slot are each pivotally connected with an eccentric block, and the center of gravity of the eccentric block is located on the fixed ring disc. With this solution, the eccentric block can support the weight of the bottleneck sleeve, preventing the bottleneck sleeve entering the fixed ring disc from directly sliding out of the slot.

[0023] A compactor may also be provided on the other side of the pre-pressor, and the compactor is used to compact the bottle neck sleeve after pre-pressing.

[0024] A push rod is installed under the pressure ring bracket, and the push rod is pushed by cylinder 2. The push rod is located above the bayonet and faces the enclosure. With this solution, the push rod is used to fix the medicinal glass bottle to ensure that the pre-pressor can keep corresponding to the position of the medicinal glass bottle.

[0025] The present invention has the following advantages: 1) The purpose of the present invention is to provide a one-pot preparation process for synthesizing isoflurane with mild reaction conditions, low damage to equipment, simple process, green and environmentally friendly.

[0026] 2) The present invention uses a relatively low reaction temperature, and the reaction conditions are relatively mild, thus avoiding the potential safety hazards caused by high temperature reactions, making it easy to control the reaction, and at the same time, the reaction operation process and post-processing are simple; 3) The isoflurane prepared by the present invention can be well applied in veterinary medicine, and the encapsulation method is unique; 4) The process provided by the present invention is simple and has mild conditions, which is more suitable for industrial production. It can reduce the preparation cost while obtaining high-yield and high-purity products, showing better reaction advantages and economic advantages.

[0027] The preparation method has simple steps and simple subsequent treatment, and the etherification and chlorination are completed in one pot, and a high-purity product is obtained. In addition, isoflurane has a unique encapsulation technology in veterinary drug preparations and can be well applied in the pharmaceutical and chemical fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0029] Figure 1 This is the H NMR spectrum of isoflurane prepared in Example 1; Figure 2 is the infrared spectrum of isoflurane prepared in Example 1; Figure 3 This is a gas chromatographic analysis chart of isoflurane prepared in Example 1; Figure 4 This is a packaging flow chart of isoflurane prepared in Example 1; Figure 5 This is a structural diagram of the installation mechanism of the bottleneck sleeve during the packaging process of this application; Figure 6 This is a schematic structural diagram from another perspective of the bottleneck sleeve installation structure during the packaging process of this application.

[0030] Numbers in the figure: 11. Limit channel, 12. Conveyor belt, 21. Turntable, 22. Bayonet, 23. Enclosure, 31. Ring sorting plate, 32. Ring guide, 41. Pressing ring bracket, 42. Fixed ring plate, 43. Cylinder one, 44. Pre-compressor, 45. Slot, 46. Eccentric block, 47. Compactor, 51. Cylinder two, 52. Push rod. DETAILED DESCRIPTION

[0031] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0032] Example 1

[0033] The present application provides a method for preparing isoflurane, and the process is as follows: In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of sodium chloride solid, 25.2 g (0.45 mol, 0.9 equivalents) of potassium hydroxide, and after dissolving, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 17.7 g (0.05 mol, 0.05 equivalents) of octane di(tetrafluoroborate), and finally pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixed solution, stir, and react at 80°C for 5 h. After the reaction is completed, filter with a Buchner funnel to obtain a crude product, and then collect the 48~49°C fraction by rectification to obtain 76.6 g of isoflurane product with a yield of 83.3%.

[0034] The H NMR spectrum of the prepared product is shown in Figure 1 As shown: 1 H NMR (400 MHz, Chloroform-d) δ 6.47 (dd,J = 72.1, 69.8 Hz, 1H), 6.07 (qd,J = 4.1, 1.0 Hz, 1H).

[0035] The infrared spectrum of the prepared product is shown in Figure 2 As shown, 2900~3000 cm -1 The absorption peak at 1375 cm is the CH stretching vibration, indicating the alkyl group in the isoflurane molecule. -1 and 1450 cm -1The absorption peak is related to the bending vibration of CH, which is caused by the bending vibration of isoflurane-CH3, 1100~1300 cm -1 The strong absorption peak indicates the CF bond in the isoflurane molecule. The CF bond in fluorinated hydrocarbons has strong infrared absorption, 1050~1150 cm -1 The absorption peak in the region is due to the stretching vibration of the CO ether bond, 600~800 cm -1 The absorption peak at is related to the vibration of the C-Cl bond and represents the chlorine element in isoflurane.

[0036] The above-mentioned H NMR spectrum and IR spectrum prove that isoflurane was successfully synthesized in this case.

[0037] Figure 3 This is the gas chromatogram of isoflurane. We can conclude that the purity of isoflurane is 100%.

[0038] Replacement Example The following replacement example has the same configuration as that of Example 1, and the differences are shown in Table 1.

[0039] Table 1: Comparison of the effects of different implementation plans Serial number Solvents Reaction temperature / ℃ Reaction time / h <![CDATA[Molar equivalent of CHF2Cl]]> KOH molar equivalent NaCl molar equivalent Yield / % Example 1 <![CDATA[H2O]]> 80 5 1.5 0.9 1.3 83.3 Replacement Example 1 DMF 80 5 1.5 0.9 1.3 61.2 Replacement Example 2 THF 80 5 1.5 0.9 1.3 45.5 Replacement Example 3 Acetonitrile 80 5 1.5 0.9 1.3 65.3 Replacement Example 4 Dioxane 80 5 1.5 0.9 1.3 47.7 Replacement Example 5 <![CDATA[H2O]]> 60 5 1.5 0.9 1.3 63.2 Replacement Example 6 <![CDATA[H2O]]> 90 5 1.5 0.9 1.3 72.8 Replacement Example 7 <![CDATA[H2O]]> 120 5 1.5 0.9 1.3 35.6 Replacement Example 8 <![CDATA[H2O]]> 80 4 1.5 0.9 1.3 65.1 Replacement Example 9 <![CDATA[H2O]]> 80 8 1.5 0.9 1.3 83.0 Replacement Example 10 <![CDATA[H2O]]> 80 5 1.0 0.9 1.3 72.6 Replacement Example 11 <![CDATA[H2O]]> 80 5 2.0 0.9 1.3 47.4 Replacement Example 12 <![CDATA[H2O]]> 80 5 1.5 0.5 1.3 58.1 Replacement Example 13 <![CDATA[H2O]]> 80 5 1.5 1.2 1.3 81.3 Replacement Example 14 <![CDATA[H2O]]> 80 5 1.5 0.9 0.8 65.6 Replacement Example 15 <![CDATA[H2O]]> 80 5 1.5 0.9 1.5 78.4 .

[0040] Replacement Examples 1 to 4 verified the effects of different reaction solvents such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dioxane (1,4-dioxane), acetonitrile (acetonitrile) on the preparation effect: compared with Example 1, the yield was the best when water (H2O) was used as the reaction solvent, and the yields of THF, DMF, acetonitrile, and dioxane decreased in turn. Considering comprehensively, water and THF were the preferred reaction solvents.

[0041] Replacement Examples 5 to 7 verify the effect of different reaction temperatures in the range of 60 to 120°C: the yield of about 70% can be achieved by keeping the reaction temperature below 90°C. After comprehensive consideration, 60 to 90°C is the appropriate reaction temperature. Combined with Example 1, the reaction temperature is appropriately controlled at 80 to 90°C. Combined with Replacement Examples 8 and 9, the entire reaction time (etherification + chlorination) can be controlled at 4 to 8 hours.

[0042] Replacement Examples 10 to 15 verified the influence of different feed ratios: taking KOH as a representative, the amount of alkali used in the reaction process is 0.5 to 1.5 times the molar amount of trifluoroethanol, and 1.2 to 1.5 times is preferred; the molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:0.75 to 2:0.65 to 1.5 to achieve a better reaction yield. When the feed ratio is controlled at 1:1.0 to 1.5:1.2 to 1.3, the yield can be maintained at around 80%.

[0043] The preferred scheme is as follows: using H2O as solvent, 0.5 mol of trifluoroethanol, 1.5 times the molar amount of difluorochloromethane as trifluoroethanol, 1.5 times the molar amount of NaCl as trifluoroethanol, and 0.9 times the molar amount of KOH as trifluoroethanol, reacting at 80°C for 5h is the optimal condition, and the reaction yield is 83.3%.

[0044] Example 2 The preparation process of this embodiment is as follows: In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of sodium chloride solid, 25.2 g (0.45 mol, 0.9 equivalents) of potassium hydroxide, and after dissolving, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 15.8 g (0.05 mol, 0.05 equivalents) of N-fluorobisbenzenesulfonamide, and finally pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixed solution, stir, and react at 80°C for 5 h. After the reaction is completed, filter with a Buchner funnel to obtain a crude product, and then collect the 48~49°C fraction to obtain 68.2 g of isoflurane product with a yield of 74.2%.

[0045] Example 3 In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of sodium chloride solid, 18.0 g (0.45 mol, 0.9 equivalents) of sodium hydroxide, and after dissolving, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 17.7 g (0.05 mol, 0.05 equivalents) of octane di(tetrafluoroborate), and finally pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixed solution, stir, and react at 80°C for 5 h. After the reaction is completed, filter with a Buchner funnel to obtain a crude product, and then collect the 48~49°C fraction by rectification to obtain 69.8 g of isoflurane product with a yield of 76.0%.

[0046] Example 4 In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of sodium chloride solid, 45.5 g (0.45 mol, 0.9 equivalents) of triethylamine, and after dissolving, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 17.7 g (0.05 mol, 0.05 equivalents) of octane di(tetrafluoroborate), and finally pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixed solution, stir, and react at 80°C for 5 h. After the reaction is completed, filter with a Buchner funnel to obtain a crude product, and then collect the 48~49°C fraction by rectification to obtain 49.6 g of isoflurane product with a yield of 53.9%.

[0047] Application Examples Combination Figure 4 The packaging flow chart of Example 1 is used to package the product prepared in Example 1.

[0048] The packaging process is as follows: 1. Bottle washing and drying POP.100007 Collection of inner packaging materials: Collect a certain number of pharmaceutical glass bottles and twist-off aluminum caps for pharmaceutical glass bottles according to batch production instructions.

[0049] Bottle washing: The operator places the medicinal glass bottle in a sink, rinses it with drinking water three times, and then places it in a purified water tank and rinses it three times with purified water. The washed medicinal glass bottle is placed in a bottle blowing tank, and the water on the bottle surface is blown out with compressed air.

[0050] Bottle drying: Push the cart into the hot air circulation oven and start drying. Set the drying temperature to 60±5℃ and the drying time to 60-70 min.

[0051] 2. Liquid preparation POP.100010 The operator places the delivery tube into the isoflurane raw material barrel and uses a peristaltic pump to draw a fixed amount of isoflurane into the liquid storage tank according to the filling weight required in the production instruction.

[0052] 3. Bottle sorting, ring sorting, and cap sorting POP.100010 Bottle unscrambling: Place clean medicinal glass bottles at the bottle unscrambling station, turn on the turntable 21 for bottle unscrambling, rotate the glass bottles to the delivery port of the filling machine, turn on "delivery" in the operation interface, and let the bottles enter the limiting channel 11. The side of the limiting channel 11 close to the turntable 21 is arc-shaped.

[0053] Ring sorting: Pour the bottle neck sleeve into the ring sorting plate 31, turn on the "ring sorting" function, and when the bottle neck sleeve fills the ring guide channel 32, the ring sorting is completed.

[0054] Cap sorting: Pour the aluminum caps into the oscillator, turn on "cap sorting", and the cap sorting is completed when the aluminum caps fill the track.

[0055] 4. Filling, ring pressing, capping POP.100010 Open the transfer tank valve, turn on the power, set the filling parameters, start the filling conveyor belt (driven by a motor, the conveyor belt width is adapted to the width of the medicinal glass bottles), manually place 5 empty medicinal glass bottles for limiting, adjust the filling machine parameters, and after the filling volume stabilizes, switch to automatic operation and start filling.

[0056] Torque test: Take two empty bottles for torque test before and after filling. The value is qualified only when it is between 0.7 and 1.7 N×m.

[0057] Filling quantity adjustment: Use weighing method to check the filling quantity. The filling quantity of each bottle of medicine should not be less than the marked filling quantity, and the weight difference should be ≤±3%.

[0058] Weight check: During filling, carry out sampling inspection every 30±5 minutes, take 6 bottles each time and record the weight. The visual appearance should be intact, and the aluminum cap thread should not be cracked or loose.

[0059] 5. Light inspection POP.100011 Connect the main power of the clarity tester and turn on the light inspection lamp.

[0060] The filling line is turned on, and the product is sampled every 30±5 minutes. Six bottles are taken each time and sent to the central control room for light inspection and record. The sampled products are manually inspected visually. If unqualified products are found, the delivery should be stopped, and the unqualified products should be manually picked out before continuing the filling operation.

[0061] Qualification standard: The appearance of the glass bottle is clean, without color spots, sand spots, cracks, or flaws; the aluminum cap is not loose or crooked. The twist-off aluminum cap has no breaks at the connection points, has a regular and clean appearance, no leakage, and no other poor appearance; the product in the bottle is clear and transparent, without glass chips, metal chips, fibers and lumps with a length or particle size exceeding 2 mm, and other obviously visible foreign matter.

[0062] In the above process, The assembly process of the neck sleeve and the clean pharmaceutical glass bottle is as follows Figure 5 , Figure 6 As shown: The corresponding assembly device mainly includes a transmission mechanism, a turntable 21, a ring adding mechanism, a ring pressing mechanism, a ring pressing bracket 41, a connector, etc.

[0063] The transmission mechanism includes two limiting channels 11 and a conveyor belt 12. The turntable 21 is located between the two limiting channels 11. The medicinal glass bottles pass through the turntable 21 and the pressure ring mechanism in sequence. Multiple medicinal glass bottles can be placed in the limiting channels 11. The conveyor belt 12 is driven by a motor. The limiting channels 11 are respectively installed on the conveyor belt 12. The width of the conveyor belt 12 is adapted to the width of the medicinal glass bottles. The two limiting channels 11 are arc-shaped near the turntable 21, which is convenient for the medicinal glass bottles to enter the turntable 21 mechanism.

[0064] The turntable 21 is driven by a motor, and a plurality of bayonet holes 22 are evenly distributed on the outside of the turntable 21. A surround 23 is fixedly connected to the frame along the outside of the turntable 21. The medicinal glass bottles are clamped on the inner side of the surround 23 and the outer side of the bayonet holes 22. The turntable 21 is rotated by the motor, and the bayonet holes 22 and the surround 23 can clamp the medicinal glass bottles transmitted by the transmission mechanism.

[0065] The ring adding mechanism includes a ring sorting disk 31 and a ring guide 32. The ring sorting disk 31 is arranged on one side of the rotating disk 21. The outer side of the ring sorting disk 31 is fixedly connected with the ring guide 32. The other end of the ring guide 32 is connected to the ring pressing mechanism. Multiple bottleneck sleeves are placed in the ring sorting disk 31. The bottleneck sleeves in the ring sorting disk 31 can slide into the ring pressing mechanism along the ring guide 32.

[0066] The pressing ring mechanism includes a pressing ring bracket 41, a fixing ring sleeve 42, a pre-pressor 44, a clamp, a pressing device 47 and the like.

[0067] A push rod 52 is installed below the pressure ring bracket 41. The push rod 52 is pushed by the cylinder 2 51. The push rod 52 is located above the bayonet 22 and faces the enclosure 23. The push rod 52 is used to fix the medicinal glass bottle driven by the turntable 21. The pressure ring bracket 41 is fixedly connected to the frame. The pressure ring bracket 41 is located just above the junction of the turntable 21 and the enclosure 23. A fixed ring disc 42 is slidably connected to the pressure ring bracket 41; a connector for clamping the bottle neck sleeve is provided on the fixed ring disc 42, and a pre-compressor 44 is provided above the connector.

[0068] The fixed ring disk 42 slides through the cylinder 43, and the connector can support the bottleneck sleeve on the fixed ring disk 42. The pre-pressurizer 44 can push the bottleneck sleeve on the fixed ring disk 42 to the medicinal glass bottle fixed by the push rod 52, and preliminarily fix the bottleneck sleeve on the medicinal glass bottle.

[0069] A slot 45 can be formed on the fixed ring disc 42 to form a snap-in device. The slot 45 cooperates with the guide ring 32 and the bottleneck sleeve. When the bottleneck sleeve needs to be snap-in, the slot 45 is located at the end of the guide ring 32. When the bottleneck sleeve needs to be installed, the slot 45 is located above the bayonet 22. The fixed ring disc 42 can drive the bottleneck sleeve to move from the end of the guide ring 32 to the top of the medicinal glass bottle. An eccentric block 46 is pivotally connected to each of the two opposite side walls of the slot 45. The center of gravity of the eccentric block 46 is located on the fixed ring disc 42. The eccentric block 46 can support the weight of the bottleneck sleeve to prevent the bottleneck sleeve entering the fixed ring disc 42 from directly sliding out of the slot 45.

[0070] A compactor 47 is disposed on the other side of the pre-pressurizer 44 , and the compactor 47 is used to compact the bottle neck sleeve after pre-pressing.

[0071] During the above-mentioned packaging operation, first, the medicinal glass bottle is placed on the conveyor belt 12, and the medicinal glass bottle is transported to the bayonet 22 of the turntable 21 along the conveyor belt 12. As the turntable 21 rotates, the medicinal glass bottle moves to one side of the push rod 52, and the push rod 52 is started to fix the bottle body position of the medicinal glass bottle. The bottleneck sleeve passes through the ring plate 31 and the guide ring channel 32 in sequence until it moves to the two eccentric blocks 46, and the cylinder 1 43 is started to push the bottleneck sleeve to the top of the medicinal glass bottle fixed by the push rod 52, and the pre-pressor 44 is started to pre-press the bottleneck sleeve on the neck of the medicinal glass bottle, and the turntable 21 is rotated to move the medicinal glass bottle to the bottom of the compactor 47, and the compactor 47 is started to fix the bottleneck sleeve on the medicinal glass bottle, thereby realizing the automatic installation and packaging of the bottleneck sleeve on the medicinal glass bottle, saving labor costs.

[0072] The reaction in this case has the advantages of mild conditions and easy scale-up production, and solves the problems of high toxicity of raw materials, low yield, large interference of byproducts on subsequent treatment, and many steps required for purification in the prior art. The preparation method of the present invention has simple steps and simple subsequent treatment, and can obtain high-purity products. In addition, isoflurane has a unique encapsulation technology in veterinary preparations and can be well applied in the field of medicine and chemical industry.

[0073] The above-mentioned embodiments only express several feasible implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing isoflurane, characterized in that: Using trifluoroethanol and difluorochloromethane as starting materials, adding a selective fluorine reagent and NaCl solid, trifluoroethanol and difluorochloromethane are etherified, and under the action of the selective fluorine reagent, the obtained etherified intermediate is chlorinated with NaCl, and the reaction temperature of the etherification and chlorination is 60-120°C, so that isoflurane is prepared in one pot without taking the intermediate. The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:0.75~2:0.65~1.

5. The selective fluorine reagent is octane di(tetrafluoroborate) salt or N-fluorobisbenzenesulfonamide.

2. The method for preparing isoflurane according to claim 1, characterized in that: The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:1.0~1.5:1.2~1.

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3. The method for preparing isoflurane according to claim 1, characterized in that: The reaction temperature is 60~90℃.

4. The method for preparing isoflurane according to claim 1, characterized in that: The amount of the selective fluorine reagent is 5-10% of the molar amount of trifluoroethanol.

5. The method for preparing isoflurane according to claim 1, characterized in that: The method further comprises a reaction solvent, which is any one of water, tetrahydrofuran, N,N-dimethylformamide, dioxane and acetonitrile.

6. The method for preparing isoflurane according to claim 1, characterized in that: The method further comprises a base, wherein the base is one or a mixture of multiple of KOH, NaOH and triethylamine.

7. The method for preparing isoflurane according to claim 6, characterized in that: The amount of the base used is 0.5 to 1.5 times the molar amount of trifluoroethanol.

8. The method for preparing isoflurane according to any one of claims 1 to 7, characterized in that: After the chlorination reaction is completed, the crude product is filtered through a Buchner funnel to obtain a crude product, which is then distilled in sequence to obtain refined isoflurane.

9. A method for packaging isoflurane, characterized in that: Here are the steps: Step 1: After cleaning the medicinal glass bottle, use compressed air to blow out the water on the surface of the medicinal glass bottle, place the medicinal glass bottle in a hot air circulation oven, and set the temperature of the hot air circulation oven to 60±5℃, and the drying time to 60-70 min. Step 2: Connect a delivery pipe to the isoflurane raw material barrel, use a peristaltic pump to quantitatively extract isoflurane into a liquid storage tank, and then send it to a transfer tank through the liquid storage tank. Step 3: Place the medicinal glass bottles dried in step 1 to the bottle sorting station, turn on the turntable for bottle sorting, rotate the medicinal glass bottles to the conveying port of the filling machine, and make the medicinal glass bottles enter the limiting channel; pour the bottleneck sleeve into the ring sorting plate, and complete the ring sorting after the bottleneck sleeve fills the guide ring track; pour the aluminum caps into the oscillator, and complete the cap sorting after the aluminum caps fill the track. Step 4: Open the transfer tank valve, turn on the power, set the filling parameters, start the filling conveyor, manually place five empty medicinal glass bottles for position limiting, adjust the filling machine parameters, and after the filling volume stabilizes, switch to automatic operation and start filling; The filling process includes filling, ring pressing, and capping in sequence, and the capping is completed and then transferred to the outsourcing room via a conveyor belt. Before and after filling, take two empty bottles for torque test. The value is qualified if it is between 0.7 and 1.7 N×m. Step 5. Connect the main power of the clarity tester, turn on the light inspection light, sample the products on the filling line every 30±5 minutes, and take six bottles each time to send to the central control room for light inspection and record. The qualified standards are: the glass bottle has a clean appearance, without color spots, sand spots, cracks, or flaws; the aluminum cap is not loose, not crooked, and there is no breakage at the connecting point of the aluminum cap. The shape is regular and clean, there is no leakage, and there are no other appearance defects; the product in the bottle is clear and transparent, without glass chips, metal chips, or obviously visible foreign matter with a length or particle size exceeding 2 mm.

10. The method for packaging isoflurane according to claim 9, characterized in that: The assembly device for the neck sleeve and the clean medicinal glass bottle includes a transmission mechanism, a turntable, a ring adding mechanism, a ring pressing mechanism, and a ring pressing bracket. The transmission mechanism includes two limiting channels and a conveyor belt. The turntable is located between the two limiting channels. The conveyor belt is driven by a motor. The limiting channels are respectively installed on the conveyor belt. The width of the conveyor belt is adapted to the width of the medicinal glass bottle. The two limiting channels are arc-shaped near the turntable. Multiple medicinal glass bottles are placed in the limiting channels to facilitate the medicinal glass bottles to enter the turntable. The turntable is driven by a motor, and a plurality of bayonet ports are evenly distributed on the outside of the turntable. A panel is arranged along the outside of the turntable, and the medicinal glass bottle is clamped between the panel and the bayonet port. When the turntable rotates, the bayonet port and the panel clamp the transferred medicinal glass bottle. The ring adding mechanism comprises a ring sorting disk and a ring guide channel, one end of the ring guide channel is connected to the ring sorting disk, and the other end is arranged corresponding to the ring pressing mechanism, and multiple bottlenecks are placed in the ring sorting disk and slide into the ring pressing mechanism along the ring guide channel; The pressing ring mechanism includes a pressing ring bracket, a fixed ring sleeve, a pre-pressor, a slot, and a compactor. The pressing ring bracket is located directly above the junction of the turntable and the enclosure. The pressing ring bracket is slidably connected with a fixed ring disc, and the fixed ring disc slides through a cylinder. The fixed ring disc is provided with a slot for clamping the bottleneck sleeve, and the slot is matched with the guide ring channel and the bottleneck sleeve. A pre-pressor is provided above the slot. When the bottleneck sleeve is clamped, the slot is connected to the guide ring channel. When the bottleneck sleeve is installed, the slot is located above the bayonet, and the fixed ring disc drives the bottleneck sleeve to move from the end of the guide ring channel to above the medicinal glass bottle. An eccentric block capable of supporting the weight of the bottleneck sleeve is pivotally connected to two opposite side walls of the slot, and the center of gravity of the eccentric block is located on the fixed plate; A push rod is installed below the pressure ring bracket, the push rod is located above the bayonet and is pushed by a cylinder; The medicinal glass bottle is transported to the bayonet of the turntable by the conveyor belt. As the turntable rotates, the bottle body moves to one side of the push rod, which is started to fix the position of the bottle body. The bottleneck sleeve passes through the ring sorting disk and the guide ring channel in turn until it moves to the two eccentric blocks. Cylinder 1 is started to push the bottleneck sleeve to the top of the medicinal glass bottle body fixed by the push rod, the pre-pressor is started to pre-press the bottleneck sleeve on the neck of the bottle body, the turntable is rotated to move the bottle body to the bottom of the compactor, and the compactor is started to fix the bottleneck sleeve on the medicinal glass bottle, thereby realizing the automatic packaging of the bottleneck sleeve for medicinal glass bottles.

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