Process for the preparation and packaging of isoflurane

Abstract

The application provides a preparation method and a packaging method of isoflurane, and belongs to the technical field of halogen-containing acyclic compounds. Trifluoroethanol and difluoro-chloromethane are used as starting materials, a selective fluorine reagent and NaCl solid are added, and the trifluoroethanol and the difluoro-chloromethane are etherified. Under the action of the selective fluorine reagent, the obtained etherification intermediate is chlorinated with NaCl, the reaction temperature of etherification and chlorination is 60-120 DEG C, and one-pot isoflurane preparation without intermediate taking is carried out. The preparation method has simple steps, simple subsequent treatment, and can obtain a product with high purity.

Description

Technical Field

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

[0002] Isoflurane is a key drug in modern anesthesia. It belongs to the halogenated hydrocarbon class of anesthetics and is commonly used as an inhalation anesthetic. Its safety and effectiveness have led to its widespread use in medical settings. Compared to other anesthetics, isoflurane has a superior anesthetic effect, enabling rapid induction and maintenance of anesthesia. Its anesthetic effect is primarily achieved by inhibiting nerve conduction in the central nervous system. Its pharmacological effects are relatively mild, effectively maintaining a stable state during anesthesia. During anesthesia, isoflurane can reduce peripheral vascular resistance, leading to a decrease in blood pressure, but does not cause severe cardiac depression. Overall, isoflurane is a relatively safe and stable volatile anesthetic. Its mild pharmacological effects and adjustability have made it a key drug in modern anesthesia.

[0003] There are many existing processes for preparing isoflurane. For example, US Pat. No. 3,535,425 (1970) uses trifluoroethanol and dimethyl sulfate to react under alkaline conditions to produce the corresponding methyl ether. This ether is then chlorinated and fluorinated to produce the corresponding ether. This ether is then chlorinated under light to produce isoflurane. However, this reaction is demanding, requiring not only a temperature above 150°C but also negative pressure. US Pat. No. 4,855,511 (1988) uses acetoacetic acid as a starting material and reacts it with thionyl chloride or phosphorus pentachloride to produce an acyl chloride. This is then chlorinated and fluorinated to produce isoflurane. The dimethyl sulfate introduced is a highly toxic substance, and the chlorination process produces a large number of byproducts. Hydrogen fluoride is highly corrosive and toxic, resulting in severe environmental pollution. CN 101830781 A uses (2,2,2-trifluoroethyl)-difluoromethyl ether (etherate) as the 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 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 the 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 irradiation, but this method is expensive 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, without the need to remove the intermediate for purification or other treatments. It is easy to scale up production, and solves the problems in the prior art such as the high toxicity of the raw materials, low yield, large interference of by-products with subsequent treatments, and the large number of purification steps required.

[0005] Specifically, this application is implemented through the following solutions:

[0006] A method for preparing isoflurane comprises the following steps: using trifluoroethanol and difluorochloromethane as starting materials, adding a selective fluorine reagent and solid NaCl, etherifying the trifluoroethanol and difluorochloromethane, and chlorinating the obtained etherified intermediate with NaCl under the action of the selective fluorine reagent. The reaction temperatures for the etherification and chlorination are both 60-120° C., thereby preparing isoflurane in a one-pot process without the need for intermediate extraction.

[0007] The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:0.75~2:0.65~1.5,

[0008] The selective fluorine reagent for the reaction is octane bis(tetrafluoroborate) salt, N-fluorobisbenzenesulfonamide (NFSI); its structural formula is as follows: .

[0009] The reaction equation for the one-pot isoflurane preparation process is as follows: .

[0010] The above reaction conditions are mild, the damage to equipment is low, the process is simple, and it is green and environmentally friendly.

[0011] Furthermore, as a preference:

[0012] The molar ratio of trifluoroethanol, difluorochloromethane and sodium chloride is 1:1.0~1.5:1.2~1.3.

[0013] The reaction temperature is 60~90℃, preferably 80~90℃.

[0014] The amount of the selective fluorine reagent is 5-10% of the molar amount of trifluoroethanol.

[0015] During the one-pot isoflurane preparation process, a reaction solvent is further added. The reaction solvent is any one of water (H2O), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dioxane (1,4-dioxane), and acetonitrile.

[0016] During the one-pot isoflurane preparation process, a base is further added, wherein 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 the molar amount of trifluoroethanol.

[0017] After the chlorination reaction is completed, the crude product is filtered using a Buchner funnel, and then distilled to obtain refined isoflurane (fraction at 48-49°C).

[0018] Also provided is a method for encapsulating isoflurane prepared by the above method, comprising the following steps:

[0019] 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 hot air circulation oven temperature to 60±5℃ and the drying time to 60~70 minutes;

[0020] 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 the transfer tank through the liquid storage tank.

[0021] 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 limited channel; pour the bottle neck sleeve into the ring sorting disk, and complete the ring sorting after the bottle neck sleeve fills the guide ring track; pour the aluminum cap into the oscillator, and complete the cap sorting after the aluminum cap fills the track.

[0022] Step 4: Open the transfer tank valve, turn on the power, set the filling parameters, start the filling conveyor, manually place 5 empty pharmaceutical glass bottles for position limiting, adjust the filling machine parameters, and after the filling volume stabilizes, switch to automatic operation and start filling;

[0023] 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.

[0024] 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.

[0025] Step 5. Connect the main power of the clarity tester, turn on the light inspection light, and sample the products on the filling line every 30±5 minutes. Take 6 bottles each time and send them to the central control room for light inspection and record. The qualified standards are: the glass bottle is clean in appearance, without color spots, sand spots, cracks, or defects; the aluminum cap is not loose, not crooked, and the aluminum cap connection point is not broken. 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.

[0026] In the above process, the corresponding devices for assembling the bottleneck sleeve with the clean medicinal glass bottle mainly include a transmission mechanism, a turntable, a ring adding mechanism, a ring pressing mechanism, a ring pressing bracket, a connector, etc.

[0027] The transport mechanism consists of two limited channels and a conveyor belt. A turntable is located between the two limited channels, and pharmaceutical glass bottles pass through the turntable and the pressure ring mechanism in sequence. Multiple pharmaceutical glass bottles can be placed in the limited channels. The conveyor belt is driven by a motor, and the limited channels are mounted on the conveyor belt. The width of the conveyor belt is adapted to the width of the pharmaceutical glass bottles. The two limited channels are curved on the side closest to the turntable to facilitate the entry of pharmaceutical glass bottles into the turntable mechanism.

[0028] 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.

[0029] The ring-adding mechanism consists of a ring-sorting disc and a ring guide. The disc is mounted on one side of the turntable, with the ring guide fixedly attached to its outer side. The other end of the guide is connected to the ring-pressing mechanism. Multiple bottle necks are placed inside the disc, and the bottle necks inside the disc slide along the guide into the ring-pressing mechanism.

[0030] The pressing ring mechanism includes a pressing ring bracket, a fixing ring sleeve, a pre-pressor, a connector, a pressing device, etc.

[0031] The pressure ring bracket is fixedly connected to the frame and located directly above the intersection of the turntable and the enclosure. A fixed ring disc is slidably connected to the pressure ring bracket. The fixed ring disc is equipped with a connector that engages the bottle neck sleeve, and a pre-compressor is installed above the connector. The fixed ring disc slides via cylinder 1. With this solution, the connector supports the bottle neck sleeve on the fixed ring disc, and the pre-compressor pushes the bottle neck sleeve from the fixed ring disc onto the pharmaceutical glass bottle, initially securing the bottle neck sleeve to the bottle.

[0032] The fixing ring disc has slots that mate with the guide ring and bottle neck sleeve. When the bottle neck sleeve is attached, the slot is located at the end of the guide ring, and when the bottle neck sleeve is installed, the slot is located above the latch. With this solution, the fixing ring disc can move the bottle neck sleeve from the end of the guide ring to the top of the pharmaceutical glass bottle.

[0033] An eccentric block is pivotally connected to each of the two opposite side walls of the slot, and the center of gravity of the eccentric block is located on the fixed ring disk. With this solution, the eccentric block can support the weight of the bottle neck sleeve and prevent the bottle neck sleeve from sliding directly out of the slot after entering the fixed ring disk.

[0034] A compactor may also be provided on the other side of the pre-pressurizer, and the compactor is used to compact the bottle neck sleeve after pre-pressing.

[0035] A push rod is installed below the pressure ring bracket and 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 pharmaceutical glass bottle and ensure that the pre-press can maintain the corresponding position of the pharmaceutical glass bottle.

[0036] The present invention has the following advantages:

[0037] 1) The purpose of the present invention is to provide a one-pot process for synthesizing isoflurane with mild reaction conditions, low damage to equipment, simple process, green and environmentally friendly.

[0038] 2) The present invention utilizes 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;

[0039] 3) The isoflurane prepared by the present invention can be well used in veterinary medicine, and the encapsulation method is unique;

[0040] 4) The process provided by the present invention is simple and has mild conditions, making it more suitable for industrial production. It reduces preparation costs while obtaining high-yield and high-purity products, showing better reaction and economic advantages.

[0041] The preparation method is concise, with simple subsequent processing. Etherification and chlorination are completed in a single pot, yielding a high-purity product. Furthermore, isoflurane has unique encapsulation technology for veterinary drug formulations, making it well-suited for use in the pharmaceutical and chemical industries. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. 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 any creative work.

[0043] Figure 1 This is the H NMR spectrum of isoflurane prepared in Example 1;

[0044] Figure 2 This is the infrared spectrum of isoflurane prepared in Example 1;

[0045] Figure 3 This is a gas chromatographic analysis chart of isoflurane prepared in Example 1;

[0046] Figure 4 This is a packaging flow chart of isoflurane prepared in Example 1;

[0047] Figure 5This is a structural diagram of the installation mechanism of the bottleneck sleeve during the packaging process of this application;

[0048] Figure 6 This is a structural schematic diagram from another perspective of the bottleneck sleeve installation structure during the packaging process of this application.

[0049] Numbers in the figure: 11. Limit channel, 12. Conveyor belt, 21. Turntable, 22. Bayonet, 23. Enclosure, 31. Ring sorting plate, 32. Guide ring channel, 41. Pressing ring bracket, 42. Fixed ring plate, 43. Cylinder 1, 44. Pre-compressor, 45. Slot, 46. Eccentric block, 47. Compactor, 51. Cylinder 2, 52. Push rod. DETAILED DESCRIPTION

[0050] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, 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 efforts shall fall within the scope of protection of this application.

[0051] Example 1

[0052] The present application provides a method for preparing isoflurane, and the process is as follows:

[0053] In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of solid sodium chloride, and 25.2 g (0.45 mol, 0.9 equivalents) of potassium hydroxide. 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 bis(tetrafluoroborate). Finally, pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixture, stir, and react at 80°C for 5 hours. After completion of the reaction, filter using a Buchner funnel to obtain the crude product, which is then rectified and collected from the 48-49°C fraction to obtain 76.6 g of isoflurane (83.3% yield).

[0054] 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).

[0055] The infrared spectrum of the prepared product is shown in Figure 2As 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 -1 The absorption peak is related to the bending vibration of CH, 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.

[0056] The above-mentioned H NMR spectrum and IR spectrum prove that isoflurane was successfully synthesized in this case.

[0057] Figure 3 This is the gas chromatogram of isoflurane. We can conclude that the purity of isoflurane is 100%.

[0058] Replacement Example

[0059] The following replacement examples have the same configuration as in Example 1, with the differences shown in Table 1.

[0060] Table 1: Comparison of the effects of different implementation plans

[0061] Serial number solvent Reaction temperature / ℃ Reaction time / h <![CDATA[CHF2Cl摩尔当量]]> 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 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 .

[0062] Alternative Examples 1 to 4 verified the effects of different reaction solvents, such as tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dioxane (1,4-dioxane), and acetonitrile, on the preparation results: Compared with Example 1, the yield was the best when water (H2O) was used as the reaction solvent. The yields of THF, DMF, acetonitrile, and dioxane decreased in sequence. Taking all factors into consideration, water and THF were the preferred reaction solvents.

[0063] Alternative Examples 5-7 demonstrate the effects of varying reaction temperatures within the 60-120°C range: Yields approaching 70% can be achieved by maintaining the reaction temperature below 90°C. After comprehensive consideration, a suitable reaction temperature of 60-90°C is considered optimal. Combined with Example 1, the reaction temperature is optimally controlled at 80-90°C. Combined with Alternative Examples 8 and 9, the entire reaction time (etherification + chlorination) can be controlled to 4-8 hours.

[0064] Replacement Examples 10 to 15 verified the effects of different feed ratios: taking KOH as a representative, the amount of base used during the reaction was 0.5 to 1.5 times the molar amount of trifluoroethanol, and 1.2 to 1.5 times was optimal; a molar ratio of trifluoroethanol to difluorochloromethane to sodium chloride of 1:0.75 to 2:0.65 to 1.5 could achieve a better reaction yield. When the feed ratio was controlled at 1:1.0 to 1.5:1.2 to 1.3, the yield could be maintained at around 80%.

[0065] The preferred solution is as follows: using H2O as the solvent, 0.5 mol of trifluoroethanol, 1.5 times the molar amount of difluorochloromethane, 1.5 times the molar amount of trifluoroethanol of NaCl, and 0.9 times the molar amount of trifluoroethanol of KOH, and reacting at 80°C for 5 h is the optimal condition, and the reaction yield is 83.3%.

[0066] Example 2

[0067] The preparation process of this embodiment is as follows:

[0068] In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of solid sodium chloride, and 25.2 g (0.45 mol, 0.9 equivalents) of potassium hydroxide. 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. Finally, pass 64.5 g (0.75 mol, 1.5 equivalents) of chlorodifluoromethane into the mixture. Stir and react at 80°C for 5 hours. After completion of the reaction, filter using a Buchner funnel to obtain the crude product. The fraction at 48-49°C is then rectified to obtain 68.2 g of isoflurane, a 74.2% yield.

[0069] Example 3

[0070] In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of solid sodium chloride, and 18.0 g (0.45 mol, 0.9 equivalents) of sodium hydroxide. After dissolution, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 17.7 g (0.05 mol, 0.05 equivalents) of octane bis(tetrafluoroborate). Finally, pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixture, stir, and react at 80°C for 5 h. After completion of the reaction, filter using a Buchner funnel to obtain the crude product, which was then rectified and collected from the 48-49°C fraction to obtain 69.8 g of isoflurane, with a yield of 76.0%.

[0071] Example 4

[0072] In a sealed container, add 100 ml of water, 37.7 g (0.65 mol, 1.3 equivalents) of solid sodium chloride, and 45.5 g (0.45 mol, 0.9 equivalents) of triethylamine. After dissolution, add 50.0 g (0.5 mol, 1.0 equivalents) of trifluoroethanol and 17.7 g (0.05 mol, 0.05 equivalents) of octane bis(tetrafluoroborate). Finally, pass 64.5 g (0.75 mol, 1.5 equivalents) of difluorochloromethane into the mixture, stir, and react at 80°C for 5 h. After completion of the reaction, filter using a Buchner funnel to obtain the crude product, which was then rectified and collected from the 48-49°C fraction to obtain 49.6 g of isoflurane, with a yield of 53.9%.

[0073] Application Examples

[0074] Combine Figure 4 , and encapsulate the product prepared in Example 1.

[0075] The packaging process is as follows:

[0076] 1. Bottle washing and drying POP.100007

[0077] 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.

[0078] Bottle washing: The operator places the pharmaceutical glass bottles in a sink and rinses them three times with drinking water. After washing, the bottles are placed in a purified water tank and rinsed three times with purified water. The washed bottles are then placed in a bottle blowing tank and compressed air is used to blow out the water on the bottle surface.

[0079] 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 minutes.

[0080] 2. Liquid preparation POP.100010

[0081] The operator places the delivery tube into the isoflurane raw material barrel and uses a peristaltic pump to extract a fixed amount of isoflurane into the liquid storage tank according to the filling weight required by the production instructions.

[0082] 3. Bottle sorting, ring sorting, and cap sorting POP.100010

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 4. Filling, ring pressing, capping POP.100010

[0087] Open the transfer tank valve, turn on the power, set the filling parameters, start the filling conveyor (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 limit, adjust the filling machine parameters, and after the filling volume stabilizes, switch to automatic operation and start filling.

[0088] Torque test: Take two empty bottles for torque test before and after filling. The value must be between 0.7 and 1.7 N×m to be qualified.

[0089] Filling quantity adjustment: Use weighing method to check the filling quantity. The filling quantity of each bottle of liquid medicine should not be less than the marked filling quantity, and the weight difference should be ≤±3%.

[0090] Weight check: During the filling process, random sampling inspection shall be carried out every 30±5 minutes. Six bottles shall be sampled each time and the weight shall be recorded. The visual appearance shall be intact and the aluminum cap threads shall not be cracked or loose.

[0091] 5. Light inspection POP.100011

[0092] Connect the main power of the clarity tester and turn on the light inspection lamp.

[0093] The filling line is started and products are sampled every 30 ± 5 minutes. Six bottles are sampled each time and sent to the central control room for visual inspection and record keeping. The sampled products are manually inspected visually. If any unqualified products are found, the conveyor system is stopped and the unqualified products are manually sorted out before resuming the filling operation.

[0094] Qualification standard: The appearance of the glass bottle is clean, without color spots, sand spots, cracks, or defects; the aluminum cap is not loose or crooked,

[0095] The twist-off aluminum cap has no breakage at the connection points, has a regular and clean appearance, no leakage, and no other appearance defects; 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.

[0096] In the above process,

[0097] The assembly process of the neck sleeve and the clean pharmaceutical glass bottle is as follows Figure 5 、 Figure 6 As shown:

[0098] 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.

[0099] The transport mechanism includes two limited channels 11 and a conveyor belt 12. A turntable 21 is located between the two limited channels 11. Pharmaceutical glass bottles pass through the turntable 21 and the pressure ring mechanism in sequence. Multiple pharmaceutical glass bottles can be placed in the limited channels 11. The conveyor belt 12 is driven by a motor. The limited channels 11 are mounted on the conveyor belt 12. The width of the conveyor belt 12 is adapted to the width of the pharmaceutical glass bottles. The two limited channels 11 are curved on the side near the turntable 21 to facilitate the entry of pharmaceutical glass bottles into the turntable 21 mechanism.

[0100] 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 panel 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 panel 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 panel 23 can clamp the medicinal glass bottles transmitted by the transmission mechanism.

[0101] The ring-adding mechanism includes a ring-sorting disk 31 and a ring guide 32. The disk 31 is positioned to one side of the turntable 21. The guide 32 is fixedly connected to the outside of the disk 31, and the other end of the guide 32 is connected to the ring-pressing mechanism. Multiple bottle necks are placed within the disk 31, and the bottle necks within the disk 31 can slide along the guide 32 into the ring-pressing mechanism.

[0102] 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.

[0103] A push rod 52 is installed below the pressure ring bracket 41. The push rod 52 is pushed by the second cylinder 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 bottles brought by the turntable 21. The pressure ring bracket 41 is fixedly connected to the frame and is located directly above the intersection of the turntable 21 and the enclosure 23. A fixed ring disc 42 is slidably connected to the pressure ring bracket 41; the fixed ring disc 42 is provided with a connector for engaging the bottle neck sleeve, and a pre-compressor 44 is provided above the connector.

[0104] The fixed ring disk 42 slides through the cylinder 1 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.

[0105] A slot 45 can be formed on the fixed ring disc 42 to form a snap-fit ​​device. The slot 45 cooperates with the guide ring 32 and the bottle neck sleeve. When the bottle neck sleeve needs to be snapped in, the slot 45 is located at the end of the guide ring 32. When the bottle neck sleeve needs to be installed, the slot 45 is located above the latch 22. The fixed ring disc 42 can drive the bottle neck sleeve 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 opposing 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 bottle neck sleeve and prevent the bottle neck sleeve from directly sliding out of the slot 45 after entering the fixed ring disc 42.

[0106] A compactor 47 is provided on the other side of the pre-pressurizer 44 , and the compactor 47 is used to compact the bottle neck sleeve after pre-pressing.

[0107] 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 sorting disk 31 and the guide ring 32 in turn 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-compressor 44 is started to pre-compress 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 of the bottleneck sleeve on the medicinal glass bottle and packaging, saving labor costs.

[0108] This reaction offers the advantages of mild conditions and ease of scale-up. It addresses existing issues such as high toxicity of raw materials, low yields, significant interference of byproducts with subsequent processing, and the numerous purification steps required. The preparation method of the present invention features concise steps and simple subsequent processing, yielding a high-purity product. Furthermore, isoflurane possesses unique encapsulation technology for veterinary drug formulations, making it well-suited for pharmaceutical and chemical applications.

[0109] The above-described embodiments merely represent several feasible implementation methods of the present invention. The description thereof is relatively specific and detailed, but it should not be understood as limiting the scope of the invention. The embodiments are not intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. Any equivalent implementation or modification that does not depart from the scope of the present invention should be included in the technology of the present invention.

Claims

1. A method for preparing isoflurane, characterized in that: In a sealed container, add 100 ml of water, 1.3 equivalents of solid sodium chloride, and 0.9 equivalents of potassium hydroxide. After dissolving, add 1.0 equivalents of trifluoroethanol and 0.1 equivalents of octane di(tetrafluoroborate). Finally, pass 1.5 equivalents of difluorochloromethane into the mixture, stir, and react at 80°C for 5 hours. After the reaction is complete, filter with a Buchner funnel to obtain the crude product, which is then distilled to collect the 48-49°C fraction to obtain isoflurane. The prepared isoflurane was packaged using the following method: Step 1: Place the cleaned medicinal glass bottles in a bottle blowing tank, use compressed air to blow out the water on the surface of the medicinal glass bottles, place the medicinal glass bottles in a hot air circulation oven, and set the hot air circulation oven temperature to 60±5℃, and the drying time to 60~70 minutes. Step 2: Place the delivery tube in the isoflurane raw material barrel, use a peristaltic pump to quantitatively extract the prepared isoflurane into the liquid storage tank, and then send it to the transfer tank through the liquid storage tank. Step 3: Place the clean medicinal glass bottles on the bottle sorting station, turn on the turntable for bottle sorting, rotate the medicinal glass bottles to the filling machine conveying port, and make the medicinal glass bottles enter the limited channel; pour the bottle neck sleeve into the ring sorting disc, and complete the ring sorting after the bottle neck sleeve fills the guide ring track; pour the aluminum cap into the oscillator, and complete the cap sorting after the aluminum cap fills 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 pharmaceutical glass bottles for position limiting, adjust the filling machine parameters, and after the filling volume stabilizes, switch to automatic operation and start filling; In the above process, The assembly device for the bottleneck sleeve and the clean medicinal glass bottle includes a transmission mechanism, a turntable, a ring adding mechanism, a ring pressing mechanism, a ring pressing bracket, and a connector. 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. 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 on one side close to 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 holes are evenly distributed on the outside of the turntable. A panel is provided on the frame along the outside of the turntable, and the medicinal glass bottles are clamped on the inside of the panel and the outside of the bayonet holes. When the turntable rotates, the bayonet holes and the panel holes clamp the transferred medicinal glass bottles. The ring adding mechanism includes a ring sorting disc and a ring guide. The ring sorting disc is arranged on one side of the turntable. One end of the ring guide is connected to the ring sorting disc and the other end is connected to the ring pressing mechanism. Multiple bottle necks are placed in the ring sorting disc and slide into the ring pressing mechanism along the ring guide. The pressing ring mechanism includes a pressing ring bracket, a fixing ring sleeve, a pre-pressor, a slot, and a pressing device. A push rod is installed under the pressure ring bracket, which is pushed by cylinder 2. The push rod is located above the bayonet and faces the enclosure. The push rod is used to fix the medicinal glass bottle brought by the turntable; the pressure ring bracket is fixedly connected to the frame, and the pressure ring bracket is located just above the junction of the turntable and the enclosure. A fixed ring disk is slidably connected to the pressure ring bracket; a connector for clamping the bottle neck sleeve is provided on the fixed ring disk, and a pre-compressor is provided above the connector. The fixed ring disc slides through the cylinder 1, and the connector can support the bottle neck sleeve on the fixed ring disc. The pre-pressor can push the bottle neck sleeve on the fixed ring disc to the medicinal glass bottle fixed by the push rod, and preliminarily fix the bottle neck sleeve on the medicinal glass bottle. A slot is provided on the fixed ring disc to form a connector, and the slot cooperates with the guide ring and the bottle neck sleeve. When the bottle neck sleeve needs to be connected, the slot is located at the end of the guide ring track. When the bottle neck sleeve needs to be installed, the slot is located above the bayonet. The fixed ring disc drives the bottle neck sleeve to move from the end of the guide ring track to above the medicinal glass bottle. An eccentric block is pivotally connected to each of the two opposite side walls of the slot. The center of gravity of the eccentric block is located on the fixed ring disc. The eccentric block can support the weight of the bottle neck sleeve to prevent the bottle neck sleeve entering the fixed ring disc from directly sliding out of the slot. A compactor is provided on the other side of the pre-pressurizer, which is used to compact the bottle neck sleeve after pre-pressing. During the above-mentioned packaging operation, the medicinal glass bottle is placed on the conveyor belt, and the medicinal glass bottle is transported to the bayonet of the turntable along the conveyor belt. As the turntable rotates, the medicinal glass bottle moves to one side of the push rod, and the push rod is started to fix the bottle body position of the medicinal glass bottle. The bottleneck sleeve passes through the ring sorting disk and the guide ring channel in turn until it moves to the two eccentric blocks, and the cylinder 1 is started to push the bottleneck sleeve to the top of the medicinal glass bottle fixed by the push rod, and the pre-compressor is started to pre-compress the bottleneck sleeve on the neck of the medicinal glass bottle, and the turntable is rotated to move the medicinal glass bottle 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 installation of the bottleneck sleeve on the medicinal glass bottle and packaging.

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