CN112142575B - Preparation method of desflurane - Google Patents
Preparation method of desflurane Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
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- C07C41/34—Separation; Purification; Stabilisation; Use of additives
- C07C41/40—Separation; Purification; Stabilisation; Use of additives by change of physical state, e.g. by crystallisation
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/30—Details relating to random packing elements
- B01J2219/302—Basic shape of the elements
- B01J2219/30203—Saddle
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Abstract
The invention belongs to the technical field of medicinal chemistry, relates to a preparation method of desflurane, and particularly provides a preparation method of desflurane as a fluorine-containing inhalation anesthetic, wherein the method combines chemical reaction and rectification treatment, and firstly uses isoflurane as a raw material to obtain a desflurane crude product through fluorination reaction; and then, the rectification filler is modified, the impurities in the desflurane crude product, particularly trichlorofluoromethane which is difficult to remove, are effectively separated by utilizing the dual functions of the modification filler, the purity of the refined product reaches over 99.99 percent, and the trichlorofluoromethane which is the impurity is not detected.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of desflurane.
Background
Desflurane is a fluorine-containing inhalation anesthetic marketed by Bettel corporation of America in 1992, has a low metabolism level, a low boiling point (23 ℃), a blood/gas distribution coefficient of 0.42 which is lower than that of other fluorine-containing inhalation anesthetics, so that the induction and recovery of anesthesia are fast, the depth of anesthesia is easy to adjust, and the desflurane is widely used in surgery.
There are many reports on the synthesis of desflurane. Among the many known methods, the most common method is to prepare crude desflurane by one-step fluorination using isoflurane as a starting material. Patent US3897502 uses elemental fluorine as fluorinating agent to directly fluorinate ether 2-difluoromethoxy-1,1,1-trifluoroethane. However, the long reaction time, the low reaction temperature and the high risk of fluorine make the process difficult to adapt to commercial applications. Patent CN200680006159 discloses a method for reacting isoflurane with hydrogen fluoride in a gas phase environment under the catalysis of chromic oxide, which can react under relatively mild conditions with less by-products. Patent GB2219292 discloses a process in which isoflurane is reacted with an alkali metal fluoride such as sodium fluoride, potassium fluoride, or cesium fluoride at 210 ℃, and a phase transfer catalyst and sulfolane are used as a reaction solvent, although the reaction time of the process is greatly shortened, the reaction requires a higher reaction temperature. Although the prior literature reports numerous processes for the preparation of desflurane, it is inevitable that there remains significant unreacted isoflurane and hydrogen fluoride, difluoromethyl-2,2,2-trifluoroethyl ether, dichlorofluoromethane, trichlorofluoromethane, symmetrical octafluorodiethylethyl ether, and other unknown impurities in the reaction product. Therefore, in order to obtain a product which meets the pharmaceutical standards, the crude product needs to be subjected to a post-treatment. CN101119953B discloses purification of desflurane and hydrogen fluoride azeotrope by water washing and then separation of desflurane from azeotrope by fractional distillation to remove residual hydrogen fluoride. CN102617298 discloses a rectification purification method of crude product of desflurane, but the purity of the product obtained by the method is only 99.89%, and part of impurities are still difficult to remove. Although most of the impurities can be removed by conventional distillation or separation methods, some impurities are difficult to remove, such as trichlorofluoromethane. Mainly because the boiling point of trichlorofluoromethane is 23.8 ℃, the boiling point of desflurane is 23.5 ℃, the boiling points of trichlorofluoromethane and desflurane are extremely close, and the trichlorofluoromethane and the desflurane are difficult to separate by adopting a conventional rectification or separation mode. In order to improve the purity of desflurane products and obtain products with higher safety and better drug effect, researches and researches on a method for separating desflurane and trichlorofluoromethane which is a difficult impurity to remove more effectively are still urgently needed, but relevant documents are not recorded in the prior art.
Disclosure of Invention
Aiming at the problems of high impurity content and difficult removal of a plurality of impurities in desflurane in the prior art, the invention provides a method for preparing high-purity desflurane. The method combines chemical reaction and rectification treatment, realizes effective separation of impurities in the desflurane crude product, particularly trichlorofluoromethane which is difficult to remove, by modifying the rectification filler and utilizing the dual action of the modified filler, and is simple to operate, mild in condition, high in yield and suitable for industrial application.
The specific technical content of the invention is as follows:
a preparation method of desflurane mainly comprises the following steps:
a. adding sulfolane and dry potassium fluoride into an autoclave, stirring in a sealed manner, introducing high-purity nitrogen into a reaction system, maintaining the pressure, vacuumizing, adding isoflurane, heating for reaction, cooling the autoclave to room temperature at room temperature after the reaction is finished, introducing circulating cooling liquid into the autoclave, cooling, opening the autoclave when the pressure is not changed any more, transferring the reaction liquid and residues into a round-bottom flask, heating for distillation, and collecting fractions to obtain a desflurane crude product;
b. adding the crude desflurane into a rectifying still of a rectifying tower, heating the rectifying still until the desflurane boils in the still and keeping the desflurane in a rectifying column to perform total reflux; continuously refluxing for a period of time when the reflux reaches a stable state, then controlling the reflux ratio, and collecting front fraction from the top end of the rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio, collecting the positive fraction at the top end of the rectifying tower in stages to obtain a desflurane refined product, and stopping collecting when the temperature of the top of the rectifying tower is higher than 25 ℃.
Preferably, the mass volume ratio of the potassium fluoride to the sulfolane in the step a is 1:1 to 5, preferably 1:2,g/ml; the pressure maintaining time is 1-2 h; the mol ratio of the isoflurane to the potassium fluoride is 1:3 to 5, preferably 1:4.5; the reaction temperature is 80-110 ℃, and preferably 90 ℃; the reaction time is 40-60 h, preferably 55h; the temperature reduction temperature is 0 to-5 ℃.
Preferably, the inner packing of the rectification column in the step b comprises: raschig rings, pall rings, ladder rings, arc saddle shapes, rectangular saddle shapes, corrugated fillers, pulse fillers and combinations thereof; more preferred are rectangular saddle and pulse fillers;
preferably, the inner packing of the rectification column in the step b is a modified packing, wherein the modifier used is tributyl phosphine, sodium thiosulfate or a combination of the tributyl phosphine and the sodium thiosulfate;
further preferably, the preparation method of the modified filler comprises the following steps: directly coating tributyl phosphine on the surface of the filler; or soaking the filler in 20-25% sodium thiosulfate solution for 30-60 min and then drying the filler; or sodium thiosulfate is directly added into the gaps of the filler; it is also possible to use a combination of the several ways described above to prepare modified fillers containing mixed modifiers.
Preferably, the boiling temperature in the rectifying still in the step b is controlled to be 20-50 ℃; more preferably 25 to 35 ℃;
preferably, the continuous reflux time after the stable state in the step b is 0.5 to 3.0 hours; preferably 1.0 to 1.5 hours;
preferably, the steady-state reflux ratio in step b is controlled to be 2 to 7:1; more preferably 3 to 5:1;
preferably, the reflux ratio of the step b is reduced to 1-2: 1;
preferably, the step of collecting in stages in step b is: respectively collecting the positive fractions at 22-23 ℃, 23-24 ℃ and 24-25 ℃ at the top end of the rectifying tower, respectively detecting the purity of the obtained fractions, and intensively collecting the qualified products.
Preferably, the desflurane crude product in the step a is prepared by taking isoflurane as a raw material and performing potassium fluoride fluorination; wherein the crude desflurane product contains trichlorofluoromethane as an impurity.
Preferably, the rectification column in the step b has a diameter of 4-7 cm and a length of 100-150 cm.
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a method for preparing and purifying desflurane, the purity of a desflurane crude product prepared by the method is 88%, the residual quantity of unreacted isoflurane is 10.23%, the content of trichlorofluoromethane as an impurity is 0.27%, the purity of the desflurane after rectification and purification reaches up to 99.995% by modifying a filler in the rectification process and controlling the rectification parameters such as reflux temperature, reflux ratio and the like, and trichlorofluoromethane and isoflurane which are difficult to remove impurities are not detected.
2. The invention provides a modified filler for rectification, which can effectively separate common impurities and effectively absorb impurities which are difficult to remove, particularly trichlorofluoromethane, and finally complete the efficient purification of desflurane.
3. The preparation method and the rectification treatment process of the modified filler provided by the invention are simple and convenient, are easy to operate and are suitable for large-scale production.
Drawings
FIG. 1 is a gas chromatogram of a crude desflurane product.
FIG. 2 is a gas chromatogram of a purified product of desflurane.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are all within the scope of the present invention as claimed.
Example 1
Preparation of a desflurane crude product: adding 400mL of sulfolane and 200g of dry potassium fluoride into an autoclave, stirring in a sealed manner, introducing high-purity nitrogen into a reaction system, maintaining the pressure for 1 hour, vacuumizing, adding 141g of isoflurane, heating to 90 ℃, reacting for 55 hours, cooling the autoclave to room temperature after the reaction is finished, introducing circulating cooling liquid into the autoclave to cool to-5 ℃, cooling to-5 ℃ for 4-5 hours until the pressure is not changed, opening the autoclave, transferring the reaction liquid and residues into a round-bottom flask, heating and distilling, collecting fractions, obtaining 103.6g of crude desflurane product with the GC content of 88.00% (see attached figure 1), and obtaining the yield of 80.5%.
And (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 35 ℃ to boil the desflurane in the still and keeping the desflurane in a rectifying column (the filler adopts saddle-shaped filler; the diameter of the rectifying column is 5cm, and the length of the rectifying column is 100 cm) to perform total reflux; and when the reflux reaches a stable state, continuously refluxing for 1.5h, and then controlling the reflux ratio to be 3:1, collecting front fraction from the top end of a rectifying tower; and when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 2:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining the refined desflurane: 16.72g, yield: 83.6% (desflurane absolute yield 95.2%). The preparation method of the packing in the rectification column comprises the following steps: the filler is soaked in 20-25% sodium thiosulfate solution for 60min and then dried, and tributylphosphine is directly smeared on the surface of the filler.
Gas chromatography conditions for desflurane purity detection: a chromatographic column: CSH-Rtx-200 105m.times.0.32mm, 1.50. Mu.m. A detector: a flame ionization detector. Chromatographic conditions are as follows: sample inlet temperature: 150 ℃, detector temperature: at 220 deg.c. Temperature programming: maintaining at 30 deg.C for 11min, increasing to 50 deg.C at 20 deg.C/min for 13min, increasing to 200 deg.C at 15 deg.C/min, and maintaining for 15min. Sample introduction amount: 3 μ L, split ratio 10, carrier gas flow rate 2.8mL/min.
Gas chromatography detection shows that the residual amount of unreacted isoflurane before purification is 10.23% (peak time is 14.068 min), the content of trichlorofluoromethane as an impurity is 0.27% (peak time is 9.578 min), trichlorofluoromethane and isoflurane are not detected in purified desflurane, and the GC content of the purified desflurane is 99.99% (see figure 2).
Example 2
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 25 ℃ to boil the desflurane in the still and keeping the desflurane in a rectifying column (pulse packing is used as the packing; the diameter of the rectifying column is 5cm, and the length of the rectifying column is 100 cm) to perform total reflux; and (3) continuing refluxing for 3h when the refluxing reaches a stable state, and then controlling the reflux ratio to be 4:1, collecting front fraction from the top end of a rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 1:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining refined desflurane: 17.11g, yield: 85.5 percent. The preparation method of the packing in the rectification column comprises the following steps: the filler is soaked in 20-25% sodium thiosulfate solution for 60min and then dried.
The gas chromatography detection conditions were the same as in example 1, but trichlorofluoromethane was not detected in the purified desflurane in this example, and the mass purity of the purified desflurane was 99.99%.
Example 3
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 50 ℃ to boil the desflurane in the rectifying still and keeping the desflurane in a rectifying column (the filler adopts Raschig ring filler; the diameter of the rectifying column is 4cm, and the length of the rectifying column is 120 cm) to perform total reflux; and when the reflux reaches a stable state, continuing refluxing for 0.5h, and then controlling the reflux ratio to be 5:1, collecting front fraction from the top end of a rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 2:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining refined desflurane: 17.04g, yield: 85.2 percent. The preparation method of the packing in the rectification column comprises the following steps: the filler is soaked in 20-25% sodium thiosulfate solution for 60min and then dried.
The detection conditions of gas chromatography are the same as example 1, trichlorofluoromethane is not detected in the desflurane purified by the example, and the mass purity of the desflurane purified by the example is 99.99%.
Example 4
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 35 ℃ to boil the desflurane in the still and keeping the desflurane in a rectifying column (the packing adopts pall ring packing; the diameter of the rectifying column is 5cm, and the length of the rectifying column is 100 cm) to perform total reflux; and (3) continuing refluxing for 1h when the refluxing reaches a stable state, and then controlling the reflux ratio to be 2:1, collecting front fraction from the top end of a rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 1:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining the refined desflurane: 16.98g, yield: 84.9 percent. The preparation method of the packing in the rectification column comprises the following steps: the filler is soaked in 20-25% sodium thiosulfate solution for 60min and then dried.
The detection conditions of gas chromatography are the same as example 1, trichlorofluoromethane is not detected in the desflurane purified by the example, and the mass purity of the desflurane purified by the example is 99.99%.
Example 5
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 35 ℃ to boil the desflurane in the rectifying still and keeping the desflurane in a rectifying column (corrugated packing is used as the packing; the diameter of the rectifying column is 7cm, and the length of the rectifying column is 150 cm) to perform total reflux; and when the reflux reaches a stable state, continuing refluxing for 1.5h, and then controlling the reflux ratio to be 6:1, collecting front fraction from the top end of a rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 2:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining refined desflurane: 16.82g, yield: 84.1 percent. The preparation method of the packing in the rectification column comprises the following steps: and directly coating tributyl phosphine on the surface of the filler.
The gas chromatography detection conditions were the same as in example 1, but trichlorofluoromethane was not detected in the purified desflurane in this example, and the mass purity of the purified desflurane was 99.99%.
Example 6
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 35 ℃ to boil the desflurane in the still and keeping the desflurane in a rectifying column (the filler adopts saddle-shaped filler; the diameter of the rectifying column is 5cm, and the length of the rectifying column is 100 cm) to perform total reflux; and when the reflux reaches a stable state, continuing refluxing for 1.5h, and then controlling the reflux ratio to be 7:1, collecting front fraction from the top end of a rectifying tower; and when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 3:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining refined desflurane: 16.06g, yield: 80.3 percent. The preparation method of the packing in the rectifying column comprises the following steps: the filler is soaked in 20-25% sodium thiosulfate solution for 60min and then dried.
The detection conditions of gas chromatography are the same as example 1, trichlorofluoromethane is not detected in the purified desflurane in this example, and the mass purity of the purified desflurane is 99.89%.
Comparative example 1
The crude desflurane is prepared as in example 1;
and (3) purifying a desflurane crude product: adding 20g of desflurane crude product into a rectifying still of a rectifying tower, heating the rectifying still to 35 ℃ to boil the desflurane in the still and keeping the desflurane in a rectifying column (unmodified saddle-shaped packing is used as the packing; the diameter of the rectifying column is 5cm, and the length of the rectifying column is 100 cm) to perform total reflux; and when the reflux reaches a stable state, continuing refluxing for 1.5h, and then controlling the reflux ratio to be 3:1, collecting front fraction from the top end of a rectifying tower; when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio to 2:1, respectively collecting the positive fractions at the top end of the rectifying tower at the temperature of 22-23 ℃, 23-24 ℃ and 24-25 ℃, stopping collecting when the temperature at the top of the rectifying tower is higher than 25 ℃, respectively detecting the purity of the obtained fractions, and then collecting in a centralized manner to obtain the refined desflurane product. Obtaining refined desflurane: 15.96g, yield: 79.8 percent.
The detection conditions of gas chromatography are the same as example 1, and the content of trichlorofluoromethane in the desflurane purified by the example is detected to be 0.21%, and the mass purity of the purified desflurane is 99.76%.
Claims (12)
1. A preparation method of desflurane is characterized by mainly comprising the following steps:
1) Preparation of a desflurane crude product: adding sulfolane and dry potassium fluoride into an autoclave, stirring in a sealed manner, introducing high-purity nitrogen into a reaction system, maintaining pressure, vacuumizing, adding isoflurane, heating for reaction, cooling the autoclave to room temperature after the reaction is finished, introducing circulating cooling liquid into the autoclave, cooling, opening the autoclave when the pressure is not changed any more, transferring the reaction liquid and residues into a round-bottom flask, heating for distillation, and collecting fractions to obtain a desflurane crude product;
2) Refining desflurane:
a. adding the crude desflurane into a rectifying still of a rectifying tower, heating the rectifying still until the desflurane boils in the still and keeping the desflurane in a rectifying column to perform total reflux;
b. continuously refluxing for a period of time when the reflux reaches a stable state, then controlling the reflux ratio, and collecting front fraction from the top end of the rectifying tower;
c. when the temperature of the top end of the rectifying tower reaches 22 ℃, reducing the reflux ratio, collecting the positive fraction at the top end of the rectifying tower in stages to obtain high-purity desflurane, and stopping collecting when the temperature of the top end of the rectifying tower is higher than 25 ℃; wherein the content of the first and second substances,
the reaction temperature in the step 1 is 80-110 ℃;
the inner filler of the rectification column in the step a is modified filler, wherein the inner filler is selected from Raschig rings, pall rings, ladder rings, arc saddle type, rectangular saddle type, corrugated filler, pulse filler or a combination thereof, and the used modifier is tributylphosphine, sodium thiosulfate or a combination of the tributylphosphine and the sodium thiosulfate.
2. The method of claim 1, wherein the mass to volume ratio of potassium fluoride to sulfolane in step 1 is from 1: 1-5,g/ml; the pressure maintaining time is 1-2 h; the mol ratio of the isoflurane to the potassium fluoride is 1:3 to 5; the reaction time is 40-60 h; the temperature reduction temperature is 0 to-5 ℃.
3. The method of claim 1, wherein the packing material in the rectification column in step a is selected from a rectangular saddle type packing material and a pulse type packing material.
4. The method of claim 1, wherein the modified filler is prepared by: directly coating tributyl phosphine on the surface of the filler; or soaking the filler in 20-25% sodium thiosulfate solution for 30-60 min and then drying the filler; or sodium thiosulfate is directly added into the gaps of the filler; or a combination of the above.
5. The method according to any one of claims 1 to 4, wherein the temperature of the rectifying still in the step a is controlled to 20 to 50 ℃.
6. The method according to claim 5, wherein the temperature of the rectifying still in step a is controlled to be 25 to 35 ℃.
7. The process according to any one of claims 1 to 4, wherein the time for continuing the reflux after reaching the steady state in step b is from 0.5 to 3.0 hours; controlling the reflux ratio of the step b to be 2-7: 1.
8. the method of claim 7, wherein the time for continuing the reflux after reaching the steady state in step b is 1.0 to 1.5 hours.
9. The method of claim 7, wherein the reflux ratio of step b is controlled to be 3~5:1.
10. the process according to any one of claims 1 to 4, wherein the reflux ratio in step c is reduced to 1 to 2:1; the step of staged collection in step c is: respectively collecting the positive fractions at 22-23 ℃, 23-24 ℃ and 24-25 ℃.
11. The process according to any one of claims 1-4, wherein the crude desflurane product comprises trichlorofluoromethane.
12. The process according to any one of claims 1 to 4, wherein the rectification column of step a has a diameter of 4 to 7cm and a length of 100 to 150cm.
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| GB8912072D0 (en) * | 1988-05-31 | 1989-07-12 | Central Glass Co Ltd | Process of preparing 1,2,2,2-tetrafluoroethyl-difluoromethyl ether |
| CN101119953A (en) * | 2005-02-15 | 2008-02-06 | 碳卤化合物产品公司 | Separation/purification of desflurane from hydrogen fluoride |
| CN101830781A (en) * | 2010-03-02 | 2010-09-15 | 山东省医药工业研究所 | A kind of synthetic method of isoflurane |
| CN105523903A (en) * | 2016-01-30 | 2016-04-27 | 华东医药（西安）博华制药有限公司 | Purification method of sevoflurane |
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2019
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| GB8912072D0 (en) * | 1988-05-31 | 1989-07-12 | Central Glass Co Ltd | Process of preparing 1,2,2,2-tetrafluoroethyl-difluoromethyl ether |
| CN101119953A (en) * | 2005-02-15 | 2008-02-06 | 碳卤化合物产品公司 | Separation/purification of desflurane from hydrogen fluoride |
| CN101830781A (en) * | 2010-03-02 | 2010-09-15 | 山东省医药工业研究所 | A kind of synthetic method of isoflurane |
| CN105523903A (en) * | 2016-01-30 | 2016-04-27 | 华东医药（西安）博华制药有限公司 | Purification method of sevoflurane |
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