CN103804151A - Preparation method of sevoflurane - Google Patents
Preparation method of sevoflurane Download PDFInfo
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- CN103804151A CN103804151A CN201310549528.XA CN201310549528A CN103804151A CN 103804151 A CN103804151 A CN 103804151A CN 201310549528 A CN201310549528 A CN 201310549528A CN 103804151 A CN103804151 A CN 103804151A
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- methyl ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
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Abstract
The invention discloses a preparation method of sevoflurane. The sevoflurane is prepared from hexafluoroisopropanol, formaldehyde equivalent, aluminum trichloride, a phase transfer catalyst, hindered amine and a metal fluorinating agent as raw materials. The preparation method has the advantages of high yield, high purity, few byproducts and the like, can realize recycling of some raw materials, and is low in cost, easy to control industrially, environment-friendly and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to can inhalational anesthetic preparation method, is specifically related to a kind of preparation method of Ultane.
Background technology
Ultane, is again Sevoflurane or seven fluorine isopropenyl methyl ethers, chemical name: methyl fluoride-2, the fluoro-1-of 2,2-tri-(trifluoromethyl) ethyl ether, is a kind of inhaling type narcotic medicine of inducing and maintaining for general anesthesia.Be compared to other inhaling type narcotic, as for fluorine ether (CF
3cHFOCHF
2), isofluranum (CF
3cHClOCHF
2), ohio-347 (ClFCHCF
2oCHF
2), Ultane has the ideal behavior of contemporary inhalation anesthetic---lose fast consciousness with restorative fast, therefore go through, after listing, to have caused larger concern in the U.S. from nineteen ninety-five.
Through the technical development of nearly decades, Ultane preparation method has experienced several developmental stage around the difference of fluorizating agent, make preparation condition become not harsh, preparation technology and become simple, post-treating method and three waste discharge reduce, and productive rate and purity improves greatly, thereby the large-scale industrialization making is produced being more prone to of becoming and is realized.Patent US3683092 has introduced and has utilized BrF
3prepare the method for Ultane as fluorizating agent.First the method utilizes hexafluoroisopropanol and the two hexafluoro sec.-propyl methyl ethers of trioxymethylene preparation, then utilizes BrF
3fluoridize and prepare Ultane with two hexafluoro sec.-propyl methyl ethers.This preparation method's weak point is exactly that productive rate is low, and by product is more.Patent US4996371 has reported that the hexafluoro isopropoxy acetic acid that uses hexafluoroisopropanol, monobromo-acetic acid to make under alkaline condition is intermediate, and the latter passes through BrF again
3prepare Ultane, productive rate 90%.
Due to BrF
3expensive, Ultane preparation process fluorizating agent used has been transferred to take anhydrous HF as main.Patent US4250334 has reported that the one kettle way that hexafluoroisopropanol, polyoxymethylene, the vitriol oil, anhydrous hydrogen fluoride are raw material prepares Ultane, transformation efficiency 33-38%.Patent US5990359 reported under room temperature pressurized conditions, and 98% vitriol oil, hexafluoroisopropanol, fluorine methyl ether (formaldehyde and HF preparation) react and prepare Ultane, productive rate 55-60%.Patent US5811596 has reported and has reacted and prepare Ultane with 96% sulfuric acid, anhydrous HF, productive rate >=80% with polyethers.Patent US5886239 has reported a kind of novel method of utilizing the excellent specific property of obstruction ammonium salt to prepare Ultane.First the method utilizes obstruction amine (as triethylamine) and anhydrous HF blend for some time to form a kind of amine salt, utilizes this amine salt and hexafluoro isopropyl chloride methyl ether to carry out fluoridation and prepares Ultane.Patent CN1244187C has also reported a kind of method that obstruction ammonium salt is prepared Ultane of improving, and Ultane productive rate has been brought up to 79%.
Utilize anhydrous HF to prepare Ultane because experiment condition is comparatively harsh as fluorizating agent, to experimental installation require high, the expense dropping into is large, also has larger potential safety hazard, and the fluorizating agent of seeking alternative anhydrous HF has been positioned at basic metal fluorochemical by people for this reason.Patent US3689571 takes the lead in having reported the method for preparing Ultane by two-step approach.First the method utilizes chlorine and two hexafluoro sec.-propyl methyl ethers to prepare hexafluoro isopropyl chloride methyl ether, and the latter carries out fluoridation with anhydrous K F again in tetrahydrofuran solvent.Patent US6100434 has reported that hexafluoroisopropanol, polyoxymethylene, aluminum trichloride (anhydrous) prepare hexafluoro isopropyl chloride methyl ether, then uses alkali metal fluosilicate agent to prepare Ultane, productive rate 71%.Patent US6245949 has reported that hexafluoroisopropanol and polyoxymethylene are at ZnCl
2exist lower reaction to obtain two hexafluoroisopropanol polyoxymethylene derivatives, utilize anhydrous AlCl
3chloromethylation obtains hexafluoro isopropyl chloride methyl ether, then with under anhydrous K F and PEG-400 condition prepares Ultane, productive rate 51%.
Patent CN1699319C has reported by changing activating fluorinated dose of different activators (18-hat-6) and has carried out halogen exchange reaction and prepare Ultane, productive rate >=85%.Patent CN101337863B has reported under sour katalysis, hexafluoroisopropanol and formaldehyde equivalent first form two hexafluoroisopropanol formal derivatives, recycle this thing and aluminum trichloride (anhydrous) and form hexafluoro isopropyl chloride methyl ether, finally utilize KF to fluoridize and prepare Ultane, yield 84.0%.
Patent WO2008037039 and WO2008037040 have reported a kind of method of preparing Ultane, by lentamente the vitriol oil being added to hexafluoroisopropanol, formaldehyde equivalent and chlorination reagent mixture, prepare chloromethyl ether, thereby and then add fluorizating agent reaction to obtain Sevoflurane.But chlorination reagent is defined as oxalyl chloride, phosphorus dichloride, phosphorus pentachloride, phosphorous oxychloride and sulfur oxychloride by these two pieces of patents.
Although disclose in the prior art the multiple method of preparing Ultane take hexafluoroisopropanol as raw material, still there is many deficiencies in these methods, for example, be unsuitable for suitability for industrialized production, and not exclusively, productivity ratio is lower in reaction, and raw material needs to reclaim; Severe reaction conditions is as needed pressurization, equipment to need corrosion-resistant; Reaction reagent or solvent non-ambient close friend.In addition also there is the shortcoming of many its complicated components of by product in these methods.Therefore, still there is at present a kind of demand of preparing Ultane novel method of exploitation, overcome the many deficiencies and the shortcoming that in prior art, exist, realize better the industrialization of Sevoflurane.
Summary of the invention
The object of the invention is to overcome deficiency of the prior art, provide a kind of productive rate high, be easy to the Ultane preparation method of suitability for industrialized production.
Technical scheme of the present invention provides a kind of preparation method of Ultane: hexafluoroisopropanol, formaldehyde equivalent and aluminum chloride are prepared to hexafluoro isopropyl chloride methyl ether, washing, crude product distillation purifying; Hexafluoro isopropyl chloride methyl ether and fluorizating agent are added in the mixed solution being made up of phase-transfer catalyst and obstruction amine in batches and reacted, and crude product distillation purifying obtains Ultane.
The preparation method that technique scheme provides according to the present invention, comprises following steps:
1) hexafluoroisopropanol and aluminum chloride 0-10 ℃ are mixed to constant temperature stirring reaction 0.5-2 hour, add formaldehyde equivalent, reaction 0.5-4 hour, then rises to 20-40 ℃ of constant temperature and stirs 10-30 hour; After reaction finishes, add aqueous hydrochloric acid washing, organic layer distills to obtain hexafluoro isopropyl chloride methyl ether;
2) hexafluoro isopropyl chloride methyl ether step 1) being made and fluorizating agent divide 2-4 to criticize to be added to by phase-transfer catalyst and hinder in the mixed solution that amine form, react 1-10 hour respectively at 50-150 ℃, and crude product distillation purifying obtains Ultane.
The preparation method that technique scheme provides according to the present invention, in some embodiments, described aluminum chloride is aluminum trichloride (anhydrous).
The preparation method that technique scheme provides according to the present invention, in some embodiments, described formaldehyde equivalent is formaldehyde, trioxymethylene, paraformaldehyde, 1,3,5-trioxane or its combination.
The preparation method that technique scheme provides according to the present invention, in some embodiments, described fluorizating agent is fluoride salt, fluorine hydrogenation salt or its combination.
The preparation method that technique scheme provides according to the present invention, in some embodiments, described fluoride salt is Potassium monofluoride, Sodium Fluoride, Calcium Fluoride (Fluorspan), Neutral ammonium fluoride or its combination, fluorine hydrogenation salt is potassium bifluoride, sodium hydrogen fluoride, ammonium acid fluoride or its combination.
The preparation method that technique scheme provides according to the present invention, in some embodiments, described phase-transfer catalyst is hexaoxacyclooctadecane-6-6, triglycol, polyoxyethylene glycol (PEG), Diethylene Glycol dimethanol or its combination.
Wherein, in some embodiments, described polyoxyethylene glycol (PEG) is PEG-200, PEG-300, PEG-400 or PEG-600 or its combination.
This preparation method that technique scheme provides according to the present invention, in some embodiments, described obstruction amine is compound shown in following formula
Wherein X, Y and Z be independently selected from methyl, ethyl, sec.-propyl, the tertiary butyl or neo-pentyl, and in X, Y and Z, at least one is made up of sec.-propyl, the tertiary butyl or neo-pentyl.
The preparation method that technique scheme provides according to the present invention, in some embodiments, described obstruction amine is DIPEA.
The preparation method that technique scheme provides according to the present invention, in some embodiments, the mol ratio of hexafluoroisopropanol and aluminum chloride is 1:1-1.5.
The preparation method that technique scheme provides according to the present invention, in some embodiments, the mol ratio of hexafluoroisopropanol and formaldehyde equivalent is 1:0.2-0.5.
The preparation method that technique scheme provides according to the present invention, in some embodiments, the mol ratio of hexafluoro isopropyl chloride methyl ether and fluorizating agent is 1:1-2.
The preparation method that technique scheme provides according to the present invention, in some embodiments, the mol ratio of hexafluoro isopropyl chloride methyl ether and phase-transfer catalyst is 1:0.1-0.4.
The preparation method that technique scheme provides according to the present invention, in some embodiments, hexafluoro isopropyl chloride methyl ether is 1:0.001-0.06 with the mol ratio that hinders amine.
The preparation method that technique scheme provides according to the present invention, in some embodiments, the mol ratio of the every batch of hexafluoro isopropyl chloride methyl ether and fluorizating agent is 1:1-2.
The preparation method that technique scheme provides according to the present invention, in some embodiments, aqueous hydrochloric acid concentration is 6mol/l.
Term of the present invention " formaldehyde equivalent " refers to the following fact: under room temperature, for the formaldehyde of gas is easy to change into derivative, described derivative behavior is similar to gaseous formaldehyde and for industry.This analog derivative is called as formaldehyde equivalent and those skilled in the art are so familiar with, and includes but not limited to formaldehyde, trioxymethylene, paraformaldehyde, 1,3,5-trioxane, and their mixture.
Technical scheme of the present invention provides a kind of preparation method of Ultane, prepares Ultane take hexafluoroisopropanol, formaldehyde equivalent, aluminum trichloride (anhydrous), phase-transfer catalyst, obstruction amine and metal pentafluoride agent as raw material.Overcome deficiency of the prior art, had the advantages such as productive rate is high, purity is high, by product is few, and can realize the recycling of part material, cost is low, be easy to Industry Control, environmental friendliness, is applicable to large-scale industrial production.
Embodiment
The following stated be the preferred embodiment of the present invention, what the present invention protected is not limited to following preferred implementation.It should be pointed out that on the basis of conceiving in these innovation and creation for a person skilled in the art, some distortion and the improvement made, all belong to protection scope of the present invention.
Embodiment 1
Aluminum trichloride (anhydrous) 340g and hexafluoroisopropanol 400g are added in a flask with three necks,round bottom with churned mechanically 2000mL, under 0 ℃ of ice-water bath condition, stirring reaction is after 1 hour, again toward wherein adding paraformaldehyde 74g, sustained reaction 1 hour, remove ice-water bath, sustained reaction 24 hours under 25 ℃ of conditions, the HCl gas producing in reaction process adopts device for absorbing tail gas processing.After reaction finishes, toward the hydrochloric acid soln that adds 850mL6N in muddy reaction product, muddy solid slowly dissolves and produces layering, separatory takes off the transparent micro-yellow hexafluoro isopropyl chloride methyl ether liquid of layer, distill, productive rate is that 89%, GC purity assay is 99.86%.
Embodiment 2
200g hexafluoro isopropyl chloride methyl ether, 300mL PGE-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 1 hour under 80 ℃ of oil bath conditions.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 78.31g altogether, GC purity assay is 61.63%, yield 42.3%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 3
200g hexafluoro isopropyl chloride methyl ether, 300mL PGE-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 3 hours under 80 ℃ of oil bath conditions.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 140.7g altogether, GC purity assay is 96.89%, yield 76%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 4
200g hexafluoro isopropyl chloride methyl ether, 300mL PGE-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 6 hours under 80 ℃ of oil bath conditions.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 126.54g altogether, GC purity assay is 83.89%, yield 90%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 5
200g hexafluoro isopropyl chloride methyl ether, 300mL PGE-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 9 hours under 80 ℃ of oil bath conditions.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 172.17g altogether, GC purity assay is 79.41%, yield 93%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 6
200g hexafluoro isopropyl chloride methyl ether, 300mL PEG-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 3 hours under 80 ℃ of oil bath conditions.After reaction finishes, question response product is cooled to after normal temperature, then adds 100g hexafluoro isopropyl chloride methyl ether and 50g Potassium monofluoride, is placed under the oil bath condition of 80 ℃ back flow reaction 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 151.9g altogether, GC purity assay is 97.35%, yield 83%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 7
200g hexafluoro isopropyl chloride methyl ether, 300mL PEG-400 and 100g Potassium monofluoride are joined in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux to reflux 3 hours under 80 ℃ of oil bath conditions; After cooling to room temperature, repeat to add 100g hexafluoro isopropyl chloride methyl ether and 50g Potassium monofluoride twice, and react under same temperature of reaction and reaction times condition.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 153.7g altogether, GC purity assay is 94.30%, yield 82%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 8
By 300mL PGE-400,100g Potassium monofluoride and 2.22g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 200g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 157.4g altogether, GC purity assay is 94.40%, yield 85%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 9
By 300mL PGE-400,100g Potassium monofluoride and 6.67g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 200g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 161.62g altogether, GC purity assay is 90.13%, yield 87.30%, it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 10
By 300mL PGE-400,100g Potassium monofluoride and 13.32g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 200g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 168.52g altogether, GC purity assay is 82.35%, yield 91.03%, it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 11
By 300mL PGE-400,100g Potassium monofluoride and 2.22g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 200g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After reaction finishes, question response product is cooled to after normal temperature, toward wherein adding 100g hexafluoro isopropyl chloride methyl ether and 50g Potassium monofluoride, is placed under the oil bath condition of 80 ℃ back flow reaction 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 163.0g altogether, GC purity assay is 96.70%, yield 88%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Embodiment 12
By 300mL PGE-400,100g Potassium monofluoride and 2.22g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 1000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 200g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After cooling to room temperature, repeat to add 100g hexafluoro isopropyl chloride methyl ether and 50g Potassium monofluoride twice, and react under same temperature of reaction and reaction times condition.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 161.11g altogether, GC purity assay is 97.20%, yield 87%, and it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Comparative example
By 300mL PGE-400,300g Potassium monofluoride and 6.67g N, N-diisopropylethylamine joins in the single necked round bottom flask of a 2000mL with magnetic agitation and reflux, blending and stirring 1 hour under 50 ℃ of oil bath conditions, add after cooling to room temperature 600g hexafluoro isopropyl chloride methyl ether, be placed under 80 ℃ of oil bath conditions reflux 3 hours.After reaction finishes, add the deionized water dissolving of 150mL, under condition of normal pressure, distill, collect all cuts, obtain Ultane crude product 409.69g altogether, GC purity assay is 95.21%, yield 73.9%, it is 99.97% that crude product obtains Ultane fine work purity after rectifying.
Contrast existing technique, take to add in batches hexafluoro isopropyl chloride methyl ether and Potassium monofluoride, yield improves 5-20%, and simultaneous reactions thing utilization ratio is high, environment saving.
Claims (16)
1. a preparation method for Ultane, is characterized in that: hexafluoroisopropanol, formaldehyde equivalent and aluminum chloride are prepared to hexafluoro isopropyl chloride methyl ether, washing, crude product distillation purifying; Hexafluoro isopropyl chloride methyl ether and fluorizating agent are added in the mixed solution being made up of phase-transfer catalyst and obstruction amine in batches and reacted, and crude product distillation purifying obtains Ultane.
2. preparation method according to claim 1, is characterized in that comprising following steps:
1) hexafluoroisopropanol and aluminum chloride 0-10 ℃ are mixed to constant temperature stirring reaction 0.5-2 hour, add formaldehyde equivalent, reaction 0.5-4 hour, then rises to 20-40 ℃ of constant temperature and stirs 10-30 hour; After reaction finishes, add aqueous hydrochloric acid washing, organic layer distills to obtain hexafluoro isopropyl chloride methyl ether;
2) hexafluoro isopropyl chloride methyl ether step 1) being made and fluorizating agent divide 2-4 to criticize to be added to by phase-transfer catalyst and hinder in the mixed solution that amine form, react 1-10 hour respectively at 50-150 ℃, and crude product distillation purifying obtains Ultane.
3. preparation method according to claim 1 and 2, is characterized in that, described aluminum chloride is aluminum trichloride (anhydrous).
4. preparation method according to claim 1 and 2, is characterized in that, described formaldehyde equivalent is selected from formaldehyde, trioxymethylene, paraformaldehyde, 1,3,5-trioxane or its combination.
5. preparation method according to claim 1 and 2, is characterized in that, described fluorizating agent is selected from fluoride salt, fluorine hydrogenation salt or its combination.
6. preparation method according to claim 5, is characterized in that, described fluoride salt is Potassium monofluoride, Sodium Fluoride, Calcium Fluoride (Fluorspan), Neutral ammonium fluoride or its combination, and fluorine hydrogenation salt is potassium bifluoride, sodium hydrogen fluoride, ammonium acid fluoride or its combination.
7. preparation method according to claim 1 and 2, is characterized in that, described phase-transfer catalyst is hexaoxacyclooctadecane-6-6, triglycol, polyoxyethylene glycol, Diethylene Glycol, dimethanol or its combination.
8. preparation method according to claim 7, is characterized in that, described polyoxyethylene glycol is PEG-200, PEG-300, PEG-400 or PEG-600 or its combination.
9. preparation method according to claim 1 and 2, is characterized in that, described obstruction amine is compound shown in following formula,
Wherein X, Y and Z be independently selected from methyl, ethyl, sec.-propyl, the tertiary butyl or neo-pentyl, and in X, Y and Z, at least one is made up of sec.-propyl, the tertiary butyl or neo-pentyl.
10. preparation method according to claim 7, is characterized in that, described obstruction amine is DIPEA.
11. preparation methods according to claim 1 and 2, the mol ratio that it is characterized in that hexafluoroisopropanol and aluminum chloride is 1:1-1.5.
12. preparation methods according to claim 1 and 2, the mol ratio that it is characterized in that hexafluoroisopropanol and formaldehyde equivalent is 1:0.2-0.5.
13. preparation methods according to claim 1 and 2, the mol ratio that it is characterized in that hexafluoro isopropyl chloride methyl ether and fluorizating agent is 1:1-2.
14. preparation methods according to claim 1 and 2, the mol ratio that it is characterized in that hexafluoro isopropyl chloride methyl ether and phase-transfer catalyst is 1:0.1-0.4.
15. preparation methods according to claim 1 and 2, is characterized in that hexafluoro isopropyl chloride methyl ether and the mol ratio that hinders amine are 1:0-0.06.
16. preparation methods according to claim 2, is characterized in that, described aqueous hydrochloric acid concentration is 6mol/l.
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Cited By (4)
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|---|---|---|---|---|
| CN106994455A (en) * | 2016-11-02 | 2017-08-01 | 中央硝子株式会社 | The cleaning method of Sevoflurane tank and the storage method of Sevoflurane |
| CN108689808A (en) * | 2017-04-06 | 2018-10-23 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of chloromethyl hexafluoro isopropyl ether |
| WO2021072774A1 (en) * | 2019-10-18 | 2021-04-22 | 鲁南贝特制药有限公司 | Method for synthesizing sevoflurane |
| CN114057546A (en) * | 2021-05-07 | 2022-02-18 | 安徽伟祥新材料有限公司 | Preparation method of 3-fluoro-1-propanol |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106994455A (en) * | 2016-11-02 | 2017-08-01 | 中央硝子株式会社 | The cleaning method of Sevoflurane tank and the storage method of Sevoflurane |
| CN106994455B (en) * | 2016-11-02 | 2019-08-30 | 中央硝子株式会社 | The cleaning method of Sevoflurane tank and the storage method of Sevoflurane |
| CN108689808A (en) * | 2017-04-06 | 2018-10-23 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of chloromethyl hexafluoro isopropyl ether |
| CN108689808B (en) * | 2017-04-06 | 2021-11-16 | 江苏恒瑞医药股份有限公司 | Preparation method of chloromethyl hexafluoroisopropyl ether |
| WO2021072774A1 (en) * | 2019-10-18 | 2021-04-22 | 鲁南贝特制药有限公司 | Method for synthesizing sevoflurane |
| CN114502527A (en) * | 2019-10-18 | 2022-05-13 | 鲁南贝特制药有限公司 | Synthetic method of sevoflurane |
| CN114502527B (en) * | 2019-10-18 | 2024-06-14 | 鲁南贝特制药有限公司 | Synthesis method of sevoflurane |
| CN114057546A (en) * | 2021-05-07 | 2022-02-18 | 安徽伟祥新材料有限公司 | Preparation method of 3-fluoro-1-propanol |
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