CN100484910C - By-product extraction in sevoflurane production process and transformation of sevoflurane into hexafluoroisopropanol - Google Patents
By-product extraction in sevoflurane production process and transformation of sevoflurane into hexafluoroisopropanol Download PDFInfo
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- CN100484910C CN100484910C CNB2006100686736A CN200610068673A CN100484910C CN 100484910 C CN100484910 C CN 100484910C CN B2006100686736 A CNB2006100686736 A CN B2006100686736A CN 200610068673 A CN200610068673 A CN 200610068673A CN 100484910 C CN100484910 C CN 100484910C
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Abstract
This invention discloses a method for extracting byproduct of sevoflurane manufacture and converting it into hexafluoroisopropanol.
Description
Technical field
The present invention relates to a kind of suitability for industrialized production methyl fluoride-2,2, the extraction of by product and be converted into the method for hexafluoroisopropanol in 2-three fluoro-1-(trifluoromethyl) ethyl ether (Sevoflurane) processes.
Technical background
Find that in recent years fluorinated ether has effective suction narcoticness.Be included in these narcotic is desflurane (CF
3CHFOCHF
2), isoflurane (CF
3CHClOCHF
2), ohio-347 (C1FCHCF
2OCHF
2) and Sevoflurane ((CF
3)
2CHOCH
2F).Because the losing consciousness property fast of Sevoflurane is with restorative fast---this is to suck narcotic ideal behavior the present age, and it becomes a kind of particularly advantageous suction narcotic.Approximately with 1%～5% volume with mixture oxygen or contain the gas phase mixture of the oxygen that is enough to keep respiratory capacity, by inlet passage radially the warm-blooded animal of breathe air Sevoflurane is provided.
United States Patent (USP) 3683092 and 3689571 has disclosed the use Sevoflurane as sucking narcotic, and by chloromethyl 2,2,2-three fluoro-1-(trifluoromethyl) ethyl ether and excessive Potassium monofluorides, in 120 ℃ high boiling solvent, replace the synthetic method of the reaction of chloromethyl with fluorine.These patents also disclose the reaction by hexafluoroisopropanol and methyl-sulfate and sodium hydroxide solution, fluoridize the methyl 2,2 of gained subsequently with bromine trifluoride, and 2-three fluoro-1-(trifluoromethyl) ethyl ethers are produced the method for Sevoflurane.United States Patent (USP) 4328376 discloses the method in separation of sevoflurane from be similar to the byproduct alkene that produces the method described in the United States Patent (USP) 3689571.
Other synthetic routes of Sevoflurane are referring to following patent publications: United States Patent (USP) 3897502---methyl 2,2, and 2-three fluoro-1-(trifluoromethyl) ethyl ethers are fluoridized with the argon that contains 20% fluorine; United States Patent (USP) 4250334 and 4469898---utilize hydrogen fluoride, formaldehyde and sulfuric acid or other dewatering agents to carry out the chloromethylation of hexafluoroisopropanol; With PCT International Application No. WO 97/25303---hexafluoroisopropanol and two (methyl fluoride) ether reactions.
People such as Okazaki have described a kind of electrochemical fluorination reaction that obtains fluoromethyl ether in fluorine chemistry (Fluorine Chem.1974,4 (4), 387).German Patent 25 20 962 introduced 125 ℃～149 ℃ with fluorine chromic oxide in the presence of, synthesize fluoromethyl ether by monochloromethyl-ether and hydrogen fluoride.People such as Bensoam are at Tetrahedron Lett., introduced in 1979,4,353 by with the synthetic fluoromethyl ether of halogen exchange of tetrahydroxy fluorine phosphorane.German Patent 2,823 969 discloses a kind of method that comprises the organic fluoride of a fluoro methyl ether by corresponding organic chloride or bromide and elite hydrofluorination amine prepared in reaction.Hydrofluorination triethylamine and hydrofluorination pyridine are the object lessons that is used for preparing the fluorizating agent of such organic fluoride, and the productive rate of fluorochemical generally is about 40～80%.Chinese patent 1244187 has improved this technology, has obtained result preferably.
In addition, United States Patent (USP) 4874901 has been reported under high temperature and highly compressed condition, chloromethyl 2,2, and 2-three fluoro-1-(trifluoromethyl) ethyl ethers and the reaction of pure Potassium monofluoride, but reaction conversion ratio is lower.
Summary of the invention
Experiment is found, when utilizing chloromethyl-2,2, when 2-three fluoro-1-(trifluoromethyl) ethyl ethers and excessive Potassium monofluoride prepare Sevoflurane in alcoholic solvent (as PEG400 (polyoxyethylene glycol), triglycol, ethylene glycol etc.), there is 10%～20% by product to cause that the Sevoflurane yield is lower, cost is higher approximately.
Purify and Spectrum Analysis through separating, find that byproduct of reaction is hexafluoroisopropanol and alcoholic solvent formal product, its structure is as follows:
X is H, lower alkoxy, senior alkoxyl group in the formula.The representational example that is present in the compound of following formula comprises X=H, CH
2CH
2OH, (CH
2CH
2O)
nH (n=2～300) etc.
Be meant the saturated alkyl that contain 1～6 carbon atom as the term " low alkyl group " that uses herein, and, except other has the stipulator, should be straight chain.Be meant the saturated alkoxyl group that contain 1～6 carbon atom as the term " lower alkoxy " that uses herein, and, except other has the stipulator, should be straight chain, or cyclic.Be meant the saturated alkoxyl group that contain greater than 6 carbon atoms as the term " senior alkoxyl group " that uses herein, and, except other has the stipulator, should be straight chain.Be meant 2～300 arbitrary integer as the term " n " that uses herein.
Following explanation in the presence of small amount of acid, chloromethyl-2,2,2-three fluoro-1-(trifluoromethyl) ethyl ether and alcoholic solvent reaction process:
So this area needs a kind of method (as shown below) of by product being extracted, is converted into then hexafluoroisopropanol.Hexafluoroisopropanol is the raw material of preparation Sevoflurane.
Technological process of the present invention is: under acidic conditions, crude product is dissolved in the solvent reacts, temperature of reaction is 0 ℃～50 ℃, and the reaction times is 1～12 hour; The reaction solvent that adopts is alcohols, halohydrocarbon or water, is specially in methyl alcohol, ethanol, propyl alcohol, Virahol, chloroform, methylene dichloride, the water one or more.
Embodiment
The following examples can make those skilled in the art understand the present invention more comprehensively, but do not limit the present invention in any way.
1. the extraction of by product:
Monochloromethyl-ether (432g), Potassium monofluoride (140g) and PEG400 (450g) are added one have in the 1000ml single port bottle of magnetic agitation and reflux, heating reflux reaction 5 hours, reaction finishes, distill Sevoflurane 312g, yield: 78%.
In vinasse, add 600ml water, leave standstill after the stirring and dissolving, use the separating funnel layering, lower floor is collected, for the by product crude product, standby.
2. by product is converted into hexafluoroisopropanol:
In aforesaid operations, add entry (100ml), concentrated hydrochloric acid (10ml) in the by product crude product of gained, stirred 6 hours under the room temperature,, collect 56～58 ℃ of cuts with the oil bath heating, about 50g, purity is 98% (GC).
Owing to described the present invention according to its special embodiment, some is modified and equivalent variations is conspicuous for the technician who is proficient in this field and comprises within the scope of the invention.
Claims (3)
1. method of the by product in the Sevoflurane production process being extracted, is converted into then hexafluoroisopropanol, it is characterized in that under the concentrated hydrochloric acid existence condition, by product is converted into hexafluoroisopropanol, then by distill hexafluoroisopropanol, the reaction solvent for use is alcohols, halohydrocarbon or water, temperature of reaction is 0 ℃～50 ℃, and the reaction times is 1～12 hour, and the structure of by product is shown below:
X is H or the saturated lower alkoxy of straight chain that contains 1～6 carbon atom or contains saturated senior alkoxyl group of straight chain or CH greater than 6 carbon atoms in the formula
2CH
2OH or (CH
2CH
2O)
nH, wherein " n " is meant any one round values in 2～300.
2. method according to claim 1 is characterized in that reacting solvent for use and is specially in methyl alcohol, ethanol, propyl alcohol, Virahol, chloroform, methylene dichloride, the water one or more.
3. method according to claim 1, the collection cut temperature that it is characterized in that by product is converted into the reaction of hexafluoroisopropanol is 56 ℃～58 ℃.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100686736A CN100484910C (en) | 2006-09-08 | 2006-09-08 | By-product extraction in sevoflurane production process and transformation of sevoflurane into hexafluoroisopropanol |
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|---|---|---|---|
| CNB2006100686736A CN100484910C (en) | 2006-09-08 | 2006-09-08 | By-product extraction in sevoflurane production process and transformation of sevoflurane into hexafluoroisopropanol |
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|---|---|
| CN1915950A CN1915950A (en) | 2007-02-21 |
| CN100484910C true CN100484910C (en) | 2009-05-06 |
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Application publication date: 20070221 Assignee: Lunan New Era Biological Technology Co., Ltd. Assignor: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Contract record no.: 2012370000295 Denomination of invention: Extracting and transforming by-product collected from procedure for producing sevoflurane into hexafluoroisopropanol Granted publication date: 20090506 License type: Exclusive License Record date: 20121226 |
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Effective date of registration: 20151223 Address after: 273400 Shandong province Feixian County North Ring Road No. 1 Patentee after: Lunan New Era Biological Technology Co., Ltd. Address before: 273400 Shandong city of Linyi province Feixian County County North Ring North East first Patentee before: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. |