CN1699319A - Process for preparing fluoro methyl ether - Google Patents
Process for preparing fluoro methyl ether Download PDFInfo
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- CN1699319A CN1699319A CN 200510071849 CN200510071849A CN1699319A CN 1699319 A CN1699319 A CN 1699319A CN 200510071849 CN200510071849 CN 200510071849 CN 200510071849 A CN200510071849 A CN 200510071849A CN 1699319 A CN1699319 A CN 1699319A
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- fluoro
- activator
- alkyl group
- low alkyl
- ether
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Abstract
The invention relates to a process for preparing propylene glycol ester, more specifically fluoromethyl-2,2,2-trifluo-1-(trifluoromethyl) ethyl ether (sevoflurane), wherein the precursor reacts with fluorides at the presence of activating agents.
Description
Technical field
The present invention relates to each fluoro methyl ether, particularly methyl fluoride-2,2 of a kind of system, the method for 2-three fluoro-1-(trifluoromethyl) ethyl ethers (Sevoflurane).
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 (ClFCHCF
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 utilizes hydrogen fluoride, formaldehyde and sulfuric acid or other dewatering agents to carry out the chloromethylation of hexafluoroisopropanol with 4469898-; With PTC 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.
According to the present invention, provide the synthetic method of some fluoro methyl ether, particularly Sevoflurane that relatively the productive rate of all technology will be high.
Summary of the invention
According to the invention provides the method that a kind of activator exists following activating fluorinated thing and the corresponding fluoro methyl ether of some a chloro methyl ether production, in particular, the present invention relates to a kind of production fluoro methyl 2-2-2-three fluoro-1-(three fluoro methyl) ethyl ether (is Sevoflurane: (CF
3)
2CHOCH
2F) method, it comprises activating fluorinated thing of activator and the reaction of chloro methyl 2-2-2-three fluoro-1-(three fluoro methyl) ethyl ether.
The present invention relates generally to that a kind of ethers, polyethers, crown ether-like, the activating fluorinated thing of alcohols activator and a chloro methyl ether are to obtain the method for a corresponding fluoro methyl ether.The raw material of a chloro methyl ether of the present invention is known compound and is represented by following general formula:
R is fluoro low alkyl group, fluorine or chlorine in the formula, R
1And R
2Independently be selected from hydrogen, low alkyl group, branching low alkyl group, fluoro low alkyl group, fluorine and chlorine, condition is R, R
1Or R
2In at least one be fluoro low alkyl group, low alkyl group or branching low alkyl group.The corresponding fluoro methyl ether that an above-mentioned chloro methyl ether and Potassium monofluoride obtain being expressed from the next under the activator activation:
R, R in the formula
1Or R
2As above defined.
In preferred embodiments, the present invention relates to a kind of by activator activation chloro methyl 2-2-2-three fluoro-1-(three fluoro methyl) ethyl ether and fluorochemical reaction, production fluoro methyl 2-2-2-three fluoro-1-(three fluoro methyl) ethyl ethers (that is Sevoflurane).
Spendable in the method for the invention activator is selected from the compound of following formula: X-O-CH
2CH
2(OCH
2CH
2) n-O-Y, wherein X and Y are hydrogen, low alkyl group or senior alkyl, and X and Y also can be interconnected to form cyclic ethers, and n is any integer of 0～300.The representational example that is present in the compound of following formula comprises X=Y=H (that is: ethylene glycol), X=CH
2CH
2OH, Y=H (that is: glycol ether), X=Y=CH
2CH
2OH (that is: triglycol), XY=(CH
2CH
2O)
4CH
2CH
2(that is: hexaoxacyclooctadecane-6-6), or polyoxyethylene glycol etc.In embodiment preferred of the present invention, activator is a hexaoxacyclooctadecane-6-6.
Spendable in the method for the invention fluorochemical is Potassium monofluoride, Sodium Fluoride, Neutral ammonium fluoride etc.
In the method for the invention the consumption of spendable activator be fluorochemical weight 5%～80%.In embodiment preferred of the present invention, the consumption of activator be fluorochemical weight 20～50%.
Mean 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.Mean the saturated alkyl that contain greater than 6 carbon atoms as the term " senior alkyl " that uses herein, and, except other has the stipulator, should be straight chain, the saturated alkyl of preferred 7～20 carbon atoms.Mean 0～300 any integer as the term " n " that uses herein.Mean as the term " fluoro low alkyl group " that uses herein and to contain 1～6 carbon atom, and the saturated alkyl that is replaced by at least one fluorine.Preferred fluoro low alkyl group is three fluoro methyl.
It is known to be used to activator in the reaction of the present invention and to be those of skill in the art general in the chemical field.Although the activator of reaction described herein is preferably hexaoxacyclooctadecane-6-6 herein, be to use described activator high yield to be provided for described building-up reactions.In addition, according to the present invention, the activator of certain molar equivalent is enough to activating fluorinated thing and mixes with a chloro methyl ether, mixture heating up is enough to cause then the appropriate time that forms product one fluoro methyl ether for one section.
Of the present invention by the conversion reaction of the activating fluorinated thing of activator and a chloro methyl ether to a fluoro methyl ether, can there be solvent or at solvent, for example the high boiling point inert solvent carries out under the existence as tetramethylene sulfone, methane amide, ethanamide etc.In preferred version of the present invention, reaction is the solvent that adds being with or without, and carries out under the situation of an an amount of or excessive chloro methyl ether reagent and use, and monochloro methane also can play solvent.According to the present invention, a chloro methyl ether can carry out under the normal atmosphere or in airtight pressurized vessel under temperature range is 25 ℃～100 ℃ high temperature to the conversion reaction of a fluoro methyl ether.In the preferred embodiments of the invention, reaction is to carry out under the reflux temperature of a chloro methyl ether.
Be to surpass before not used the activator significant improvement of (as described in the United States Patent (USP) 4874901) for making a chloro methyl ether use activator in the present invention to the conversion of a fluoro methyl ether.The yield of the product that is obtained and transformation efficiency are much higher than product yield and the transformation efficiency that does not use activator to obtain all the time in the present invention, and this is confirmed by the embodiment that is provided below this paper.Using activator to obtain uniform high yield in the method for the invention is the method for not introduced so far.
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.
Embodiment 1
Monochloromethyl-ether 500g, Sodium Fluoride 100g and ethylene glycol 45g are added one have in the 500mL single port bottle of magnetic agitation and reflux, heating reflux reaction 5 hours, reaction finishes, distill 432.2g,, contain Sevoflurane 96.5% by analysis, yield: 90.3%.
Embodiment 2
Monochloromethyl-ether 500g, Potassium monofluoride 140g, tetramethylene sulfone 400mL and hexaoxacyclooctadecane-6-6 60g are added one to be had in the 1000mL single port bottle of magnetic agitation and reflux, heating reflux reaction 2 hours, reaction finishes, distill the 419.6g product, contain Sevoflurane 95.3% by analysis, yield: 86.6%.
Embodiment 3
Monochloromethyl-ether 500g, Potassium monofluoride 80g and hexaoxacyclooctadecane-6-6 30g adding one are had in the 500mL single port bottle of magnetic agitation and reflux, heating reflux reaction 4 hours, reaction finishes, distill the 236.6g product, and recovery 204.2g monochloromethyl-ether, product contains Sevoflurane 98.8% by analysis, yield: 84.6%.
Embodiment 4
Monochloromethyl-ether 500g, Potassium monofluoride 140g and PEG400 60g adding one are had in the 500mL single port bottle of magnetic agitation and reflux, heat temperature raising back flow reaction 4 hours, reaction finishes, distill the 411.7g product, contain Sevoflurane 98.5% by analysis, yield 87.8%.
Embodiment 5
Monochloromethyl-ether 500g, Neutral ammonium fluoride 90g, triglycol 40g are added one have in the 500mL single port bottle of magnetic agitation and reflux, be heated to 85 ℃, back flow reaction 6 hours, reaction finishes, distill the 350g product, contain Sevoflurane 96.9% by analysis, yield 73.9%.
Embodiment 6
Monochloromethyl-ether 500g, Potassium monofluoride 140g, ethanamide 500g and triglycol 60g are added one have in the 500mL single port bottle of magnetic agitation and reflux, be heated to 85 ℃, back flow reaction 6 hours, reaction finishes, distill the 431.2g product, contain Sevoflurane 97.9% by analysis, yield 91.4%.
Embodiment 7
Monochloromethyl-ether 500g, Potassium monofluoride: 40g and 18-hat-6 60g adding one are had in the 500mL single port bottle of magnetic agitation and reflux, heat temperature raising back flow reaction 4 hours, reaction finishes, distill the 348.8g product, contain Sevoflurane 98.1% by analysis, yield 92.6%.
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 (11)
1. the method for a fluoro methyl ether that is expressed from the next in the preparation of the activating fluorinated thing of activator and a corresponding chloro methyl ether
R is fluoro low alkyl group, fluorine or chlorine in the formula, R
1And R
2Be independently selected from hydrogen, low alkyl group, branching low alkyl group, fluoro low alkyl group, fluorine or chlorine, condition is R, R
1Or R
2In at least one is fluoro low alkyl group, low alkyl group or branching low alkyl group.
2. according to the process of claim 1 wherein that described activator is expressed from the next: X-O-CH
2CH
2(OCH
2CH
2) n-O-Y, wherein X and Y are hydrogen, lower alkoxy or senior alkoxyl group, and X and Y also can be interconnected to form cyclic ethers, and n is any integer of 0～300; Condition is that among X and the Y at least one is for hydrogen, lower alkoxy or senior alkoxyl group.
3. according to the method for claim 2, wherein said activator is selected from ethylene glycol, hexaoxacyclooctadecane-6-6, sweet triol or polyoxyethylene glycol.
4. according to each method of claim 1-3, wherein the consumption of activator be fluorochemical weight 5%～80%.
5. according to the method for claim 4, wherein the consumption of activator be fluorochemical weight 20%～50%.
6. according to each method of claim 1-5, wherein said fluorochemical is Sodium Fluoride, Potassium monofluoride or Neutral ammonium fluoride.
7. according to the method for claim 6, wherein said fluorochemical is a Potassium monofluoride.
8. according to the process of claim 1 wherein that a described fluoro methyl ether is a fluoro methyl 2,2,2 three fluoro-1-(three fluoro methyl) ethyl ether, a described chloro methyl ether is a chloro methyl 2,2, and 2-three fluoro-1-(three fluoro methyl) ethyl ether and described activator are hexaoxacyclooctadecane-6-6.
9. according to the process of claim 1 wherein that described reaction is to carry out in the presence of solvent.
10. according to the method for claim 9, wherein reaction is what to carry out under the reflux temperature of reaction mixture.
11. according to the process of claim 1 wherein the reaction be be not added solvent in the presence of, use excessive monochloromethyl-ether raw material to carry out.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510071849 CN1293030C (en) | 2005-05-25 | 2005-05-25 | Process for preparing fluoro methyl ether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510071849 CN1293030C (en) | 2005-05-25 | 2005-05-25 | Process for preparing fluoro methyl ether |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1699319A true CN1699319A (en) | 2005-11-23 |
| CN1293030C CN1293030C (en) | 2007-01-03 |
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|---|---|---|---|
| CN 200510071849 Active CN1293030C (en) | 2005-05-25 | 2005-05-25 | Process for preparing fluoro methyl ether |
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|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199076A (en) * | 2010-03-25 | 2011-09-28 | 上海源力生物技术有限公司 | Method for preparing sevoflurane |
| CN104529721A (en) * | 2015-01-16 | 2015-04-22 | 河北一品制药有限公司 | Industrial preparation 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 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101314560B (en) * | 2008-07-02 | 2011-06-15 | 鲁南制药集团股份有限公司 | Process for synthesizing Sevoflurane |
-
2005
- 2005-05-25 CN CN 200510071849 patent/CN1293030C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199076A (en) * | 2010-03-25 | 2011-09-28 | 上海源力生物技术有限公司 | Method for preparing sevoflurane |
| CN102199076B (en) * | 2010-03-25 | 2014-05-14 | 上海源力生物技术有限公司 | Method for preparing sevoflurane |
| CN104529721A (en) * | 2015-01-16 | 2015-04-22 | 河北一品制药有限公司 | Industrial preparation method of sevoflurane |
| CN104529721B (en) * | 2015-01-16 | 2017-04-19 | 河北一品制药有限公司 | Industrial preparation 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1293030C (en) | 2007-01-03 |
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Application publication date: 20051123 Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Shandong Xinshidai Pharmaceutical Industry Co., Ltd. Contract record no.: 2013370000263 Denomination of invention: Process for preparing fluoro methyl ether Granted publication date: 20070103 License type: Exclusive License Record date: 20131210 |
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