CN1276906C - Preparation method of isoflurane - Google Patents
Preparation method of isoflurane Download PDFInfo
- Publication number
- CN1276906C CN1276906C CN 200410098725 CN200410098725A CN1276906C CN 1276906 C CN1276906 C CN 1276906C CN 200410098725 CN200410098725 CN 200410098725 CN 200410098725 A CN200410098725 A CN 200410098725A CN 1276906 C CN1276906 C CN 1276906C
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- CN
- China
- Prior art keywords
- isoflurane
- chlorine
- autoclave
- introducing
- stirring
- Prior art date
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- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960002725 isoflurane Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims abstract description 7
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims abstract description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- ZASBKNPRLPFSCA-UHFFFAOYSA-N 2-(difluoromethoxy)-1,1,1-trifluoroethane Chemical compound FC(F)OCC(F)(F)F ZASBKNPRLPFSCA-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- 238000005286 illumination Methods 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract 1
- 238000006266 etherification reaction Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000012795 verification Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- JPGQOUSTVILISH-UHFFFAOYSA-N enflurane Chemical compound FC(F)OC(F)(F)C(F)Cl JPGQOUSTVILISH-UHFFFAOYSA-N 0.000 description 1
- 229960000305 enflurane Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003983 inhalation anesthetic agent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a preparation method of isoflurane. Trifluoroethanol, N-methyl pyrrolidone and freon-22 are used as initial raw materials, and isoflurane can be obtained through two reactions of etherification and chlorination. A technical scheme adopted by the present invention has the advantages of stable operation, smooth technology, easy quality control and high yield. After the verification of pilot tests and mass test production, the present invention is completely suitable for the requirements of industrial production.
Description
Technical Field
The invention relates to a preparation method of an organic compound, in particular to a preparation method of 1-chloro-2, 2, 2-trifluoroethyl difluoromethyl ether (isoflurane), belonging to the field of pharmaceutical chemicals.
Background
Isoflurane is a general inhalation anesthetic, an isomer of enflurane. Animal experiments and clinical researches show that isoflurane has the advantages of low biochemical transformation,low toxicity to liver and kidney, small circulation inhibition, good muscle relaxation effect, rapid and stable induction and revival, no spasmodic brain wave, good recovery, small side effect and the like.
Literature reports that the preparation method of isoflurane is more, but the process conditions are more complicated, the synthesis route is long, and the cost is high. U.S. Pat. No. 3,35425 (1970) discloses a process for the preparation of isoflurane, which comprises the reaction scheme:
dimethyl sulfate used in the route is a highly toxic product, hydrogen fluoride has strong corrosivity, and antimony pentachloride is expensive, so the requirements on reaction equipment and operation are high, and the cost is high. U.S. Pat. No. 3,983,477 (1972) discloses another isoflurane synthesis process, which comprises two steps:
b.
the isoflurane is inhaled into the whole anesthetic, so the requirement on the quality of the product is high, and the limit check is particularly strict. The reaction condition range of the route is too wide, the yield of isoflurane is difficult to ensure, the impurity content of the final product is higher, and the repeated rectification is difficult to meet the standard regulation requirement.
Disclosure of Invention
The invention aims to improve the defects of the prior art on the basis of the prior art and provide a preparation method of isoflurane, which has stable operation, controllable quality, higher yield and lower cost.
The technical scheme adopted by the invention comprises the following steps:
a. adding Trifluoroethanol (TFE), N-methylpyrrolidone (NMP) and freon-22 (F-22) into an autoclave, sealing, introducing nitrogen, adding a 50% sodium hydroxide aqueous solution at 5-18 ℃ under stirring, controlling the temperature in the autoclave to be 35-40 ℃, and introducing nitrogen into the autoclave to 18-20 kg/cm after the addition is finished2The reaction was stirred for 3 hours.
b. Transferring the reaction liquid in the kettle into a distillation kettle, heating in water bath under stirring for fractionation, collecting the fraction below 30 ℃ to be 2, 2, 2-trifluoroethyl difluoromethyl ether (CF)3CH2OCHF2) Distilling the remainder to recover TFE for feeding in next batch。
c. And c, pressing the 2, 2, 2-trifluoroethyl difluoromethyl ether obtained in the step b into a chlorination tank, introducing a small amount of chlorine under illumination, controlling the reaction temperature to be 15-20 ℃ after the color of the chlorine in the chlorination tank disappears, metering and introducing the chlorine so that the introduction amount of the chlorine is 45% of the molar amount of the 2, 2, 2-trifluoroethyl difluoromethyl ether, and then reacting for 30 minutes at 15-20 ℃.
d. And c, distilling the reaction liquid in the step c, and collecting the fraction below 40 ℃ as the recovered etherate for the next chlorination. Washing the residue once with 50% sodium hydroxide water solution at 5 deg.c, washing with cold water to neutrality, drying with anhydrous calcium chloride, natural trickling to obtain isoflurane product, and rectifying to purify to obtain isoflurane product.
The reaction route is as follows:
on the basis of the prior art, the invention greatly improves the yield of isoflurane by strictly controlling reaction conditions, maintains the impurity content at a lower level, and ensures that the product quality meets the requirement. The technical scheme adopted by the invention has the advantages of stable operation, smooth process, easy quality control and greatly improved yield, and the method is verified by pilot plant test to be suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples.
Example 1: preparation of 2, 2, 2-trifluoroethyl difluoromethyl ether
Adding TFE200g and NMP80g into an autoclave, sealing the autoclave, starting stirring, adding 173g of Freon-22 (F-22), then filling nitrogen into the autoclave, adding 368g of 50% NaOH aqueous solution at 5 ℃ under stirring, controlling the temperature in the autoclave to be 36 ℃, filling nitrogen into the autoclave to 18-20 kg/cm after the addition is finished2The reaction was stirred for 3 hours. Transferring the reaction solution in the kettle into a distillation kettle, heating and fractionating in water bath under stirring, collecting the fraction below 30 ℃ to obtain CF3CH2OCHF2180g of residue, and continuing distillation, recovering 60.5g of TFE60, 60% conversion, 86% yield (calculated as TFE consumed).
Example 2: preparation of isoflurane
300g (2.0mol) of 2, 2, 2-trifluoroethyl difluoromethyl ether is put into a chlorination tank, stirring and a fluorescent lamp are started, a small amount of chlorine is introduced, and after the color of the chlorinein the chlorination tank disappears, the speed of introducing the chlorine is controlled by a gas flowmeter, so that the chlorine is completely reacted without overflowing. Controlling the reaction temperature in a water bath at 15-20 ℃, introducing 0.9mol of chlorine, and then reacting for 30 minutes at 15-20 ℃. The reaction solution was distilled, and a fraction below 40 ℃ was collected as an etherate to obtain 150 g. And cooling the residue to 5-10 ℃, slowly dropwise adding a sodium hydroxide solution under stirring, stirring for 10 minutes after adding, standing for 10 minutes, putting the lower-layer chloride solution into a storage tank, washing with water for three times, putting the lower-layer chloride solution into a drying tank, adding calcium chloride, stirring and drying for 5 hours, and naturally dripping filtered isoflurane crude product 148.6g, wherein the conversion rate is 40% and the yield is 80% (calculated according to consumed 2, 2, 2-trifluoroethyl difluoromethyl ether).
Claims (1)
1. A preparation method of isoflurane is characterized by comprising the following steps:
a. adding trifluoroethanol, N-methyl pyrrolidone and Freon-22 into an autoclave, sealing, introducing nitrogen, adding a 50% sodium hydroxide aqueous solution at 5-18 ℃ while stirring, controlling the temperature in the autoclave to be 35-40 ℃, and introducing nitrogen into the autoclave to 18-20 kg/cm after the addition is finished2Stirring and reacting for 3 hours;
b. transferring the reaction liquid in the kettle into a distillation kettle, heating and fractionating in a water bath under stirring, collecting the fraction below 30 ℃ into 2, 2, 2-trifluoroethyl difluoromethyl ether, continuously distilling the remainder, and recovering trifluoroethanol for feeding in the next batch;
c. b, pressing the 2, 2, 2-trifluoroethyl difluoromethyl ether obtained in the step b into a chlorination tank, introducing a small amount of chlorine under illumination, controlling the reaction temperature to be 15-20 ℃ after the color of the chlorine in the chlorination tank disappears, metering and introducing the chlorine so that the introduction amount of the chlorine is 45% of the molar amount of the 2, 2, 2-trifluoroethyl difluoromethyl ether, and then reacting for 30 minutes at 15-20 ℃;
d. and c, distilling the reaction liquid in the step c, collecting fractions below 40 ℃ as recovered etherate for next chlorination, washing the remainder once with a 50% sodium hydroxide aqueous solution at 5 ℃, washing with cold water to be neutral, drying with anhydrous calcium chloride, naturally trickling and filtering to obtain an isoflurane crude product, and rectifying and purifying to obtain the isoflurane finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098725 CN1276906C (en) | 2004-12-15 | 2004-12-15 | Preparation method of isoflurane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098725 CN1276906C (en) | 2004-12-15 | 2004-12-15 | Preparation method of isoflurane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1651377A CN1651377A (en) | 2005-08-10 |
| CN1276906C true CN1276906C (en) | 2006-09-27 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410098725 Expired - Fee Related CN1276906C (en) | 2004-12-15 | 2004-12-15 | Preparation method of isoflurane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1276906C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462929B (en) * | 2009-01-08 | 2011-07-20 | 中国中化集团公司 | Preparation of furane used as inhalation anesthetic |
| JP5871633B2 (en) * | 2012-01-24 | 2016-03-01 | 関東電化工業株式会社 | Bis (1,1-dichloro-3,3,3-trifluoropropyl) ether and method for producing the same |
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2004
- 2004-12-15 CN CN 200410098725 patent/CN1276906C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1651377A (en) | 2005-08-10 |
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| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Denomination of invention: Preparation method of isoflurane Granted publication date: 20060927 License type: Exclusive License Open date: 20050810 Record date: 20100908 |
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| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2010370000509 Date of cancellation: 20121226 |
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| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20050810 Assignee: SHANDONG NEW TIME PHARMACEUTICAL Co.,Ltd. Assignor: LUNAN PHARMACEUTICAL Group Corp. Contract record no.: 2013370000264 Denomination of invention: Preparation method of isoflurane Granted publication date: 20060927 License type: Exclusive License Record date: 20131210 |
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| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20060927 |