CN103360219A - Synthesis method of high-purity propofol - Google Patents
Synthesis method of high-purity propofol Download PDFInfo
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- CN103360219A CN103360219A CN2012100993458A CN201210099345A CN103360219A CN 103360219 A CN103360219 A CN 103360219A CN 2012100993458 A CN2012100993458 A CN 2012100993458A CN 201210099345 A CN201210099345 A CN 201210099345A CN 103360219 A CN103360219 A CN 103360219A
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- CN
- China
- Prior art keywords
- propofol
- purity
- synthetic method
- sorbent material
- disoprofol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960004134 propofol Drugs 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 239000012043 crude product Substances 0.000 claims abstract description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 claims description 13
- 239000002594 sorbent Substances 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 5
- 238000004807 desolvation Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 18
- 239000012535 impurity Substances 0.000 abstract description 13
- 239000000047 product Substances 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 8
- 238000009835 boiling Methods 0.000 abstract description 2
- 239000003463 adsorbent Substances 0.000 abstract 2
- -1 benzoic acid-2,6-diisopropyl benzene ester Chemical class 0.000 abstract 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 239000007788 liquid Substances 0.000 description 9
- 239000012085 test solution Substances 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000006555 catalytic reaction Methods 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of high-purity propofol. The method comprises the following steps: enabling industrial 2,6-diisopropyl phenol to react with benzoyl chloride to generate benzoic acid-2,6-diisopropyl benzene ester; hydrolyzing the benzoic acid-2,6-diisopropyl benzene ester to generate a propofol crude product; removing a solvent of the propofol crude product at reduced pressure; and adding a certain ratio of adsorbent, rectifying at reduced pressure, and collecting stable fraction, so as to obtain the high-purity propofol. By adopting the method disclosed by the invention, the adsorbent is added at the rectifying stage, so that impurities with similar chemical structures and boiling points are effectively removed; the content of a single impurity in the product is not higher than 0.01%; the total impurity is not higher than 0.05%. By adopting the method, the quality of the propofol is obviously improved; the technological reproducibility is good.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to particularly a kind of synthetic method of high-purity propofol.
Background technology
Disoprofol has another name called Disoprivan, the chemical name 2,6-Bis(1-methylethyl)phenol, and English name propofol is widely used a kind of outstanding anaesthetic clinically, its chemical structure is as follows:
It is a kind of safely and effectively anesthesia induction agent, is again a kind of good intravenous anesthetics.Effect rapidly and steadily, the shot weak point of holding time, it is rapid and clearheaded to revive, and without excited phenomenon, and has certain analgesic activity, is widely used in countries in the world.
Disoprofol uses phenol to be raw material usually in the traditional technology, and reaction is synthetic under High Temperature High Pressure.Phenol toxicity is larger, and the technique of chemical plant production 2,6-Bis(1-methylethyl)phenol is comparatively ripe, thereby medicinal Disoprofol adopts industry 2 more, the preparation of 6-diisopropyl benzene phenol treating mainly comprises: rectifying method of purification, low temperature crystallization method of purification, column chromatography and esterification catalysis method.
Patent WO9610004 has studied the esterification catalysis method in great detail, and the method is with industrial 2,6-Bis(1-methylethyl)phenol and Benzoyl chloride reaction, generates phenylformic acid-2, and the 6-6-diisopropyl benzene ester is removed impurity through recrystallization, namely gets the Disoprofol of purifying through hydrolysis, rectifying again.The method is easy and simple to handle, has avoided the repeatedly rectifying of complexity in the rectifying method of purification and the low temperature crystallization in the low temperature crystallization method of purification, and reaction yield is high, and low to the purity requirement of industrial 2,6-Bis(1-methylethyl)phenol, is very suitable for suitability for industrialized production.
Inventor company is studied the method, and discovery the method can effectively be controlled the content of impurity E mentioned in the European Pharmacopoeia standard, G, J (structure is as follows).
But have a unknown impuritie (confirmed as afterwards impurity B, structure is as follows) content higher:
This impurity is similar to the Disoprofol chemical structure, comprises that the physico-chemical property such as boiling point is very close, is difficult to separate from Disoprofol in the refining process of esterification catalysis.All found this material in the commercially available Disoprofol bulk drug, content is suitable with the former handicraft product of inventor company.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of high-purity propofol, when being rectification under vacuum behind esterification catalysis, the method adds sorbent material, utilize different to Disoprofol and impurity absorption ability of sorbent material, in rectifying, realize separating of impurity and Disoprofol.
The invention provides a kind of synthetic method of high-purity propofol, with industry 2,6-diisopropyl phenol and Benzoyl chloride reaction generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2, the hydrolysis of 6-6-diisopropyl benzene ester generates the Disoprofol crude product, with Disoprofol crude product decompression desolvation, add a certain proportion of sorbent material, rectification under vacuum, collect stable cut, thereby obtain highly purified Disoprofol.
The synthetic method of high-purity propofol provided by the invention, described sorbent material are various chromatography fillers.
The synthetic method of high-purity propofol provided by the invention, described sorbent material are preferably a kind of in silica gel, diatomite, the neutral alumina.
The synthetic method of high-purity propofol provided by the invention, the ratio that described sorbent material adds is 1%-30% (is preferably 3%-20%, most preferably is 5%-15%).
The present invention synthesizes to get high-purity propofol, detects through HPLC, adopts test solution, contrast solution comparison, the result shows below the content to 0.01% of impurity B, far below the requirement of European Pharmacopoeia 0.05%, the content of impurity E, G, J further reduces, and total impurities is lower than 0.05%.
Method of the present invention is not carried out great change to the esterification catalysis method for refining, kept the method easy and simple to handle, avoid complicated repeatedly rectifying and low temperature crystallization, reaction yield is high, to industry 2, the advantage that the purity requirement of 6-diisopropyl phenol is low, the foreign matter content of while product is significantly better than the European Pharmacopoeia standard-required, and this technique also has good circulation ratio.
Description of drawings
Fig. 1 is the HPLC collection of illustrative plates of the test solution of embodiment 1 product;
Fig. 2 is the HPLC collection of illustrative plates of the contrast solution of embodiment 1 product;
Fig. 3 is the HPLC collection of illustrative plates of the test solution of embodiment 2 products;
Fig. 4 is the HPLC collection of illustrative plates of the contrast solution of embodiment 2 products;
Fig. 5 is the HPLC collection of illustrative plates of the test solution of embodiment 3 products;
Fig. 6 is the HPLC collection of illustrative plates of the contrast solution of embodiment 3 products.
Embodiment
The following examples will be further described the present invention, but not thereby limiting the invention.
Industrial 2,6-Bis(1-methylethyl)phenol and Benzoyl chloride reaction are generated phenylformic acid-2, the 6-6-diisopropyl benzene ester, phenylformic acid-2, the hydrolysis of 6-6-diisopropyl benzene ester generates the Disoprofol crude product, and the Disoprofol crude product is the extraction liquid after the hydrolysis.
With the extraction liquid after the hydrolysis, the decompression desolvation obtains faint yellow oily thing 84.2g, adds diatomite 4.2g, rectification under vacuum, and vacuum tightness 29-30mmHg, interior temperature cut in the time of 116 ℃ is stable, collects altogether cut 63.7g, is colourless liquid.
Related substance detects:
High performance liquid chromatograph (Shimadzu 20A), and normal hexane, acetonitrile, dehydrated alcohol (chromatographically pure, Wo Kai).
Chromatographic column: silica gel is weighting agent (Alltima silica, 5 μ m, 4.6*250mm), moving phase: normal hexane-acetonitrile-dehydrated alcohol (990: 7.5: 1.0), flow velocity 1.0ml/min detects wavelength 275nm, column temperature room temperature, sample size 10 μ L.
The preparation of detection liquid: it is an amount of that precision takes by weighing this product, and normal hexane is diluted to 100mg/mL as test solution; It is an amount of that precision is measured test solution, and normal hexane is diluted to the contrast solution of 0.1mg/mL.
The liquid phase test result record of test solution and contrast solution is as follows:
Liquid phase result shows that the single contaminant maximum level is no more than 0.01%, and total impurities is no more than 0.03%, obviously is better than the European Pharmacopoeia standard.
With the extraction liquid after the hydrolysis, the decompression desolvation obtains faint yellow oily thing 87.6g, adds silica gel 8.8g, rectification under vacuum, and vacuum tightness 29-30mmHg, interior temperature cut in the time of 116 ℃ is stable, collects altogether cut 62.5g, is colourless liquid.
The high performance liquid phase testing method is carried out according to embodiment 1.
The liquid phase test result record of test solution and contrast solution is as follows:
Liquid phase result shows that the single contaminant maximum level is no more than 0.006%, and total impurities is no more than 0.02%, obviously is better than the European Pharmacopoeia standard.
With the extraction liquid after the hydrolysis, the decompression desolvation obtains faint yellow oily thing 87.6g, adds neutral alumina 13.1g, rectification under vacuum, and vacuum tightness 29-30mmHg, interior temperature cut in the time of 116 ℃ is stable, collects altogether cut 58.6g, is colourless liquid.
The high performance liquid phase testing method is carried out according to embodiment 1.
The liquid phase test result record of test solution and contrast solution is as follows:
Liquid phase result shows that the single contaminant maximum level is no more than 0.006%, and total impurities is no more than 0.02%, obviously is better than the European Pharmacopoeia standard.
Claims (6)
1. the synthetic method of a high-purity propofol, with industry 2,6-diisopropyl phenol and Benzoyl chloride reaction generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2, the hydrolysis of 6-6-diisopropyl benzene ester generates the Disoprofol crude product, it is characterized in that: with Disoprofol crude product decompression desolvation, add a certain proportion of sorbent material, rectification under vacuum, collect stable cut, thereby obtain highly purified Disoprofol.
2. according to the synthetic method of high-purity propofol claimed in claim 1, it is characterized in that: described sorbent material is various chromatography fillers.
3. according to the synthetic method of high-purity propofol claimed in claim 2, it is characterized in that: described sorbent material is a kind of in silica gel, diatomite, the neutral alumina.
4. according to the synthetic method of high-purity propofol claimed in claim 1, it is characterized in that: the ratio that described sorbent material adds is 1%-30%.
5. according to the synthetic method of high-purity propofol claimed in claim 4, it is characterized in that: the ratio that described sorbent material adds is 3%-20%.
6. according to the synthetic method of high-purity propofol claimed in claim 5, it is characterized in that: the ratio that described sorbent material adds is 5%-15%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210099345.8A CN103360219B (en) | 2012-04-06 | 2012-04-06 | A kind of synthetic method of high-purity propofol |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210099345.8A CN103360219B (en) | 2012-04-06 | 2012-04-06 | A kind of synthetic method of high-purity propofol |
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| Publication Number | Publication Date |
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| CN103360219A true CN103360219A (en) | 2013-10-23 |
| CN103360219B CN103360219B (en) | 2015-08-19 |
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| CN201210099345.8A Active CN103360219B (en) | 2012-04-06 | 2012-04-06 | A kind of synthetic method of high-purity propofol |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104649867A (en) * | 2013-11-21 | 2015-05-27 | 辽宁药联制药有限公司 | Preparation method of propofol |
| CN105777497A (en) * | 2014-12-26 | 2016-07-20 | 辽宁药联制药有限公司 | Treatment method for propofol rectification front cut fraction |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55164638A (en) * | 1979-06-11 | 1980-12-22 | Mitsui Petrochem Ind Ltd | Purification of phenol |
| US5589598A (en) * | 1994-09-28 | 1996-12-31 | Zambon Group S.P.A. | Process of purification of 2,6-diisopropylphenol |
| US5696300A (en) * | 1994-07-01 | 1997-12-09 | Archimica Spa | Propofol purification |
| CN101081804A (en) * | 2007-06-04 | 2007-12-05 | 西安力邦制药有限公司 | Refining method for propofol injection |
| CN101139258A (en) * | 2007-09-11 | 2008-03-12 | 西安力邦制药有限公司 | Production method for refining propofol by dynamic accumulative distillation |
-
2012
- 2012-04-06 CN CN201210099345.8A patent/CN103360219B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55164638A (en) * | 1979-06-11 | 1980-12-22 | Mitsui Petrochem Ind Ltd | Purification of phenol |
| US5696300A (en) * | 1994-07-01 | 1997-12-09 | Archimica Spa | Propofol purification |
| US5589598A (en) * | 1994-09-28 | 1996-12-31 | Zambon Group S.P.A. | Process of purification of 2,6-diisopropylphenol |
| CN101081804A (en) * | 2007-06-04 | 2007-12-05 | 西安力邦制药有限公司 | Refining method for propofol injection |
| CN101139258A (en) * | 2007-09-11 | 2008-03-12 | 西安力邦制药有限公司 | Production method for refining propofol by dynamic accumulative distillation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104649867A (en) * | 2013-11-21 | 2015-05-27 | 辽宁药联制药有限公司 | Preparation method of propofol |
| CN104649867B (en) * | 2013-11-21 | 2017-02-15 | 辽宁药联制药有限公司 | Preparation method of propofol |
| CN105777497A (en) * | 2014-12-26 | 2016-07-20 | 辽宁药联制药有限公司 | Treatment method for propofol rectification front cut fraction |
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| CN103360219B (en) | 2015-08-19 |
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