CN103360219B - A kind of synthetic method of high-purity propofol - Google Patents
A kind of synthetic method of high-purity propofol Download PDFInfo
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- CN103360219B CN103360219B CN201210099345.8A CN201210099345A CN103360219B CN 103360219 B CN103360219 B CN 103360219B CN 201210099345 A CN201210099345 A CN 201210099345A CN 103360219 B CN103360219 B CN 103360219B
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- Prior art keywords
- disoprofol
- sorbent material
- synthetic method
- crude product
- phenylformic acid
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- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229960004134 propofol Drugs 0.000 title claims abstract description 35
- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- 239000002594 sorbent Substances 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 6
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000010931 ester hydrolysis Methods 0.000 claims abstract description 4
- -1 phenylformic acid-2,6-diisopropyl benzene Chemical compound 0.000 claims abstract description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 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
- 238000000034 method Methods 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 8
- 238000009835 boiling Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000012085 test solution Substances 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 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
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction 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
- 238000006555 catalytic reaction Methods 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
- 238000006243 chemical reaction Methods 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
- 238000007670 refining Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 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
- 239000000945 filler Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of synthetic method of high-purity propofol, the method is: by industry 2,6-diisopropyl phenol and Benzoyl chloride react and generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2,6-diisopropyl benzene Ester hydrolysis generates Disoprofol crude product, by Disoprofol crude product removed under reduced pressure solvent, add a certain proportion of sorbent material, rectification under vacuum, collect stable cut, thus obtain highly purified Disoprofol; The inventive method adds sorbent material in stage of rectification, effectively eliminates the impurity that chemical structure is similar, boiling point is close, and in product, single foreign matter content is not all higher than 0.01%, and total impurities is not higher than 0.05%.The method significantly improves the quality of Disoprofol, and technique circulation ratio is good.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of synthetic method of high-purity propofol particularly.
Background technology
Disoprofol has another name called Disoprivan, chemical name 2,6-Bis(1-methylethyl)phenol, English name propofol, and be widely used a kind of outstanding anaesthetic clinically, its chemical structure is as follows:
It is one anesthesia induction agent safely and effectively, is again a kind of good intravenous anesthetics.Effect rapidly and steadily, a shot is held time short, is revived rapid and clearheaded, without excited phenomenon, and is had certain analgesic activity, widely use in countries in the world.
In traditional technology, Disoprofol uses phenol for raw material usually, Reactive Synthesis at high temperature under high pressure.Phenol toxicity is comparatively large, and the technique that chemical plant produces 2,6-Bis(1-methylethyl)phenol is comparatively ripe, thus the many employing industry 2 of medicinal Disoprofol, prepared by 6-diisopropyl benzene phenol treating, mainly comprise: rectifying method of purification, low temperature crystallization method of purification, column chromatography and esterification water solution.
Patent WO9610004 has studied esterification water solution in great detail, and the method is reacted at industrial 2,6-Bis(1-methylethyl)phenol and Benzoyl chloride, generates phenylformic acid-2,6-6-diisopropyl benzene ester, through recrystallization removing impurity, then through the Disoprofol be hydrolyzed, namely rectifying obtain purifying.The method is easy and simple to handle, and avoid the low temperature crystallization in rectifying repeatedly complicated in rectifying method of purification and low temperature crystallization method of purification, 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.
The present inventor company is studied the method, finds that the method effectively can control impurity E mentioned in European Pharmacopoeia standard, the content of G, J (structure is as follows).
But have a unknown impuritie (confirmed as impurity B afterwards, structure is as follows) content higher:
This impurity is similar to Disoprofol chemical structure, comprises the physico-chemical properties such as boiling point very close, is difficult to be separated from Disoprofol in the process that esterification catalysis is refining.All find that there is this material in commercially available Disoprofol bulk drug, content is suitable with the former handicraft product of the present inventor company.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of high-purity propofol, the method adds sorbent material when being the rectification under vacuum after esterification catalysis, utilize sorbent material to the difference of Disoprofol and impurity absorption ability, in rectifying, realize being separated of impurity and Disoprofol.
The invention provides a kind of synthetic method of high-purity propofol, by industry 2,6-diisopropyl phenol and Benzoyl chloride react and generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2,6-diisopropyl benzene Ester hydrolysis generates Disoprofol crude product, by Disoprofol crude product removed under reduced pressure solvent, add a certain proportion of sorbent material, rectification under vacuum, collect stable cut, thus obtain highly purified Disoprofol.
The synthetic method of high-purity propofol provided by the invention, described sorbent material is various chromatography fillers.
The synthetic method of high-purity propofol provided by the invention, described sorbent material is preferably the one in silica gel, diatomite, 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 obtain high-purity propofol, detects through HPLC, adopts test solution, contrast solution comparison, the content of result display impurity B is reduced to less than 0.01%, far below the requirement of European Pharmacopoeia 0.05%, the content of impurity E, G, J reduces further, and total impurities is lower than 0.05%.
Method of the present invention does not carry out great change to esterification catalysis method for refining, maintain the method easy and simple to handle, avoid complicated rectifying repeatedly 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 product is significantly better than European Pharmacopoeia standard requirement simultaneously, and this technique also has good circulation ratio.
Accompanying drawing explanation
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 product;
Fig. 4 is the HPLC collection of illustrative plates of the contrast solution of embodiment 2 product;
Fig. 5 is the HPLC collection of illustrative plates of the test solution of embodiment 3 product;
Fig. 6 is the HPLC collection of illustrative plates of the contrast solution of embodiment 3 product.
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 are reacted and generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2,6-diisopropyl benzene Ester hydrolysis generates Disoprofol crude product, and Disoprofol crude product is the extraction liquid after hydrolysis.
Embodiment 1
By the extraction liquid after hydrolysis, removed under reduced pressure solvent, obtains pale yellow oil 84.2g, adds diatomite 4.2g, rectification under vacuum, vacuum tightness 29-30mmHg, and interior temperature cut 116 DEG C time is stablized, and collecting cut 63.7g altogether, is colourless liquid.
Related substance detects:
High performance liquid chromatograph (Shimadzu 20A), normal hexane, acetonitrile, dehydrated alcohol (chromatographically pure, Wo Kai).
Chromatographic column: silica gel is weighting agent (Alltima silica, 5 μm, 4.6*250mm), moving phase: normal hexane-acetonitrile-dehydrated alcohol (990: 7.5: 1.0), flow velocity 1.0ml/min, determined wavelength 275nm, column temperature room temperature, sample size 10 μ L.
Detection liquid is prepared: it is appropriate that precision takes this product, and normal hexane is diluted to 100mg/mL as test solution; It is appropriate that precision measures 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, and single contaminant maximum level is no more than 0.01%, and total impurities is no more than 0.03%, is obviously better than European Pharmacopoeia standard.
Embodiment 2
By the extraction liquid after hydrolysis, removed under reduced pressure solvent, obtains pale yellow oil 87.6g, adds silica gel 8.8g, rectification under vacuum, vacuum tightness 29-30mmHg, and interior temperature cut 116 DEG C time is stablized, and collecting cut 62.5g altogether, is colourless liquid.
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, and single contaminant maximum level is no more than 0.006%, and total impurities is no more than 0.02%, is obviously better than European Pharmacopoeia standard.
Embodiment 3
By the extraction liquid after hydrolysis, removed under reduced pressure solvent, obtains pale yellow oil 87.6g, adds neutral alumina 13.1g, rectification under vacuum, vacuum tightness 29-30mmHg, and interior temperature cut 116 DEG C time is stablized, and collecting cut 58.6g altogether, is colourless liquid.
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, and single contaminant maximum level is no more than 0.006%, and total impurities is no more than 0.02%, is obviously better than European Pharmacopoeia standard.
Claims (3)
1. the synthetic method of a high-purity propofol, by industry 2,6-diisopropyl phenol and Benzoyl chloride react and generate phenylformic acid-2,6-6-diisopropyl benzene ester, phenylformic acid-2,6-diisopropyl benzene Ester hydrolysis generates Disoprofol crude product, it is characterized in that: by Disoprofol crude product removed under reduced pressure solvent, add a certain proportion of sorbent material, rectification under vacuum, collect stable cut, thus obtain highly purified Disoprofol;
Described sorbent material is the one in silica gel, diatomite, neutral alumina; The ratio that described sorbent material adds is 1%-30%.
2. according to the synthetic method of high-purity propofol according to claim 1, it is characterized in that: the ratio that described sorbent material adds is 3%-20%.
3. according to the synthetic method of high-purity propofol according to claim 2, 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 CN103360219A (en) | 2013-10-23 |
| CN103360219B true 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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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55164638A (en) * | 1979-06-11 | 1980-12-22 | Mitsui Petrochem Ind Ltd | Purification of phenol |
-
2012
- 2012-04-06 CN CN201210099345.8A patent/CN103360219B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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