CN102731265A - Preparation method of high-purity propofol - Google Patents
Preparation method of high-purity propofol Download PDFInfo
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- CN102731265A CN102731265A CN2012101918952A CN201210191895A CN102731265A CN 102731265 A CN102731265 A CN 102731265A CN 2012101918952 A CN2012101918952 A CN 2012101918952A CN 201210191895 A CN201210191895 A CN 201210191895A CN 102731265 A CN102731265 A CN 102731265A
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- KCLPJCBWFBTEKM-UHFFFAOYSA-N CC(C)c(cccc1C(C)C)c1OCc(cc1)ccc1[N+]([O-])=O Chemical compound CC(C)c(cccc1C(C)C)c1OCc(cc1)ccc1[N+]([O-])=O KCLPJCBWFBTEKM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of high-purity propofol. The method comprises the steps shown below, wherein R is selected from chlorine, bromine or sulfonate. The method provided by the invention is advantaged in intelligent idea, simple process, and suitability for industrialized productions. The purity of the prepared propofol is above 99.9%, and the prepared propofol satisfies various medical pharmaceutical standards.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, relate to a kind of preparation method of high purity Propofol.
Background technology
Propofol (propofol, chemical name: 2, the two isopropyl-phenols of 6-are to be used for generally clinically at present that anesthesia induction, anesthesia are kept, a kind of novel quick, fugitive intravenous anesthetic of ICU urgent patient sedative.It has anesthesia induction rapid-action, revive rapidly and functional rehabilitation perfect, advantage such as the postoperative nausea and vomiting incidence is low.
In the traditional synthesis, the preparation method of Propofol adopts phenol aluminium as catalyzer, and phenol and propylene alkylated reaction under the condition of HTHP makes.Because this reaction needs is carried out under the condition of HTHP, and heat release is violent, reaction is difficult to accurate control.Therefore, react in the prepared product and inevitably contain a large amount of isomer impurities, the purity of Propofol has only about 60%, and is because Propofol is close with its isomer boiling point, very difficult through the fractionation purifying.
From the consideration of drug safety, various countries have all proposed very high requirement to the purity of medical Propofol, and the content of each single impurity has also been made strict restriction.
How to improve the purity of Propofol, become the focus of present research to satisfy medical needs.The Chinese patent of publication number CN101538191 discloses a kind of compound method of high purity Propofol; With 2-isopropyl-phenol, propylene is raw material; Louis acid catalysis such as triethyl aluminum, reaction under pressure 0.4-0.6Mpa, synthesis of high purity Propofol; Have only 92.7% but its purity is the highest, and the purity that requires raw material 2-isopropyl-phenol is more than 99%; Publication number is that the U.S. Patent application of US5589598 discloses a kind of highly purified Propofol preparation method, the Propofol acidylate is obtained the solid of ester, behind the purifying; Hydrolysis again, underpressure distillation can obtain the Propofol of purity more than 99%; But because the hydroxyl steric hindrance is bigger on the Propofol; Adopt chloride method to become ester, acyl chlorides is comparatively responsive to moisture, and equipment also is corrosive.Therefore seeking high purity Propofol simply quick, with low cost, that be fit to suitability for industrialized production is very important.
Summary of the invention
The objective of the invention is to provides a kind of preparation method of high purity Propofol to the deficiency that exists in the prior art.This preparation method is skillfully constructed, flow process is simple, is fit to suitability for industrialized production, and prepared Propofol purity reaches more than 99.9%, meets each item medicinal standard.
For realizing above-mentioned purpose, the technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of high purity Propofol may further comprise the steps:
Wherein, R is selected from: chlorine, bromine or sulphonate.
A kind of preparation method of high purity Propofol may further comprise the steps:
A, Propofol is dissolved in the solvent, in the presence of alkaline reagents, makes Compound C through condensation reaction with general formula (B) compound;
B, Compound C make Compound D through reduction;
C, Compound D and sour salify purifying make compd E;
D, compd E reduce under the catalytic hydrogenation condition and take off benzyl, and pickling is gone monomethylaniline, and underpressure distillation makes required high purity Propofol.
As optimal way; In the said steps A; Said solvent is selected from N, one or more in N '-N, DMSO 99.8MIN., N-Methyl pyrrolidone, hexamethylphosphoramide, acetonitrile, THF, dioxane, ethylene glycol monomethyl ether, methyl alcohol, ethanol or the Virahol.
As optimal way, in the said steps A, alkaline reagents is selected from Pottasium Hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium amide, sodium hydride, triethylamine, Trimethylamine 99 or pyridine.
As optimal way, the R group of said general formula (B) compound is selected from p-toluenesulfonic esters, to phenylfluoroform sulphonate, methanesulfonates or triflate.
As optimal way, in the said steps A, the mol ratio of Propofol bullion A, general formula (B) compound, alkali is 1:1-10:1-10.
Further preferred, in the said steps A, the mol ratio of Propofol bullion A, general formula (B) compound, alkali is 1:1-2:1-2.
As optimal way, in the said steps A, condensation reaction time is 1-24 hour.
Further preferred, in the said steps A, condensation reaction time is 2-6 hour.
As optimal way, in the said steps A, setting-up point is a room temperature.
As optimal way, among the said step B, going back original reagent is tin protochloride, iron powder, zinc powder, Sulfothiorine or Hydrazine Hydrate 80.
Further preferred, the said original reagent of going back is a Hydrazine Hydrate 80.
As optimal way, among the said step B, the mol ratio of going back original reagent and Compound C is 1-10:1.
Further preferred, going back original reagent is Hydrazine Hydrate 80, and the dosage mol ratio of Hydrazine Hydrate 80 and Compound C is 2-6:1.
As optimal way, among the said step C, acid is mineral acid.
Further preferred, said mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid.
Preferred again, said mineral acid is a hydrochloric acid.
As optimal way, among the said step C, purification process is that prepared salt is added in the solvent, feeds the alcoholic solution of hydrogen chloride gas or adding hydrogenchloride again, stirring and crystallizing.
Further preferred, among the said step C, the solid of separating out is further recrystallization or crystallization purifying in solvent.
Preferred again, said solvent is selected from water, C
1-C
4In alcohol, acetone, acetonitrile or the THF one or more.
As optimal way, among the said step D, reduction reaction temperature is 0-100 ℃, and reaction solvent is selected from THF, ETHYLE ACETATE, C
1-C
4In alcohol or the acetone one or more, reaction pressure are 0.1-1MPa, and catalyzer is palladium carbon or Raney's nickel.
Further preferred, said reduction reaction temperature is 20-40 ℃.
Further preferred, said reduction reaction pressure is 0.1-0.5MPa.
The contriver is to each sequence of steps of Propofol purification process, and solvent species adds ratio, and parameters such as the time of reaction, temperature, pressure have been carried out a large amount of research.Through a large amount of experiments; Our surprised discovery is when adopting the Propofol purification process that the present invention put down in writing; This method is done as a whole reaching out of expected effect; Can foreign matter content in the Propofol be dropped to below the ICH requirement, single Control of Impurities meets medicinal standard in per mille.HPLC records its purity and reaches (peak area normalization method) more than 99.9%, and other routine inspections also meet medicinal requirements.
The present invention prepares and do not adopt acyl chlorides in the process, and is insensitive to moisture, and equipment is not produced corrosion, simplified preparation technology, reduced production cost.
The ether derivant of the preparation Propofol of the invention property, and through the salify purifying, solved the difficult problem of Propofol purifying, the USP that has also overcome US5589598 obtains the solid of ester, the drawback of repurity through the Propofol acidylate.Because Propofol becomes behind the ester because the unstable of phenolic ester can produce new impurity when purifying, its stability of ether derivant that the present invention prepares Propofol is higher than its ester derivative, through obtaining highly purified Propofol behind the salify purifying.
Beneficial effect of the present invention is: the present invention is skillfully constructed, flow process is simple, is fit to suitability for industrialized production, and prepared Propofol purity reaches more than 99.9%, meets each item medicinal standard.
Embodiment
Disclosed all characteristics in this specification sheets, or the step in disclosed all methods or the process except mutually exclusive characteristic and/or the step, all can make up by any way.
Embodiment 1:2,6-diisopropyl phenol (178g; 1mol) be dissolved among the 200ml DMF (N, N '-N), keep 25 ° of temperature below the C; Add in batches salt of wormwood (152g, 1.1mol), stir half a hour after; Be added dropwise to that (238g, 1.1mol), controlled temperature is no more than 25 ° of C to the nitrobenzyl bromine.After dripping, insulation reaction 4 hours.After having reacted, add 600ml water, use the 300ml dichloromethane extraction respectively three times, saturated aqueous common salt 200ml washing dichloromethane layer once, anhydrous sodium sulfate drying is evaporated to dried oily matter 266.38g, yield 85%.
Oily matter is dissolved in the 2000ml ethanol, add iron trichloride (25.93g, 0.16mol), gac (25.20g; 2.10mol), stir when being warming up to 80 ℃, slowly drip 80% Hydrazine Hydrate 80 (311ml; 5.1mol), dripped complete insulation reaction 2 hours, filtered while hot; Filtrating is concentrated into dried 222g 2, and the 6-diisopropyl phenyl is to amino benzyl oxide, yield 92%.
500ml ethanol is joined in the resistates, and 0 ° of C drips the ethanolic soln 862ml of 1mol/L hydrogenchloride, continues to stir after 12 hours, filters.With the white solid that obtains recrystallization in 95% ethanol, stir two hours after-filtration, with twice of refrigerative 50ml washing with alcohol solid in advance.40 ° of C vacuum-dryings of solid obtain 2 to constant weight, and the 6-diisopropyl phenyl is to amino benzyl oxide hydrochloride 213g, yield 85%, HPLC purity>99.9%.
With 2, (201.5g 0.63mol) is dissolved in the 800ml ETHYLE ACETATE 6-diisopropyl phenyl to amino benzyl oxide hydrochloride; (96.6ml 0.69mol), 21g 10%Pd/C, feeds hydrogen to add triethylamine; After the stirring at room 24 hours, filter, filtrating is used 100ml 1N salt acid elution 3 times respectively; Saturated aqueous common salt 100ml washs once, and anhydrous sodium sulfate drying is evaporated to dried.The resistates underpressure distillation obtains highly purified Propofol 100.3g, yield 90%, HPLC purity>99.9%.
Embodiment 2:
2,6-diisopropyl phenol (178g; 1mol) be dissolved in the 200ml acetone, keep 25 ° of temperature below the C, add in batches salt of wormwood (152g, 1.1mol), stir half a hour after, be added dropwise to that (238g, 1.1mol), controlled temperature is no more than 25 ° of C to the nitrobenzyl bromine.After dripping, insulation reaction 4 hours.After having reacted, add 600ml water, use the 300ml dichloromethane extraction respectively three times, saturated aqueous common salt 200ml washing dichloromethane layer once, anhydrous sodium sulfate drying is evaporated to dried oily matter 266.38g, yield 85%.
Oily matter is dissolved in the 2000ml ethanol, and (959g, 4.23mol), 70 ℃ are reacted 4h to add stannous chloride dihydrate.After reaction finishes, be cooled to room temperature, be concentrated into dried, add 500ml water after; Transfer to more than the PH to 11 with 10% aqueous sodium hydroxide solution, use the 300ml ethyl acetate extraction respectively three times, anhydrous sodium sulfate drying; Be concentrated into dried 216.8g 2, the 6-diisopropyl phenyl is to amino benzyl oxide, yield 90%.
500ml ethanol is joined in the resistates, and 0 ℃ of ethanolic soln 765ml that drips 1mol/L hydrogenchloride continued to stir after 12 hours, filtered.With the white solid that obtains recrystallization in 95% ethanol, stir two hours after-filtration, with twice of refrigerative 50ml washing with alcohol solid in advance.40 ℃ of vacuum-dryings of solid obtain 2 to constant weight, and the 6-diisopropyl phenyl is to amino benzyl oxide hydrochloride 200g, yield 82%, HPLC purity>99.9%.
With 2, (180g 0.56mol) is dissolved in the 700ml ETHYLE ACETATE 6-diisopropyl phenyl to amino benzyl oxide hydrochloride; (86.3ml 0.62mol), 18g 10%Pd/C, feeds hydrogen to add triethylamine; After the stirring at room 24 hours, filter, filtrating is used 100ml 1N salt acid elution 3 times respectively; Saturated aqueous common salt 100ml washs once, and anhydrous sodium sulfate drying is evaporated to dried.The resistates underpressure distillation obtains highly purified Propofol 90.8g, yield 91%, HPLC purity>99.9%.
Embodiment 3:
2,6-diisopropyl phenol (89g; 0.5mol) be dissolved in the 100ml THF, keep 25 ° of temperature below the C, add in batches yellow soda ash (58.3g, 0.55mol), stir half a hour after, be added dropwise to that (119g, 0.55mol), controlled temperature is no more than 25 ° of C to the nitrobenzyl bromine.After dripping, insulation reaction 4 hours.After having reacted, add 300ml water, use the 150ml dichloromethane extraction respectively three times, saturated aqueous common salt 100ml washing dichloromethane layer once, anhydrous sodium sulfate drying is evaporated to dried oily matter 120g, yield 76.5%.
Oily matter is dissolved in the 1000ml ethanol, add iron trichloride (11.67g, 0.07mol), gac (11.34g; 0.95mol), stir when being warming up to 80 ℃, slowly drip 80% Hydrazine Hydrate 80 (140ml; 2.30mol), dripped complete insulation reaction 2 hours, filtered while hot; Filtrating is concentrated into dried 94.9g 2, and the 6-diisopropyl phenyl is to amino benzyl oxide, yield 87%.
250ml ethanol is joined in the resistates, and 0 ℃ of methanol solution 431ml that drips 1mol/L hydrogenchloride continued to stir after 12 hours, filtered.With the white solid that obtains recrystallization in methyl alcohol, stir two hours after-filtration, with twice of refrigerative 25ml methanol wash solid in advance.40 ℃ of vacuum-dryings of solid obtain 2 to constant weight, and the 6-diisopropyl phenyl is to amino benzyl oxide hydrochloride 87.8g, yield 82%, HPLC purity>99.9%.
With 2, (50g 0.315mol) is dissolved in the 400ml methyl alcohol 6-diisopropyl phenyl to amino benzyl oxide hydrochloride; (24.15ml 0.17mol), the 5g Raney's nickel, feeds hydrogen to add triethylamine; After the stirring at room 24 hours, filter, filtrating is used 25ml 1N salt acid elution 3 times respectively; Saturated aqueous common salt 50ml washs once, and anhydrous sodium sulfate drying is evaporated to dried.The resistates underpressure distillation obtains highly purified Propofol 25g, yield 90%, HPLC purity>99.9%.
Embodiment 4:
The preparation method of present embodiment is identical with embodiment 1, and when difference was to prepare Compound C, used alkali was sodium hydroxide, and temperature of reaction is no more than 25 ° of C, and the reaction times is 3 hours, yield 82%, HPLC purity>99.9%.
Embodiment 5:
The preparation method of present embodiment is identical with embodiment 1, and difference is that recrystallization solvent is an acetone behind the salify, yield 92%, HPLC purity>99.9%.
Embodiment 6:
The preparation method of present embodiment is identical with embodiment 1, and pressure was 0.3MPa when difference was to take off benzyl, yield 88%, HPLC purity>99.9%.
Claims (21)
1. the preparation method of a high purity Propofol is characterized in that may further comprise the steps:
Wherein, R is selected from: chlorine, bromine or sulphonate.
2. the preparation method of a kind of high purity Propofol according to claim 1 is characterized in that may further comprise the steps:
A, with the Propofol dissolving crude product in solvent, in the presence of alkaline reagents, make Compound C with general formula (B) compound through condensation reaction;
B, Compound C make Compound D through reduction;
C, Compound D and sour salify purifying make compd E;
D, compd E reduce under the catalytic hydrogenation condition and take off benzyl, and pickling is gone monomethylaniline, and underpressure distillation makes required high purity Propofol.
3. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: in the said steps A, the dosage mol ratio of Propofol bullion, general formula (B) compound, alkaline reagents is: 1:1-10:1-10.
4. the preparation method of a kind of high purity Propofol according to claim 3 is characterized in that: in the said steps A, the dosage mol ratio of Propofol bullion, general formula (B) compound, alkaline reagents is: 1:1-2:1-2.
5. the preparation method of a kind of high purity Propofol according to claim 2; It is characterized in that: in the said steps A; Said solvent is selected from N, one or more in N '-N, DMSO 99.8MIN., N-Methyl pyrrolidone, hexamethylphosphoramide, acetonitrile, THF, dioxane, ethylene glycol monomethyl ether, methyl alcohol, ethanol or the Virahol.
6. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: in the said steps A, alkaline reagents is selected from Pottasium Hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium amide, sodium hydride, triethylamine, Trimethylamine 99 or pyridine.
7. the preparation method of a kind of high purity Propofol according to claim 1 and 2 is characterized in that: the R group of said general formula (B) compound is selected from p-toluenesulfonic esters, to phenylfluoroform sulphonate, methanesulfonates or triflate.
8. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: in the said steps A, condensation reaction time is 1-24 hour.
9. the preparation method of a kind of high purity Propofol according to claim 8 is characterized in that: in the said steps A, condensation reaction time is 2-6 hour.
10. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: in the said steps A, setting-up point is a room temperature.
11. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: among the said step B, going back original reagent is tin protochloride, iron powder, zinc powder, Sulfothiorine or Hydrazine Hydrate 80; Said dosage mol ratio of going back original reagent and Compound C is 1-10:1.
12. the preparation method of a kind of high purity Propofol according to claim 11 is characterized in that: the said original reagent of going back is a Hydrazine Hydrate 80, and the dosage mol ratio of Hydrazine Hydrate 80 and Compound C is 2-6:1.
13. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: among the said step C, acid is mineral acid.
14. the preparation method of a kind of high purity Propofol according to claim 13 is characterized in that: said mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid.
15. the preparation method of a kind of high purity Propofol according to claim 14 is characterized in that: said mineral acid is a hydrochloric acid.
16. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: among the said step C, purification process is that prepared salt is added in the solvent, feeds the alcoholic solution of hydrogen chloride gas or adding hydrogenchloride again, stirring and crystallizing.
17. the preparation method of a kind of high purity Propofol according to claim 16 is characterized in that: among the said step C, the solid of separating out is further recrystallization or crystallization purifying in solvent.
18. the preparation method according to claim 16 or 17 described a kind of high purity Propofols is characterized in that: said solvent is selected from water, C
1-C
4In alcohol, acetone, acetonitrile or the THF one or more.
19. the preparation method of a kind of high purity Propofol according to claim 2 is characterized in that: among the said step D, reduction reaction temperature is 0-100 ℃, and reaction solvent is selected from THF, ETHYLE ACETATE, C
1-C
4In alcohol or the acetone one or more, reaction pressure are 0.1-1MPa, and catalyzer is palladium carbon or Raney's nickel.
20. the preparation method of a kind of high purity Propofol according to claim 19 is characterized in that: said reduction reaction temperature is 20-40 ℃.
21. the preparation method of a kind of high purity Propofol according to claim 19 is characterized in that: said reduction reaction pressure is 0.1-0.5MPa.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896743A (en) * | 2012-12-28 | 2014-07-02 | 四川海思科制药有限公司 | 2,6-diisopropyl-4-fluorophenol or salt and crystal form thereof as well as preparation method and application thereof |
| CN104649867A (en) * | 2013-11-21 | 2015-05-27 | 辽宁药联制药有限公司 | Preparation method of propofol |
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|---|---|---|---|---|
| CN1100084A (en) * | 1993-09-08 | 1995-03-15 | 东国制药株式会社 | Process for producing ortho-isopropylated phenol derivatives |
| CN101538191A (en) * | 2009-05-06 | 2009-09-23 | 西安力邦制药有限公司 | Synthetic method of high-purity propofol |
| CN101687746A (en) * | 2007-05-09 | 2010-03-31 | 法莫科佛股份有限公司 | therapeutic compounds |
| CN101715437A (en) * | 2007-05-09 | 2010-05-26 | 法莫科佛股份有限公司 | Stereoisomers propofol therapeutic compounds |
| WO2011161687A1 (en) * | 2010-06-23 | 2011-12-29 | Harman Finochem Limited | Process for preparing extra pure 2, 6-diisopropyl phenol |
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2012
- 2012-06-12 CN CN201210191895.2A patent/CN102731265B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1100084A (en) * | 1993-09-08 | 1995-03-15 | 东国制药株式会社 | Process for producing ortho-isopropylated phenol derivatives |
| CN101687746A (en) * | 2007-05-09 | 2010-03-31 | 法莫科佛股份有限公司 | therapeutic compounds |
| CN101715437A (en) * | 2007-05-09 | 2010-05-26 | 法莫科佛股份有限公司 | Stereoisomers propofol therapeutic compounds |
| CN101538191A (en) * | 2009-05-06 | 2009-09-23 | 西安力邦制药有限公司 | Synthetic method of high-purity propofol |
| WO2011161687A1 (en) * | 2010-06-23 | 2011-12-29 | Harman Finochem Limited | Process for preparing extra pure 2, 6-diisopropyl phenol |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103896743A (en) * | 2012-12-28 | 2014-07-02 | 四川海思科制药有限公司 | 2,6-diisopropyl-4-fluorophenol or salt and crystal form thereof as well as preparation method and application thereof |
| CN103896743B (en) * | 2012-12-28 | 2017-04-05 | 四川海思科制药有限公司 | A kind of preparation method of 2,6 diisopropyl, 4 fluorophenol |
| 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 |
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Effective date of registration: 20160829 Address after: Phoenix North Qianwei County Road 614000 Sichuan Yujin Town, Leshan City Patentee after: Sichuan Guorui Pharmaceutical Co., Ltd. Address before: 611130 Wenjiang, Chengdu, Chengdu, Wenjiang cross strait science and Technology Industrial Park Patentee before: Baili Pharmaceutical Co., Ltd., Sichuan Prov. |