CN101768164A - Naloxone hydrochloride compound with high purity - Google Patents
Naloxone hydrochloride compound with high purity Download PDFInfo
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- CN101768164A CN101768164A CN201010100170A CN201010100170A CN101768164A CN 101768164 A CN101768164 A CN 101768164A CN 201010100170 A CN201010100170 A CN 201010100170A CN 201010100170 A CN201010100170 A CN 201010100170A CN 101768164 A CN101768164 A CN 101768164A
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Abstract
The invention relates to a naloxone hydrochloride compound, in particular to a naloxone hydrochloride compound with high purity obtained by a method, belonging to the technical field of medicine. By acid-base reaction, polyamide resin elution and activated carbon absorption, the purity of the naloxone hydrochloride is greatly improved, the product quality of preparation is optimized, and clinic pharmacy safety is ensured; and the method has the advantages of simple process, low cost and high yield, and is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of naloxone hydrochloride compound, can obtain highly purified naloxone hydrochloride, belong to medical technical field by this method.
Background technology
Naloxone hydrochloride, chemical name is: 17-allyl group-4.5a-epoxy group(ing)-3.14-dihydroxyl morphinan-6-ones hydrochloride dihydrate, molecular formula: C
19H
21NO
4HCl2H
2O, molecular weight: 399.87, structural formula is shown in following formula (I):
Naloxone hydrochloride is the opiate receptor antagonistic, and itself is parmacodynamics-less activity almost, but each opioid receptor of energy competitive antagonism has very strong avidity to the μ acceptor.Be used to remove the respiration inhibition due to the opioid drug combined anesthesia medicine postoperative clinically, and waken patient, it is excessive to be used for opioid drug, is used for acute alcoholism.
The synthetic method of naloxone hydrochloride has a lot of reports both at home and abroad, but purity is relatively poor, causes the quality of the pharmaceutical preparations defective, has influenced clinical application.
Summary of the invention
The method of usually synthetic naloxone is as being starting raw material with the thebaine, through oxidation, hydrogenation, acidylate, cyaniding, boron tribromide deoxidation methyl, hydrolysis, N
2Allylation totally 7 steps reaction obtains naloxone, and total recovery is about 40.5%.Because in this synthetic method, in entire reaction course, this step of demethyl is very crucial, at present, deoxidation methyl method commonly used has the boron tribromide method, methylsulfonic acid/DL-methionine(Met) method, hydrobromic acid method.The boron tribromide method is comparatively commonly used in naloxone is synthetic, but in its reaction process, each atom with lone-pair electron all will combine with the boron tribromide of a part in the reaction substrate, so the mol ratio of boron tribromide consumption is up to 7 times in the preparation of the naloxone of bibliographical information, and boron tribromide reagent itself costs an arm and a leg, the cost height; The temperature of reaction of boron tribromide method need be controlled at below 10 ℃ in addition, and toxicity is bigger again, is not suitable for scale production.This wherein methylsulfonic acid/DL-methionine(Met) method have the characteristics of cheap low toxicity, also be naloxone synthetic in a good deoxidation methyl method; But the reaction of the deoxidation methyl of literature method is in the end of whole piece route, so total recovery is not very high.In addition, because the variation of reaction conditions is easy to generate impurity, for example the by product that not exclusively brings of demethyl is therefore relatively poor in the general purity of naloxone crude product of suitability for industrialized production, causes the quality of the pharmaceutical preparations defective, has influenced clinical application in above-mentioned reaction process.
In order to overcome above-mentioned defective, we have adopted the method for multiple purifying naloxone crude product, silicagel column for example, alumina column, materials such as macroporous resin carry out chromatographic separation to the naloxone crude product to be handled, product after processing purity after the analysis of HPLC method does not still reach satisfied degree, further test is found, use the polymeric amide packed column, aqueous ethanolic solution with the certain volume ratio carries out wash-out, remove isolating first component of pillar wash-out, use the further again wash-out of aqueous ethanolic solution of another ratio then, obtain the second component naloxone, select for use second component to carry out aftertreatment and obtain final product, purity reaches the purity of pharmacopeia defined after the analysis of HPLC method, satisfied conduct application pharmaceutically.
Therefore, the object of the present invention is to provide a kind of process for purification of naloxone hydrochloride compound, pass through acid-base reaction, carry out wash-out twice with polyamide resin column then, then product is dissolved in solvent, charcoal absorption, reach the purpose of refining purifying, finally obtain highly purified naloxone hydrochloride compound, optimized the quality of formulation products, ensured safety of clinical administration.
The process for purification of naloxone hydrochloride compound provided by the invention comprises the steps:
(1) add entry to the naloxone hydrochloride crude product, stirring and dissolving slowly adds alkali to separating out the insolubles naloxone;
(2) insolubles is packed into polyamide resin column at first uses the aqueous ethanolic solution (V/V) of 10-15% to carry out wash-out, removes isolating first component of pillar wash-out, and the aqueous ethanolic solution (V/V) of using 80-90% then is further wash-out again, obtains second component;
(3) then described second component is dissolved in the solvent, the charcoal absorption purifying filters, and collects filtrate;
(4) to filtrate dripping hydrochloric acid solution, finally obtain highly purified naloxone hydrochloride compound.
Above-mentioned described process for purification, wherein said alkali is highly basic or strong base-weak acid salt, is selected from sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, S-WAT, sodium-acetate, is preferably sodium bicarbonate.
Above-mentioned described process for purification, wherein said first component is impure than polycomponent, second component is for containing the naloxone component.
Above-mentioned described process for purification, wherein said solvent is selected from methylene dichloride, normal hexane, Skellysolve A, acetonitrile, acetone, ethanol, Virahol, propyl carbinol, is preferably methylene dichloride.
Above-mentioned described process for purification, naloxone hydrochloride and alkali reaction to pH value of solution value is 8-10, is preferably 8.5-9.5.
Above-mentioned described process for purification, naloxone and hydrochloric acid reaction to pH value of solution value is 4-6, is preferably 4.5-5.5.
Above-mentioned described process for purification, wherein purge process was heated to 40-60 ℃ of whip attachment 10-30 minute for adding the gac of overall solution volume 0.1-0.2 (g/ml).
As the present invention's one preferred embodiment, the process for purification of described naloxone hydrochloride compound comprises the steps:
(1) to the water of naloxone hydrochloride crude product by 3-10 times of volume of adding, stirring and dissolving slowly adds alkali to separating out the insolubles naloxone, filters, and 40-50 ℃ of drying under reduced pressure gets the naloxone crude product;
(2) insolubles is packed into polyamide resin column at first uses the aqueous ethanolic solution (V/V) of 10-15% to carry out wash-out, removes isolating first component of pillar wash-out, and the aqueous ethanolic solution (V/V) of using 80-90% then is further wash-out again, obtains second component;
(3) then described second component is dissolved in the solvent, adds the gac of overall solution volume 0.1-0.2 (g/ml), be heated to 40-60 ℃ of whip attachment 10-30 minute, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 0.5-2mol/L is 4-5 in filtrate, separates out insolubles, and stirring at room reaction 20-30 minute is filtered, and 40-50 ℃ of drying under reduced pressure gets the naloxone hydrochloride highly finished product.
The process for purification of naloxone hydrochloride compound provided by the invention, by acid-base reaction, the polyamide resin wash-out is handled, and charcoal absorption has improved the purity of naloxone hydrochloride greatly, has optimized the quality product of preparation, has ensured safety of clinical administration; Present method technology is simple, and cost is low, and the yield height is suitable for suitability for industrialized production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
The preparation of polyamide resin column, accurately take by weighing respectively 20 and 80g 100-200 order polymeric amide dried resin in beaker, fully dissolve with distilled water, clean, stand-by, test in the exchange column of it can being packed at the trial.The high performance liquid chromatograph that the present invention uses is LC-VP (day island proper Tianjin), and other reagent all is analytical pure.Measure the purity of final product according to the method for routine.
Making with extra care of embodiment 1 naloxone hydrochloride
(1) 100g naloxone hydrochloride crude product is dissolved in the 1000ml water, stirred 10 minutes, slowly adding 5% sodium hydroxide solution to pH value is 9.5, separates out insolubles, and stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure, naloxone 75.3g;
(2) naloxone 10g is packed into 200ml polyamide resin, at first use 10% aqueous ethanolic solution (V/V) to carry out wash-out, remove isolating first component of pillar wash-out, use 80% the further again wash-out of aqueous ethanolic solution (V/V) then, obtain second component, collect on the pillar and tell the second maximum elution fractions;
(3) component of collecting is added in the 200ml methylene dichloride, add the gac of 0.3g, be heated to 50 ℃ of whip attachment 15 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 0.5mol/L is 3 in filtrate, separates out insolubles, and stirring at room reaction 30 minutes is filtered, and 50 ℃ of drying under reduced pressure get naloxone hydrochloride highly finished product 10.0g, and total recovery is 81.9%, and it is 99.65% that HPLC detects purity.
Making with extra care of embodiment 2 naloxone hydrochlorides
(1) 100g naloxone hydrochloride crude product is dissolved in the 1000ml water, stirred 10 minutes, slowly adding 5% sodium hydroxide solution to pH value is 9.5, separates out insolubles, and stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure, naloxone 74.6g;
(2) naloxone 15g is packed into 300ml polyamide resin, at first use 10% aqueous ethanolic solution (V/V) to carry out wash-out, remove isolating first component of pillar wash-out, use 80% the further again wash-out of aqueous ethanolic solution (V/V) then, obtain second component, collect on the pillar and tell the second maximum elution fractions;
(3) component of collecting is added in the 300ml methylene dichloride, add the gac of 0.4g, be heated to 40 ℃ of whip attachment 20 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 1.0mol/L is 3.5 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 50 ℃ of drying under reduced pressure get naloxone hydrochloride highly finished product 14.8g, and total recovery is 80.8%, and it is 99.52% that HPLC detects purity.
Making with extra care of embodiment 3 naloxone hydrochlorides
(1) 100g naloxone hydrochloride crude product is dissolved in the 1000ml water, stirred 10 minutes, slowly adding 5% sodium hydrogen carbonate solution to pH value is 10.0, separates out insolubles, and stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure, naloxone 75.2g;
(2) naloxone 15g is packed into 300ml polyamide resin, at first use 15% aqueous ethanolic solution (V/V) to carry out wash-out, remove isolating first component of pillar wash-out, use 85% the further again wash-out of aqueous ethanolic solution (V/V) then, obtain second component, collect on the pillar and tell the second maximum elution fractions;
(3) component of collecting is added in the 300ml methylene dichloride, add the gac of 0.4g, be heated to 40 ℃ of whip attachment 30 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 2.0mol/L is 3.0 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 50 ℃ of drying under reduced pressure get naloxone hydrochloride highly finished product 15.1g, and total recovery is 84.1%, and it is 99.60% that HPLC detects purity.
Making with extra care of embodiment 4 naloxone hydrochlorides
(1) 100g naloxone hydrochloride crude product is dissolved in the 1000ml water, stirred 10 minutes, slowly adding 8% sodium acetate soln to pH value is 9.3, separates out insolubles, and stirring reaction 20 minutes filters, 50 ℃ of drying under reduced pressure, naloxone 73.3g;
(2) naloxone 10g is packed into 200ml polyamide resin, at first use 15% aqueous ethanolic solution (V/V) to carry out wash-out, remove isolating first component of pillar wash-out, use 90% the further again wash-out of aqueous ethanolic solution (V/V) then, obtain second component, collect on the pillar and tell the second maximum elution fractions;
(3) component of collecting is added in the 200ml methylene dichloride, add the gac of 0.3g, be heated to 45 ℃ of whip attachment 25 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 2.0mol/L is 3.5 in filtrate, separates out insolubles, and stirring at room reaction 20 minutes is filtered, and 50 ℃ of drying under reduced pressure get naloxone hydrochloride highly finished product 10.0g, and total recovery is 81.8%, and it is 99.32% that HPLC detects purity.
Making with extra care of embodiment 5 naloxone hydrochlorides
(1) 100g naloxone hydrochloride crude product is dissolved in the 1000ml water, stirred 10 minutes, slowly adding 6% sodium sulfite solution to pH value is 9.7, separates out insolubles, and stirring reaction 15 minutes filters, 45 ℃ of drying under reduced pressure, naloxone 73.8g;
(2) naloxone 15g is packed into 200ml polyamide resin, at first use 10% aqueous ethanolic solution (V/V) to carry out wash-out, remove isolating first component of pillar wash-out, use 90% the further again wash-out of aqueous ethanolic solution (V/V) then, obtain second component, collect on the pillar and tell the second maximum elution fractions;
(3) component of collecting is added in the 300ml methylene dichloride, add the gac of 0.5g, be heated to 50 ℃ of whip attachment 20 minutes, filter decarburization, collect filtrate;
(4) hydrochloric acid soln to the pH value of dropping 1.5mol/L is 3.0 in filtrate, separates out insolubles, and stirring at room reaction 25 minutes is filtered, and 45 ℃ of drying under reduced pressure get naloxone hydrochloride highly finished product 15.1g, and total recovery is 82.1%, and it is 99.32% that HPLC detects purity.
Claims (8)
1. the naloxone hydrochloride compound shown in the formula (I) comprises the steps:
(1) add entry to the naloxone hydrochloride crude product, stirring and dissolving slowly adds alkali to separating out the insolubles naloxone;
(2) insolubles is packed into polyamide resin column at first uses the aqueous ethanolic solution (V/V) of 10-15% to carry out wash-out, removes isolating first component of pillar wash-out, and the aqueous ethanolic solution (V/V) of using 80-90% then is further wash-out again, obtains second component;
(3) then described second component is dissolved in the solvent, the charcoal absorption purifying filters, and collects filtrate;
(4) to filtrate dripping hydrochloric acid solution, finally obtain highly purified naloxone hydrochloride compound.
2. process for purification according to claim 1 is characterized in that described alkali is highly basic or strong base-weak acid salt.
3. process for purification according to claim 2 is characterized in that described alkali is sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, S-WAT, sodium-acetate.
4. process for purification according to claim 1 is characterized in that described solvent is methylene dichloride, normal hexane, Skellysolve A, acetonitrile, acetone, ethanol, Virahol, propyl carbinol.
5. process for purification according to claim 1, it is characterized in that with alkali reaction to pH value of solution value be 8-10.
6. process for purification according to claim 5, it is characterized in that with alkali reaction to pH value of solution value be 8.5-9.5.
7. process for purification according to claim 1, it is characterized in that with hydrochloric acid reaction to pH value of solution value be 4-6.
8. process for purification according to claim 7, it is characterized in that with hydrochloric acid reaction to pH value of solution value be 4.5-5.5.
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| CN2010101001709A CN101768164B (en) | 2010-01-25 | 2010-01-25 | Naloxone hydrochloride compound with high purity |
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| JP2015504856A (en) * | 2011-12-06 | 2015-02-16 | ハー・ルンドベック・アクチエゼルスカベット | Method for recovering nalmefene hydrochloride |
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| JP2015504856A (en) * | 2011-12-06 | 2015-02-16 | ハー・ルンドベック・アクチエゼルスカベット | Method for recovering nalmefene hydrochloride |
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Assignee: Hainan Lingkang Pharmaceutical Co., Ltd. Assignor: Hainan Shu Er Pharmaceutical Research Co., Ltd. Contract record no.: 2011990001062 Denomination of invention: Naloxone hydrochloride compound with high purity Granted publication date: 20110914 License type: Exclusive License Open date: 20100707 Record date: 20111128 |
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