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WO1997019083A1 - Procede pour extraire et purifier de la morphine a partir d'opium - Google Patents

Procede pour extraire et purifier de la morphine a partir d'opium Download PDF

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Publication number
WO1997019083A1
WO1997019083A1 PCT/US1996/018793 US9618793W WO9719083A1 WO 1997019083 A1 WO1997019083 A1 WO 1997019083A1 US 9618793 W US9618793 W US 9618793W WO 9719083 A1 WO9719083 A1 WO 9719083A1
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WO
WIPO (PCT)
Prior art keywords
basic
solution
methanol
extracting
alcohol
Prior art date
Application number
PCT/US1996/018793
Other languages
English (en)
Other versions
WO1997019083A9 (fr
Inventor
Junning Ma
Robert C. Corcoran
Original Assignee
The Board Of Regents Of The University And Community College System Of Nevada On Behalf Of The University Of Nevada-Reno
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/753,061 external-priority patent/US6054584A/en
Application filed by The Board Of Regents Of The University And Community College System Of Nevada On Behalf Of The University Of Nevada-Reno filed Critical The Board Of Regents Of The University And Community College System Of Nevada On Behalf Of The University Of Nevada-Reno
Priority to AU10815/97A priority Critical patent/AU1081597A/en
Publication of WO1997019083A1 publication Critical patent/WO1997019083A1/fr
Publication of WO1997019083A9 publication Critical patent/WO1997019083A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Definitions

  • This invention relates to an improved process for the extraction and purification of morphine from opium.
  • the object of this invention is to provide a more economical method of preparing morphine that utilizes less environmentally toxic solvents.
  • Morphine is useful as an analgesic drug. It is also used as the starting material for the preparation of codeine, which is another analgesic and antitussive drug. Morphine occurs naturally in opium to the extent of 9 to 17% by weight, depending upon the opium source.
  • the present invention relates to a process for extracting morphine from opium.
  • the process of the invention answers the deficiencies of prior art processes.
  • opium is extracted with a basic alcoholic solution.
  • the basic alcoholic solution is filtered and the alcohol removed from the filtrate to leave a residue.
  • the residue is then extracted with a basic aqueous solution having a pH of at least 1 1 .
  • the basic aqueous solution may be filtered to remove any solid matter remaining after the aqueous extraction step, and may then be stirred with a sufficicnl amount of a salt to avoid emulsion formation.
  • the basic aqueous solution is then extracted with a substantially water-immiscible solvent such as benzene or toluene.
  • adjusting the pH of the basic aqueous solution to pH 8.5 to 9.5 allows the morphine to precipitate and be recovered.
  • Figure 1 depicts a preferred process according to the invention for extracting and purifying morphine from opium.
  • morphine is extracted from opium by stirring and/or heating, or preferably refluxing, opium in a basic solution of an alcohol, preferably methanol at about pH 9.
  • the pH may be adjusted by the addition of an inorganic base (alkali hydroxide, or carbonate), ammonia, and the like.
  • inorganic bases include, but are not limited to, sodium hydroxide and potassium hydroxide.
  • the resulting residue, which contains the alkaloids, is mixed or extracted with an basic aqueous solution having a pH of at least 1 1 , preferably an aqueous solution of an alkali hydroxide.
  • an basic aqueous solution having a pH of at least 1 1 preferably an aqueous solution of an alkali hydroxide.
  • This converts the morphine free base present into its anionic (morphinatc) fo ⁇ n which is soluble in basic solutions at pH values of 1 1 or above.
  • Other opium alkaloids are relatively insoluble and, in general, at least partially precipitate out ofthe basic aqueous solution.
  • the remaining alkaloids are separated from the morphine- containing basic aqueous solution by extraction with a substantially water-immiscible solvent, such as toluene or benzene.
  • the morphine free base is precipitated out ofthe resulting aqueous solution by adjusting the pll of the aqueous filtrate to pll 8.5 to 9.5.
  • the pH to precipitate the morphine ranges from about 9 to 9.3, and most preferably is about 9.1. This is accomplished by adding either an organic acid or a mineral acid. The yield and purity of morphine produced by this procedure are economically satisfactory.
  • the morphine obtained from this process may then be further purified by known methods or utilized directly in a further process to convert it into codeine.
  • the extraction of morphine from opium may be accomplished by stirring and/or heating, preferably refluxing, opium with a basic solution of an alcohol capable dissolving morphine in its neutral, cationic, and/or anionic form.
  • the alcohol is a C r C 6 alcohol.
  • Particularly preferred alcohols include methanol, ethanol, and isopropanol. Mixtures of alcohols may also be used.
  • Methanol the preferred solvent for the invention, is a excellent solvent for extracting alkaloids from opium. Almost all of the alkaloids, especially morphine, are highly soluble in methanol.
  • the alkaloids are soluble in methanol in their neutral, cationic, or anionic forms.
  • an alkali, alkaline earth, or other suitable base to adjust the pH of the alcohol, to about 9, makes the extraction process more efficient. This results in more alkaloids and less impurities being extracted into the alcohol.
  • Refluxing opium in a basic solution of the alcohol, preferably methanol at about pH 9, for approximately one to two hours extracts more than 90% of the morphine present.
  • 5 g of opium, cut into small pieces may be extracted by reflux with 0.2 to 0.6 g, preferably 0.4 g, of sodium hydroxide in 25 ml of methanol for 1 to 2 hrs.
  • An additional extraction of the opium with a basic alcohol, such as methanol at pH 9, can recover essentially all of the alkaloids from opium.
  • the second extract can either be combined with the first extract or can be used lo extract another batch of opium. Separation ofthe alcohol extract from the undissolved residue by filtration or other similar means is generally easy and fast. Unlike an aqueous extraction process, the assistance of filter aid at this step is generally unnecessary.
  • aqueous extracts or organic solutions e.g. toluene
  • a small amount of filter aid may be added to the alcohol extract before distillation to prevent the alcohol extract from foaming and bumping.
  • the recovered alcohol particularly methanol. can be recycled and used for another extraction without further purification.
  • morphine is usually kept as an acid salt due to concerns regarding the stability of morphine in basic solutions. To test the stability of morphinate in basic aqueous solutions, morphinatc was analyzed by High Performance Liquid Chromatography (HPLC) and then allowed to stay overnight at room temperature. The morphinate was then reanalyzed by HPLC. No loss of morphine was found.
  • the residue remaining after removing the alcohol is then extracted with a basic aqueous solution having a pH of at least 1 1.
  • the basic aqueous solution is a solution of an alkali hydroxide such as sodium hydroxide or potassium hydroxide. Solutions of other bases may also be used. Maintaining the pH ofthe aqueous extract at this pFI and preferably within a relatively narrow preferred range allows high quality morphine to be obtained with good recovery. At lower pH values, greater amounts of morphine may be lost in the initial precipitate. At higher pH values, less impurities may be extracted into toluene. Maintaining the pH in the range of 11.5 to 11.9 is, therefore, preferred.
  • the basic aqueous solution may optionally be filtered to remove any solid material remaining after the aqueous extraction step. Filtering the basic aqueous solution at this point removes insoluble non-morphine alkaloids. Any precipitate may be washed with -in additional quantity of the basic aqueous solution to ensure increased recovery of the morphine.
  • the basic aqueous solution or filtrate if filtered, is then extracted with a substantially water-immiscible organic solvent to remove the remaining alkaloids from the basic aqueous filtrate.
  • Suitable solvents include, but are not limited to, benzene, toluene, xylene, diethyl ether, and chloroform. Separation ofthe resulting aqueous and organic phases may be accomplished by techniques known in the art.
  • non-morphine alkaloids are supposed to precipitate out of concentrated aqueous solutions at pH values around 1 1-12.
  • the presence of concentrated morphinate ions may increase the solubility of the other alkaloids.
  • substantial amounts of non- morphine alkaloids may remain in solution.
  • Direct extraction of the basic aqueous solution or filtrate, if filtered, with a substantially water-immiscible solvent can remove those alkaloids, but may result in formation of an emulsion.
  • the aqueous solution/filtrate may, before extraction with the substantially water-immiscible solvent, first be treated with a sufficient amount of an alkali metal salt or alkaline earth metal salt, for example 0.5 to 5 grams salt for each 5 grams of opium.
  • Preferred salts are, for example, lithium chloride, lithium bromide, lithium acetate, sodium chloride, sodium bromide, sodium acetate, potassium chloride, potassium bromide, or potassium acetate.
  • a preferred amount of the salt is 0.5 to 2 grams per 5 grams of opium.
  • Sodium chloride and sodium acetate are preferred salts with sodium acetate being particularly preferred.
  • the extract may then preferably filtered again to get rid of any gummy or other precipitate prior to extracting with a substantially water-immiscible solvent, such as benzene or toluene.
  • the sequence of the morphine purification procedure may, however, affect the recovery of morphine. For example, if, to avoid emulsion formation upon extraction, a salt is added to the basic aqueous solution before it is filtered after the aqueous extraction step, as much as about 20% of the morphine may precipitate out along with the other alkaloids. Accordingly, the recovery of morphine will be substantially lower.
  • a small amount, generally about 8%, of the morphine may be extracted into the solvent. This may be recovered by back extraction with additional basic solution, for instance, a sodium hydroxide solution. Any loss of mo ⁇ hine in the aqueous mother liquor, about 2%, may be recovered by additional extraction with the solvent.
  • additional basic solution for instance, a sodium hydroxide solution.
  • Any loss of mo ⁇ hine in the aqueous mother liquor, about 2%, may be recovered by additional extraction with the solvent.
  • the use of toluene is preferred, particularly over benzene, in the process of the invention.
  • Any alkaloids precipitated on a filter aid or paper in the process may be recovered by extraction with an alcohol, preferably methanol.
  • the filter aid can be used again without further purification.
  • the other opiate alkaloids that were extracted into the substantially water- immiscible solvent may be combined wilh the alkaloids which precipitated from the aqueous extract at pH 1 1.5 to 1 1.9 and further purified by other known methods.
  • the pH of the basic aqueous solution/filtrate is adjusted to about 8.5 to 9.5 to precipitate the morphine.
  • the pH is adjusted to 9 to 9.3 and more preferably to 9.1.
  • the pH may be adjusted using an acid such as, for example, sulfuric acid, hydrochloric acid or acetic acid.
  • a 50% acetic acid in water solution is used.
  • the precipitated mo ⁇ hine may then be recovered using techniques known in the art such as filtration or decantation.
  • the recovered morphine is preferably washed with water before drying.
  • Figure 1 depicts a preferred process ofthe invention. The whole process, from extraction of opium to precipitation of purified mo ⁇ hine, can generally be completed in one day. This is much more efficient than other existing commercial purification methods.
  • EXAMPLE 5 g of opium were cut into small pieces and extracted by reflux with 0.4 g of sodium hydroxide in 25 ml of methanol for 1 to 2 hrs. The methanol extract was then filtered to remove particulate materials. After addition of 1 g of filter aid to the methanol extract, which contained 465 to 485 mg of morphine, the methanol was removed under reduced pressure. The residue was then mixed with 5.5 ml of 1.0 N sodium hydroxide solution at 35 ° C for 10 min. and the pH adjusted to about 1 1.5 to 1 1.9 with 50% acetic acid in water. This aqueous extract was then filtered and the precipitate washed with 5.5 ml of 0.01 N sodium hydroxide solution.
  • the combined aqueous filtrate was stirred with 0.5 g of sodium acetate for 10 minutes and filtered again.
  • the fi I Irate was then extracted twice wilh 5 ml of toluene and Ihc pi I of the aqueous filtrate was then adjusted to pll 9.1 , with 50% acetic acid in water.
  • the mixture was allowed to remain for a period of 6-10 hrs at room temperature for complete precipitation and was then filtered.
  • This precipitate was washed with water and dried at room temperature.
  • This final precipitate contained 400-426 mg of morphine, which represented a recovery of 86-88%) based upon the amount of mo ⁇ hine in the initial methanol extract.
  • the purity of morphine following this procedure was 84% to 86% by weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un procédé pour extraire de la morphine contenue dans de l'opium. Dans ce procédé, l'opium est extrait au moyen d'une solution alcoolique basique. Cette solution alcoolique basique est filtrée et l'alcool est retiré du filtrat pour laisser un résidu. Le résidu est ensuite extrait au moyen d'une solution aqueuse basique ayant un pH d'au moins 11. Cette solution aqueuse basique peut être filtrée pour que soit éliminée toute matière solide restant après l'étape d'extraction aqueuse, et ladite solution aqueuse basique peut ensuite être agitée avec un sel en quantité suffisante pour éviter la formation d'émulsion. La solution aqueuse basique ou le filtrat aqueux basique est ensuite extrait avec du benzène ou du toluène. L'ajustement du pH du filtrat aqueux basique dans des limites comprises entre 8,5 à 9,5 permet ensuite à la morphine de précipiter et d'etre recupérée.
PCT/US1996/018793 1995-11-21 1996-11-21 Procede pour extraire et purifier de la morphine a partir d'opium WO1997019083A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10815/97A AU1081597A (en) 1995-11-21 1996-11-21 Process for extracting and purifying morphine from opium

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US741895P 1995-11-21 1995-11-21
US60/007,418 1995-11-21
US08/753,061 1996-11-19
US08/753,061 US6054584A (en) 1996-11-19 1996-11-19 Process for extracting and purifying morphine from opium

Publications (2)

Publication Number Publication Date
WO1997019083A1 true WO1997019083A1 (fr) 1997-05-29
WO1997019083A9 WO1997019083A9 (fr) 1997-10-16

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PCT/US1996/018793 WO1997019083A1 (fr) 1995-11-21 1996-11-21 Procede pour extraire et purifier de la morphine a partir d'opium

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102749402A (zh) * 2012-08-07 2012-10-24 公安部禁毒情报技术中心 吗啡盐酸盐标准物质的制备方法
CN110713494A (zh) * 2019-09-20 2020-01-21 甘肃省药物碱厂 一种从高纯度吗啡中除去杂质的处理方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 98, no. 2, 10 January 1983, Columbus, Ohio, US; abstract no. 8160w, TROJANEK, JAN ET AL: "Extraction of opium alkaloids." XP002025579 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102749402A (zh) * 2012-08-07 2012-10-24 公安部禁毒情报技术中心 吗啡盐酸盐标准物质的制备方法
CN110713494A (zh) * 2019-09-20 2020-01-21 甘肃省药物碱厂 一种从高纯度吗啡中除去杂质的处理方法

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