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WO2009106910A1 - Processus de préparation d'émodine d'aloès - Google Patents

Processus de préparation d'émodine d'aloès Download PDF

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Publication number
WO2009106910A1
WO2009106910A1 PCT/IB2008/000451 IB2008000451W WO2009106910A1 WO 2009106910 A1 WO2009106910 A1 WO 2009106910A1 IB 2008000451 W IB2008000451 W IB 2008000451W WO 2009106910 A1 WO2009106910 A1 WO 2009106910A1
Authority
WO
WIPO (PCT)
Prior art keywords
aloin
aloe
emodin
oxidation
process according
Prior art date
Application number
PCT/IB2008/000451
Other languages
English (en)
Inventor
Guido Di Napoli
Alessandro Di Napoli
Original Assignee
Laboratoire Medidom S.A.
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
Application filed by Laboratoire Medidom S.A. filed Critical Laboratoire Medidom S.A.
Priority to PCT/IB2008/000451 priority Critical patent/WO2009106910A1/fr
Priority to ARP090100511A priority patent/AR072768A1/es
Publication of WO2009106910A1 publication Critical patent/WO2009106910A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures

Definitions

  • the present invention relates to a process for preparing aloe-emodin by oxidation of aloin.
  • Aloe-emodin is a well-known compound widely used as an intermediate in the preparation of a number of therapeutically active compounds such as rhein and diacerein, for example as described in US 5,652,265 and EP0928781 , and certain anthracyclines, for instance doxorubicin and related compounds as described in US 4,215,062.
  • Aloe-emodin and derivatives thereof have also been described for use in the treatment of cancer.
  • EP1289513 describes the use of aloe-emodin in the treatment of neuroectodermal tumours.
  • Use of aloe-emodin as an inhibitor of angiogenesis is described in WO2004/058185.
  • Aloe-emodin has also been described for the treatment of psoriasis, for instance as in US 5,852,060, and for the treatment of the symptoms associated with burns, for instance as in DE 3,447,953, amongst others.
  • US 5,652,265 describes the oxidation of aloin by means of iron (III) chloride with a hydrochloric acid catalyst, or with iron (II) sulphate using a sulphuric acid catalyst.
  • the ferric salt is required in large quantities to carry out the oxidation.
  • a ratio of ferric salt to aloin of 5:1 to 15:1 w/w is described.
  • CN 1810759 describes an alternative process in which aloin is refluxed with hydrochloric acid and then treated with a solution of aluminium (III) chloride in hydrochloric acid.
  • WO 2006/051400 there is described a process for the preparation of aloe- emodin from aloin whereby aloin is oxidized to aloe-emodin by treatment with an oxygen-containing gas in a polyalcohol, in the presence of an acid.
  • aloe-emodin may be easily and advantageously prepared from crude aloin, without the need for chromium compounds or other toxic or harmful reagents, using a process which is simple, economical and can be easily scaled up to industrial level.
  • the present invention has been achieved on a basis of these results.
  • Objects of the present invention are achieved by a process for preparing aloe- emodin according to claim 1.
  • Disclosed herein is a process for preparing aloe-emodin from aloin comprising oxidation of aloin by treatment with an oxygen-containing gas in an acidic reaction medium in the presence of a copper salt catalyst.
  • the process of the present invention comprises oxidation of aloin represented by the following formula (I):
  • the aloin is oxidized by treatment with an oxygen-containing gas in an acid reaction medium, in the presence of a copper salt catalyst.
  • the process of the invention advantageously provides effective oxidation of aloin, even from a starting material aloin having a low degree of purity.
  • the aloin starting material may have a purity of from 1% to 100%. Accordingly as the starting material may be used pure aloin, commercially available aloin (for example in the form of aloe stone) or crude aloin, preferably crude aloin in the form of an extract from different plant species containing at least 1% of aloin.
  • the process of the present invention advantageously enables the preparation of aloe-emodin at a good yield and with satisfactory purity from crude aloin containing from 5% to 20% pure aloin.
  • crude aloin having a purity of 5 to 20%, as extracted from aloe-species, for example acibar the extract of aloe- vera without any purification or treatment may be advantageously used as starting material.
  • Such crude aloin is widely commercially available and inexpensive.
  • Aloin may also be used in the form a solid aloin, e.g. having a purity of aloin from 20% to 100%. Particularly, commercially available forms of aloin may be envisaged, such as aloe stone, containing for example from 20% to 40% pure aloin.
  • the oxidation reaction is carried out in an acidic reaction media.
  • the acid reaction media preferably comprises one or more mineral acids, and may be for example hydrochloric acid or sulphuric acid. Preferably 0.5 M to 6.0 M hydrochloric acid or sulphuric acid may be used. In a preferred embodiment the oxidation is carried out in hydrochloric acid.
  • the oxidation of aloin is carried out in the presence of a copper salt catalyst, particularly a copper (I) salt or copper (II) salt.
  • suitable copper salts include specifically, but not exclusively, chloride, sulphate, bromide or nitrate salts.
  • chloride or sulphate salts of copper are used, particularly copper (I) chloride or copper (II) chloride.
  • the copper salt compound is used in a catalytic amount ranging from 0.5% to 30% w/w with respect to aloin.
  • the copper salt catalyst compound is used in an amount of from 1.5% to 5.0% w/w with respect to aloin.
  • the oxidation is carried out at a temperature in the range from 40 0 C to 125 0 C, more preferably at a temperature in the range from 80 0 C to 90 0 C.
  • the aloin starting material may be suspended in the acid reaction medium at room temperature and then dissolved by heating.
  • the acid reaction medium may be preheated before addition of the aloin. No organic solvents are required for dissolution of the aloin, and the oxidation of aloin is advantageously carried out in the absence of organic solvent.
  • Oxidation of the aloin is carried out by active treatment with an oxygen-containing gas.
  • the reaction mixture comprising the aloin starting material in an acid reaction media is subjected to a gas over-pressure of an oxygen-containing gas in the presence of the copper salt catalyst.
  • the oxidation of aloin may be carried out by introducing the oxygen-containing gas in a continuous way into the heated reaction mixture, or may be performed in a pressure reactor.
  • aloin is suspended in the acid reaction medium with the copper salt catalyst, the reaction mixture is heated to the reaction temperature, and the oxygen-containing gas is then bubbled in a continuous way into the heated solution until the reaction is completed.
  • the degree of conversion to aloe-emodin, and completion of the reaction may be determined by conventional analysis techniques, for example by HPLC analysis.
  • Oxygen gas or air is preferably introduced into the heated solution at a flow rate of about 5-50 L/hour, more preferably about 15-30 L/hour.
  • the time required for completion of the reaction depends on the oxygen-containing gas flow rate and on the oxygen concentration of the oxygen-containing gas.
  • the oxidation may be usually be carried out over about 3-12 hours, generally about 5-7 hours.
  • the heated reaction mixture is added to the reaction chamber, and then air or oxygen gas introduced into the reaction chamber to a pressure of about 1.0-5.0 bar absolute pressure.
  • the pressure is maintained by oxygen-containing gas addition until constant pressure is observed.
  • oxygen gas is used, the reaction is suitably carried out under a gas pressure of about 1.2-2.5 bar, for example around 2 bar. If the oxidation is carried out using air as the oxygen-containing gas, the reaction is preferably carried out under a gas pressure of about 1.2-10 bar absolute pressure, preferably 2-5 bar.
  • the aloe-emodin containing oxidation product residue may be separated from the reaction mixture by filtration. The aloe-emodin concentration in the oxidation- product solid residue depends largely on the purity of the starting aloin, generally ranging from about 20% to 60% w/w.
  • the oxidation of aloin containing 5%-20% pure aloin gives a residue that contains about 20% to 40% of aloe- emodin
  • the oxidation of aloin containing 90% to 95% pure aloin gives an oxidation product residue containing up to 60% of aloe-emodin.
  • a conversion rate from aloin to aloe-emodin of at least 65% may be obtained starting from aloin having a purity as low as 5%.
  • the reaction time will depend on the reaction conditions, amongst others on the concentration of oxygen in the oxygen-containing gas and on the gas pressure applied.
  • the oxidation of aloin by treatment with an oxygen-containing gas in a pressure reactor may generally be carried out over 3-15 hours, for instance 6-12 hours.
  • the oxidation reaction will usually be followed by a conventional treatment of the aloe-emodin containing reaction product residue, to isolate the crude aloe-emodin.
  • Recovery of the aloe-emodin may, for example, be carried out by extraction using an organic solvent, such as toluene or dichloromethane.
  • aloe- emodin may be extracted by soxhlet or nutcha filter using toluene or dichloromethane as solvent.
  • the crude aloe-emodin may be recovered at more than 85% with an aloe-emodin purity of at least 75%. If desired the extraction of crude aloe-emodin product may be followed by purification of the crude aloe-emodin by conventional processes, e.g. by crystallization, to obtain aloe-emodin in pure form.
  • the mother liqueurs from the oxidation reaction i.e. the filtrate, containing acid and copper salt catalyst, obtained in the filtration of the aloe- emodin containing oxidation product residue after completion of the oxidation, may be re-used directly, without any treatment or purification, as reaction media for subsequent oxidation reactions of aloin to aloe-emodin.
  • the initial acid and copper salt catalyst can be re-used in 1 to 10 further oxidations.
  • the initial acid and copper salt catalyst used in a first oxidation reaction can be advantageously be re-used in up to 4 further oxidations of aloin to aloe-emodin without significant reduction in aloe-emodin yield.
  • the re-use of the acid and the copper salt catalyst in this way provides clear economical and environmental benefits.
  • the aloe-emodin produced by the process of the present invention may advantageously be used in the production of rhein and diacerein.
  • aloe-emodin may be obtained at a good yield and good level of purity from crude aloin having a purity as low as 5%.
  • the process according to the invention is also economical since crude aloin having a purity of 5% to 20% aloin may be used as the starting material, inexpensive reagents may be used in the process, and further since the acid reaction medium and copper salt catalyst may be re-used in multiple oxidations.
  • Example 1 Oxidation of Aloin 30 (HPLC 31 % aloin)
  • the mother liqueurs were used in four successive operations:
  • aloe-emodin 55.3g of aloe-emodin was obtained as an orange solid, yield 92%, aloe-emodin purity 80%.
  • Example 2 Oxidation of Acibar (Aloin HPLC 5.1 %) (I) 0.7L of HCI 5M was poured into a reaction flask and then 35Og acibar (Laboratoire Medidom, Switzerland) (5.11% of aloin) was added over 5 minutes at room temperature (20-25 0 C) with vigorous stirring. The mixture was stirred for 20 minutes and then was heated for one hour to 80 0 C. 5.Og copper (I) chloride was added and a gas diffuser was introduced into the flask. Oxygen gas was introduced at a flow rate of 30 L/h. The mixture was heated at 90 0 C for 7 hours with continuous oxygen gas flow and stirring. A dark brown solid was formed. The gas diffuser was removed and oxygen gas addition was stopped.
  • the mother liqueurs were used in two successive operations: (2) The mother liqueurs of the 1 st oxidation were poured into the flask and 327g acibar (5%-11% aloin) was added. The oxidation reaction was carried out as above. 24.3 g of brown solid was obtained, containing 30.4% of aloe-emodin.
  • HCI 3M 1L of HCI 3M was poured into a reaction flask and 7Og aloin 90 (Laboratoire Medidom, Switzerland) (90% purity aloin) was added over 5 minutes at room temperature (20-25 0 C) with vigorous stirring. The mixture was stirred for 20 minutes and then was heated in one hour at 80 0 C. 3.5g copper (I) chloride was added and a gas diffuser was introduced into the flask. Oxygen gas was introduced at a flow rate of 30 L/h. The mixture was heated at 90 0 C for 7 hours with continuous oxygen gas flow and stirring. A dark brown solid was formed. The gas diffuser was removed and oxygen gas flow stopped. The resulting suspension was cooled at room temperature overnight.
  • 7Og aloin 90 (Laboratoire Medidom, Switzerland) (90% purity aloin) was added over 5 minutes at room temperature (20-25 0 C) with vigorous stirring. The mixture was stirred for 20 minutes and then was heated in one hour at 80 0 C. 3.5g copper (I) chloride was added and

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un processus de préparation d'émodine d'aloès à partir d'aloïne qui consiste à oxyder de l'aloïne par un traitement avec un gaz contenant de l'oxygène, dans un milieu de réaction acide, en présence d'un catalyseur à base de sel de cuivre.
PCT/IB2008/000451 2008-02-29 2008-02-29 Processus de préparation d'émodine d'aloès WO2009106910A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IB2008/000451 WO2009106910A1 (fr) 2008-02-29 2008-02-29 Processus de préparation d'émodine d'aloès
ARP090100511A AR072768A1 (es) 2008-02-29 2009-02-13 Proceso para la preparacion de aloe-emodina

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2008/000451 WO2009106910A1 (fr) 2008-02-29 2008-02-29 Processus de préparation d'émodine d'aloès

Publications (1)

Publication Number Publication Date
WO2009106910A1 true WO2009106910A1 (fr) 2009-09-03

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AR (1) AR072768A1 (fr)
WO (1) WO2009106910A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215062A (en) 1978-05-22 1980-07-29 University Of Kansas Endowment Association Anthracycline synthesis
DE3447953A1 (de) 1983-04-28 1986-02-20 Mihai Dipl.-Chem. Dr. 7000 Stuttgart Alexa Arzneimittel zur behandlung der schmerzsymptomatik bei verbrennungen
WO1996030034A1 (fr) * 1995-03-29 1996-10-03 Wisconsin Alumni Research Foundation Production de rheine et de ses derives
US5852060A (en) 1996-03-22 1998-12-22 Moady Marzook Antipsoriatic compositions, method of making, and method of using
EP0928781A1 (fr) 1997-12-30 1999-07-14 Laboratoire Medidom S.A. Procédé de préparation de rhéine et de ses dérivés diacylés
EP1289513A2 (fr) 2000-05-31 2003-03-12 Universita' Degli Studi Di Padova Utilisation de l'aloe-emodine dans le traitement des tumeurs neuroectodermiques
WO2004058185A2 (fr) 2002-12-23 2004-07-15 Cedars-Sinai Medical Center Antiangiogenese par inhibition de l'activite de la proteine kinase ck2
WO2006051400A1 (fr) 2004-11-12 2006-05-18 Laboratoire Medidom S.A. Procede pour l'elaboration d'aloe-emodine
CN1810759A (zh) 2006-02-16 2006-08-02 江阴南极星生物制品有限公司 大黄酸的制备方法

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215062A (en) 1978-05-22 1980-07-29 University Of Kansas Endowment Association Anthracycline synthesis
DE3447953A1 (de) 1983-04-28 1986-02-20 Mihai Dipl.-Chem. Dr. 7000 Stuttgart Alexa Arzneimittel zur behandlung der schmerzsymptomatik bei verbrennungen
WO1996030034A1 (fr) * 1995-03-29 1996-10-03 Wisconsin Alumni Research Foundation Production de rheine et de ses derives
US5652265A (en) 1995-03-29 1997-07-29 Wisconsin Alumni Research Foundation Production of rhein and rhein derivatives
US5852060A (en) 1996-03-22 1998-12-22 Moady Marzook Antipsoriatic compositions, method of making, and method of using
EP0928781A1 (fr) 1997-12-30 1999-07-14 Laboratoire Medidom S.A. Procédé de préparation de rhéine et de ses dérivés diacylés
EP1289513A2 (fr) 2000-05-31 2003-03-12 Universita' Degli Studi Di Padova Utilisation de l'aloe-emodine dans le traitement des tumeurs neuroectodermiques
WO2004058185A2 (fr) 2002-12-23 2004-07-15 Cedars-Sinai Medical Center Antiangiogenese par inhibition de l'activite de la proteine kinase ck2
WO2006051400A1 (fr) 2004-11-12 2006-05-18 Laboratoire Medidom S.A. Procede pour l'elaboration d'aloe-emodine
EP1666446A1 (fr) * 2004-11-12 2006-06-07 Laboratoire Medidom S.A. Procédé pour préparation du rhéine et diacerhéine
CN1810759A (zh) 2006-02-16 2006-08-02 江阴南极星生物制品有限公司 大黄酸的制备方法

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