AU610820B2 - Process for obtaining a tropa-alcaloid raw extract from undried plant elements - Google Patents

Description

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4. The basic application referred to in paragraph 2 of this Declaration was the first application miade in a Convention country in respect of the invention the subject of the application.

Declared at Ynge.Iheim this 02nd day of October 1987 BOEHRINGER INGELHEIM KG I PPP SIGN X I AU-AI1-69495/8 7 PETRANSTO CTR GESI EIGENTtM INTERNATIONALE ANMELDUNG VEROFFENTLIGHT NACH DEM VERTRAG OBER DIE INTERNATJONALE-ZUSAMM ENARBEIT AUF DEM GEBIET DES PATENTWESENS (PCT) (51) Internationale Patentklassif" on In r Ztionale Verdiffentlichungsrnimmer: WO 87/ 04710 C07D 451/10 nte tionales Veroffentlichvngsdatv.n: 13. August 1987 (13.08.87) (21) Internationales Aktenzeichen: PCT/E P87/00048 (22) Internationales Anmeldedatum: 3 1. Januar 1987 (3 1.01.87) (81) Bestimmungsstaaten: AU, BR.

Veriiffentlicht jAfit in ternationalern Reclierch enberich t.

Vor A blauif derfiir A nderungen der A nsprilche :ugelassenen Frist. Verdffenrlichung wird wviederholt falls Anderungen em trejffen.

P 36 03 678.1 (31) Prioritiitsaktenzeichen: (32) PrioritAtsda tum: (33) PrioritAtsland: 6. Februar 1986 (06.02.86) {SECION34(4)(a) DIRECTION SEE FOLIOJ~---.-~ N A M E D IR E C T E D mi 1 ,13c~ i .4 orr.x- -ozwJ/ ingel- rA,.

heimn am Rhein SCHW ALL, Horst ;Im Herze- 4Sfp18 nacker 34, D-6535 Gau-Algesheim EP18 (74) Anwalt: BOERRINGER INGELHEIM ZENTRALEAurA GMBH; Postfach 200, ZA Patente, D-6507 Ingelheim am Rhein 0 LJ4 G 1q~lc, (54) Title: PROCESS FOR OBTAINING A TROPA-ALCALOID RAW EXTRACT FROM UNDRIED PLANT ELE-

M/ENTS

(54) Bezeichnung: VERFARREN ZUR GEWINNUNG EINES TROPA-ALKALOID-ROHEXTRAKTES AUS UNGE- TROCKNETEN PFLANZEN4TEILEN (57) Abstract New process for obtaining tropa-alcaloid raw extracts, in particular scopolamine and/or hyoscyamine from undried plant elements.

(57) Zusanimenfassung Emn neues Verfahren zur Gewinnung von Tropa-Alkaloid-Rohextrakten, insbesondere von Scopolamin- und/oder Hyoscyamin-Rohextrakten aus ungetrockneten Pflanzenteilen.

17Y 52 148T Process for obtaining a crude tropa-alkaloid extract from undried plant parts

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2 The invention relates to a new process for obtaining crude tropa-alkaloid extracts, particularly crude scopolamine and/or hyoscyamine extracts from undried plant parts.

It is known to obtain scopolamine as well as hyoscyamine or both components together solely by extraction from plants or plant parts Hamerslag; The Technology and Chemistry of Alkaloids; D. van Nostrand Comp. Inc. Toronto, New York, London, 1950).

To prepare the crude alkaloid extract, dried plant parts are treated either with aqueous acids or with aqueous bases and the extract is then re-extracted with a suitable solvent.

From the variety of publications which have appeared on this subject the following may be mentioned: Recovery of scopolamine from Datura stramonium or Atropa belladonna by extraction with aqueous ammoniacal solution and benzene, 1,2-dichloroethane or toluene according to IN 130 397 (CA 91 181 445 W).

Extraction of Duboisia leichhardtii, Datura alba or Scopolia carniolica with aqueous ammoniacal solution and a hydrocarbon fraction (Naphtha no 1) according to JP-A-75-49,412 (CA 83 65 453 h).

Extraction of plants of the genus Datura with an ammoniacal water-ethanol mixture according to FR-A-2 405 947 (CA 91 198 926 b).

Extraction of Datura sanguinea or Datura metel with an aqueous acid preferably sulphuric or hydrochloric acid and di-, tri- or tetrachloromethane according to EC 151.

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-3- In a recent study, the extraction of scopolamine from Datura innoxia in alkaline (NH 3 and acidic

(H

2 S0 4 HCI) aqueous medium was compared, the best results being obtained with 1% hydrochloric acid (Farmacia, (1973) 21, 403; CA 80 100142 t) The extraction processes known from the prior art have the disadvantage that the quality of the crude extract obtained by aqueous alkaline or aqueous acidic extraction depends to a very great extent on the pH of the extracting agent used, and side reactions such as hydrolytic decomposition of the alkaloid or alkaloid ester are avoided only at certain pH values and with certain extraction times.

As a result of the acidic or basic character of the extracting agent, furthermore, other undesirable plant ingredients are dissolved and make further processing of the crude extract more difficult.

Surprisingly, it has now been found that tropaa1lkaloid extracts can be obtained in a high yield and with good purity from undried plant parts from an alkaloid-containing plant.

The invention thus relates to a process for preparing a crude tropa-alkaloid extract from undried plant parts from an alkaloid-containing plant, characterised in that a) the plant parts are extracted directly with water once or several times or b) the plant parts are squeezed out by means of a press and if desired the residue is b l treated once or several times with water and pressed out again and, if desired, 1 i- -4c) the aqueous crude extracts obtained in a) or b) (crude miscella) are concentrated, after the solids contained therein have been separated off, and if desired d) the concentrate obtained in c) is extracted with a suitable organic solvent.

The crude miscella, crude miscella concentrate or crude concentrate obtained by the process according to the invention is substantially free from undesirable contaminants which would have an unfavourable effect on the quality of the end product (scopolamine and/or hyoscyamine).

Plants which contain tropa-alkaloids include, inter alia: Datura genera such as Datura stramonium, Datura alba, Datura metel, Datura sanguinea or Datura innoxia Atropa genera such as Atropa belladonna, Duboisia genera such as Duboisia leuichhardtii Scopolia genera such as Scopolia carniolica Tropa-alkaloids are a group of alkaloids known per se; examples include scopolamine, hyoscyamine and atropine.

The term "undried plant parts" indicates primarily the plant parts which are above the ground such as the stem, leaves, blossoms and fruits, which are further processed directly after harvesting without being dried.

Plant parts may also, however, be plant parts from cell or suspension cultures.

I fi ^y T v r 0 The extraction of the plant parts with water can be carried out at any desired temperature, i.e.

at temperatures between 0 and 1000C, the boiling point of water. However, temperatures of 10 to 0 C are preferred and the temperature range from 150 to 40 0 C is particularly preferred.

The process according to the invention has a number of essential advantages. Apart from improving the quality of the crude miscellas or crude miscella concentrate or crude alkaloid extract there are the following advantages: simplifying the processing: there is no need to carry out the drying of the harvested plant parts which was necessary according to the prior art.

The crude miscella or extract may be produced at or in the immediate vicinity of the place of cultivation, so that the residue obtained from the process can be put back onto the cultivation area as a useful fertiliser or mulch. A particular advantage is the fact that the vegetable extraction residues do not come into contact with organic solvents or other chemicals alien to the plant. Thus they can be deposited without a second thought or used as fertilisers or mulches.

Moreover, in the process according to the invention, stems and other plant parts may also be used, whereas in the extraction processes known from the prior art only the dried leaves are used.

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r I-R 7 6 With the process according to the invention there is no need for the neutralisation step which is required in alkaline or acid extraction, and this is advantageous both in terms of the safety of the operation and from an ecological point of view.

Moreover, during neutralisation, racemisation of the alkaloids is observed, significantly impairing the quality of the product.

The crude miscella is the aqueous extract or the pressed juice, i.e. an aqueous solution or emulsion or suspension of the crude alkaloid.

The crude extract is the extract which can be obtained by extracting the crude miscella with an extraction agent which is immiscible with water or of only limited miscibility with water. These extraction processes are well known in the art. Suitable extraction agents include: chlorinated hydrocarbons such as dichloromethane, trichloromethane, tetrachloride methane, dichloroethane, trichloroethane, tetrachloroethane; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethylether; cyclic ethers such as tetrahydrofuran, etc.

hydrocarbons such as naphtha fractions, petroleum ether.

In a preferred embodiment the process according to the invention is carried out as a combination of pressing and extraction in a multi-step process.

In the first step the undried (fresh) alkaloid

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7 plant parts are pressed with a suitable press and the residue thus obtained is extracted with water in countercurrent in a two step process and then the resulting aqueous extract (crude miscella) is combined with the pressed juice (crude miscella) and further processed.

Screw presses are particularly preferred since the shear forces occurring ensure that the plant material is pressed with a particularly high yield.

The crude miscella obtained from the aqueous extract and/or pressed juice may if desired be filtered and concentrated to form the crude miscella concentrate by methods known per se, by distillation or by diffusion. Mild distillative concentration with a plate-type evaporator is particularly preferred.

The following examples illustrate the invention without restricting it.

r- -i 1- 8 Example 1 la Preparation of a plant miscella concentrate In the first step 1000 kg of freshly harvested moist Datura sanguinea drug (corresponding to 120 kg of dry drug) are chopped up with a cutter and ground in a mill with an 8 x 8 mm screen.

The moist drug thus obtained is pressed in a screw press with a 1 mm round-hole screen. 798 kg of pressed juice I and 202 kg of residue I are obtained.

In the second step the residue is placed in a stirring vessel with the pressed juice III and stirred for minutes at ambient temperature and then pressed again in a screw press with a 1 mm round hole screen.

1052 kg of pressed juice II and 168 kg of residue II are obtained. In the third step, the residue II thus obtained is stirred with 1000 kg of water in a stirring vessel for 45 minutes at ambient temperature.

Then the entire contents of the vessel are again pressed in a screw press with a 1 mm round hole screen. 1018 kg of pressed juice III and 150 kg of residue III are obtained. The pressed juice III prepared in this step is added to the residue I in step 2 of the next batch. The residue II! obtained in the third step is spread on the land.

The pressed juices I and II obtained from the preceding steps are mixed in a suitable vessel, the pressed juice having a solids content of about 3.5% by volume.

The solids are separated off in a separator. 167 kg of solids suspension is obtained as well as 1899 kg 9 of separated matter (crude miscella) with a solids content of about 0.2 by volume.

The separated matter is concentrated down to 185 kg of concentrate using a plate-type evaporator in vacuo.

lb Preparation of the crude extract 185 kg of the concentrate obtained in Example la (solids content: about 3% by volume) are separated using a separator (method of operation: full sludge removal with displacement).

kg of solids suspension and 175 kg of separated matter are obtained.

The separated matter is then filtered clear using a plate filter. After the filter has been rinsed with 50 kg of water 195 kg of filtrate are obtained.

The filtrate is extracted with chloroform using a vibrating perforated-base column.

289 kg (195 1) of chloroform extract are obtained which is combined with 106 g of 48% hydrobromic acid and evaporated to dryness. 0.746 kg of scopolamine- HBr crude extract are isolated with a scopolamine hydrobromide content of about L I-

Claims (7)

1. A process for preparing a crude tropa-alkaloid extract from undried plant parts of an alkaloid containing plant, characterised in that an aqueous crude extract (crude miscella) is obtained by: a) directly extracting the plant parts with water at least once; and/or b) pressing the plant parts by means of a press optionally coupled with treating the remaining residue by (bl) extracting it with water one or more times and re-pressing; and optionally c) the aqueous crude extracts from steps a) or b) are concentrated after WS3. the solids contained therein have been separated off; and optionally d) the concentrate from step c) is extracted with a suitable organic solvent.

2. A process as claimed in claim 1, wherein the plant parts are first pressed in a screw press, the pressed juice thus obtained is separated off and the residue is extracted one or more times with water. 0* 0

3. A process as claimed in claim 1 or 2, wherein the extraction of the plant material is carried out with water at temperatures between 10 and 70 0 C.

4. A process as claimed in claim 3, wherein the extraction of the plant 00" material is carried out with water at temperatures between 15 and 40 0 C.

5. A process as claimed in any one of claims 1 to 4 wherein said crude tropa-alkaloid extract prepared is an extract of scopolamine and/or atropine and/or hyoscyamine. r, j -u I_ ~I INTERNATIONAL SEARCH REPORT International Application No PCT/EP87/00048 1. CLASSIFICATION OF SUBJECT MATTER (if several classiication symbols abply, Indicate all) According to International Patent Classification (IPC) or to both National Claaaification and IPC Int.Cl4: C 07 D 451/10 II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols Int.C14 C 07 D 451/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are included in the Fields Searched I III. DOCUMENTS CONSIDERED TO BE RELEVANT* Category Citation of Document, with Indication, where appropriate, of the relevant passages 1 Relevant to Claim No. ,1 Y Chemical Abstracts,Vol 79,1973(Columbus,Ohio, 1 US), S.A.Minina et al.,"Development of a method for isolating alkaloids from the aboveground part of Scopolia tangutica" see page 318,abstract No.96882u,Khim.- Farm. Zh.1973,7(6),54-7 Y US,A,2509051(N.APPLEZWEIG)23 May 1950 1 A Chemical Abstracts,Vol.79,1973(Columbus,Ohio, 1 US)see page 473,abstract No.18932w, JP-A-7326907(OKAMOTO,TOSHIHIKO) 09 April 1973 SSpecial categories of cited documents: lo later document published after the International filing date documnt defining the general tate of the art which I not or priority date and not in conflict with the application but A document defining the general state ot the art which s not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an inventive step which Is cited to establish the publication date of another document of particular relevance; the claimed invention citation or oer pecia reaon (a peci cannot be considered to involve an Inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the International filing date but In the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 14 May 1987(14.05.87) 09 June 1987(09.06.87) International Searching Authority Signature of Authorized Officer European Patent Office Form PCT/ISA/210 (second sheet) (January 1985) e L ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL APPLICATION NO. PCT/EP 87/00048 (SA 16216) This.Annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 02/06/87 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document cited in search report Publication date Patent family member(s) Publication date US-A- 2509051 None For more details about this annex see Official Journal of the European Patent Office, No. 12/82 INTERNATIONALER RECHERCHENBERIGHT Internatianales AktenzeichenPCT/EP 87 /00048 1. KLASSI FlKATION DES ANM ELDUNGSG EG ENSTAN DS (bel mehreren K lassalfik atiornssymbaien sind allea arizugebenI 6 Nech der Internatianalen Patentklassifikation IIPC) ader nach der natioalen Klassifikatian und der IPC IntCiS C 07 D 451/10

11. RECHERCHIERTE SACHGEBIETE Recherchierter Mindlestprufssoff7 Klassifikatianssystem IK lassili ka ticnssymbal a int CI.4 C 07 D 451/00 Recherchierte nicht zumn Mindestprufstoff gehorende Verdffentlichungen, sowveit diese utrdie recherchierten Sachgebiete fallen 8 Ill. EINSCHLAGIGE VEROFFENTLICHUINGEN 9 Art* Kennizeichniung der Verbffentlichungll,saweit erfarderlich unter Angabe der ma~geblichen TeileJ 2 Betr. Anspruch NrY. Y Chemical Abstracts, Band 79, 1973 (Columbus, Ohio, US), S.A. Minina et al., "Development of a method for isolating alkaloids from the aboveground part of Scopolia tangutica 1 siehe Seite 318, Zusammenfassung Nr. 96882u, 1 Khim.-F~rm. Zh. 1973, 54-7 Y US, A, 2509051 APPLEZWEIG) 23. Mai 1950 1 A Chemical Abstracts, Band 79, 1973 (Columbus, Ohio, I US) siehe Seite 473, Zusammerifassung Nr.1 18932w, JP-A--7326907 (OKAMOTO, TOSHIHIKO) 9. April 1973 Besandere Ketegarien van engegebenen Veroffenelichungen to: Veroffenetichung, die den algemeinen Stand der Technik Spdtere Veroffentlichung, die nach dam internationelen An. definiert, eber nicht als besonders bedeu tsam anzusehen ast meldedeatumn oder dem Priaritatsdatum veraffentlict warden Itees okuentdesjecocherstam dernac der inern- it und mit der Anmeldung niche kollidiert, sandern nur zuits tE' alee akumendedesu each erseh am odenc i neea Verstendnis des der Et lindung zugrundeliegenden Prlnzips sianlenAnmededsumverdfenlice wodenSt der der ihr zugrundeliegenden Theorie angegeben ist Verdffentlichung, die geeignet iat. einen Priorieitsanspruch Veroffenelichung van besanderer Bedeutung; die beanspruch- zweifeihaft erscheinen zu lessen, oder durch die des Veraf- oEfnln annctasnuoe u ridrshrTtg fentlichungsderum einer anderen im Recherchenbericht ge- eEinugknnchasnuaerufrfdeiheThg nannten 'varcffentlichung belegt werden sail ader die aus einern keit beruhend betrechtet werdlen anderen besanderen Grund angegeben ast IWe ausgefuhril Veraffentlichung van besoilaerer Bedeutung; die besinsoruch. Vera ffenel ichu ng, die sich auf eine meindliche Offenbarung' te Erfindung kann niche als auf erfinderischer Tdtigkeit be. ein Snuti~ng eie uslelun oer ndreMa~nahmen ruhend betracheet werden, wenn die Veroffentlichung mit eie Beuzn, ieAseln dr neeaer odor mehreren anderen Veroffenelichungen dieser Kate- bezehrgorie in Verbindlung gebrecht wird und diese Vwerhindung fur Vero ffenel ichu ng, die var den, internatianelen Anmeldeda- einen Fachmenn neheliegend ist sum, aber nach dems beenspruchten Priaritassdatumn veraffene- Verdffentlichung, die Mitglied derselben Patentfamlie ist IV, GESCHEINIGUNG Datumn dris Abschlusses der ineernatianalen Recherche Absendeecurn des injernationalen Recherchenberiches

14. Mai 1987 0 9 J UN 1987 Internatianale Recherchenbeharde Unterschrift des bevallmacj,~e Bedieseen Europ~isches Patentamrt 14. AN' Formbiett PCT'ISA/210 (Blatt 21 (Jenuer 19851 MINIM ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT t BER DIE INTERNATIONALE PATENTANI4ELDUNG NR. PCT/EP 87/00048 (SA 16216) In diesem Anhang sind die Mitglieder der Patentfamilien der im obengenannten internationalen Rechercheribericht ange- ffahrten Patentdokumente angegeben. Die Angaben fiber die Familienmitglieder entsprechen dem Stand der Datei des Europdischen Patentamts am 02/06/87 Diese Angaben dienei rur zur Unterrichtung und erfolgen ohne Gewdhr. Im Recherchenbe- richt angeftihrtes P atentdokument Datum der Verbffent- lichung Mitglied(er) der Patentfami lie Datum der Ver~ffent- lichung US-A- 2509051 Keine Ftir ndhere Einzelheiten zu diesem Anhang: siehe Amtsblatt des Europdischen Patentamts, Nr. 12/82 rLr