Patented Aug. 21, 1951 2,565,067

UNITED STATES PATENT OFFICE 2,565,067 PROCESS FOR OBTAINING HIGHILY CON CENTRATED ALKALOD EXTRACTS FROM PAPAVER SOMNIFERUM Water Theodor Max Deckert, Buenos Aires, Argentina, No Drawing. Application April 5, 1949, Serial No. 85,724 9 Claims. (CI. 260-285) 2 My invention relates to improvements in proc far have not been able to offer any advantages esses for the recovery of alkaloids from Papaver important enough to affect the world market price somniferum. for opiates. All medicamental and narcotic substances sim In order to illustrate in What direction indus ilar to opium contain, apart from morphine, vari trial opiate extraction has so far been guided, the able quantities of other alkaloids, naturally pres following processes may be cited: v ent in the poppy. These alkaloids have an (d) Roternel process (for further data, See appreciable influence on the activity and com Pharmazeustische Zeitung 1934, page 729). During patibility of opium compounds. To date such trials made With the purpose of extracting poppy compounds were obtained by mixing each of the 0 juice by simply crushing the capsules and adding Components in the proportions required (such alcohol or water, great losses of alkaloids were aS, for example, Pantopon, Laudanon, etc.) Only encountered. Rotermel proved how, by ferment the Opium in itself is a natural product. This ing the crushed poppy heads in the presence of Opium is the milky juice of the poppy, dried to certain bacteria and fungi, the alkaloid yield was a rubber-like brownish mass. It flows from in 5 increased. His process is as follows: The crushed cisions made in the poppies, appearing in the poppy heads are dampened With a 1% Sul form of a White sap. phuric acid Solution and allowed to ferment dur So far, other processes for obtaining natural ing 24 hours in large Wats, after having been Opium have found no practical application in Sowed with bacteria, fungi and yeast. Neutraliza therapeutics. Although, by suitable means of 20 tion is then accomplished with lime water and extraction, applied both to fresh poppy heads and the liquid is pressure-filtered, clarified and con dried ones, as well as to poppy straw, it has been centrated. The dry residue thus obtained is simi found poSSible, according to known procedures, to lar to raW opium but contains only from 8% to obtain opium alkaloid extracts; such extracts do 10% of morphine and from 2% to 4% of other not possess a Sufficient degree of purity to be 25 alkaloids. employable as Such. Through special technical (b) Hoffman's process-La Roche A.G., Basle, processes, therefore, these extracts are elaborated year 1935. In accordance with this process, ex into pure morphine aind other pure alkaloids. traction of the poppy heads and straw is effected The process according to the present invention by Water and the strongly diluted extract, by enables a mixture of alkaloids to be obtained the means of complicated devices, is re-extracted with purity and quality of Which is Such that the re a mixture of benzol and butanol, alkaloids being Sulting extract, without any further treatment thus separated, especially morphine. This latter Whatsoever, can be used as a pharmaceutical Substance is eliminated from the solvent by agi Compound. The extract of this air-dried com tating Same With an aqueous acid which, Subse pound contains from 20% to 22% of morphine quently, is neutralized. After adjustment to pH and, approximately, from 16% to 18% of acces 9, morphine is precipitated as a free base. Sory opium alkaloids. Its concentration, there (c) As third mechanical lethod of oitainiiig fore, is almost double that of natural opium. morphine we have the Riungariain's a gay proc The alkaloids contained in this extract, as well ess. In this case, the poppy heads or straw are as in the natural opium, can be separated accord- A? cut and Submitted to extraction in a diluted ing to known methods. sulfurous acid countercurrent. The very diluted The basically important part of the process solution thus obtained is concentiated by evap resides, accordingly, in the extraction of a new oration. The residue is treated as opium in order medicament which, although no pharmacological to obtain morphine, in accordance with known novelty, from the therapeutical point of view is 45 methods. - Superior to all other medicaments of the opiate The main disadvantages of all these methods group Owing to its many applications and its com proposed and used to date for the extraction of patibility, being at least equivalent with regard poppy heads and Straw, reside in the problem of to its analgesic properties. extracting and accumulating. In the first of the The fundamental novelty of the process lies in 50 operations mentioned, the resulting product is the manner in which the alkaloids are isolated accompanied by a number of inert Substances from the dried poppy heads and straw. All other consisting of albuminoids, pectins, tanning sub processes which, for the same purpose, have been stances, Sugars, resins, glue and similar coinbi employed to date, as opposed to the century-old nationS. Furthermore, the total extraction of purely agrarian method of obtaining opium, SO 55 alkaloids, even in the countercurrent process, de 2,565,067 3 4. mands a great quantity of Solvent. After their which is later on extracted with chloroform or extraction, the alkaloids are in Solution, but in a acetic ester. One kilogram of dry residue re concentration which is hardly greater than that quires two to three litres of Solvent. in which they were previously in the plant. In Of the chloroform or acetic ester Solution, order to eliminate the inert Substances, and en three-quarter parts by volume are submitted to rich the alkaloid content, all the proceSSeS, in distillation, in order to recuperate the solvent. principle, follow the same road, Which consistS The residue is treated with a small excess of in the constantly renewed extraction of the alka diluted hydrochloric acid, being evaporated to loids by employing a great number of organic dryneSS in a vacuum. A dark-brown resinous solvents, together with a continuous change in the 10. hygroscopic mass is thus obtained, being a con conditions under which the extraction takes Centrate ready for use to be referred to, in future, place, until the desired concentration and purity as "Optopon.' This concentrate can be trans has been achieved. formed at any time, according to needs and by Hardly anybody would consider such a proceSS any one of the known methods, into morphine or as an ideal solution to the problem. Those Who 5 other pure alkaloids. have worked with these methods know that ac The yield of "Optopon' per kilogram of poppy cumulation does not depend only on the pH value, heads depends, naturally, on the morphine con but on many other factorS which are beyond Con tent of those capsules, being exceedingly change trol. It repeatedly happens in the industry, in able. A Study of ten different Samples of pop spite of the strict observance of all the prescribed 20 pies, delivered by different firms, resulted in measures, that suddenly and for no apparent yields of 0.21 to 0.69%, i.e., 2.1 to 6.9 grams of reason an appreciable reduction in the yield is ''Optopon' per kilo of capsules. observed. It can even happen, sometimes, that Summarizing, the fundamental novelty of this owing to changes in the extraction proceSS, the proceSS ConsistS in: substance sought for disappears, finally, almost 25 (d) The addition of copper salt when extract altogether. ing the poppy capsules (copper sulphate, for ex For this reason, on studying the problem. Once ample). again, attention was especially directed towards: (b) Precipitation of the alkaloids from the ex (1) Preventing, by suitable aggregates added tract obtained as per (a) above, with the aid of a to the aqueous extracting means, When the poppy 30 hydro-Soluble molybdate such as, for example, heads are under treatment, that the greater part ammonium molybdate. of inert substances be transferred to the Solution, (c) A?iaintaining a pit-value of 1-2 during the purpose being to obtain a clear extract Which precipitation as per (b) above, which is made may be readily used in the steps that follow. possible by adding a strong acid such as, for (2) Separating all the morphine from this ex 35 example, nitric acid. tract, as well as other valuable alkaloids, through (d) Decomposition, by means of dry bicarbon an appropriate precipitating reaction. ate, of the Still damp centrifugate of the alkaloid Both problems have been solved. The Separa molybdate complex, the bicarboriate in question tion of the troublesome inert substances, which being, for example, sodium bicarbonate. cause the formation of unfiltrable precipitates, 40 In carrying out the foregoing process, the ini was achieved by extracting the poppy heads with tial aqueous extract may be filtered or not be an aqueous copper salt solution. An alkaline fore proceeding with the precipitation step. In molybdate, in an acid medium, is then employed using copper Sulfate in the initial extraction to cause precipitation of the alkaloids. Operation a 1% Solution is employed and the In two simple stages, thus, a precipitate is acetic ester employed in the later extraction obtained consisting of complex combinations of operation is advantageously ethyl acetate. This alkaloids, easily sedimentable. After the exceSS, final extraction may be carried out with chloro alkaloid-free liquid has been removed by filtira form, a chlorofoln-alcohol mixture of ethyiace tion or, preferably, centrifugation, an amorphous tate. sludge is obtained. 50 The industrial advantages derived from this For an approximately quantitative extraction process are: of the morphine, it is sufficient that a Volume of (1) Alkaloids can be extracted even from those the usual type of available broken poppy heads parts of the plant which contain only very small be submitted to a thirty-minute current of five quantities of morphine and other opium alkaloids, parts by volume of liquid solvent containing the 55 without thereby obtaining quantities of trouble copper salt. The extract thus obtained is of a Some inert Substances hindeling tile separation dark blue-green colour and is completely clear. of alkaloids from the extract. The pH value of the liquid solvent is 4, and it (2) Morphine, as Well as other opium alka hardly varies during the proceSS. Consequently, loids, can be quantitatively extracted from the no difficulties are encountered in selecting the 60 raw vegetable matter, by countercurrent, with materials for the extracting apparatus. out the appearance of troublesome inert Sub To separate the alkaloids from the molybdate stances that hinder the following steps, in spite complex, a very simple way has been found. The of which the raw vegetable matter is exinaustively still wet sludge obtained after centrifugation is extracted. mixed with dry bicarbonate in open receptacles 65 (3) Owing to the fungicide properties of cop or vats. in this manner, the alkaloids are set per, the copper extracts are amply protected free, although an excess of bicarbonate must be against mildew. present. After the carbon dioxide formation has (4) Due to the simple mixture of the gross ceased, the sludge must be dried. This drying unfiltrated extract with the precipitation react action is best performed at room ternperature. 70 ant, precipitate is formed within a few hours; this Should it be desired to accelerate drying by the precipitate Settles and is easily separable, having application of heat, the temperature should not a 50% alkaloid-metal combination content. In be allowed to pass 50° C. inasmuch as, should this this manner, by means of a process which does temperature be exceeded, alkaloid losses occur not require labour nor motive power, an alkaloid due to resinification. A dry residue is obtained, 75 accumulation of 250 times is achieved. 2,565,067 5 6 (5) The apparatus required for large-scale 5. A process as defined by claim 4 in which the manufacture, is neither costly nor complicated. precipitate after treatment with sodium bicar (6) The consumption of chemicals, consequent bonate is dried, extracting the resulting dried upon the opportunities offered for a simple re material with a solvent selected from the group generation of Sane, can be kept down to a mini consisting of chloroform, a chloroform-alcohol mum. The quantity of molybdate thus necessary mixture, and ethyl acetate, for recovering the for precipitation is 90% recoverable. The proc alkaloids, and removing the solvent from the eSS according to the present invention avoids extract containing the alkaloids. the usual great consumption of organic solvents, 6. A process for obtaining alkaloids from Pa (7) The process according to the present in payer SOmniferum, comprising extracted Papayer vention can be put into practice almost without SOmniferum. With an aqueous solution of a copper any expenditure for power, neither steam nor Salt of about 1% concentration to recover the gas being required and but a little electricity. alkaloids in the resulting extract, and precipitat The invention as described may be clearly ing the alkaloids from the extract by adding understood and no further explanations will be 5 thereto a hydrosoluble molybdate, and recover required by those versed in the matter. ing the alkaloids from the precipitate. AS the invention herein shown and specified 7. A process as claimed in claim. 6, in which has been described with the aid of examples which the extract is Inaiintained at a pH value of from are to be considered as illustrative and in no ways 1 to 2 during the precipitating operation. as limitations upon the invention, same may be 8. A process as claimed in claim 6, in which Subjected to changes without thereby departing the precipitation of the alkaloids in the extract is from its essential nature, as clearly defined in the effected by treating the extract with ammonium following claims. molybdate. I claim: 9. A process for the production of highly con 1. A process for obtaining alkaloids from 25 centrated Starting materials for the preparation Papayer Somniferum, comprising extracting Po of opium alkaloids from Papaver somniferum, paper SOmniferum with a 1% aqueous solution of comprising extracting the Papaver somniferum Copper Sulfate, precipitating the alkaloids from with an aqueous solution of a copper salt of about the resulting extract by adding ammonium molyb. 1% concentration to recover the alkaloids in the date thereto, and carrying out the precipitating resulting aqueous extract, precipitating the alka Operation at a pH value of from 1 to 2 by adding loids from the aqueous extracts by adding thereto acid to the extract, separating the resulting a hydroSoluble molybdate while maintaining the precipitate from the extract and recovering the extract at a pH value of from 1 to 2, and re alkaloids therefrom. covering the alkaloids from the precipitate. 2. A process as defined by claim 1 in which WALTER THEODOR MAX DECKERT. nitric acid is added to the aqueous extract to maintain the pH value thereof at from 1 to 2 REFERENCES CITED during the precipitation operation. The following references are of record in the 3. A process as defined by claim 2 in which the file of this patent: recovered precipitate is treated while damp with 40 UNITED STATES PATENTS an excess of a bicarbonate. 4. A process as defined in claim 3 in which the Number Name Date recovered precipitation is treated while damp 1447,400 Stoll ------Mar. 6, 1923 With a 10% excess of sodium bicarbonate.