WO2011161691A1 - A direct method for preparing quinine hydrochloride from cinchona bark - Google Patents

Abstract

The disclosure of invention relates to a cost effective and pharmaceutically acceptable process for the direct extraction method for quinine hydrochloride from Cinchona bark. In the present invention, wherein a mixture of Cinchona alkaloids were extracted with an organic solvent from Cinchona bark and the alkaloids were precipitated out from the acidified aqueous layer by adjusting optimal pH using NaOH solution. Precipitate was subjected to water purification and quinine hydrochloride was crystallized at ambient temperature.

Description

P T/IN2011/000404

Title: - A direct method for preparing quinine hydrochloride from Cinchona bark

Field of the Invention:-

Quinine (cinchonan-9-ol, 6'-methoxy-, (8. alpha. 9R)-) is an antiprotozoal and an antimyotonic, and is known for the treatment of malaria caused by Plasmodium species, the treatment and prophylaxis of nocturnal recumbency leg muscle cramps, and the treatment of babesiosis caused by Babesia microti. Quinine is structurally similar to quinidine, which is also an antiprotozoal, but can function as an antiarrhythmic. The said Cinchona alkaloid isolated from the bark of several species of Cinchona trees, the medicinally active bark, which is stripped from the tree, dried and powdered, contains a variety of alkaloids having their antimalarial property. In 1820, quinine (( ?)-(6- methoxyquinolin-4-yl) ((2S, 4S, 8R) - 8-vinylquinuclidin-2-yl) methanol) was identified as an active compound. Since then, cinchona alkaloids especially, quinine have played a pivotal medicinal role. Approximately 700 metric tons of cinchona alkaloids are now extracted from the bark of Cinchona annually. Nearly half of this is used in the food and beverages industry as a bitter additive and much of the remaining quinine and quinidine is used as an important antimalarial drug and muscle relaxant compound and as a cardiac depressant (antiarrhythmic).

Cinchona trees remain the only economically practical source of quinine.

However, under wartime pressure, research towards its synthetic production was undertaken.

Prior art:-

A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering. Since then, several more efficient quinine total syntheses have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. U.S. Patent Application No.20090239900, which teaches more specifically, the quinine or quinidine salt included in the combination product according to the present invention may be any commercially available quinine or quinidine salt, or hydrate thereof, such as but not limited to quinine sulphate, quinine sulphate dihydrate, quinine monohydrochloride, quinine monohydrochloride dihydrate, quinine bisulfate, quinine bisulfate heptahydrate, quinine hydrobromide, quinine dihydrochloride, quinine dihydrobromide, quinidine hydrochloride, quinidine hydrochloride monohydrate and quinidine sulfate dihydrate (cinquine).

CN 101402634 (A) the invention discloses a method for separating and purifying alkaloid in Peruvian bark. By a method for separating and purifying quina through soaking and extracting of acid aqueous solution and enriching of ion exchange resin, the invention greatly reduces the application amount of organic solvents, obviously reduces the energy consumption required by the concentration of the organic solvents, greatly reduces the production cost on the basis of ensuring that extraction yield rate is not lower than solvent method and lightens the adverse effect on the environment. The method has the advantages that the method changes extracting media, avoids the water extraction of the organic solvents, adopts the repeatedly regenerated ion exchange resin as a concentration and enrichment method, avoids the heating concentration and reduces the energy consumption.

DE 3704850 (A1 );- The invention relates to a process for the extraction of quinine from ground cinchona by extraction with supercritical C02 at a pressure of 100 to 500 bar and a temperature of 80 to 120@C. The extracted quinine is precipitated as quinine sulphate in a separation vessel which is partly filled with sulphuric acid.

GB 758173 (A), Quinine is extracted from the ground product obtained from the alkaline maceration of cinchona bark by treating it with a solvent mixture of at least one hydrocarbon and a chlorinated hydrocarbon, ketone or alcohol. Preferred proportions are 5-22 parts by volume of the latter to 100 parts of the hydrocarbon. Examples show the use of the following particular solvent mixtures: 85-95 per cent of naphtha with 5-15 per cent of isopropanol, 88-92 per cent of turpentine with 8-12 per cent of isoamyl alcohol, 88-92 per cent of hydrocarbons of B.Pt. 170-222 DEG C. (85 per cent aromatics) with 8-12 per cent of methyl isobutyl carbinol, 82-88 per cent of xylene with 12-18 per cent of methyl ethyl ketone, and 88-92 per cent of schist oil with 8-12 per cent of chloroform. CN 101088999 (A) The present invention provides several processes of preparing 3-amino quinine dihydrochloride. The first process includes the oximation and reduction of 3-quininone hydrochloride material to obtain 3-amino quinine, and the reaction with hydrochloric acid to form 3-amino quinine dihydrochloride. The second process includes the direct reduction of 3-quininone hydrochloride material in the presence of noble metal catalyst to obtain 3-amin oquinine, and the reaction with hydrochloric acid to form 3-amino quinine dihydrochloride. The third process includes the oximation, etherification and reduction of 3-quininone hydrchloride material to obtain 3-amino quinine, and the reaction with hydrochloric acid to form 3-amino quinine dihydrochloride. These processes are simple, high in yield, low in production cost and suitable for use in industrial production.

Objective of the present invention

An object of the present invention is that, there are no economically viable methods for the preparation of quinine hydrochloride. The existing method for manufacturing quinine hydrochloride is from the sulphate form of quinine. Quinine hydrochloride via quinine sulphate increases the cost of production and loss of active molecule.

Further very important object of the present invention is that the said invention relates a method of preparing quinine hydrochloride directly from Cinchona bark is commercially significant and great achievement which method is non - obvious in the filed of alkaloid chemistry.

Summery of the invention,

Quinine is a basic amine and always presented as a salt. Various preparations of quinine salt include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. The most generally used form of quinine salt was the sulphate, but more recently the hydrochloride has come into favor as it is much more soluble in water. The sulphate is taken up only by 725 parts of water, while the hydrochloride is dissolved by 35 parts. Each is readily dissolved with acid, bisulphate in 9 parts and the acid hydrochloride in 0.6 part of water. The presence of excess of acid is a disadvantage in intramuscular or intravenous injection and especially the solubility of the neutral hydrochloride weighs heavily in the favor of quinine hydrochloride.

Description of the invention

Quinine is a basic amine and always presented as a salt. Various preparations of quinine salt include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. The most generally used form of quinine salt was the sulphate, but alleged invention relates to a direct method for preparation of quinine hydrochloride from cinchona bark comprising the following steps, taking a known quantity of dried and pulverized Cinchona bark is mixed with quicklime in the ration of 0.5: 0.9 preferably 1 :0.4 and 6% caustic solution was added to this mixture. The blend was thoroughly mixed and kept aside for 6 to 12 hours preferably 8 to 10 hr. After the specified time the blend was extracted with oreganice solvent selected from Toluene, chloroform, acetone, methanol, ethanol, at the ratio of 0.5:6 preferably 1 :5 at 40 to 60 degree temperature more preferably at 50° C for 2 to 4 hours preferably for 3 hrs.

The second and third extraction was carried out with 0.5:4 more preferably 1 :3 blend and Toluene ratio for 2 to 4 hours preferably 3 hrs separately. The extracts were collected together and filtered through high flow bed. The filtrate was extracted with 5% hydrochloric acid and the mixture was stirred properly for 10 to 40 minutes preferably 30 minutes. The solution was kept undisturbed until to get separate the toluene and aqueous layer. When two layers were completely separated out, the aqueous layer was collected and adjusted the pH 4 to 5 with using 5% NaOH. Maximum amount of precipitate was allowed to form by adding NaOH solution. The crude precipitate of various cinchona alkaloids was filtered and subjected to dry at 40° C using hot air. Crude precipitate and hot distilled water (1 :5) were slowly and continuously stirred with 15% activated charcoal for 30 minutes at 65° C. The mixture was filtered hot and the filtrate was continuously stirred in order to reach a temperature of 30° C. Crystallization was observed at ambient temperature. The crystals were dried at 40° C with hot air. When the moisture content was about 6 to 10% the crystals was subjected to various analytical tests such as solubility, pH, SOR, and HPLC to conform national and international pharmacopeias.

Example 1

Pulverized Cinchona bark of 100 gm was soaked with quicklime (2 gm) and 6-8% KOH solution. The blend was vigorously mixed and kept undisturbed for 10-15 hr. The above mixture was extracted continuously with Acetone of 800 ml, 200 ml, and 200 ml respectively for 3 hr separately at 60° C. The extract was filtered, pooled together and acidified with 100 ml of 2 % HCl and the mixture was stirred continuously to mix the fractions properly. The solvent mixture was allowed to stand for 1 hr to get the layer separated out. The aqueous layer was collected and the pH was adjusted to 4.5 to 5 with 3% LIQ NH3 solution to obtain precipitate. The precipitate was filtered and dried at a temperature of 45 °C. Crude precipitate was added to five times quantity of distilled water containing 20% activated carbon at 80° C. The mixture was continuously stirred for 30 minutes. The filtrate obtained at hot was continuously stirred for crystallization. Crystallization was observed at 10-15° C temperature. The crystals were taken for various analyses.

Example 2

Five hundred gm of Cinchona bark was mixed with milk of lime 150 ml and 3 to 5% caustic soda solution and the mixture was kept for 10 to 12 hr after mixing properly. The mixture was extracted with MeOH (1.5 1) for 9 hr at 70° C. After filtering the extract, the extract was acidified with 1% HCl and the two layers were allowed to separate it out. The aqueous layer pH was adjusted to 4.5 to 5.5 with 1% NaOH solution to obtain crude precipitate. After the filtration the precipitate was dried at 45°C. Crude precipitate was dissolved in distilled water (1 :5). Activated charcoal was added to the mixture at 65° C. The mixture was gradually and continuously stirred for 30 minutes and filtered hot. Crystals were obtained at ambient temperature. The crystals were subjected for various analyses.

Claims

What is Claimed,

1. A direct method for preparation of quinine hydrochloride from cinchona bark comprising the following steps, i. Taking a known quantity of dried and pulverized Cinchona bark, mixed with quicklime in the ratio of 0.5: 0.9 and 6% caustic solution was added to this mixture.

ii. Blend obtained at step (i) was thoroughly mixed and kept aside for 6 to 12 hours after the specified time the blend was extracted using organic solvents at the ratio of 0.5:6 at 40 to 60 degree temperature for 2 to 4 hours preferably ,

iii. The second and third extraction was carried out using 0.5:4 blend and solvent ratio for 2 to 4 hours separately; the extracts were collected together and filtered through high flow bed. iv. The filtrate obtained at step (iii) was extracted with 5% hydrochloric acid and the mixture was stirred properly for 10 to 40 minutes, the solution was kept undisturbed until to get separate organic and aqueous layer, when two layers were completely separated out,

v. The aqueous layer obtained at step iv was collected and adjusted the pH 4 to 5 using 5% NaOH. Until to get maximum amount of precipitate was formed by addition of NaOH solution,

vi. The crude precipitate obtained at above step of various cinchona alkaloids was filtered and dried at 40° C using hot air, vii. To above resultant crude precipitate added hot distilled water ( 1 :5) slowly under constant stirring with 15% activated charcoal for 30 minutes at 65° C,

vii. The reaction mixture obtained at step vii allowed to filtered hot and the filtrate was continuously stirred until to reach a temperature of 30 C, followed by crystallization at ambient temperature, and dried at 40° C with hot air,

2. A direct method as claimed in claim 1 , wherein the organic solvents used are selected from toluene, methanol, ethanol, chloroform, acetone,more particularly toluene,

3. A direct method as claimed in claim 1 , wherein the Cinchona bark is mixed with quicklime in the ration of 0.5: 0.9 preferably 1 :0.4,

4. A direct method as claimed in claim 1, wherein the blend was thoroughly mixed and kept aside for 6 to 12 hours preferably 8 to 10 hr,

5. A direct method as claimed in above claims, wherein the blend was

extracted with Toluene at the ratio of 0.5:6 preferably 1 :5 at 40 to 60 degree temperature more preferably at 50° C for 2 to 4 hours preferably for 3 hrs,

6. A direct method as claimed in claim 1 , wherein the second and third

extraction was carried out using 0.5:4 more preferably 1 :3 blend and Toulene ratio for 2 to 4 hours preferably 3 hrs separately, followed by Alteration at high flew bed,

7. A direct method as claimed in claim 1 , wherein the filtrate was extracted with 5% hydrochloric acid and the mixture was stirred properly for 10 to 40 minutes preferably 30 minutes,

8. A direct method as claimed in claim 1 , wherein the two layers were

completely separated out, and the aqueous layer was collected and adjusted the pH 4 to 5 using 5% NaOH, precipitate was formed by adding NaOH solution, said crude precipitate cinchona alkaloids was filtered and dried using hot air, at 40° C ,

9. A direct method as claimed in above claims , wherein the crude precipitate and hot distilled water (1 :5) were added slowly under constant stirring using 15% activated charcoal for 30 minutes at 65° C,

10. A direct method as claimed in claim 1 and 9 wherein the s filtered hot and the filtrate was continuously stirred until to reach a temperature of 30° C the crystals were dried at 40° C with hot air,