Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-29
2001-06-05
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C210S364000
Reexamination Certificate
active
06242617
ABSTRACT:
The present invention relates to pharmaceutical industry, to the sesquiterpene lactones and, particularly, to the method of production of lyophilized hydrochloride 1&bgr;, 10&bgr;-epoxy-13-dimethylamino-guaia-3(4)-en-6,12-olide of the following formula
which has antitumour activity and can be used to develop new preparations for chemotherapy of malignant tumours.
The method of production of arglabin lyophilized having antitumour activity from the natural material-flower baskets and leaves of endemic plant
Artemisia glabella Kar. et Kir.
was described in preliminary patent of the Republic of Kazakstan, N 5277, cl.CO7D 307/93, A61K, 31/365, 1997).
According to this method initially dry grinded natural material is treated by a solvent in the extractor, then extracted substances (resin) are purified from worthless products through treatment by 60% acqueous solution of ethyl alcohol. The resin produced at the stage of purification is divided into separate components by the method of column chromatography on silicogel. The said column is eluted with benzene and the fractions containing arglabin are separated. Benzene is distilled and technical arglabin is produced which is further subjected to crystallisation, amination and hydrochloration. In this method amination is carried out by dimethylamine with production of a solution containing arglabin. Then the alcohol solution of aminoarglabin is barbotaged by chlorine hydride and the target product—aminoarglabin hydrochloride is produced. Amination and hydrochloration reactions are controlled by the methods of thin layer chromotography. Technical hydrochloride of aminoarglabin is purified by crystallization with subsequent drying and lyophilization.
Disadvantages of the above method are its rather low yield of target products in the amination and hydrochloration reactions.
Different devices are used for extraction, for example, the device consisting of extractor with a jacket in the extraction zone, evaporator, condenser and heater (the USSR author's certificate N 1117071, cl. BO1D 11/02, 1984).
The USSR author's certificate N 670310, cl. BO1D 11/02, 1979 describes the device for gas-liquid extraction consisting of evaporator, condenser and extractor, where the extracted mixture is heated by the heat produced at condensation of extragent vapours transported from evaporator, said heat is transmitted through the wall of the extractor.
The disadvantage of all these devices is periodicity of their operation what cannot provide high productivity. These devices also do not provide extraction of the extragent from waste material what results in great losses of the extragent. In the USSR author's certificate N 1117071 reacting mixture is heated by an additional power supply what increases power consumption in the process of extract production.
The USSR author's certificate N 1426611, cl. BO1D 11/00, 1988 describes the device for extraction in the solid-liquid system consisting of the body, extraction chamber with changeable container, evaporator and condenser which enables to distill the extragent from the solid phase by a warm inert gas at the final stage of extraction. This device also does not provide continuous operation and, respectively, has low productivity. Besides, when volatile extragents are distilled by a warm gas while condenser is cooled by the water, the whole extragent can be taken away with the gas without its condensation in the condenser. For example, according to our calculations, to distill chloroform by a gas with initial temperature 70° C. and to cool it in the condenser to 20° C., 5 m
3
of gas are required for evaporation of 1 kg of chloroform and for its condensation partial pressure of chloroform in the gas must be not lower than the saturation partial pressure at 20° C. what corresponds to the content of 1 kg of chloroform in 1 m
3
of gas. Thus, partial pressure of chloroform in the gas in the above example is 5 times lower than that required for condensation, i.e. no condensation is possible in the condenser and all the chloroform will leave the condenser together with the gas.
There are also some special devices for solvent removal from the waste material, for example, the method and device for removal of the solvent from solid substances, consisting of a capacity for waste material contact with heat-carrying agent, separators for extragent and heat-carrying agent separation, condensers for extragent vapours. (Patent EPV N00356338, cl. BO1D 11/00, 1990).
Such devices are complicated and energy consuming, besides, when waste material is reloaded from the extraction device to other devices, it is impossible to prevent extragent losses or it is necessary to use complex hermetic devices for reloading.
The closest to the claimed device is a section blade extractor of dry natural material of continuous operation consisting of cylindric body divided by partitions with openings into not less than three sections, separation and humidity chamber, shaft mounted on the same axis with the body with reloading ladles, mixing blades and loader are attached to said shaft (the USSR author's certificate N 1627208, cl. BO1D 11/02, 1991).
This design provides increase in productivity as compared with the above devices but this increase is not sufficient. The disadvantage of this design is also high extragent consumption as this device does not enable to extract extragent from waste material what results in extragent losses. The usage of other known devices to extract extragent from waste material considerably increases the cost of the installation and requires additional devices providing reloading and transportation of wet waste raw material without extragent emission to the environment.
The purpose of the present invention is to develop a method and device which could provide high yield of target product, complete extraction of the extract from raw material, increase in productivity of the extraction device, reduction of power supply, minimization of extragent losses, exclusion of extragent emission in the environment and, thus, guarantee of environmentally safe production.
According to the invention these tasks are solved by claims
1
and
3
of the claims. Preferred embodiments of the invention are given in dependent claims.
The method of production of lyophilized hydrochloride 1&bgr;, 10&bgr;-epoxy-13-dimethylamino-guaia-3(4)-en-6,12-olide-antitumour preparation arglabin lyophilized from endemic plant
Artemisia glabella Kar.et Kir.
comprises resin extraction from raw material, its purification from worthless side substances, separation of said resin into separate components by column chromatography with production of technical Arglabin which is further subjected to recrystallization, amination and hydrochloration with production of aminoarglabin hydrochloride and its further recrystallization, drying, lyophilization and high quality identification, where preferred amination is carried out by solution of crystallic arglabin in alcohol with addition of dimethylamine in said alcohol solution till pH of the solution reaches 12.3-12.4, and where to extract aminoarglabin hydrochloride from said solution containing aminoarglabin alcohol is distilled and chloroform is filled in, the remaining water is removed, said solution is filtered said chloroform is evaporated and alcohol added, then the solution is barbotaged by chlorine hydrine to 5.0-5.5 pH solution, alcohol is evaporated and ethylathetate added.
It is preferable to carry out high quality identification of arglabin by IR-spectroscopy.
In the claimed method stages of amination and hydrochloration under given operation parameters of pH-solutions provide high yield of 13-dimethylaminoalglabin and 13-dimethylaminoalglabin hydrochloride reactions. In its turn, it provides high output of target product.
The invention also includes the device to implement this method. Technical result of the present invention is achieved by the device for lyophilized arglabin extraction from natural raw material consisting of horizontal extractor including cylindrical bod
Rader & Fishman & Grauer, PLLC
Trinh Ba K.
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