RU2439057C2 - Method of obtaining antiemetic medication - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to method of obtaining optically pure antiemetic medication, R-(+)-ondansetron, which includes the following stages: a) processing of ondansetron hydrochloride with base, which is selected from group, containing metal hydroxide and carbonate or bicarbonate; b) processing of free ondansetron base with R/S-(+)-n-toluyl tartrate acid in mixture of dimethylforamide and water obtaining salt of 3-R/S-ondansetron-n-toluene tartrate acid; c) fractional recrystallisation of salt of 3-R/S- ondansetron-n-di-toluene tartrate acid from mixture of dimethylformamide and water, if necessary, in presence of primer obtaining salt of 3-R-(+)- ondansetron-n-di-toluene tartrate acid of required enantiomer purity; and processing by base with obtaining free base of 3-R-(+)- ondansetron, and at first ondansetron salt is dissolved in water at room temperatute, after which dimethylformamide is added to solution, with further heating of mixture to 80-85°C, cooling to 60°C and filtration at that temperature, ratio of water and dimethylformamide volume in mixture constituting 2:1; d) processing of free base of R-(+)-ondansetron with hydrochloric acid in presence of alcohol as solvent obtaining 3-R-(+)-ondansetron hydrochloride.

EFFECT: claimed method is less time-consuming and ensures higher product purity in comparison with known methods-analogues.

4 cl, 9 ex

Description

FIELD OF THE INVENTION

The present invention relates to an improved, industrially feasible method for producing R - (+) - ondansetron, i.e. R - (+) - ondansetron in the form of a base and its pharmaceutically acceptable salts and / or hydrates with high optical purity.

State of the art

The present invention relates to an improved, industrially feasible method for producing R - (+) - ondansetron, i.e. R - (+) - ondansetron in the form of a base and its pharmaceutically acceptable salts and / or hydrates with high optical purity.

Ondansetron hydrochloride dihydrate, i.e. zofran (1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one) is a white or yellowish powder, soluble in water and in normal saline.

http://www.accessdata.fda.gov/drugsaftda_docs/label/2010/020103s029,020605s013,020

781s0131bl.pdf

There is evidence (see EP 0101562 B) that the (R) ondansetron isomer (compound I) has pronounced antiemetic activity and is used to alleviate nausea and vomiting caused by the use of anticancer chemotherapeutic drugs and an increased dose of radiation therapy.

There are reports that optically pure R - (+) - ondansetron can be used in the treatment of cognitive diseases, such as dementia and age-related memory impairment, as a competitive antagonist of serotonin receptors of the 5-HT ₃ subtype.

The ondansetron in the form of a free base is a 1: 1 racemic mixture of optical isomers called the enantiomers R and S. The racemic mixture of the ondansetron free base is a dihydrate and is administered orally as a hydrochloride salt. The racemic mixture of the ondansetron free base is an antagonist of the 5-hydroxytryptamine receptor (5-Ht3 or serotonin). For many years, the role of serotonin and, accordingly, the pharmacology of the ondansetron free base has been studied in relation to various conditions (Phillis, JW, The Pharmacology of Synapses, Pergamon Press, Monograph 43, 1970; Frazer, A. et al. Annual Rev. Of Pharmacology and Therapeutics 30, 307-348, 1990).

Compound (II): A racemic mixture of compound (I)

For drugs, stereochemical purity is important, especially in cases where the prescribed drug detects chirality. It is known that the L-form of β-adrenergic blocking agent propranolol is 100 times more active than the D-isomer. The great importance of optical purity is due to the fact that some isomers are not just inert, but can actually worsen the condition, as was the case with the drug thalidomide, whose D-enantiomer is a safe sedative and the L-enantiomer is a strong teratogen.

Ondansetron in the form of a free base has antiemetic activity and provides treatment and reduction of symptoms of various diseases in various conditions, but at the same time causes some harmful side effects. It was found that the optically pure R - (+) isomer of the ondansetron free base is an effective antiemetic that can be used as adjunctive therapy to eliminate the nausea and vomiting caused by chemo and radiotherapeutic agents, while the usual side effects are reduced: headache, constipation, fatigue, sedation, lethargy, increased transaminase levels that are associated with the racemic mixture, i.e. a mixture of R (+) and S (-) isomers (EP 1022025 and EP 0591434).

EP 0191562 describes the preparation of a mixture of ondansetron enantiomers and separation of the mixture using R / S-toluyl-di-p-toluyl tartaric (tartaric acid). The free ondansetron base as a result of treatment with (-) ditoluyl tartrate in methanol leads to the formation of the R, S-salt, which upon crystallization from aqueous DMF forms the R-ondansetron tartrate salt. The described separation procedure leads to the formation of the desired R-ondansetron tartrate salt with a yield of less than 30% after crystallization in 25-44 volumes of DMF for 3 days with an enantiomeric purity (excess) (e.u.) of 95%, as determined by NMR. The known method of separation does not allow to obtain a pharmaceutically acceptable product with a high degree of chiral purity. In connection with the foregoing object of the present invention is the provision of a method for the preparation of R (+) ondansetron in the form of a free base with a high degree of chiral purity (equal to at least 99% e.e.).

The use of the R (+) ondansetron stereoisomer in the form of a free base leads to a clear dose-dependent increase in efficacy, the reduction of undesirable side effects and an improvement in the therapeutic index. Therefore, it is desirable to ensure the creation of such a pharmaceutical composition that would primarily use the R - (+) isdansetron isomer in the form of a free base and essentially did not contain the S - (-) stereoisomer of ondansetron.

Thus, there is a need to develop a method for producing enantiomerically pure ondansetron, which would provide

(a) higher optical purity

(b) shortening the time cycle

(c) reduction in labor costs and increase in profitability of production.

OBJECTS OF THE INVENTION

The first objective of the invention is to develop a method for producing R-ondansetron with the highest degree of purity.

The second objective of the invention is to develop a method for producing R-ondansetron in a shortened period of time.

The third objective of the invention is to develop a method for producing R-ondansetron with less labor with greater profitability.

The implementation of the invention

The present invention is directed to the production of R - (+) - zofran in the form of a free base having a chiral purity close to 99.5% e.e. The invention also provides for the production of R - (+) - ondansetron having a chiral purity of about 99%.

The present invention discloses a method for producing a salt of compound (I), comprising the steps of:

a) obtaining the racemic ondansetron as a free base by treating the ondansetron hydrochloride with a base selected from the group consisting of metal hydroxide or carbonate or bicarbonate;

b) treating the 3-R / S-p-toluyl ondansetron free base with tartaric acid in aqueous dimethylformamide (DMF), seeding with the corresponding 3-R-ondansetron-p-toluyl tartaric acid salt to obtain the 3-R / S-ondansetron-p salt Toluyl tartaric acid of compound (II);

c) recrystallization of the ondansetron salt of 3-R / S-p-toluyl tartaric acid using aqueous dimethylformamide (DMF) as a solvent and obtaining the R - (+) - enantiomer of compound (I);

d) obtaining R - (+) - ondansetron by treating Hcl in alcohol.

The ondansetron free base is obtained from a 2-water salt of its hydrochloride by treatment with metal hydroxide or carbonate or bicarbonate, in which the metal is selected from the group represented by alkali or alkaline earth metals. A preferred alkali metal is sodium and potassium. A preferred base is an alkali metal hydroxide selected from the group consisting of sodium hydroxide or potassium hydroxide.

The solvent used is selected from the group consisting of halogenated solvents. The solvent may be a halogen-substituted hydrocarbon such as CHCl ₃ , CH ₂ Cl ₂ , etc., or aqueous alcohol, methanol, ethanol. Preferably, the alcohol solution is treated with aqueous bicarbonate. The base thus obtained can be isolated by filtration. The selection of the free base is carried out in the second stage. The separating agent may be selected from either R- or S-p-toluyl tartaric acid.

The next step involves the separation of the salt of 3-R / S-p-toluyl tartaric acid by crystallization. The solvent used for crystallization may be selected from the group consisting of esters, amides, ketones, alcohols, water, or mixtures thereof. A preferred solvent is an amide. The amide is selected from the group consisting of dimethylformamide or dimethylacetamide. Amide solvent can be used in combination (2: 1) with water.

The present invention has the following advantages: the desired salt is obtained as a result of fractional recrystallization from a combination (2: 1) amide: water, which is completely completed in 15-24 hours, for comparison - in 72 hours in methods known from the prior art. The time cycle was significantly shortened by the addition of seed crystals of the DPTTA salt R - (+) ondansetron. Another advantage of the present method is that this method requires a smaller volume of the combined solvent, i.e. DMF and water (5-25), compared with methods known from the prior art (25-44), in which the volume of DMF is 25 times greater. The preferred ratio of DMF to water is 2: 1.

DMF is used in a 3-12-fold excess relative to the weight of the di-p-toluene salt. In addition, the final product, namely R - (+) - ondansetron, is obtained with an enantiomeric excess equal to 99.5% e.u., compared with methods known from the prior art that provide 90-95% enantiomeric purity. The content of the S-isomer is reduced to less than 1% and minimized by recrystallization.

The isolation of enantiomers from their racemic mixture can be carried out using a mixture of resolving agents. A mixture of separating agents is selected based on structural similarity. Various ratios of resolving agents can be selected in order to ensure that enantiomers of the highest purity are obtained without decreasing the yield and with the best efficiency. Separating agents are selected from the group consisting of combinations of tartaric acid, substituted tartaric acid, etc.

The present description sets forth the principles, preferred embodiments and methods of carrying out the claimed invention. However, the claimed invention is not limited to the particular embodiments presented in the description, since they are aimed only at illustration, but not at limitation. Experts with experience can make variations and changes without departing from the essence of the invention.

The invention is illustrated in more detail by the following examples, which serve only to illustrate and do not limit the scope of the present invention.

Example 1

3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one as the free base (ondansetron in the form of a free base).

Ondansetron hydrochloride (255 g) was added to 625 ml of water and 2.025 L of DMF. The reaction mixture is stirred for 5-10 minutes until a clear solution is obtained, then heated to 65-70 ° C and 27 g of NaOH dissolved in 500 ml of water and having room temperature are added dropwise. The reaction temperature was raised to 80 ° C and maintained at this level for 30 minutes until the formation in the reaction of the ondansetron free base in sity, which was then cooled.

Example 2

3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one-di-p -toluyl-L-tartar salt.

To the reaction mixture obtained in accordance with Example 1, 263 g of di-para-toluyl tartaric acid were added. Then, seed crystals of 0.2 g of (R) -DPTA ondansetron salt in the form of a free base are added to obtain a DPTA salt after filtration.

Example 3

3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one-di-p -toluyl-L-tartar salt (DPTTA salt).

2 volumes of DMF in which the wet cake obtained in accordance with Example 2 was dissolved were charged into a round bottom flask. The reaction mixture was stirred. Add 1 volume of water to the flask. The temperature was raised to 80-85 ° C and the reaction mixture was kept at a temperature of 80-85 ° C for 2 hours, then gradually cooled to 60 ° C over two hours. The reaction mixture was filtered and the precipitate was well dried (165 g).

Example 4

3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one-di-p -toluoyl-L-tartar salt.

2312 ml of water and 925 g of 3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) are charged into a round-bottom flask with stirring. -4H-carbazole-4-one-di-p-toluyl-L-tartar salt. 4675 ml of DMF was added to the mixture. The reaction mixture is heated until a clear solution is obtained, then cooled, seeded and allowed to stand overnight. The reaction mixture is filtered, the precipitate is washed with water, then with methanol. The resulting product is dried.

Yield = 420g

% yield = 91%

Purity = 97.96%

Example 5

3-R-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one-di-p-toluyl -L-tartar salt.

1350 ml of water and 450 g of 3-R, S-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) are charged into a round-bottom flask with stirring. -4H-carbazole-4-one-di-p-toluoyl-L-tartar salt. The reaction mixture is heated to boiling under reflux. 2700 ml of DMF was added to the reaction mixture and heated until the mixture became clear, then cooled, seeded and allowed to stand overnight. The reaction mixture is filtered, the precipitate is washed with water, then with methanol. The resulting product is dried.

Yield = 185.6 g

% yield = 82%

Purity = 99.66%

Example 6

3-R-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one.

Prepare a solution of sodium bicarbonate (260 g in 2.20 l of water). 1.76 L of sodium bicarbonate solution and DPTTA salt (165 g) prepared in accordance with Example 3 were added to a round bottom flask, then the remaining sodium bicarbonate solution was added. The temperature of the reaction mixture was raised to 45-50 ° C and maintained for two hours. The reaction mixture is filtered while hot. The wet cake was washed with 3.415 kg of DMF and dried by vacuum distillation of the solvent. The wet cake is washed with water.

Example 7

3-R-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one.

180 g of the optically pure active tartaric acid active salt prepared in accordance with Example 5 was charged into a round bottom flask. The reaction mixture was stirred at 40 ° C and 480 ml (8%) of NaHCO ₃ solution was added dropwise with stirring. The precipitate formed is filtered off and washed with water. The wet cake is then extracted with chloroform. The chloroform extracts are combined and dried.

Yield = 67.5 g

% yield = 87.6%

Purity = 99.7%

Example 8

3-R-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one hydrochloride dihydrate.

640 g of isopropyl alcohol are added to a round bottom flask. The wet cake obtained in accordance with Example 4 was added to the flask with stirring. 202 g of concentrated Hcl and then 140 ml of water are also added to the flask. The temperature of the reactor is increased to 70-75 ° C and maintained until the solution becomes clear. Heating is continued for 10 minutes. The reaction mixture was filtered to give R-ondansetron hydrochloride dihydrate (purity 99.5%; yield 91.3%).

Example 9

3-R-1,2,3,9-tetrahydro-9-methyl-3 - ((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazol-4-one hydrochloride dihydrate.

900 ml of isopropyl alcohol are added to a round bottom flask. The free base obtained in accordance with Example 7 was added to the flask with stirring. 52.16 ml of concentrated Hcl and then 180 ml of water are also added to the flask. The temperature of the reactor is increased to 70-75 ° C and maintained until the solution becomes clear. Heating is continued for 10 minutes. The reaction mixture was diluted with isopropyl alcohol. The solution was kept overnight for crystallization, then filtered, washed with cold isopropanol and R-ondansetron hydrochloride dihydrate was obtained.

Yield = 133 g

% yield = 87%

Purity = 97.8%

Claims (4)

1. The method of obtaining R - (+) - ondansetron, which includes stages:
a) treating ondansetron hydrochloride with a base which is selected from the group consisting of metal hydroxide or carbonate or bicarbonate;
b) treating the free base of the ondansetron R / S - (+) - p-toluyl tartaric acid in a mixture of dimethylformamide and water to obtain a 3-R / S-ondansetron-p-di-toluenyl tartaric acid salt;
c) fractional recrystallization of a 3-R / S-ondansetron-p-di-toluolyl tartaric acid salt from a mixture of dimethylformamide and water, optionally in the presence of a seed, to obtain a 3-R - (+) - ondansetron-p-di-toluol tartaric acid salt required enantiomeric purity; and treatment with a base to obtain the free base of 3-R - (+) - ondansetron, first the ondansetron salt is dissolved in water at room temperature and then dimethylformamide is added to the solution, after which the mixture is heated to 80-85 ° C, then cooled to 60 ° C and at this temperature is filtered, and the ratio of the volumes of water and dimethylformamide in the mixture is 2: 1;
d) treating the free base of R - (+) - ondansetron with hydrochloric acid in the presence of alcohol as a solvent to obtain 3-R - (+) - ondansetron hydrochloride. 2. The method according to claim 1, where in step (c), the base is an alkali metal hydroxide, preferably sodium hydroxide. 3. The method according to claim 1, in step (d) wherein the alcohol is propanol. 4. The method according to claim 1, where in stage (d) the enantiomeric purity of R (+) - ondansetron is ≥99.0%.