KR101345725B1 - Novel process for the preparation of an antiemetic compound - Google Patents

Abstract

The present invention relates to the preparation of optically pure nausea inhibitor drugs. Embodiments of the present invention disclose a process for the preparation, which is industrially viable, reduces monocycle time, and provides high purity carbazole derivatives.

Vomiting inhibitor, carbazole

Description

Novel process for the preparation of an antiemetic compound

The present invention relates to a process for preparing R-(+)-Ondansetron, i.e., R-(+)-Zofran base and its pharmaceutically acceptable salts and hydrates thereof, It is practical, improved and provides high optical purity.

Ondansetron HCl dihydrate, ie Zofran, ie 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole- 4-one is a white to greyish white powder that dissolves in water and standard saline.

http://www.fda.gov/cder/foi/nda/99/20781 _- Zofran.pdf

The (R) isomer of Zofran (Compound I) has strong vomiting inhibitory activity and has been reported to be useful in improving nausea and vomiting caused by cancer chemotherapy agents and excessive radiation therapy (European Patent No. 0191562).

Optically pure R-(+)-ondansetron is a competitive antagonist of serotonin receptor subtype 5-HT ₃ and has been reported to be useful in treating cognitive disorders such as dementia and age-related memory impairment (damage).

Zofran free base is a mixture of optical isomers called R optical isomers and S optical isomers, and is a 1: 1 racemic mixture thereof. The racemate mixture of the zofran free base is a dihydrate and is administered as hydrochloride. The racemic mixture of the jofran free base is an antagonist of the 5-hydroxytriphtamine (5-HT3 or serotonin) receptor. The action of serotonin, and thus the pharmacology of jofran free base, has been widely associated with various conditions for many years (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): Racemic Mixture of Compound (I)

In the case of drugs, stereochemical purity is of the utmost importance, especially if the drugs prescribed are chiral. The L-form of propranolol, a β-adrenergic blocker, is known to be 100 times stronger than the D-isomer. While D-optical isomers are safe sedatives, optical purity is important because L-optical isomers may be substantially harmful rather than simply inactive, such as thalidomide, a powerful teratogenic substance.

Zofran free bases induce activity that inhibits vomiting and provide for the reduction and treatment of symptoms in a variety of conditions and disorders, but may also provide some side effects. The optically pure R-(+) isomer of zoperan free base is an effective vomiting inhibitor and useful as an adjuvant to improve nausea and vomiting caused by chemotherapy or radiation therapy in the treatment of cancer, whereas headache, fatigue , Reduces sedation, drowsiness and common side effects such as increased transaminases concentrations associated with mixtures of R (+) and S (-) isomers, ie racemic mixtures (European Patents 102025 and Europe Patent No. 0591434).

In EP 0191562, preparation of a mixture of optical isomers of zofran has been reported, and a method of resolution from the mixture using R / S-ditruyltinate was reported in EP 0191562. . Treatment of Zofran free base with (-) ditoluyl tartrate in methanol yields R, S-salts. Crystallization from aqueous DMF yields this 3R-salt. The cleavage method reported above produces the required 3R-salts with a yield of 30% or less and only after 95 days crystallization in 25-fold DMF to produce 95% e.e. by NMR. The known splitting methods do not produce pharmaceutically acceptable products with high chiral purity. Accordingly, it is an object of the present invention to provide a method for preparing R (+) zopran free base with high purity (ie at least 99% e.e.).

By using the R-(+) isomer of zofran free base, the efficacy is defined in terms of dosage, reducing side effects and improving the therapeutic index. Accordingly, it is desirable to provide pharmaceutical compositions that consist predominantly of the R-(+) isomer of Zofran free base and are substantially free of the S-(-) stereoisomer of Zofran free base.

Therefore, there is a need to develop a method for producing optically isomericly pure bran while (a) further increasing optical purity, (b) reducing cycle time, and (c) reducing labor and equipment.

It is a first object of the present invention to provide a method for preparing R-zofranin with higher optical purity.

It is a second object of the present invention to provide a method for preparing R-zofran with a reduced time cycle.

It is a third object of the present invention to provide a process for the production of R-zofran, which reduces labor and provides a cost-effective production process.

Embodiments of the invention relate to the preparation of an R-(+)-zofran free base having a chiral purity of about 99.5% e.e. The present invention also provides R-(+)-zofran having a chiral purity of about 99%.

The present invention

a) treating the zofran with a base selected from the group consisting of metal hydroxides or metal carbonates or metal bicarbonates to produce a zofran free base;

b) treating said jofran free base with 3-R / S-p-toluyl tartaric acid to obtain 3-R / S-p-toluyl tartaric acid salt of compound (II);

c) crystallizing the 3-R / S-p-toluyl tartaric acid salt using an aqueous solution of DMF as a solvent to obtain an R-(+)-enantiomer of compound (I); and

d) a process for the preparation of salts of compound (I) which comprises preparing R-(+)-zofran by treating R-(+)-zofran free base with HCl in alcohol. .

Zofran free bases are prepared by treating the hydrochloride dihydrate salts of the Zofran free base with hydroxides of metals or carbonates of metals or bicarbonates of metals, the metals being selected from the group consisting of alkali metals or alkaline earth metals. The alkali metal is preferably selected from sodium or potassium. The base is preferably an alkali 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 halogenated hydrocarbon such as CHCl ₃ , CH ₂ Cl ₂ or the like or methanol or ethanol as an aqueous alcohol. Preferably the alcoholic solution is treated with aqueous bicarbonate solution. The formed free base may be separated by filtration. The cleavage of the free base is carried out in the second step. Split formulations may be selected from either R or Sp-toluyl tartaric acid.

An additional step involves the separation of 3-R / S-p-toluyl tartaric acid salt by crystallization. The solvent used for the crystallization may be selected from the group consisting of esters, amides, ketones, alcohols, water or mixtures thereof. Preferred such solvents are amides. The amides used are selected from the group consisting of dimethyl formamide or dimethyl acetamide. Amide solvents can be used together in combination with water.

The invention is advantageous in the following respects: in order for the overall reaction to be completed, it takes 72 hours in the prior art, whereas in the present invention it is completed within 15-24 hours. The cycle time is substantially reduced due to the addition of nuclei of the DP- (di-para-toluoyl tartaric acid) salt of R-(+)-zofran. Another advantage of the present invention is that a 25-fold volume of DMF is required in the prior art process, while a smaller volume of the combined solvent of DMF and water is required in the present invention. The preferred ratio of DMF and water is 2: 1. The volume of DMF is in the range 5-12 times by weight of the salt. In addition, the final product, R-(+)-zofran, is obtained at 99.5% e.e. when compared to the prior art methods. S-isomers are reduced to less than 1% and minimized by recrystallization.

Said splitting can be carried out by using a mixture of splitting formulations. Mixtures of the divided formulations are selected according to their structural similarity. Various mixing ratios of the split formulations can be applied to obtain higher optical isomer purity and better efficacy without loss of yield. The cleavage formulation is selected from the group consisting of a combination of tartaric acid, substituted tartaric acid, and the like.

The principles, preferred embodiments and examples of the present invention have been disclosed above. However, the invention to be protected herein should not be construed as limited to the particular forms disclosed. For they should be regarded as illustrative rather than limiting the invention. Modifications and variations may be made by those skilled in the art without departing from the principles of the invention.

Although the invention is described in more detail by the following examples, these examples are not intended to limit the scope of the invention.

Example 1: 3-R, S-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole- 4-one free base (zofran free base)

Zofran (255 gm) was added to 625 mL of water and 2.025 L of DMF. The reaction mixture was stirred for 5-10 minutes to obtain a clear solution. The reaction mixture was heated to 65-70 ° C. 27 gm of NaOH dissolved in 500 ml of water was added dropwise to the reaction mixture at room temperature. The temperature of the reaction mixture was raised to 80 ° C. and maintained for 30 minutes to produce zoperran free base in situ .

Example 2: 3-R, S-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole- 4-on-di-p-toluyl-L-tartrate salt (racemate)

To the reaction mixture obtained from Example 1, 263 gm of di-para-toluyl tartaric acid was added. 0.2 gm of (R) -DPTA salt of zofran free base was added and the DPTA salt was obtained after filtration.

Example 3: 3-R-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole-4- On-di-p-toluyl-L-tartrate salt

Wet solids obtained from Example 2 and twice the volume of solids of DMF were filled in a round bottom flask. The reaction mixture was stirred. One volume of water was charged to the flask. The temperature of the flask was raised to 80-85 ° C. The reaction mixture was maintained at 80-85 ° C. for 2 hours. The reaction mixture was cooled to 60 ° C. over two hours. The reaction mixture was filtered and dried (165 gm).

Example 4: 3-R-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole-4- On-di-p-toluyl-L-tartrate salt

2312 ml of water and 3-R, S-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole- The 4-on-di-p-toluyl-L-tartrate salt was packed into a round bottom flask and stirred. 4675 ml of DMF was added to the reaction mixture. The reaction mixture was heated until a clear solution. The reaction mixture was cooled down and allowed to nucleate and then maintained for one night. The reaction mixture was filtered, washed with water and then with methanol. The resulting preparation was dried.

Yield = 420 gm

% 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-carbazole-4- On-di-p-toluyl-L-tartrate salt

1350 ml of water and 3-R, S-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole- 450 g of 4-on-di-p-toluyl-L-tartrate salt were charged into a round bottom flask and stirred. The reaction mixture was heated to reflux. 2700 mL DMF was added into the reaction mixture. The reaction mixture was further heated until the reaction mixture became clear. The reaction mixture was cooled down, allowing crystal nuclei to form and then maintained for one night. The reaction mixture was filtered, washed with water and then with methanol. The resulting preparation was dried.

Yield = 185.6 gm

% 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-carbazole-4- Whole free base

Sodium bicarbonate solution (260 gm in 2.20 L water) was prepared. To the round bottom flask was added 1.76 L of sodium bicarbonate solution and DPTA salt (165 mg) prepared from Example 3. After complete addition, the remaining sodium bicarbonate solution was added. The temperature of the reactor was raised to 45-50 ° C. and maintained for two hours. The reaction mixture was filtered under hot conditions. The resulting less dry solid was washed with 3.415 Kg of DMF and the product was filtered under reduced pressure and dried. The less dry solid was washed with water.

Example 7: 3-R-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole-4- Whole free base

To the round bottom flask, 180 gm of pure optically active tartrate salt obtained from Example 5 was added. The reaction was stirred at 40 ° C. The reaction mixture was added dropwise with stirring 480 mL of aqueous NaHCO ₃ solution (8%). The resulting solid was filtered off and washed with water. The less dry solid was further extracted with chloroform. Chloroform extracts were combined and dried.

Yield = 67.5 gm

% 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-carbazole-4- Hydrochloride dihydrate

640 gm of isopropyl alcohol was placed in a round bottom flask. The wet solid obtained from Example 4 was stirred with addition into the flask. HCl was added to the flask. 140 ml of water was further added. The temperature of the reactor was raised to 70-75 ° C. to give a clear solution. Heating was maintained for 10 minutes. The reaction mixture was filtered to give R-zofran (99.5%).

Example 9: 3-R-1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl) methyl) -4H-carbazole-4- Hydrochloride dihydrate

900 ml of isopropyl alcohol was placed in a round bottom flask. The free base obtained in Example 7 was stirred with addition into the flask. 52.16 mL of concentrated HCl was added to the flask. Further 180 ml of water were added. The temperature of the reactor was raised to 70-75 ° C. to give a clear solution. Heating was maintained for 10 minutes. The reaction mixture was diluted with isopropyl alcohol. The reaction solution was kept overnight for crystallization. The reaction mixture was filtered and washed with cold isopropanol to give R-zofran.

Yield = 133 gm

% Yield = 87%

Purity = 97.8%

The present invention is advantageous in the following points.

In order to complete the entire reaction, it takes 72 hours in the prior art, while in the present invention the overall reaction is completed within 15-24 hours. The monocycle time is substantially reduced due to the addition of seed crystals of the DPTA salt of R-(+)-zofran. Another advantage of the present invention is that a 25-fold volume of DMF is required in the prior art process, while a smaller volume of the combined solvent of DMF and water is required in the present invention. The preferred ratio of DMF and water is 2: 1. The volume of DMF is in the range 5-12 times by weight of the salt. In addition, the final product, R-(+)-zofran, is obtained at 99.5% e.e. when compared to the prior art methods. S-isomers are reduced to less than 1% and are minimized by recrystallization.

Claims (7)

a) treating the zofran with a base selected from the group consisting of metal hydroxides or metal carbonates or metal bicarbonates to produce a zofran free base; b) treating said jofran free base with 3-R / S-p-toluyl tartaric acid to obtain 3-R / S-p-toluyl tartaric acid salt of the racemic mixture of compound (I), Compound (I) is

Wherein R ₁ is CH ₃ and R ₂ is

Being; c) crystallizing the 3-R / S-p-toluyl tartaric acid salt using an aqueous solution of DMF as a solvent to obtain an R-(+)-enantiomer of the compound (I); and d) preparing R-(+)-zofran by treating R-(+)-zofran free base with HCl in alcohol. The method of claim 1, wherein the base of step a) is a metal hydroxide. The method of claim 2, wherein the base is sodium hydroxide. The method of claim 1, wherein the alcohol used in step d) is isopropanol. delete delete delete