PL217646B1 - Method of manufacturing of zolmitriptan with high pharmaceutical purity - Google Patents

Description

Description of the invention

The subject of the invention is a process for the preparation of zolmitriptan with high pharmaceutical purity and a novel zolmitriptan salt that can be used in this process.

Zolmitriptan, (S) -4 - {[3- (dimethylaminoethyl) -1H-indol-5-yl] methyl]} - 2-oxazolidin-one, is a selective 5-HT1 receptor agonist, the active ingredient of a drug indicated in the treatment of migraine .

One of the methods for the preparation of zolmitriptan, known from the patents PL 166 214 B1 (EP 0486 666 B1) and PL 188 805 B1 (EP 0 843 672 B1), involves a six-step synthesis starting from (L) -4-nitrophenylalanine. The last step in the synthesis is the formation of the indole ring by the Fischer method by reacting (S) -4- (4-hydrazinobenzyl) -2-oxazolidinone with an acetal derivative of dimethylamino-butanal, (3,3-diethoxypropyl) dimethylamine. The synthesis proceeds via an intermediate diazonium salt and an azine derivative, which can form undesirable side reaction products, which means that the crude brown oil post-reaction mixture contains a large amount of impurities. Particularly troublesome are the residues of compounds containing the azine chromophore group. These compounds are difficult to remove even by crystallization and treatment with conventional absorbing agents such as activated carbon.

In the experimental part of Patent PL 166 214 B1 (example 1, step f), the target compound is isolated by chromatography on a silica gel column, eluting in the form of an oil. This method is of little use for the large-scale synthesis of pharmaceutical substances. The crystallization of the oil from isopropanol (example 2) leads to the obtaining of the product in a crystalline form, but not only is it still contaminated, as evidenced by the wide melting range, but it crystallizes in the form of a solvate containing 0.5 water molecules and 0.9 isopropanol molecules . This solvate requires further processing to obtain a non-solvated substance suitable for the preparation of solid drug forms with a uniform active substance content.

In the patent specification PL 188 805 B1, crude zolmitriptan is purified by boiling in an ethyl acetate solution containing 10% ethanol with activated carbon and crystallizing the product as a solvate with ethyl acetate. The solvate is then converted to the unsolvated compound by stirring in 20% aqueous acetone. The disclosed process allows for the isolation of zolmitriptan from the crude mixture, but obtaining a pharmaceutical grade substance requires additional crystallization, which makes the purification process laborious and inefficient.

Another method of purifying zolmitriptan is disclosed in PCT international application WO 2008/007390 A2. After isolating the product by extraction with chloroform, the extract was heated with activated carbon and concentrated. The filtered crude powder product is dissolved hot in 40% acetonitrile in water and decolorized with active carbon, and then, after isolating the crystals formed, it is recrystallized from 2-propanol with water, decolorizing once more with activated carbon. Although this procedure results in a product with a purity of over 99.8%, it requires a number of operations, with successive exchanges of solvents, hot filtration, and multiple decolorization of the solutions with activated carbon.

Due to the standards set out by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), pharmaceutical substances approved for human use must meet certain purity requirements, i.e. be characterized by the so-called pharmaceutical grade. Moreover, the presence of even trace amounts of color impurities in the substance may disqualify it from the point of view of its suitability for the preparation of finished drug forms, especially oral tablets.

Thus, whenever pharmaceutical grade is mentioned in the following description, it is to be understood that according to the requirements of ICH the term refers to zolmitriptan or a salt thereof with a pharmaceutically acceptable acid containing less than 0.1% of unidentified individual impurities or less than 0.4%. all unidentified pollutants together. The prior art methods for purifying and decolorizing zolmitriptan substances, even if effective, require further simplification, which has been the object of the present invention.

It has turned out that zolmitriptan can be obtained with high pharmaceutical purity and a white color, while avoiding the above-described disadvantages, if the crude product of the Fischer condensation reaction, after isolation, is converted into a salt with oxalic acid, which can be further processed according to the invention.

PL 217 646 B1

The invention makes use of the possibility of zolmitriptan forming addition salts with inorganic or carboxylic acids by attaching the hydrogen atom of the acid molecule to any salt-forming moiety of the molecule, especially nitrogen atoms.

The patent PL 166 214 B1 discloses, inter alia, the salts of zolmitriptan with maleic, hydrochloric, succinic and benzoic acids.

It turned out that despite the potential for zolmitriptan to form salts with acids in various molar proportions, a constant stoichiometry salt with a pharmaceutically acceptable oxalic acid is easily formed, which salt can be successfully used to clean the substance to pharmaceutical purity.

The invention includes all salts of zolmitriptan with oxalic acid as well as their solvates, including hydrates.

In particular, the invention includes a salt of zolmitriptan with oxalic acid in a molar ratio of zolmitriptan base to acid as 1: 1, represented by the formula (1a)

in a crystalline form, and its use in the preparation of zolmitriptan with high pharmaceutical purity.

The essence of the invention is a process for the preparation of zolmitriptan of high pharmaceutical purity, which consists in separating crude zolmitriptan from the reaction mixture after the Fischer condensation reaction, converting it into a salt with oxalic acid, subjecting the salt to purification, and then releasing zolmitriptan free base from the salt.

The crude zolmitriptan according to the invention is obtained in the manner known from patents PL 166 214 B1 and PL 188 805 B1 by the diazotization of (S) -4- (4-aminobenzyl) -2-oxazolidinone of the formula 2, followed by reduction of the resulting salt diazonium to the hydrazine derivative of formula 3, which is converted into the target product by reaction with (3,3-diethoxypropyl) dimethylamine (formula 4). The reduction is carried out with sulfur compounds, preferably sodium sulfite.

The process of obtaining zolmitriptan salt with oxalic acid comprises sequentially extracting the crude zolmitriptan with a water-immiscible solvent, distilling off the solvent, dissolving the residue in a polar solvent, and combining with oxalic acid.

Extraction of zolmitriptan is carried out from an aqueous solution having a pH of 12-14 with a water-immiscible solvent, preferably ethyl acetate, at elevated temperature, e.g. at a temperature of 40-60 ° C.

The polar solvent used in the preparation of the oxalate salt is preferably ethyl alcohol.

The resulting zolmitriptan oxalate which precipitates out of the solution is dried and crystallized after filtration. Crystallization is carried out by hot dissolving the precipitate in a polar solvent, preferably ethyl alcohol containing up to 50% of water, and decolorizing with active carbon. Depending on the purity of the raw zolmitriptan starting material, a one-time crystallization is generally sufficient to obtain the final pharmaceutical grade material. For the purification of zolmitriptan with an initial purity of about 80% (determined by HPLC), two recrystallizations may be necessary, as illustrated in the attached example.

To isolate the free base of zolmitriptan, the oxalate crystals are suspended in water, made alkaline to pH> 11, and the base is isolated by extraction with a water-immiscible solvent and distilling off the solvent.

The zolmitriptan base is purified in a manner known per se by recrystallization, for example from isopropyl alcohol with ethyl acetate, followed by maceration of the crystalline precipitate in 20% acetone / water solution.

PL 217 646 B1

Crystalline salt of zolmitriptan with oxalic acid in the ratio of zolmitriptan base to acid 1: 1, hereinafter referred to as zolmitriptan oxalate, is characterized by an X-ray powder diffraction pattern having the following peaks with 2 wartości X-ray deflection angles expressed in (°), interplanar distances d in (°) and relative intensities in relation to the most intense diffraction line, I / I0 (%):

T a b e l a 1. List of reflection angles (2Θ), interplanar distances (d) and relative intensities (I / I0)

2Θ (°) d (A) I / I0 (%) 4.93 17.89 1 7.01 12.61 1 9.73 9.08 12 9.97 8.86 2 10.91 8.10 6 13.88 6.38 27 15.39 5.75 5 15.62 5.67 8 15.91 5.56 2 16.70 5.30 4 17.58 5.04 10 18.35 4.83 10 19.38 4.57 41 20.02 4.43 27 20.38 4.35 71 20.80 4.26 18 21.75 4.08 thirty 22.05 4.03 57 22.54 3.94 16 24.80 3.59 100

Zolmitriptan oxalate has a melting point derived from the Differential Scanning Calorimetry (DSC) curve as "onset" being the intersection of the tangents drawn to the baseline and the rising peak line Tonset = 229.97 ° C.

The invention further relates to a process for the preparation of a salt of zolmitriptan with oxalic acid wherein the zolmitriptan base or salt thereof, suspended or dissolved in an organic solvent or a mixture thereof with water, is reacted with oxalic acid or a derivative thereof. oxalic acid is obtained in a molar ratio to base from 1: 1 to 1.5: 1. Preferably, the organic solvent is ethyl alcohol.

The method according to the invention makes it possible to obtain zolmitriptan base with a purity of more than 99.8% (determined by HPLC), a content of individual impurities not exceeding 0.05% and a white color. The method can be used for the purification of crude zolmitriptan obtained by the Fischer condensation method, containing up to 20% of impurities.

The following examples illustrate the process of the invention without limiting its scope.

Examples

Analytical methods

The melting point was determined by differential scanning calorimetry using a Mettler Toledo DSC 822 apparatus in an aluminum crucible, in the temperature range 40-200 ° C, in the dynamic segment with a heating rate of 10 ° C / min, preceded by an isothermal segment (40 ° C for 3 minutes). ). The melting point value was determined in two ways: as "extrapolate peak", which is the intersection of the tangent curves drawn to the peak, and as "onset", which is the intersection of the tangents drawn to the baseline and the rising peak's line.

Diffraction measurements were made on the Rigaku MiniFlex X-ray powder diffractometer for CuKa radiation, λ = 1.54056 A with the following parameters:

• Measuring angle 2Θ from 3 ° to 40 ° • Scanning speed Δω 0.5 ° / min • Counting range, every 0.03 ° • Measurement temperature - room temperature • Detector - scintillation counter

The measured diffractograms were developed and analyzed using the DHN_PDS program.

P r z k ł a d 1

Synthesis of zolmitriptan from (S) -4- (4-aminophenylmethyl) -2-oxazolidinone

In a round bottom flask with a capacity of 500 mL was placed (S) -4- (4-aminophenylmethyl) -2-oxazolidinone (39 g, 0.2 M), HCl (56 mL), and distilled water (150 mL). It was cooled to 5 ° C in a cooling bath (acetone + dry ice) and to this solution was added dissolved NaNO2 (13.8 g, 0.2 M) in water (40 mL), followed by stirring at this temperature for 15 minutes. .

A solution of Na2SO3 (75.6 g, 0.6 M) in distilled water (200 mL) was placed in a separate 500 mL three-necked flask equipped with a thermometer, reflux condenser, and dropping funnel. The solution was cooled in a bath (acetone + dry ice) to 5 ° C and the previously prepared diazonium salt was added while keeping the temperature at 5 ° C. After stirring at this temperature for 30 minutes, the temperature was slowly brought to 55 ° C, HCl (57mL) was added and heated to 60 ° C. Heated at this temperature for 4 h. Then it was heated to 90 ° C and 4,4-diethoxy-N, N-dimethylbutyl-1-amine (38.0 g) was added dropwise. After the dropwise addition, the mixture was heated to reflux (90-94 ° C) and heated at this temperature for 1 hour, then cooled to room temperature (solution pH ~ 1). The solution was extracted with ethyl acetate (2x100 mL) and solid NaOH (35 g) was added to the aqueous layer until pH 12 + 14 (solution temperature reached 50-55 ° C). The warm solution was extracted with ethyl acetate (2x200 mL) and the combined extracts were concentrated on an evaporator. Zolmitriptan was obtained in the form of a thick brown oil.

P r z k ł a d 2

Zolmitriptan oxalate

The crude zolmitriptan from the previous step, as a solidified mass of 81.57% purity (HPLC), was dissolved warm in ethyl alcohol (160 mL) and then added dropwise to an ethanolic solution of oxalic acid dihydrate (25.2 g, 0.2 mol, in 160 mL). After one hour of stirring at room temperature, the salt obtained, as a brown crystalline precipitate, was filtered off, washed with a little ethyl alcohol and dried at room temperature.

P r z k ł a d 3

Crystallization of zolmitriptan oxalate

The precipitate of zolmitriptan oxalate (approx. 70 g) was dissolved at boiling point in a solution of 50% ethyl alcohol in water (440 mL), activated carbon (1.6 g) was added to discoloration, heated to reflux for approx. 30 min, and then filtered through Celite and allowed to crystallize. The light brown crystalline precipitate of the pre-purified zolmitriptan oxalate salt (56 g) was filtered, washed with ethyl alcohol, dried at room temperature.

The precipitate of zolmitriptan oxalate (56 g) with a purity of 97.70% was redissolved at boiling point in a solution of 50% ethyl alcohol in water (500 mL), activated carbon (1.25 g) was added until it was discolored, heated to a boiling point of approx. min, then filtered through Celite and allowed to crystallize overnight. The obtained crystalline cream solid (45.31 g) of zolmitriptan oxalate salt was filtered off, washed with chilled acetone and dried at room temperature. Purity (HPLC): 99.06%.

P r z k ł a d 4

Extraction of zolmitriptan base

The precipitate of zolmitriptan oxalate (45.31 g) was suspended in water (350 mL), basified with solid NaOH to pH 12. The resulting aqueous solution was extracted warm (after alkalinization the solution temperature approx. 55 ° C) with ethyl acetate (2 x 200 mL ). The combined organic extracts were concentrated to give 34.5 g of a slightly cream solid zolmitriptan.

PL 217 646 B1

P r z k ł a d 5

Purification of the zolmitriptan base

The zolmitriptan precipitate was dissolved in isopropyl alcohol (75 mL), activated charcoal was added to discoloration, heated under reflux for 30 min, and then filtered into a 500 mL flask. 225 mL of ethyl acetate was added to the obtained filtrate and left on a magnetic stirrer at room temperature to crystallize. The next day, after cooling to 5 ° C, a slightly cream-colored precipitate of zolmitriptan (29.4 g) was filtered off. The resulting precipitate was suspended in 20% acetone in water (90 mL), stirred at room temperature for 24 h, cooled to 5 ° C, filtered and washed with ethyl acetate (10 mL). The precipitate was dried for 20 h in a vacuum oven at 45 ° C. A white fine crystalline precipitate of zolmitriptan was obtained. Yield 21.58 g (37.5%) based on the starting substrate. Purity (HPLC): 99.91% (no impurity above 0.05%).

Claims (19)

A method for the production of zolmitriptan of high pharmaceutical purity, characterized in that after the Fischer condensation reaction, crude zolmitriptan is separated from the reaction mixture, converted into a salt with oxalic acid, the salt is subjected to purification, and then the free zolmitriptan base is freed from the salt. 2. The method according to p. A process as claimed in claim 1, characterized in that the crude zolmitriptan is separated from the reaction mixture having a pH above 11. 3. The method according to p. 2. The process of claim 2, characterized in that the pH of the post-reaction mixture is 12-14. 4. The method according to p. The process of claim 1, wherein the crude zolmitriptan is isolated by extraction with a water-immiscible solvent. 5. The method according to p. The process of claim 4, wherein the water-immiscible solvent is ethyl acetate. 6. The method according to p. The process of claim 4, wherein the extraction is carried out at 40-60 ° C. 7. The method according to p. The process of claim 1, wherein the salt of zolmitriptan with oxalic acid is purified by crystallization from a polar solvent combined with decolorization with activated carbon. 8. The method according to p. The process of claim 7, wherein the salt of zolmitriptan with oxalic acid is purified by crystallization from a polar solvent. 9. The method according to p. The process of claim 8, wherein the polar solvent is ethyl alcohol with up to 50% water. 10. The method according to p. The process of claim 1, characterized in that the zolmitriptan free base is released from the oxalic acid salt by the action of an aqueous solution of an inorganic base and is isolated by extraction. 11. The method according to p. The process of claim 10, wherein the extraction is carried out with ethyl acetate. 12. The method according to p. The process of claim 10, wherein the zolmitriptan base is isolated from the mixture having a pH above 11. 13. The method according to p. 12. The process of claim 12, wherein the pH of the mixture is 12-14. 14. The method according to p. 10. The process as claimed in claim 10, characterized in that the extraction is carried out at a temperature of 40-60 °. 15. Salts of zolmitriptan with oxalic acid and their solvates. 16. Crystalline salt of zolmitriptan with oxalic acid in the molar ratio of zolmitriptan base to acid 1: 1, represented by the formula (1a) PL 217 646 B1 17. The salt of 17, having a powder diffraction pattern containing the following peaks with the values of x-ray deflection angles 2Θ expressed in (°), interplanar distances d expressed in (A) and relative intensities in relation to the most intense diffraction line, I / I0 (%): 2Θ (°) d (A) I / I0 (%) 4.93 17.89 1 7.01 12.61 1 9.73 9.08 12 9.97 8.86 2 10.91 8.10 6 13.88 6.38 27 15.39 5.75 5 15.62 5.67 8 15.91 5.56 2 16.70 5.30 4 17.58 5.04 10 18.35 4.83 10 19.38 4.57 41 20.02 4.43 27 20.38 4.35 71 20.80 4.26 18 21.75 4.08 thirty 22.05 4.03 57 22.54 3.94 16 24.80 3.59 100 18. A process for the preparation of zolmitriptan salt with oxalic acid, characterized in that zolmitriptan base or a salt thereof, suspended or dissolved in an organic solvent or a mixture thereof with water, is reacted with oxalic acid or a derivative thereof using oxalic acid in a molar ratio to the base of 1: 1 to 1.5: 1. 19. The method according to p. The process of claim 18, wherein the organic solvent is ethyl alcohol.