ES2250001B1 - PROCESS FOR THE PURIFICATION OF ZIPRASIDONA. - Google Patents

Abstract

Process for purification of ziprasidone. The present invention relates to a process for the purification of 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H -indole-2-one of formula (I), from a composition comprising said compound, wherein said compound is reacted with maleic acid or acetic acid to obtain an acid addition salt of formula (II) in which R is ** FIGURE **

Description

Process for purification of ziprasidone.

Field of the Invention

This invention is related to the Purification of ziprasidone as a base using the salt of the same result of the addition of maleic acid or acid acetic.

Background of the invention

In the production of ziprasidone, ziprasidone in the form of a free base (i.e. 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one) it has to be dissolved in solvents, for example to be removed by insoluble contaminant filtration, to recrystallize, or to discolor However, ziprasidone in base form is very insoluble in common solvents. This is demonstrated for example in Example 2 of US 5,338,846 and in the corresponding Example 3 of EP 584 903, where it is made public that 1 kg of ziprasidone in form base requires 9 to 10 gallons of tetrahydrofuran (one gallon USA corresponds to 36.2 liters; one gallon UK corresponds to 43.4 liters) and reflux temperature (66ºC) to obtain a Ziprasidone solution in base form.

It is evident that these high volumes of Solvents that are needed are not satisfactory for industrial implementation In addition, the filtration temperature close to the reflux temperature is disadvantageous.

Therefore, the object of the present invention consists in obtaining a derivative of the ziprasidone base that is more soluble than ziprasidone itself as a base, so which reduces the need for large volumes of solvents and / or high temperatures.

Summary Description of the Invention

The inventors achieved this goal. making the addition salt of maleic acid or acetic acid on ziprasidone base: ziprasidone maleate or acetate ziprasidone The maleate or ziprasidone acetate dissolve easily, and the solution can be treated with an agent bleach and / or filter at room temperature to obtain a maleate or purified ziprasidone acetate solution of Improved quality, that is, without insoluble components / less colored.

Therefore, the invention relates to a process for the purification of the 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one of formula (I)

one

from a composition that comprises said compound, wherein said compound is made react with maleic acid or acetic acid, preferably in an amount of 0.5 to 3 molar equivalents, preferably 1 to 2 molar equivalents, and more preferably 1.1 to 1.6 molar equivalents for obtaining an addition salt of acid of the following formula (II):

2

in which R is 3 .

Next, the acid addition salt according to the above formula (II) it is separated from the components insoluble of the composition, preferably by filtration.

Alternatively, or additionally, the salt of addition of an acid according to the above formula (II), may be further treated with a bleaching agent, preferably at least with one selected from alumina, activated alumina, silica and active carbon

The acid addition salt according to the formula previous (II) can be reacted with an acid, preferably selected from hydrochloric acid, the acid hydrobromic and methanesulfonic acid, more preferably acid hydrochloric, in order to obtain an acid addition salt according to the following formula (III):

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in which R1 is halogen or CH_ {SO} {3}.

The acid addition salt according to the formula Previous (III) can be further purified by using at least one organic solvent, preferably selected from isopropanol, tetrahydrofuran, n-butanol and the butan-2-one.

The present invention further provides the use of a salt, result of the addition, of an acid, of formula (II) in a process according to any given preferred embodiments described above.

Detailed description of the invention

For the purpose of this invention, the term "ziprasidone" refers to ziprasidone in the form of a base (it is tell 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one), unless otherwise specified.

Ziprasidone in base form can be used in the present invention regardless of the process used for its production.

The addition salt of maleic acid or acid acetic according to formula (II) can be treated with any agent conventional bleach. Such conventional bleaching agents include, but is not limited to, alumina, activated alumina, silica and activated carbon.

The solution of the acid addition salt according to formula (II) can be treated with hydrochloric acid or with hydrogen chloride or with a solution of hydrogen chloride in order to precipitate ziprasi- hydrochloride.
Mrs.

Alternatively, the dissolution of the salt of addition of an acid according to formula II can be treated with a base in order to precipitate ziprasidone in base form, the which then becomes the corresponding addition salt of the acid according to formula (III). Suitable bases include the  sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonium hydroxide.

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Examples

The following chromatographic analytical method of HPLC is used to check the purity of ziprasidone:

The test is carried out in a column Kromasil C8 of 5 µm and 250 x 4.6 mm. The mobile phase is prepared by mixing 370 mL of acetonitrile with 630 mL of buffer at pH = 3.0, which is prepared from 1.2 g of KH 2 PO 4 and 0.7 g of the sodium salt of dissolved 1-pentanesulfonic acid in 630 mL of water, adjusting the pH with H 3 PO 4. This phase Mobile is mixed and vacuum filtered through a nylon filter of 0.22 µm.

The chromatograph is equipped with a detector UV set at 229 nm and the flow rate is 1.0 mL per minute at room temperature. Samples are prepared by dissolving the appropriate amount of sample to obtain 0.5 mg per mL in a mixture of acetonitrile / trifluoroacetic acid 19.6: 0.4 v / v and 20 µL are injected.

Example of reference

Preparation of ziprasidone in base form

In a beaker equipped with a magnetic stirrer 88.7 g (0.837 mol, 3.21 equivalents are loaded molars) of sodium carbonate, 600 mL of acetonitrile and 66.7 g (0.261 moles, 1.0 molar equivalents) of hydrochloride 3- (1-piperazinyl) -1,2-benzisothiazole. The resulting white suspension is stirred for 10 minutes. TO then 60.0 g (0.261 moles, 1.0 equivalents are added molars) of 5- (2-Chloroethyl) -6-Chloro-1,3-dihydro-indole-2- (2H) -one and 0.3 g (0.002 mol, 0.008 molar equivalents) of Nal. The resulting brown suspension is loaded into a 1 L reactor, which is purge with nitrogen and heat at 120-125 ° C (the internal pressure is increased up to 400-500 kPa) for 25 hours The reaction is cooled to room temperature, Stir for 30 minutes, filter and the solid is washed with acetonitrile A wet mixture of zipradisone and salts is obtained inorganic, which is washed again with acetonitrile. Mix wet resulting from ziprasidone and inorganic salts is stirred with 675 mL of water at reflux temperature for 1 h for Remove inorganic salts. The suspension is cooled to room temperature, stir for 30 minutes and filter. He solid is washed with water, obtaining 140 g of wet solid (corresponding to 87 g of dry material).

The wet solid is stirred again with water to reflux temperature for 1 h to remove inorganic salts residual The suspension is cooled to room temperature, Stir for 30 minutes and filter. The solid is washed with water, yielding 170 g of wet solid (corresponding to 81 g of dry material). An HPLC analysis reveals a purity of 97.8%

To eliminate starting materials present in The wet solid obtained in the previous step is stirred twice with 400 mL of tetrahydrofuran at reflux temperature. The solution is cooled to room temperature, stirred for 30 minutes and filtered. The solid is washed twice with 40 mL of tetrahydrofuran, obtaining 60 g of wet solid, corresponding to 54.8 g of dry material.

The solid obtained is ziprasidone in the form of base with a purity of 99.4% by HPLC, the yield being overall from the starting compounds of 51% (yield cool). Potentiometric titration with HClO 4: 100.03%.

Ziprasidone in base form obtained is it can be converted into its hydrochloride, or alternatively it can be purify to improve its quality attributes such as color and the absence of insoluble matter according to the following process.

Example 1 Ziprasidone Maleate

In a 1 L spherical reactor, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, it load 400.45 mL of a mixture of tetrahydrofuran / N, N-dimethylacetamide 1: 4 and the wet solid consisting of ziprasidone in base form obtained in the Reference Example. 24.76 g of maleic acid are added (1.6 molar equivalents) to the resulting suspension, which is stirred for 5 minutes. Then 8.0 g of activated carbon are added to the deep red suspension. After stirring for 30 minutes, the suspension is filtered on celite and the solid is washed twice with 40 mL of the same solvent mixture. Is obtained a solution of light red ziprasidone maleate, which it can be subsequently converted into its hydrochloride salt by conventional methods

Example 2 Ziprasidone Acetate

In a 100 mL spherical reactor, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, it loaded 5.96 g of wet ziprasidone (corresponding 4 g of dry ziprasidone) and 16 mL of acetic acid. After fifteen stirring minutes a solution is obtained. Then you add 0.04 g of activated carbon. After 30 minutes of stirring, the suspension is filtered on celite and the solid is washed twice with 2 mL acetic acid. A color solution is obtained light brown ziprasidone acetate, which can be converted subsequently in its hydrochloride salt by methods conventional.

Example 3 Preparation of anhydrous ziprasidone hydrochloride

In a 100 mL spherical reactor, equipped with a thermometer and a magnetic stirrer, and purged with nitrogen, it load the solution of ziprasidone acetate obtained in the Example 2. After adding 0.99 mL of aqueous hydrochloric acid 36.18% (1.2 molar equivalent) to the solution, is obtained A pink suspension It is stirred for two hours, filtered and the solid is washed twice with 2 mL acetic acid. The solid is dried under vacuum at 40 ° C until constant weight giving rise to 3.49 g of anhydrous ziprasidone hydrochloride. Overall performance from Ziprasidone in base form: 80.2%.

Example 4 Preparation of anhydrous ziprasidone hydrochloride (large scale)

In a reactor equipped with a mechanical stirrer 0.604 kg of ziprasidone in base form are loaded (corresponding to 0.5 kg of ziprasidone in the form of a dry base), 1.2 kg (1.3 L) of tetrahydrofuran and 4.88 kg (5.2 L) of N, N-dimethylacetamide. The resulting beige suspension stir for ten minutes and then 0.17 kg of maleic acid The suspension almost instantly becomes a light red solution. Filter to remove insoluble particles and the clear solution is transferred to a clean container, to which 323 mL of a solution 4.5 are added M of hydrogen chloride in isopropanol at a rate of 1 mL / min The mixture is stirred for 3 hours at 20-25 ° C, filtered and washed twice with 1 liter of tetrahydrofuran, giving rise to 0.537 kg of hydrochloride wet anhydrous ziprasidone corresponding to 0.521 kg of Dry anhydrous ziprasidone hydrochloride. Molar yield: 96%. HPLC purity: 99.9%.

Claims (13)

1. A process for the purification of 5- [2- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1,3-dihydro-2H-indole-2-one of formula (I)

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from a composition that comprises said compound, wherein said compound is made react with maleic acid or acetic acid to obtain the salt of addition of an acid of the following formula (II),

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in which R is 3 . 2. The process according to claim 1, in the that acetic acid is reacted with the compound of formula (I) in an amount of between 1 and 2 molar equivalents. 3. The process according to claim 1, in the that maleic acid is reacted with the compound of formula (I) in an amount between 0.5 and 3 molar equivalents, preferably between 1 and 2 molar equivalents, and more preferably between 1.1 and 1.6 molar equivalents. 4. The process according to any of the claims 1 to 3, wherein the maleate is separated or the acetate according to formula (II) of the insoluble components of the composition. 5. The process according to claim 4, in the that the maleate or acetate according to formula (II) is separated from the Insoluble components of the composition, by filtration. 6. The process according to any of the claims 1 to 5, wherein the maleate or acetate according to formula (II) it is further treated with an agent bleaching 7. The process according to claim 6, in the that said bleaching agent is one selected from at least alumina, activated alumina, silica or activated carbon. 8. The process according to any of the claims 1 to 7, wherein the maleate or acetate according to formula (II) with an acid in order to obtain an acid addition salt according to the formula (III). 7 in which R1 is a halogen or CH_ {SO} {3}. 9. The process according to claim 8, in the that the acid is selected from hydrochloric acid, the acid hydrobromic and methanesulfonic acid. 10. The process according to claim 9, in the that the acid is hydrochloric acid. 11. The process according to any of the claims from 8 to 10, wherein the addition salt of a acid according to formula (III) is further purified using at least one organic solvent 12. The process according to claim 11, in the that said organic solvent is one selected at least from the isopropanol, tetrahydrofuran, n-butanol and butan-2-one. 13. Use of a maleate or an acetate of the formula (II) in a process according to any of the claims of 1 at 12.