SI22489A - New procedure for preparation of levocetirizine and its intermediates - Google Patents

Abstract

The submitted invention describes a new procedure for preparation of levocetirizine and its pharmaceutically acceptable acidic addition salts by using diglycolic acid or its derivatives as well as new intermediates used in this procedure.

Description

A NEW PROCEDURE FOR THE PREPARATION OF LEVOCETYRIZINE AND ITS INTERMEDIATES

FIELD OF THE INVENTION

The present invention describes a novel process for the preparation of levocetirizine and its intermediate and its pharmaceutically acceptable salts and esters.

BACKGROUND OF THE INVENTION

Left-handed [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinylethoxyacetic acid, also known as the generic name levocetirizine, has been shown to be useful as a therapeutic agent for the treatment of allergic disease.

Levocetirizine and its salt, including its dihydrochloride, are known and effective in the treatment of allergies, including, but not limited to, chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. Levocetirizine belongs to the second generation of HI histamine receptor antagonists, which are thought to offer significant advantages over first-generation compounds. Studies have shown that levocetirizine provides a safe and effective symptomatic relief of seasonal allergies. Levocetirizine is also used to treat chronic idiopathic urticaria.

GB 2,225,321 describes a process for the preparation of cetirizine in left-handed, right-handed form or a mixture thereof comprising the hydrolysis of enantiomerically pure [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile. The hydrolysis takes place in an aqueous, alcoholic or aqueous-alcoholic medium with a base or an acid; the acid thus obtained is converted to its dihydrochloride. The optically active starting material l - [(42 chlorophenyl) phenylmethyl] -piperazine is obtained by separating the corresponding racemic compound, preferably by conversion to its diastereoisomeric salt with tartaric acid. Separation profit was relatively low, only 12.7%. The optically active intermediate obtained was further converted with chloroethoxyacetonitrile in 69% yield.

EP 617028 and EP 955295 describe a process for the preparation of optically active l - [(4-chlorophenyl) phenylmethyl] -piperazine and its conversion to cetirizine in left-handed or right-handed form or in an intermediate thereof. The preparation procedure is shown in the following scheme:

The disadvantage of this reaction is that it requires the protection of N, N-bis (2-haloethyl) amine and the consequent deprotection of the resulting intermediate.

The preparation of cetirizine and its left-sided forms proceeds in the most well-known synthesis of enantiomerically pure l - [(4-chlorophenyl) phenylmethyl] -piperazine, and consequently it seems highly desirable to provide new routes for the preparation of its enantiomers with improved optical purity and good yields.

The polymorphic form I of the crystalline left-stranded dihydrochloride salt of cetirizine and its amorphous form are described in WO 2004/050647 and WO 2004/065360. The crystalline form is prepared by crystallization from a solvent containing a ketone such as acetone, methyl ethyl ketone, dimethyl ketone, 2-pentanone and mixtures thereof. The amorphous form was prepared by evaporation of the solvent.

There is still a need for efficient synthesis of levocetirizine, novel intermediates used in the process suitable for large-scale production.

Description of the invention

The present invention provides a new effective synthesis of levocetirizine and its pharmacologically acceptable salts and novel intermediates used in this process.

A first aspect of the present invention is a process for the production of levocetirizine comprising the following steps:

i) reacting an intermediate of formula II

with a diglycolic acid derivative of the formula

O or XCO-CH ₂ -O-CH ₂ -R wherein X is OH or a halogen group and R is COOH or a group which can be converted to COOH to give the intermediate of formula IV

ii) in the case where an intermediate of formula (IV) is obtained wherein R is COOH, it can be optionally converted to a compound of formula (IV) wherein R is a group which can be converted to COOH; iii) reducing the intermediate of formula (IV) with a selective reducing agent to give the product of formula (V)

Cl

R (V), where R is as defined above iv) in the case where R is not COOH, the conversion of intermediate (V) to levocetirizine,

v) optionally converting levocetirizine to its pharmaceutically acceptable salt.

The glycolic acid derivative may be a diglycolin anhydride of formula o or a derivative of formula XCO-CH ₂ -O-CH ₂ -R wherein X is OH or a halogen group and R is COOH or a group which can be converted to COOH. The group R is selected from the group consisting of COOH, COX, where X is halogen; COOM, where M is an alkali or alkaline earth metal, N (R 1) 4, CONH ₂ ; CONRiR ₂ , COORi, CN, CHO, CH ₂ OH CH (ORi) ₂ , wherein R 1 or R ₂ may be independently selected from H, a lower alkyl group, an aryl group. The term lower alkyl refers to straight chain and branched saturated aliphatic hydrocarbon radicals having from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, etc .; or straight or branched aryl-substituted alkyl such as benzyl, triphenylmethyl. The term aryl refers to substituted or unsubstituted aryl groups.

To prepare the compounds of formula (IV), an excess or substantially equimolar amount of a diglycolic acid derivative, preferably 1.5 molar excess, most preferably 1.1 molar excess, is used. The reaction can be carried out in an organic solvent, water or a mixture thereof. If water is used as the solvent, the process can be carried out in the presence of a phase transfer catalyst. Suitable organic solvents include polymers or non-polar organic solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile; halocarbons such as chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran, 1,3-dimethoxyethane and similar aromatic hydrocarbons such as benzene, toluene, xylene. The reaction can be carried out without the presence of solvent.

The reaction temperature may be from about 0 ° C to the boiling point of the reaction mixture, with a preferred range being from about 60 ° C to the boiling point of the reaction mixture. The reaction time, which is sufficient to substantially end the reaction, is generally from 1 hour to 24 hours.

In carrying out the reaction, the reactants are thoroughly mixed, preferably by adding the diglycolic acid derivative in the solvent in parts, while stirring the solution, to the solution of the amine of formula (II) also in the solvent, and continuing with or without heating for sufficient time to complete the reaction forming the desired product of formula (IV) in the reaction mixture. The product may be recovered or purified by conventional methods such as extraction, chromatography or solvent evaporation, in whole or in part, by conventional means, and the recovery of a solid or oil which is recovered or left as a residue.

The compound of formula (IV) is further reduced by a selective reducing agent to give the product of formula (V).

The selective reducing agents may be selected from the group consisting of NaBH ₄ , optionally in the presence of carboxylic acids such as acetic acid, trifluoroacetic acid, formic acid, or in the presence of sulfonic acids; NaBH ₃ CN, optionally in the presence of carboxylic acids such as acetic acid, propanoic acid, trifluoroacetic acid; NaBH ₃ OCOR ₃ or NaBH (COOR ₃ ) ₃ , wherein R _{3 is} methyl, trifluoromethyl and the like; boranes such as borane-solvent complexes wherein the solvent is selected from tetrahydrofuran (H ₃ B-THF), dimethyl sulfide (H ₃ B-SMe ₂ , BMS), diethyl ether (H ₃ B-diethyl ether); (R ₄ ) ₃ OBF ₄ / NaBH ₄ , wherein R 4 is methyl, ethyl, propyl and the like.

A suitable solvent used in the reduction phase is an inert organic solvent which may be selected from the group consisting of ethers such as dioxane, tetrahydrofuran, t-butyl methyl ether, diethyl ether, diisopropylether, 2-methyltetrahydrofuran; carboxylic acids such as acetic acid; halogenated hydrocarbons; aromatic hydrocarbons; preferred solvents are THF and dioxane.

Because the relative activity of diborane against carboxylic acids and amides is similar, it is preferable to protect the carboxylic group with an ester group or an acid halide group. Therefore, when using boranes as a selective reducing agent, it is preferable that R in the compound of formula (IV) is different from the COOH group.

The proportions of the reducing agent against the compound of formula (IV) are from 3: 1 to 1: 1, preferably from 1.75: 1 to 1: 1, most preferably 1.2: 1 to 1: 1.

The reaction is carried out by adding a solution of the amide of formula (IV) in the solvent to the borane solution at a temperature from 0 ° C to room temperature. The resulting mixture was heated to room temperature to the boiling point of the reaction mixture and maintained at this temperature for 0.5 hours to several hours to substantially complete the reaction.

In case the group R in the product of formula (V) is not OH, conversion of intermediate (V) to levocetirizine is carried out by methods known in the art.

The compound of formula (II) used as the starting compound of the present invention can be prepared according to the process described in the present invention, or by any other known method as described in GB 2225321, EP 617028, IN 501 / MUM / 04.

Another aspect of the invention is a novel compound of formula (IV)

-R, where R is as defined above.

An intermediate of formula (IV) can be used as an intermediate for the production of levocetirizine.

The starting compound (II), (-) - 1 - [(4-chlorophenyl) phenylmethyl] piperazine can be prepared efficiently by reaction of R - (-) - 4-chlorobenzhydriamine and bis (2-haloethyl) amine hydrochloride. Surprisingly, we found that no racemization occurs during this reaction.

The reaction is shown in the following reaction scheme 1.

Reaction Scheme 1:

Bis (2-haloethyl) amine hydrochloride may be used, where X is a chlorine, bromine or iodine atom.

The reaction is carried out in the presence of an organic base that acts as a solvent and simultaneously as a hydrogen chloride scavenger. The organic bases may be selected from the group consisting of primary, secondary, tertiary alkylamines, such as n-ethylenediisopropylamine, triethylamine, diethylamine, butylcyclohexylamine, diisopropylamine, dibutylamine or heterocyclic amines such as pyrrolidine, piperidine or alkyl derivatives thereof. The mixture of different bases can be mixed in any ratio, preferably using a mixture of n-ethylenediisopropylamine and diethylamine in a volume ratio of 1: 1 to 1: 0.01, most preferably 1: 0.08.

The reaction is generally carried out at a temperature from 50 ° C to the reflux temperature of the reaction mixture, preferably from 80 ° C to the reflux of the reaction mixture. The reaction may take from 2 hours to 24 hours, preferably from 6 to 8 hours.

The mole ratio between the two reagents, namely - (-) - 4-chlorobenzhydriamine and bis (2-chloroethyl) amine hydrochloride, can vary from 1: 1 to 1: 2, preferably from 1: 1.4 to 1: 1.7. It has been found that the yield can be improved by using an excess of bis (2-chloro) ethyl amine.

After completion of the reaction, the reaction mixture was concentrated. Water and ethyl acetate were added to the residue. The pH was adjusted with sodium hydroxide solution to alkaline prior to purification using column chromatography. The pH of the reaction mixture prior to purification must be greater than 9, preferably between 10 and 11.

The reaction is preferably carried out by reaction of - (-) - 4-chlorobenzhydriamine with bis (2-chloroethylamine hydrochloride in N-ethyldiisopropylamine in the presence of diethylamine at reflux temperature for several hours, isolation can be carried out by extraction in a solvent system consisting of water and an organic solvent, such as ethyl acetate, trichloromethane, dichloromethane to give crude (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4 - [(4-methylphenyl) sulfonyl] piperazine. The resulting product can be further purified by separation using silica gel chromatography and finally crystallized from hexane to give a product with an HPLC purity greater than 98%.

Intermediate II obtained by the process of the present invention can be used for conversion to levocetirizine and optionally its pharmaceutically acceptable salt by any known method.

Levocetirizine, optionally in the form of a pharmaceutically acceptable salt such as dihydrochloride, can also be prepared by the process characterized by the reaction shown in reaction scheme 2.

Reaction Scheme 2:

hydrolysis

HCI

levocetirizine dihydrochloride (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4-piperazine of formula II is reacted with 2- (2-chloroethoxy) acetonitrile in the presence of an acid removal agent such as alkali carbonate and optionally in the presence of a small amount alkali iodide to accelerate the reaction. The reaction can be carried out in an inert solvent such as an alcohol such as ethanol, n-butyl alcohol, an aromatic hydrocarbon such as toluene, xylene, halogenated alkanes such as dichloromethane, nitriles such as acetonitrile. The most preferred solvents are n-butyl alcohol and acetonitrile. The present invention has revealed that the yields of this reaction can be significantly improved by isolating the product of [2- [4 - [(4-chlorophenyl) phenylmethyl] -1piperazinyl] ethoxy] -acetonitrile of formula III in the form of its hydrochloride. The dihydrochloride form is prepared by introducing gaseous HCl into the reaction mixture until the pH reaches a value between 3 and 0.5, preferably 1. The reaction according to the present invention proceeds in more than 90%, preferably 95%. The reaction does not cause racemization, so if an optically pure starting compound is used, the optical purity is maintained.

The reaction proceeds in better yields by using a molar excess of 2- (2-chloroethoxyacetonitrile. The optimum molar ratio of the intermediate of formula II to 2- (2-chloroethoxy) acetonitrile may vary from 1: 1.1 to 1: 4, preferably from 1: 1 , 5 to 1: 3, most preferably 1: 1.5 to 1: 2.

The reaction is carried out at a temperature between 60 ° C and 200 ° C, preferably at a temperature between 80 ° C and 120 ° C, for about 7 to 24 hours, as shown in Scheme 2.

2- (2-Chloroethoxy) acetonitrile can be prepared by any method known in the art, such as Suomen Kemistilehti (1944), 17 B, 17-19, Croatica Chemica Acta (1986), 59 (19), 307-11. The HPLC purity of 2- (2-chloroethoxy) acetonitrile entering the reaction must be at least 95%.

Hydrolysis of nitrile intermediate III is carried out either by basic or acidic hydrolysis.

In the case of basic hydrolysis, the nitrile intermediate of formula III is heated at a temperature of from 20 ° C to 110 ° C, preferably from 60 ° C to 90 ° C, in the presence of an inorganic base such as alkali hydroxide, in a solvent selected from water or alcohol, such as methanol, ethanol, propranol, 2-propanol or a mixture thereof. Preferably KOH or NaOH is used as the alkali hydroxide, and a mixture with methanol or ethanol is used as a solvent, most preferably KOH in a methanol / water mixture.

In the course of our work, we have found that an excess of alkali hydroxide can cause racemization, so the most optimal mass ratio of alkali hydroxide to intermediate III is from 1: 1 to 4: 1, preferably from 1.5: 1 to 3: 1.

The resulting levocetirizine is present in the reaction mixture in the form of an alkali salt from which acid is liberated by acidifying the reaction mixture with the help of an inorganic acid, preferably hydrochloric acid. The levocetirizine acid is then extracted with an organic solvent such as dichloromethane, toluene, ethyl acetate, preferably dichloromethane. It was found that the pH value of the aqueous solution prior to extraction is crucial for the extraction yields and should be maintained between 4 and 5, preferably between

4.2 and 4.8.

The described process for basic hydrolysis yields above 90%, HPLC (area) purity of the obtained product is above 98%.

In the case of acid hydrolysis, the intermediate of formula III is heated in the presence of an inorganic acid, such as hydrochloric acid, preferably in aqueous medium, at a temperature between 60 ° C and the reflux temperature of the reaction mixture. The levocetirizine acid is then extracted from the reaction mixture by an organic solvent such as dichloromethane, toluene, ethyl acetate, preferably dichloromethane.

The free levocetirizine acid is then converted to the dihydrochloride salt by dissolving it in a ketone solvent and introducing the HC1 gas form into the reaction mixture until the pH reaches a value between 0.5 and 3, preferably from 0.5 to 1. The ketone solvent can be selected from acetone groups, methylethyl ketones, diisobutyl ketones, diisopropyl ketones, preferably acetone.

The resulting salt may exist in the polyform form described in WO 2004/050647 or IPCOM 000146553D.

It is important to monitor the particle size of levocetirizine dihydrochloride during its preparation. The average size of the prepared particles is from 5 to 200 μπι, preferably between 20 and 150 μιη. If not stirred, crystallization from organic solvents can also give larger particles, e.g. having an average diameter of more than 200 μιη, which must be ground or treated in any other way that reduces the size of the particles, prior to their application in pharmaceutical formulations. When milled, particles with an average diameter of less than 3 μπι can be obtained. For this purpose, air-flow mills, ball mills or hammer mills are usually used as milling equipment. However, it is not enough to control only the average particle size, but also the particle size distribution.

The average particle size and particle size distribution is important to ensure that the process is industrially usable, i.e. not to cause segregation of the constituents of the tabletime mixture if it is not tableted / compressed immediately after preparation of the tabletime mixture.

The present invention is illustrated by the following examples without being limited thereto.

Examples

Example 1 (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4-piperazine.

300 ml of N-Ethyldiisopropylamine, 30 g of (-) - 4-chlorobenzhydriamine and 42 g of bis (2-chloroethyl) amine hydrochloride are filled into the reaction vessel, stirred and refluxed for 3 hours. Cool to 60 ° C, add 24 ml of diethylamine, then heat the mixture at reflux temperature for another 5 hours. When the reaction is complete, the solvent is evaporated in vacuo, a mixture of water and ethyl acetate (1: 1) is added, the pH of the aqueous phase is adjusted to a value of 10-11 with a 30% sodium hydroxide solution. Separate the organic phase and extract the aqueous phase with ethyl acetate. Wash the combined organic phases with purified water, decolorize the organic phase with activated charcoal and evaporate the filtrate in vacuo. The impurities were separated by silica gel chromatography eluting with ethyl acetate / ethanol (7: 1) and / or then with ethyl acetate / ethanol / ammonia (7: 1: 0.25). Collect the eluate and evaporate the solvent in vacuo to give an oily residue, which is further dissolved in hexane, treated with activated charcoal, heated and filtered. Cool the filtrate to 10 ° C for 1 hour, collect the precipitate and dry at 40-45 ° C under vacuum for 5-8 hours to give the product (HPLC 98-99%).

Example 2 [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile dihydrochloride

2400 ml of acetonitrile are filled into the reaction vessel, 400 g of (-) - 1 - [(4-chlorophenyl) phenylmethyl] -4-piperazine, 300 g of Na ₂ CO ₃ , 20 g of KJ and 300 g of 2- (2 -chloroethoxy) acetonitrile.

It is stirred and gradually raised to 110-115 ° C. The temperature was maintained for 20 hours when the reaction was complete, the mixture was cooled to 80-90 ° C, 25 g of activated carbon were added and stirred for 20 minutes. The charcoal is filtered off and the cake is washed with an appropriate amount of n-butanol. Dry HC1 gas is introduced into the combined filtrate until the pH reaches 0.5-1. Continue stirring the suspension for 20 minutes and filter. The cake was washed with an appropriate amount of ethanol and dried at 50-55 ° C for 10 hours to give 520 g of the title product.

Yield 95%, HPLC (area) 95%.

Example 3

Levocetirizine

Fill 3000 ml of methanol and 300 g of [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetonitrile dihydrochloride into the reaction vessel, add KOH solution prepared with 600 g KOH and 600 ml of purified water with stirring, keeping the reaction temperature below 40 ° C. Gradually raise the temperature to 70-76 ° C and maintain the reaction temperature for 24 hours. When the reaction is complete, cool the reaction mixture to 40 ^ 45 ° C and distill the methanol in vacuo. Add 1000 ml of purified water and 3000 ml of CH ₂ C1 ₂ , cool to 20-30 ° C. The pH was adjusted to 4.2 ^ 1.8 with 37% HCl. Separate the organic layer or extract the aqueous layer twice with 2000 ml of CH ₂ C1 ₂ and combine the organic layer. Dry the organic layer with 200 g of anhydrous sodium sulfate for one hour and filter. Concentrate at normal pressure until there is no more leaching and add 3000 ml of acetone to absorb residual oil. Dry HC1 gas is introduced until the pH is 0.5-1, heated to 60 ° C and refluxed for 20 minutes. Cool to 30-35 ° C, filter and wash the cake with 1000 ml of acetone. Dry at 50-55 ° C under vacuum (-0.08 ~ -0.1 MPa) for 8 hours. 280 g of product are obtained.

Example 4

R-2- (2- (4 - ((4-chlorophenyl) (phenyl) methyl) piperazin-1-yl-2-oxoethoxy) acetic acid.

g of R-1 - ((4-chlorophenyl) (phenyl) methyl) piperazine and 0.88 g of diglycolic acid anhydride were dissolved in 107 ml of acetonitrile. The reaction mixture was refluxed overnight. When the reaction is complete, the solvent is evaporated and the resulting residue dissolved in 20 ml of water with the addition of 2 ml of IM NaOH and then 10 ml of dichloromethane are added. The suspension was stirred for 20 minutes and the organic phase was separated and removed. A further portion of 10 ml of dichloromethane was added to the aqueous phase and the pH was further adjusted to 4.5 to 5. The aqueous phase was extracted twice again with 2 x 10 ml of dichloromethane. The organic phases were collected, dried over anhydrous sodium sulfate and evaporated. The crude product obtained can be used in the next step without further purification.

Example 5

Levocetirizine dihydrochloride

The oily product from the previous step was dissolved in 20 ml of dioxane and added to the solution

1.3 g NaBH ₄ . The slurry was cooled to 10 ° C and stirred with vigorous stirring

2.1 g of acetic acid in 7 ml of dioxane. The reaction mixture was refluxed for two hours, cooled to room temperature and the solids filtered off. The filtrate was evaporated, 20 ml of water was added to the residue and the pH was adjusted to 5. The aqueous phase was extracted three times with 10 ml of dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and the solvent removed in vacuo. The crude levocetirizine obtained was dissolved in 10 ml of acetone, 2 ml of 36% HCl was added and stirred for one hour. The product was filtered off and dried.

Claims (5)

Patent claims A method for the production of levocetirizine comprising the following steps: i) reacting an intermediate of formula II ci (H) with a diglycolic acid derivative of formula. O or XCO-CH ₂ -O-CH ₂ -R wherein X is OH or a halogen group and R is COOH or a group which can be converted to COOH to give the intermediate of formula IV Oh Cl, where R is as defined above; ii) in the case of an intermediate of formula (IV) wherein R is COOH, it can be optionally converted to a compound of formula (IV) wherein R is a group which can be converted to COOH; iii) reducing the intermediate of formula (IV) with a selective reducing agent to obtain a product of formula (V) wherein R is as defined above; iv) in case R is not COOH, conversion of intermediate (V) to levocetirizine; v) optionally converting levocetirizine to its pharmaceutically acceptable salt. The process of claim 1, wherein R is selected from the group consisting of COOH, COX, wherein X is halogen; COOM, where M is an alkali metal or alkaline earth metal, N (R 1) ₄ ; CONH ₂ ; CONRtR ₂ , COORj, CN, CHO, CH ₂ OH, ClfiOICh- wherein R 1 or R ₂ may be independently selected from H, a lower alkyl group, an aryl group. A process according to claim 1 or 2, wherein the selective reducing agent is selected from the group consisting of NaBH ₄ , optionally in the presence of carboxylic acids such as acetic acid, trifluoroacetic acid, formic acid, or in the presence of sulfonic acids; NaBH ₃ CN, optionally in the presence of carboxylic acids such as acetic acid, propanoic acid, trifluoroacetic acid; NaBH ₃ OCOR ₃ or NaBH (COOR ₃ ) ₃ , wherein R _{3 is} methyl, three fluoro is interfering and the like; boranes such as borane-solvent complexes where the solvent is selected from tetrahydrofuran (H ₃ B-THF), dimethyl sulfide (H ₃ B-SMe ₂ , BMS), diethyl ether (H ₃ B-diethyl ether); (R4) ₃ OBF ₄ / NaBH ₄ , wherein Rt is methyl, ethyl, propyl and the like. 4. A compound of formula (IV) Use of a compound of formula (IV) according to claim 4 as an intermediate in a process for the production of levocetirizine.