HK1181769A - Process for the preparation of glycopyrronium chloride - Google Patents

Description

Preparation method of glycopyrronium chloride

Technical Field

The invention relates to a preparation method of glycopyrronium chloride. The synthesized products are suitable for use in pharmaceutical applications, such as the treatment of respiratory diseases.

Background

Glycopyrrolate is a muscarinic M3 anticholinergic agent used to reduce salivation associated with administration of specific anesthetics and as an adjunct treatment for gastric ulcers. It has also been reported to be effective in the treatment of asthma symptoms (Hansel et al, Chest 2005; 128: 1974-.

Glycopyrrolate is commercially available and may be synthesized according to the method described in US 2956062.

Other counterions (including chloride in particular) have been mentioned as theoretical alternatives to the bromide counterions of the glycopyrronium salts. Due to the grinding difficulties associated with glycopyrronium bromide, WO2006/100453 proposes the use of iodide, acetate and sulphate salts as alternatives to glycopyrronium bromide.

The same document discloses a method for preparing alternative salts. In particular, glycopyrronium iodide can be prepared by a similar route to that reported in US2956062 for the production of glycopyrronium bromide, using N-methylpyrrolidin-3-ol (NMP) and methylhydroxycyclopentyl mandelate (MCPM). An alternative proposal is to use glycopyrronium bromide as a starting material for the manufacture of other glycopyrronium salts. For example, ion exchange techniques have been proposed as useful for replacing bromine with iodine. Another proposed method is to treat glycopyrronium bromide with silver sulfate or silver acetate to produce glycopyrronium ammonium sulfate or glycopyrronium acetate, respectively.

An important consideration for the synthesis of glycopyrronium salts is the desired composition and/or ratio of the resulting stereoisomers. Glycopyrrolate has two chiral centers corresponding to four isomeric forms including 2 pairs of diastereomers, namely (3S,2 'R) -, (3R, 2' S) -, (3R,2 'R) -and (3S, 2' S) - [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1, 1-dimethylpyrrolidine bromide. Commercially available glycopyrronium bromide consists of the purified "threo" diastereomer (3R,2 'S +3S, 2' R). Each individual glycopyrronium bromide isomer has different pharmaceutical properties.

It would be desirable to be able to synthesize pharmaceutical grade glycopyrronium chloride of suitable isomeric composition by an efficient process that can be economically carried out on a large scale.

Summary of The Invention

In a first aspect, the present invention provides a method of synthesizing glycopyrronium chloride from glycopyrronium acetate comprising the step of reacting glycopyrronium acetate with hydrogen chloride to produce glycopyrronium chloride. Preferably, the glycopyrrolate acetate is first prepared from glycopyrrolate by a process comprising the step of reacting glycopyrrolate with silver acetate to produce the glycopyrrolate acetate.

In a second aspect, the present invention provides a process for the synthesis of glycopyrronium chloride from glycopyrronium bromide, characterized in that glycopyrronium bromide is contacted with an ion exchange resin, wherein the resin is preferably pretreated with sodium chloride.

In a third aspect, the present invention provides a process for the synthesis of glycopyrronium chloride from 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine by treatment with methyl chloride, optionally followed by one or more successive recrystallizations.

In a fourth aspect, the present invention provides a process for the preparation of diastereomerically pure glycopyrronium chloride comprising dissolving glycopyrronium chloride in hot acetonitrile and then cooling the solution such that the diastereomerically pure glycopyrronium chloride crystallizes.

In another aspect, the present invention provides glycopyrronium chloride prepared by the method of the invention.

In a further aspect, the present invention provides diastereomerically pure glycopyrronium chloride, preferably having an (R, R) + (S, S) diastereomeric content of less than 20% w/w.

In a further aspect, the present invention provides a pharmaceutical composition comprising diastereomerically pure glycopyrronium chloride and/or glycopyrronium chloride prepared according to the process of the invention and one or more pharmaceutically acceptable excipients.

In a further aspect, the present invention provides diastereomerically pure glycopyrronium chloride for the prevention or treatment of any one of the following diseases: COPD (chronic bronchitis and emphysema); asthma; acute Lung Injury (ALI); cystic fibrosis; rhinitis; adult Respiratory Distress Syndrome (ARDS); urinary incontinence; irritable bowel syndrome; psoriasis; hyperhidrosis; drooling; and gastrointestinal ulcers.

Detailed description of the preferred embodiments

The present inventors have observed that glycopyrronium chloride has several advantages over glycopyrronium bromide with respect to pharmaceutical formulations. In particular, glycopyrronium chloride has a higher solubility in ethanol and HFA134 a/ethanol mixtures than glycopyrronium bromide, and has also been found to have a better compatibility with other active ingredients, in particular formoterol (formoterol).

The first synthetic method (method 1) of the present invention comprises synthesis from glycopyrronium bromide via glycopyrronium acetate as an intermediate.

In a first step, glycopyrronium bromide is reacted with silver acetate to form glycopyrronium acetate. Preferably, this step is carried out in the presence of methanol, in which silver acetate is dissolved, silver bromide is precipitated from the reaction mixture and may be removed by filtration.

Alternatively, glycopyrronium acetate may be prepared by any known method, as described in WO 2006/100453.

In a second step, glycopyrronium acetate, preferably dissolved in ethyl acetate, is reacted with hydrogen chloride and glycopyrronium chloride is crystallized out of the ethyl acetate solution.

In a subsequent step, the crude glycopyrronium chloride can be purified by any conventional method, such as by crystallization or suspension.

In a preferred purification step for glycopyrronium chloride prepared according to any one of the three processes of the present invention, glycopyrronium chloride is dissolved in acetonitrile (e.g., hot acetonitrile, e.g., at a temperature of 50 to 82 ℃, followed by crystallization by cooling (e.g., at a temperature of 0 to 20 ℃).

Method 1 is ideally suited for small scale synthesis.

The second synthesis method (method 2) is suitable for large-scale synthesis. The method relies on the application of ion exchange technology. An anion exchange resin column is prepared and activated by treatment with, for example, NaCl solution, and then loaded with glycopyrronium bromide. As glycopyrronium bromide is flowed through the column, anion exchange takes place on the column: the bromide ions are removed by the resin and exchanged with chloride as the counterion to the glycopyrronium salt. The glycopyrronium chloride is then eluted from the column with a suitable solvent or solvent mixture, such as ethanol or an ethanol/water mixture.

Suitable ion exchange resins are commercially available and include strong anion exchange resins, such asIRA900 or FAP 90. The resin content should be adjusted based on the content of glycopyrronium bromide to be loaded and the exchange capacity of the resin itself, as the amount of chlorine equivalent per kg or liter of resin. A suitable excess of resin chlorine equivalents, typically 2 to 5eq.vs. bromine equivalents to be loaded, is generally considered suitable to obtain low bromine residues.

The resin is preferably loaded into a glass column of suitable diameter and length. If not activated for chloride anion exchange, the resin may be activated by contact with an aqueous solution of sodium chloride, typically 5-10% p/v; eluting with water to remove excess sodium chloride and finally treating the column with the solvent to be used in the glycopyrronium salt eluent.

Glycopyrronium bromide is dissolved in a suitable volume of a suitable solvent and the solution is loaded onto the top of a resin column. Then, the elution solvent is applied to the column, elution being performed by gravity or by using a pump: in the case of gravity, the flow is regulated by the height of the solvent reservoir, and in the case of a pump, the flow is regulated by the speed of the pump. The solvent flow rate should be adjusted based on the bed volume so that the glycopyrronium salt remains in the column for a sufficient time.

The glycopyrronium chloride solution was collected at the column outlet: depending on the bed volume, several fractions of appropriate volume were collected. After analytical examination (e.g., by TLC), the appropriate fractions are mixed for subsequent establishment and separation.

The pooled fractions may be decolorized (e.g., using charcoal). They may be filtered, e.g. by mineral filters, e.g.The pooled fractions may be concentrated by evaporationFor example by using a rotary evaporator. For optimum purity, the residue obtained after concentration can be resuspended in ethyl acetate and concentrated again to remove water as an azeotrope.

Optional further purification may be carried out by dissolution in hot acetonitrile and crystallization by cooling as described previously.

A third synthesis method (method 3) comprises similar steps as disclosed in US 2956062: first 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine, preferably dissolved in acetone, is reacted as a mixture of (R, R), (R, S), (S, R) isomers with methyl chloride. However, methyl chloride has a very different chemical nature from methyl bromide used in the process of US 2956062. In particular, methyl chloride has a boiling point of-24.2 ℃ compared to +4 ℃ for methyl bromide. It is known, according to US2956062, that by reacting 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine with methyl bromide in toluene and/or acetone, a product is obtained having the diastereoisomeric characteristics 60% threo, 40% erythro. Prior to attempting the synthesis of the present invention, the potential diastereomeric characteristics of the intermediate obtained by treatment of 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine with methyl chloride were not predicted.

Subsequent recrystallization of glycopyrronium chloride in a solvent is referred to the equivalent procedure in US 2956062. However, the person skilled in the art could not predict whether the diastereoselectivity of the final chloride product after recrystallization was the same as that of the bromide before actually carrying out process 3 according to the invention.

In an alternative embodiment of process 3 (process 4), in step (a) the 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine in the form of a mixture of (R, S), (S, R), (S, S), (R, R) isomers is first treated with a suitable acid to crystallize the desired (R, S), (S, R) diastereoisomer as a suitable salt. In step (b), the diastereomeric purity can be increased by recrystallization of the (R, S), (S, R) -3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine salt in a suitable solvent or solvent mixture. Finally, in step (c), diastereomerically pure (R, S), (S, R) -3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine free base can be produced by base treatment of the salt obtained in step (b) and extraction in an organic solvent. Then, in step (d), the free base is converted to glycopyrronium chloride by conventional methods using toluene and/or acetone by reaction with methyl chloride, as described above.

In step (a), suitable acids for isolating the (R, S), (S, R) diastereoisomer of the desired 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine may be selected from benzoic acid, 3-chlorobenzoic acid, 3-nitrobenzoic acid, isophthalic acid, 5-nitroisophthalic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, fumaric acid and maleic acid, and the reaction is carried out at a temperature in the range of 0 to 40 ℃, preferably 10 to 30 ℃.

In step (b), a suitable solvent for crystallization of the desired (R, S), (S, R) salt may be selected from methanol, ethanol, isopropanol, methyl ethyl ketone, ethyl acetate, water and acetonitrile. The mixture is heated at a temperature of from 20 up to 80 ℃ and then cooled at a temperature of from 0 to 20 ℃ to crystallize the desired salt.

In step (c), the base treatment of the salt of the desired diastereomer may be carried out by treatment with a base selected from sodium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate. The extraction of the free base can be operated by using an organic solvent selected from toluene, ethyl acetate, isopropyl acetate and methyl t-butyl ester.

As described above, an optional purification step can be performed with hot acetonitrile followed by crystallization by cooling.

Preferably, the diastereomerically pure glycopyrronium chloride prepared according to each of the processes of the invention may be defined as having a (R, R) + (S, S) diastereomeric content of less than 40% w/w, more preferably less than 30% w/w, more preferably less than 20% w/w, more preferably less than 10% w/w, more preferably less than 5% w/w, more preferably less than 1% w/w, and most preferably less than 0.1% w/w.

The diastereomeric purity of glycopyrronium chloride can be determined by methods well known to those skilled in the art, such as HPLC, GC and NMR spectroscopy.

Pharmaceutical compositions may be prepared by mixing glycopyrronium chloride prepared according to the invention with one or more pharmaceutically acceptable excipients. Depending on the nature of the medical disease or condition to be treated and the type of patient, the pharmaceutical composition may be formulated for delivery by any suitable route, including oral, intravenous, parenteral, inhalation, intranasal, topical, subcutaneous, intramuscular, rectal, vaginal. Suitable dosage forms include known dosage forms such as tablets, capsules, powders, sustained release preparations, ointments, gels, creams, suppositories, eye drops, transdermal patches, syrups, solutions, suspensions, aerosols, solutions for nebulizers, nasal sprays, and the like. In preferred embodiments, the compositions are formulated for delivery by inhalation or intranasal route, e.g., in aerosol solutions or suspensions, as a dry powder for inhalation, or in nasal spray.

Suitable excipients include carriers, diluents, wetting agents, emulsifiers, binders, coatings, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffering substances and the like. Examples of Excipients and their use are provided in Handbook of Pharmaceutical Excipients, (Handbook of Pharmaceutical Excipients), 5 th edition, (2006), edited by Rowe et al, Pharmaceutical Press.

The appropriate dosage of glycopyrronium chloride can be readily determined by a physician and will depend on the type of patient and the nature of the condition, as well as on the mode of drug delivery. Dosage levels of from about 0.1 μ g to about 25mg per kilogram of body weight per day are useful. For the prevention or treatment of respiratory symptoms, glycopyrronium chloride may be delivered by inhalation, in which case the preferred dose may be about 0.5-100 μ g per actuation of the inhalation device, preferably about 1-40 μ g per actuation, and more preferably about 5-26 μ g per actuation.

Glycopyrronium chloride obtained according to the invention can be used for prophylactic purposes or for symptom relief for a variety of conditions including: respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) and all types of asthma. Other respiratory diseases for which the products of the invention may be beneficial are those characterised by peripheral airway obstruction as a result of inflammation and the presence of mucus, such as chronic obstructive bronchiolitis, chronic bronchitis, emphysema, Acute Lung Injury (ALI), cystic fibrosis, rhinitis, and Adult Respiratory Distress Syndrome (ARDS).

In addition, glycopyrronium chloride synthesized according to the invention may be used for the treatment of smooth muscle disorders such as urinary incontinence and irritable bowel syndrome; skin diseases such as psoriasis; hyperhidrosis and salivation; and gastrointestinal ulcers.

In one embodiment, the present invention provides the use of diastereomerically pure glycopyrronium chloride and/or glycopyrronium chloride prepared according to any of the methods of the invention in the manufacture of a medicament for the prevention or treatment of any of the following diseases: COPD (chronic bronchitis and emphysema); asthma; acute Lung Injury (ALI); cystic fibrosis; rhinitis; adult Respiratory Distress Syndrome (ARDS); urinary incontinence; irritable bowel syndrome; psoriasis; hyperhidrosis; drooling; and gastrointestinal ulcers.

In a further embodiment, the present invention provides a method for preventing or treating any of the following diseases in a patient: COPD (chronic bronchitis and emphysema); asthma; acute Lung Injury (ALI); cystic fibrosis; rhinitis; adult Respiratory Distress Syndrome (ARDS); urinary incontinence; irritable bowel syndrome; psoriasis; hyperhidrosis; drooling; and gastrointestinal ulcers comprising administering to a patient a therapeutically effective amount of diastereomerically pure glycopyrronium chloride and/or glycopyrronium chloride prepared according to any of the methods of the invention. A "therapeutically effective amount" of a substance is defined herein as an amount that results in a detectable improvement in one or more clinical symptoms of the condition being treated or an amount that measurably reduces the likelihood of the disease condition or symptoms thereof developing.

Example 1: preparation of glycopyrronium chloride according to method 1

Glycopyrronium bromide (25.0 g, 0.063 mol) was dissolved in methanol (750 ml). Silver acetate (10.5 g, 0.063 mol) was added and the mixture was stirred at 15-25 ℃ for 2 hours: a precipitate of silver bromide was obtained.

Passing the solid throughThe pad was filtered and the filtrate was concentrated in a rotary evaporator. The remaining oily glycopyrronium acetate was dissolved in ethyl acetate (150 ml) and a 4.2M solution of hydrogen chloride in ethyl acetate (18 ml, 0.076 mol) was added dropwise, causing crystallisation of glycopyrronium chloride. The suspension was stirred at 5-10 ℃ for 1 hour, then filtered, and the solid was dried.

Crude glycopyrronium chloride (18.6 g, 0.053 mmol) was dissolved in hot acetonitrile and crystallized by cooling at 5-10 ℃ for 2 hours. After filtration and drying under vacuum at 50 ℃ for 16 hours, glycopyrronium chloride (16.0 g, 0.045 mol) was collected as a white powder with a yield of 72%.

Example 2: preparation of glycopyrronium chloride according to method 2

Mixing the resinIRA900 Cl (500 g) was suspended in 1500ml of ethanol/water 50/50v/v mixture and loaded onto a 60mm internal diameter glass column with a bottom filter and valve. Passing excess solvent through the column: the bed height was about 25cm, corresponding to a bed volume of 700 ml.

Glycopyrrolate (74 g, 0.186 ml) was dissolved in 280ml of a mixture of ethanol/water 50/50v/v and loaded onto the top of the column. The solution was passed through a column, followed by ethanol as an elution solvent50/50v/v mixture of water. Eluting by gravity, and adjusting the flow rate to 15-20 ml/min; fractions of 80-100ml were collected at the bottom of the column and analyzed for glycopyrronium salt content (by TLC from pharmacopoeia): elution of glycopyrronium salt started in fraction 3, with the concentration being greatest in fractions 5-8 and then decreased until it disappeared in fraction 17. Fractions 3-16 were mixed and the resulting solution (1.4 l) was decolorized with charcoal byThe layers were filtered and concentrated in a rotary evaporator. The oily residue was suspended in ethyl acetate (740 ml) and concentrated again to remove water as an azeotrope; after partial concentration and addition of fresh ethyl acetate, glycopyrronium chloride crystallized out as a white powder. The suspension was stirred and cooled at 0 ℃ and then the solid was filtered off and dried under vacuum at 50 ℃. Glycopyrronium chloride (65.0 g, 0.175 mol) was obtained as monohydrate crystals in a yield of 94%.

The product obtained is characterized by having a purity higher than 99%, 100.1% analysis, lower than 0.1% (R, R) (S, S) diastereomer, 9.9% chlorine content, 138ppm bromine content.

Example 3: preparation of glycopyrronium chloride according to method 3

3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine (20 g) as a mixture of (R, R), (R, S), (S, S), (S, R) isomers was dissolved in acetone (80 ml). Methyl chloride (2.5 equivalents) was slowly bubbled into the solution over 6 hours while the solution was cooled at 5 ℃. After 4 hours, the product began to precipitate. The flask was closed and stirred at room temperature overnight. The crystalline white powder was filtered off and dried under vacuum: glycopyrronium chloride was isolated as an diastereomeric mixture of (R, S), (S, R)/(R, R), (S, S) 58/42 with a 63% yield.

The solid was suspended in hot acetonitrile (10 vol) and crystallized by cooling to form a product with 57% yield and 80/20(R, S), (S, R)/(R, R), (S, S) non-corresponding isomeric ratio. The crystallization procedure from acetonitrile was repeated to form glycopyrronium chloride with 71% yield and 90/10 diastereoisomeric ratio of (R, S), (S, R)/(R, R), (S, S). By repeating the crystallization from acetonitrile, the production of even higher diastereomeric purity products can be obtained.

Claims (19)

1. A process for preparing glycopyrronium chloride from glycopyrronium acetate comprising the step of reacting glycopyrronium acetate with hydrogen chloride to produce glycopyrronium chloride.

2. The process according to claim 1, wherein said glycopyrrolate acetate is first prepared from glycopyrrolate by the step of reacting glycopyrrolate with silver acetate to produce said glycopyrrolate acetate.

3. The process according to claim 2, wherein the step of reacting said glycopyrrolate with silver acetate is carried out in methanol.

4. A process according to any preceding claim wherein glycopyrronium acetate is dissolved in ethyl acetate and then hydrogen chloride is added to produce glycopyrronium chloride.

5. A process for the preparation of glycopyrronium chloride from glycopyrronium bromide, characterized in that glycopyrronium bromide is contacted with an ion exchange resin.

6. The process according to claim 5, wherein the resin is pretreated with sodium chloride.

7. A process according to claim 5 or claim 6 wherein the glycopyrronium chloride is eluted from the ion exchange resin with ethanol or an ethanol/water mixture.

8. A process for preparing glycopyrronium chloride comprising the steps of:

(a) treating 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine in the form of a mixture of (R, S), (S, R) isomers with an acid to crystallize the desired (R, S), (S, R) diastereoisomer as a suitable salt;

(b) recrystallizing the (R, S), (S, R) -3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine salt in a solvent or a mixture of solvents;

(c) producing diastereomerically pure (R, S), (S, R) -3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine free base by base treatment of the salt obtained in step (b);

(d) the free base is converted to glycopyrronium chloride by reaction with methyl chloride.

9. A process according to claim 8, wherein the suitable acid for the isolation of the (R, S), (S, R) diastereoisomer of the desired 3- [ (cyclopentyl-hydroxyphenylacetyl) oxy ] -1-methylpyrrolidine is selected from the group consisting of benzoic acid, 3-chlorobenzoic acid, 3-nitrobenzoic acid, isophthalic acid, 5-nitroisophthalic acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, fumaric acid and maleic acid.

10. The process according to claim 8, wherein the reaction of step (a) is carried out at a temperature in the range of 0 to 40 ℃.

11. The process according to claim 8, wherein suitable solvents for the crystallization of the (R, S), (S, R) salt desired in step (b) may be selected from the group consisting of methanol, ethanol, isopropanol, methyl ethyl ketone, ethyl acetate, water and acetonitrile.

12. The process according to claim 8, wherein in step (b) the crystallization mixture is heated at a temperature of 20 up to 80 ℃ and then cooled at a temperature of 0 to 20 ℃.

13. A process for preparing diastereomerically pure glycopyrronium chloride comprising the steps of dissolving glycopyrronium chloride in hot acetonitrile and then cooling the solution such that the diastereomerically pure glycopyrronium chloride crystallizes.

14. Glycopyrronium chloride prepared by a process according to any one of claims 1 to 13.

15. Diastereomerically pure glycopyrronium chloride.

16. Diastereomerically pure glycopyrronium chloride according to claim 15, having a (R, R) + (S, S) diastereomeric content of less than 10% w/w.

17. A pharmaceutical composition comprising diastereomerically pure glycopyrronium chloride and one or more pharmaceutically acceptable excipients.

18. A pharmaceutical composition comprising glycopyrronium chloride prepared by a process according to any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients.

19. Diastereomerically pure glycopyrronium chloride and glycopyrronium chloride prepared according to the process of any one of claims 1 to 13 for use in the prevention or treatment of any one of the following diseases: COPD (chronic bronchitis and emphysema); asthma; acute Lung Injury (ALI); cystic fibrosis; rhinitis; adult Respiratory Distress Syndrome (ARDS); urinary incontinence; irritable bowel syndrome; psoriasis; hyperhidrosis; drooling; and gastrointestinal ulcers.