ES2436280T3 - Shortened synthesis using paraformaldehyde or trioxane - Google Patents

Abstract

A process for preparing a compound of formula (I) wherein R is hydrogen, a formyl group, a linear, branched or cyclic (C1-C6)alkylcarbonyl group, or a phenylcarbonyl group, or a salt thereof, characterized by the following: steps of a) reacting a compound of formula (II) with a mixture of Mg and a Grignard initiator of the formula R1MgX or R1MgX/LiCl, where R1 represents C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted phenyl or phenyl-(C1-C6)alkyl, wherein said phenyl is optionally substituted, preferably with (C1-C6)alkyl, (C1-C6)alkoxy or CF3, and wherein X is selected from bromide, chloride and iodide, in a solvent to form a Grignard reagent, b) optionally reducing the temperature of the Grignard reagent to a temperature below the temperature of step a) and c) reacting the Grignard reagent with paraformaldehyde or trioxane to obtain a compound of formula(III).

Description

Shortened synthesis using paraformaldehyde or trioxane

Technical field

A process for preparing 2- (3-diisopropylamino-1-phenylpropyl) -4 (hydroxymethyl) phenol which is known as the active metabolite of tolterodine (hereinafter referred to as the "active metabolite") and its monoesters is described herein. phenolics by a shortened synthetic pathway through a Grignard reaction. The target compounds have the following formula (I):

wherein R is hydrogen, formyl, a linear, branched or cyclic (C1-C6) alkylcarbonyl group, or a phenylcarbonyl group. If R of the formula (I) is hydrogen, the formula represents the active metabolite.

A particular preferred example of the phenolic monoesters of formula (I) is fesoterodine which can be chemically defined as 2- (3-diisopropylamino-1-phenylpropyl) -4- (hydroxymethyl) phenol ester of R - (+) - isobutyric acid. Fesoterodine is represented by the formula (Ia) drawn below.

The compounds of formula (I), including the active metabolite and its phenolic monoesters of formula (I), are known from WO 99/058478.

Also described herein is a process for preparing salts of the compounds of formula (I), which specifically includes the preparation of fesoterodine salts, and more particularly the preparation of the fesoterodine hydrogen hydrogen fumarate salt.

The preparation of pharmaceutical formulations containing compounds of formula (I), such as fesoterodine, and the preparation of pharmaceutical formulations containing a pharmaceutically acceptable salt of any of the compounds of formula (I) are also disclosed, including, for example, , hydrogen hydrogen sulfate or fesoterodine hydrochloride salts.

Background

In man, in normal contractions of the urinary bladder there is, in part, the stimulation of cholinergic muscarinic receptors. Muscarinic receptors not only intervene, in part, in normal bladder contractions, but also intervene in most of the overactive bladder contractions, resulting in symptoms such as urinary frequency, urgency and urinary incontinence. for urgency

After administration of fesoterodine and other phenolic monoesters of formula (I) to mammals, for example humans, these compounds are cleaved by esterases to form the active metabolite within the organism. It is known that the active metabolite is a potent and competitive antagonist of muscarinic receptors (WO 94/11337). Fesoterodine and other phenolic esters of formula (I) thus represent potential prodrugs of the active metabolite. Fesoterodine, in particular, has been shown to be an effective drug for the treatment of overactive bladder with symptoms of urinary incontinence due to urgency, urgency and urinary frequency, as well as detrusor hyperactivity (as described in US 6,713,464 and EP-B-1,077,912).

In US 6,713,464 a synthetic strategy is described for the production of the active metabolite and

monoesters of the phenolic hydroxy group of the active metabolite such as fesoterodine as follows: In a first step, an ether solution is prepared from R - (-) - [3- (2-benzyloxy-5-bromophenyl) -3 -phenylpropyl] diisopropylamine, ethyl magnesium bromide; this solution is diluted with dry THF and cooled to -60 ° C.

5 In a second stage, pulverized solid carbon dioxide is added in small portions, and the reaction mixture is heated to room temperature. In a third stage, the reaction is quenched with an aqueous solution of ammonium chloride. In a fourth stage, the aqueous phase of the deactivated reaction mixture is adjusted to a pH of 0.95. In a fifth step, the aqueous phase is filtered with adjusted pH, and from the solid 10 R - (-) - 4-benzyloxy-3- (3-diisopropylamino-1-phenylpropyl) -benzoic acid hydrochloride can be recovered.

In a sixth step, the resulting purified benzoic acid is esterified to give its corresponding methyl ester. In a seventh stage, the methyl ester of the sixth stage is reduced by the addition of lithium aluminum hydride. After reacting for 18 hours, the reaction is quenched with water and the organic phase is dried over sodium sulfate, filtered and evaporated to dryness to provide the alcohol that gradually crystallizes from a

15 oil Below is a diagram that summarizes this multi-stage synthesis. Stages 1 to 5:

Stage 6: Stage 7:

US 6,713,464 further describes the conversion of the methyl ester into the active metabolite, and subsequent esterification to provide a phenolic monoester, such as fesoterodine.

5 WO 94/11337 also describes a multi-stage process for synthesizing the precursor of the active metabolite.

These methods described above to produce the active metabolite require numerous steps, which results in complicated purification procedures, delays, and a greater possibility of human error, thus preventing the achievement of optimum efficiency and profitability. In addition, solid carbon dioxide

10 used in the art is difficult to handle on a large scale due to the need to work at very low temperatures and to add crushed dry ice in portions, and to the difficulties in controlling the extremely exothermic nature of the reaction. In addition, the stage of reduction with lithium aluminum hydride used in the prior art generates a significant amount of large-scale waste, which is inconvenient both economically and ecologically.

15 This description aims to overcome these problems and inconveniences. Surprisingly, it has now been found that the use of paraformaldehyde or trioxane in the Grignard reaction by employing a Grignard initiator in the presence of an excess of Mg, is suitable for directly obtaining a compound of formula

(III) without previously synthesizing the corresponding ester. The use of paraformaldehyde or trioxane results in

a synthetic route shortened to fesoterodine through a compound of formula (III) by eliminating the production of benzoic acid and methyl ester intermediates, and providing an increased overall yield.

Consequently, the use of paraformaldehyde or trioxane in the Grignard reaction initiated by the use of a Grignard initiator in the presence of an excess of Mg allows a direct and more cost-effective synthetic strategy to obtain compounds of formula (I) through a compound of formula (III), thus eliminating by-products

Undesirable, such as benzoic acid derivatives, which are often formed when using a strategy that runs through the corresponding ester followed by a reduction step.

Summary

A shortened process for preparing compounds of formula (I) is described herein:

wherein R is hydrogen, a formyl group, a linear, branched or cyclic (C1-C6) alkylcarbonyl group or a phenylcarbonyl group, including the active metabolite and its phenolic monoesters, such as fesoterodine and its salts, and more particularly fesoterodine hydrogen hydrogen fumarate salt.

The shortened synthesis of compounds of formula (I) can be characterized by the following steps:

a) reacting a compound of formula (II)

10 with a Grignard and Mg initiator, preferably in a solvent, to form a Grignard reagent,

b) optionally, reduce the temperature of the Grignard reagent to a temperature lower than that of step a), and

c) reacting the Grignard reagent with paraformaldehyde or trioxane to obtain a compound of formula

(III)

15 and then further reacting the compound of formula (III) in a known manner to obtain a compound of formula (I) and optionally forming a salt.

A shortened process for preparing compounds of formula (I) is also described herein:

wherein R is hydrogen, formyl, a linear, branched or cyclic (C1-C6) alkylcarbonyl group, or a group

Phenylcarbonyl, including the active metabolite and its phenolic monoesters, such as fesoterodine and its salts, and more particularly the hydrogen hydrogen fumarate and fesoterodine hydrochloride salts, wherein said shortened process for preparing compounds of formula (I) can be characterized by the following stages:

a) combine a compound of formula (II)

with MeMgCl and Mg in a solvent to form a reaction mixture, b) optionally, reduce the temperature of the reaction mixture from step a) to a temperature below the temperature of step a), and

c) combining the reaction mixture from step a) with paraformaldehyde or trioxane, preferably paraformaldehyde, to obtain a compound of formula (III):

10 and then further reacting the compound of formula (III) in a known manner to obtain a compound of formula (I) and optionally forming a salt.

Detailed description

The synthesis shortened through a Grignard reaction with a Grignard, Mg and paraformaldehyde or trioxane initiator that can be used in the preparation of the active metabolite and its phenolic monoesters of the type described by formula (I), such as fesoterodine, and more particularly fesoterodine hydrogen hydrogen fumarate, will now be described in greater detail with reference to preferred embodiments.

In step a) of the process according to the present description, a compound of formula (II) is reacted

20 with a Grignard initiator in the presence of Mg in a solvent to form a Grignard reagent, wherein the expression "Grignard initiator", as used throughout this application, refers to compounds of the general formula R1MgX, or R1MgX / LiCl (see, for example, EP 1,582,523), wherein R1 represents C1-C12 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl or substituted (C1-C6) alkyl or unsubstituted, wherein said phenyl may be substituted, for example, with (C1-C6) alkyl, (C1-C6) alkoxy or CF3; and where X is selected from

25 bromide, chloride and iodide. R1 is preferably selected from C1-C6 alkyl, vinyl, allyl, propenyl, ethynyl, phenyl or benzyl, and more preferably it is C1-C4 alkyl.

Specific examples of Grignard initiators are: iPrMgCl, iPrMgCl / LiCl, t-BuMgCl, t-BuMgCl / LiCl, MeMgCl / LiCl

or, particularly preferably, MeMgCl.

The molar ratio of a Grignard initiator to Mg is preferably between about 1: 2 30 and about 2: 1, most preferably about 1: 1, and the mole ratio of each of a

Grignard and Mg initiator with respect to the compound of formula (II) is preferably between about 1: 1 and about 2: 1, most preferably from about 1: 1 to about

1.5: 1 If MeMgCl or a similar initiator is used in combination with LiCl, MeMgCl and LiCl, it is used in approximately equimolar amounts.

In a preferred embodiment, MeMgCl is used as the Grignard initiator. In a particularly preferred embodiment, the molar ratio of MeMgCl with respect to the compound of formula (II) is approximately

1: 1 to about 1.5: 1.

Preferably, step a) can be carried out:

a1) dissolving a compound of formula (II) in a suitable solvent to form a solution, and a2) adding said solution to a mixture of a Grignard and Mg initiator in a suitable solvent to form a Grignard reagent.

A preferred solvent to dissolve the reaction compound (II) in step a1) is toluene, although other suitable solvents can be used. Preferably, the water content in the solution containing compound

(II) is not greater than about 0.1% by weight, and most preferably not greater than about 0.05% by weight.

A preferred solvent for dissolving a Grignard initiator in reaction step a2) is THF, but other suitable ethers known to those skilled in the art, including diethyl ether and t-butyl methyl ether, can be used.

Grignard reagent formation as described in step a) is preferably carried out in a temperature range of about 40 to about 55 ° C and most preferably in a temperature range of about 40 to about 50 ° C. The reaction can be carried out with stirring (for example, stirring) until it is complete.

In a preferred embodiment, the Grignard can then be cooled to room temperature, for example up to about 20 to about 25 ° C and kept under anhydrous conditions, preferably with stirring, for the further steps of the process.

In step c) the resulting Grignard reagent is reacted with a suspension of paraformaldehyde or trioxane in THF to obtain the compound of formula (III) drawn below.

An excess of paraformaldehyde or trioxane is preferred in comparison to a compound of formula (II), an excess of paraformaldehyde or trioxane of about 1.1 times to about 50 times, and an excess of about 5 times to about 50 times being particularly preferred .

The most preferred reagent is paraformaldehyde.

In one embodiment of the present invention, the reaction of Grignard reagent with paraformaldehyde or trioxane, preferably with paraformaldehyde, is carried out at a temperature below room temperature, preferably below 10 ° C, under agitated conditions.

One option is to slowly add the Grignard reagent to paraformaldehyde or trioxane, optionally with stirring, to allow a rapid and homogeneous mixing of the reaction solution.

Another option is to add paraformaldehyde or trioxane to the Grignard reagent, optionally with stirring, at room temperature until the reaction is complete.

Step c) is completed by deactivating the reaction mixture with a suitable deactivating agent. A preferred deactivating agent is aqueous ammonium chloride, although other deactivating agents known to those skilled in the art may be used, including aqueous ethyl acetate, aqueous sodium chloride or aqueous hydrochloric acid solution.

Subsequently, a solvent change from the Grignard solvent (for example toluene and / or THF) to a suitable solvent for hydrogenation (for example methanol) can be carried out.

They are suitable processing steps after the addition of the deactivating reagent, for example

-wash with water; - remove water from the organic phase, for example by azeotropic drying; -change the solvent to a suitable solvent for hydrogenation.

The procedure described above is developed in more detail in Example 1 of the experimental part of this request.

Another preferred embodiment of the present invention is a method for preparing a compound of formula (I) such as defined above or of formula (Ib)

or a salt thereof, first forming a compound of formula (III) as defined above and then reacting this compound in a suitable manner to form a compound of formula (I) or (Ib).

In a preferred embodiment, the compound of formula (III) can be further reacted with a debenzylating reagent to obtain a compound of formula (I) or (Ib), most preferably with Pd / C, H2 in methanol.

After this reaction sequence, the compound of formula (Ib) can be isolated with a total yield of 46% for both stages. In contrast, the synthesis of the prior art according to US 6,713,464 and EP-B-1,077,912 has a reaction yield of (Ib) starting from (II) of approximately 26%.

A particularly preferred embodiment of the present invention is a process for preparing the active metabolite, and, if desired, its phenolic monoesters, including fesoterodine or a salt thereof, preferably a pharmaceutically acceptable salt of fesoterodine, and most preferably the salt of fesoterodine hydrogen hydrogen fumarate, which procedure includes the steps of:

a1) dissolving the compound of formula (II) in a solvent, such as toluene, to form a reaction mixture, a2) adding said reaction mixture to a mixture of MeMgCl, Mg and THF to form a Grignard reagent, wherein the reaction can be carried out at a reaction temperature of about 40 to about 50 ° C, b) optionally reducing the temperature of the Grignard reagent to a temperature below the temperature of step a2), and more preferably in the range from about 20 to about 25 ° C and keep the Grignard reagent at the lower temperature, optionally with stirring, and c) reacting the resulting Grignard reagent with paraformaldehyde in a solvent (for example THF), preferably at a reaction temperature by below room temperature, most preferably at a reaction temperature below 10 ° C, followed by deactivating the mixture thus obtained with an aqueous solution of ammonium chloride to obtain a compound of formula (III). An excess of paraformaldehyde is preferably used, more preferably paraformaldehyde is used in an excess of 1.1 times to 50 times, most preferably an excess of 5 times to 50 times. This compound can then be isolated or elaborated as described above.

After formation of the compound of formula (III), one option is to further react the compound of formula (III) to obtain a compound of formula (I). This can be achieved, for example, as follows:

d) debencylating the protected alcohol, to form the aforementioned active metabolite.

Another option is to convert the active metabolite into an ester thereof such as fesoterodine or a fesoterodine salt, preferably the fesoterodine hydrogen phosphate salt, by:

e) phenolic monoacylation, and

10 f) salt formation

Examples of steps d) to f) are described in, for example, US 6,858,650.

The formation of other phenolic monoesters of the active metabolite is possible through the use of other organic acid halides in step e) of the preceding scheme.

Then, the final compound (I) (phenolic monoesters of the active metabolite, including fesoterodine (Ia) or pharmaceutically acceptable salts thereof), and salts thereof, can be formulated in a known manner to obtain a medicament that can be useful, for example, for oral, parenteral or transdermal administration.

The present description is further illustrated by the following non-exhaustive examples. The examples do not

20 are intended to limit the scope of this description as defined in the following claims. The starting compound of formula (II) can be prepared in a known manner, for example as described in Experimental Part of US 6,713,464.

Examples

Example 1

Preparation of R - (-) - 4-benzyloxy-3- (3-diisopropylamino-1-phenylpropyl) -phenyl methanol of formula (III)

(a) MeMgCl stoichiometry: Mg: R - (-) - [3- (2-benzyloxy-5-bromophenyl) -3-phenylpropyl] -diisopropylamine (formula II) = 1: 5: 1: 5: 1.0

Magnesium chips (2.25 g, 0.09 mol) and THF (150 ml) were loaded in a 500 ml round bottom flask to which an agitator, addition funnel, thermometer, nitrogen inlet and apparatus had been attached Distillation The system was purged with nitrogen and the mixture was distilled to a desired volume of 100 ml. The contents of the flask were cooled to 30 ° C to 35 ° C under a nitrogen atmosphere and methylmagnesium chloride (30.4 ml, 0.09 mol) was added to the flask by means of a syringe. The mixture was allowed to age at 30 ° C for 1 hour. The mixture was heated to reflux and the toluene solution of R - (-) [3- (2-benzyloxy-5-bromophenyl) -3-phenylpropyl] diisopropylamine (formula (II)) (50 ml, 0) was added dropwise , 06 mol) by means of a pressure equalizing funnel to the reaction mixture. The reaction was stirred for 3 hours, after which the analysis indicated that the reaction was complete (HPLC). Paraformaldehyde (9.05 g, 0.30 mol) and THF (200 ml) were loaded into a 500 ml round bottom flask to which an agitator, addition funnel, thermometer, nitrogen inlet and distillation apparatus had been coupled .

The system was purged with nitrogen and the mixture was distilled to a desired volume of 100 ml. The mixture was cooled to 0 ° C to 5 ° C. The reaction solution was added to the paraformaldehyde and THF solution using a syringe and keeping the temperature below 10 ° C, with stirring. The resulting mixture was stirred for at least 1 hour. 10% Ammonium Chloride (75 ml) was added to the reaction mixture and stirred for 2 hours. The biphasic mixture was transferred to a separatory funnel, the lower aqueous layer was separated and the organic layer was washed with water (2 x 100 ml). The combined organic layers were azeotropically dried using a Dean-Stark apparatus. By concentrating under vacuum, the oily product was isolated. The product was dissolved in methanol (400 ml) and 3.0 g of 5% weight / weight palladium on carbon (with 50% weight / weight of water) was added to the resulting solution. The mixture was loaded into a 2 liter hydrogenation flask. The mixture was then stirred at 20 to 25 ° C for 6 hours under a hydrogen pressure of 3.45-3.79 bar. The reaction mixture from the reactor was added to a 1 liter flask containing 40 ml of toluene, and the reactor was washed with methanol (60 ml). The combined mixtures were filtered through a bed of Celite. The filter bed was washed with methanol (60 ml). The combined filtrates were transferred to a 2 L flask equipped with a stirrer, thermometer and distillation apparatus. The solvent was distilled off under vacuum, while maintaining a mass temperature below 25 ° C, until a residue volume of 60 to 90 ml was obtained. Toluene (450 ml) was added to the concentrated solution. Vacuum was applied again and the whole was again concentrated by distillation to a volume of 146 to 180 ml while maintaining a mass temperature below 25 ° C. Then the whole was continued to be concentrated by distillation until a residue volume of 46 to 60 ml was obtained, while maintaining a temperature of the mass below 45 ° C. Toluene (250 ml) was added and the whole was concentrated by distillation to 25 ml to 30 ml. The mixture was allowed to cool to 20 to 25 ° C and to age overnight. The resulting crystalline R - (-) - 4-benzyloxy-3- (3diisopropylamino-1-phenylpropyl) -phenyl methanol (formula (III)) was filtered, washed with toluene (40 ml) and dried under vacuum at 40 ° C.

Claims (22)

1. A process for preparing a compound of formula (I) wherein R is hydrogen, a formyl group, a linear, branched or cyclic (C1-C6) alkylcarbonyl group, or a group phenylcarbonyl, or a salt thereof, characterized by the stages of a) reacting a compound of formula (II) with a mixture of Mg and a Grignard initiator of the formula R1MgX or R1MgX / LiCl, wherein R1 represents alkyl C1-C12, C2-C6 alkenyl, C2-C6 alkynyl, substituted or unsubstituted phenyl or phenyl-C1-alkyl, wherein said phenyl is optionally substituted, preferably with (C1-C6) alkyl, C1-alkoxy -C6) or CF3, and where X is selected from bromide, chloride and iodide, in a solvent to form a Grignard reagent, b) optionally reduce the temperature of the Grignard reagent to a temperature below the stage temperature a) and C) react the Grignard reagent with paraformaldehyde or trioxane to obtain a compound of formula (III) and then further reacting the compound of formula (III) in a known manner to obtain a compound of formula (I) and optionally forming a salt. 2. The process according to claim 1, wherein the compound of formula (I) is fesoterodine having the formula (Ia) or a salt of it.

3.

The method according to claim 2 wherein the fesoterodine salt is hydrogen hydrogen fumarate.

Four.

The process according to any one of the preceding claims, wherein the Grignard initiator is selected from a group of compounds of the general formula R1MgX or R1MgX / LiCl, wherein R1 is selected from C1-C6 alkyl, vinyl, allyl, propenyl, ethynyl , phenyl and benzyl, and is preferably C1-C4 alkyl, and wherein X is selected from bromide, chloride and iodide.

5.

The method according to any one of the preceding claims, wherein the Grignard initiator is selected from the group consisting of MeMgCl, MeMgCl / LiCl, t-BuMgCl / LiCl and iPrMgCl / LiCl.

6.

The method according to any one of the preceding claims, wherein the Grignard initiator is MeMgCl.

7.

The process according to any one of the preceding claims, characterized in that in step c) paraformaldehyde is used in a molar excess of 1.1 times to 50 times compared to the compound of formula (II).

8.

The process according to any one of the preceding claims, characterized in that in step c) a solvent, preferably THF, is used.

9.

The process according to any one of the preceding claims, wherein the reaction step c) is followed by deactivating the mixture with a suitable reagent.

10.

The process according to claim 9 wherein the reagent is aqueous NH4Cl.

eleven.

The process according to any one of the preceding claims, characterized in that in step c) paraformaldehyde is reacted with the Grignard reagent to obtain a compound of formula (III).

12.

The process according to any one of the preceding claims, wherein the molar ratio of said Grignard initiator with respect to Mg is between 1: 2 and 2: 1, and the molar ratio of said Grignard initiator with respect to the compound of formula (II) is between 1: 1 and 2: 1.

13.

The process according to any one of the preceding claims, wherein the molar ratio of a MeMgCl with respect to Mg is between 1: 2 and 2: 1, and the molar ratio of a MeMgCl with respect to the compound of formula (II) is between 1: 1 and 2: 1.

14.

The process according to any one of the preceding claims, characterized in that step a) is carried out a1) by dissolving the compound of formula (II) in a suitable solvent to form a solution, and a2) adding said solution to said Grignard initiator and Mg in a suitable solvent.

fifteen.

The process according to claim 14, wherein the solvent of step a1) used to dissolve the compound of formula (II) is toluene and the solvent of step a2) is THF.

16.

The method according to any one of claims 13 to 15, wherein

-

in step a1) the compound of formula (II) is dissolved in toluene,

-

in step a2) said solution is added to MeMgCl and Mg in THF and stirred until the reaction is complete,

-

in step b) the mixture is kept under stirring as obtained in step a2),

-

in step c) the mixture is added to paraformaldehyde in THF, followed by the addition of a suitable deactivating reagent, preferably aqueous NH4Cl.

17.

The process according to any one of the preceding claims, characterized in that the reaction temperature of step a) is between 40 and 50 ° C.

18.

The process according to any one of the preceding claims, wherein the reaction temperature of step b) is reduced to a temperature between 20 and 25 ° C.

19.

The process according to any one of the preceding claims, characterized in that the reaction temperature of step c) is below 10 ° C.

twenty.

The process according to any one of the preceding claims, characterized in that step c) is followed by a debenzylation step to obtain a compound of formula (Ib)

twenty-one.

The process according to claim 20, characterized in that the debenzylation step is carried out with Pd / C, H2 in a suitable solvent.

The method according to claim 21, characterized in that the solvent is methanol. 23. A process for preparing a pharmaceutical composition containing fesoterodine hydrogen hydrogen fumarate, comprising the steps of (i) preparing fesoterodine hydrogen hydrogen fumarate by a method according to any of the preceding claims, and (Ii) formulate the fesoterodine hydrogen hydrogen fumarate thus obtained in a known manner to obtain a pharmaceutical composition.