EP2516384A1

EP2516384A1 - Novel method for the preparation of (s)-pregabalin

Info

Publication number: EP2516384A1
Application number: EP10801165A
Authority: EP
Inventors: Carles SÁNCHEZ CASALS; Alicia DOBARRO RODRÍGUEZ
Original assignee: Moehs Iberica SL
Current assignee: Moehs Iberica SL
Priority date: 2009-12-24
Filing date: 2010-12-23
Publication date: 2012-10-31
Also published as: ES2362913A1; ES2362913B1; WO2011076915A1; WO2011076915A8

Abstract

Method for the preparation of a salt (III) of pregabalin and (S)-mandelic acid with a (S, S) diastereomer content greater than 80% which comprises the following steps: (a) Hofmann reaction of (±)-3-(carbamoylmethyl)-5- methylhexanoic acid (I) to obtain racemic pregabalin (II), (b) addition of (S)-(+)-mandelic acid to obtain the corresponding diastereoisomeric salt (III) with a (S, S) diastereomer content greater than 80% (c)optionally, purification of the salt obtained in step (b); characterized in that step(b) is performed without isolating the product obtained in step(a).

Description

NOVEL METHOD FOR THE PREPARATION OF (S) -PREGABALIN

FIELD OF THE INVENTION

The present invention relates to a novel method for the preparation of (S) -pregabalin .

PRIOR ART

(S) -pregabalin or (S) - (+) -3- (aminomethyl) -5- methylhexanoic acid is an analogue of gamma-aminobutyric acid (GABA) which is known and used as anticonvulsive agent and whose chemical structure is represented by:

Patent application W093/23383 Al discloses (S)- pregabalin (called S- (+) -4-amino-3- (2-methylpropyl) butanoic acid) and its salts for the first time. The same document discloses synthesis routes for this compound that involve a large number of steps.

Later patents, patent applications or scientific articles (WO96/38405 Al, WO 96/40617 Al, WO2006/122258 Al, WO2008/062460 A2 , US2006/0270871 Al, Hoekstra et al. Organic Process Research & Development 1997, 1, 26-38) disclose other synthesis routes to obtain (S) -pregabalin .

Patent application WO 96/38405 Al discloses a method of synthesis of (S) -pregabalin wherein it makes use of racemic (±) -3- (carbamoylmethyl) -5-methylhexanoic acid. From this racemic acid two forms are disclosed of resolving the R isomer of said acid by the use of a-phenylethylamine enantiomers. The enantiomer (R) of 3- (carbamoylmethyl ) -5- methylhexanoic acid is finally subjected to a Hofmann reaction to obtain (S) -pregabalin .

Patent application WO 96/40617 Al discloses an alternative method of synthesis of the racemic mixture of (±) -3- (aminomethyl) -5-methylhexanoic acid that does not start from racemic (±) -3- (carbamoylmethyl) -5-methylhexanoic acid. The racemic mixture obtained is isolated and then resolved to (S) -pregabalin by the use of (S) - or (R) - mandelic acid.

Application WO2006/122258 Al discloses a variation in the Hofmann reaction with 3- (carbamoylmethyl ) -5- methylhexanoic acid (either racemic or enantiomer (R) thereof) wherein the Br₂ is directly added in the basic reaction medium to generate in situ the Hofmann reagent (NaBrO, in this case) . The process involves later extractions with alcoholic solvents of the aqueous reaction medium and the isolation of pregabalin (in racemic or enantiomer form (S) depending on whether it started from racemic acid or enantiomer (R) . The most optimized yield is 79.4% in the case of racemic pregabalin and 80.4 % in the case of the pregabalin enantiomer (S) .

Hoekstra et al. discloses, in Organic Process Research & Development 1997, 1, 26-38, the Hofmann reaction of (R) - (-) -3- (carbamoylmethyl) -5-methylhexanoic acid to isolate (-S) -pregabalin with a yield of 65.5%. The solid obtained is recrystallized in water/isopropanol with a yield of 90.2%. The same example appears in WO 96/38405 Al .

The same article also discloses the obtaining of a diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (S) -(+) -mandelic acid with a diastereomeric ratio of 99:1 by the addition of (S)-(+)- mandelic acid to a racemic pregabalin solution in a mixture of water/isopropanol, the purification, in the same solvent mixture and with an additional quantity of ( S )-(+) -mandelic acid, of the diastereoisomeric salt obtained, the release thereof in a water/THF mixture to isolate (S ) -pregabalin, which is finally recrystallized in water/isopropanol. The overall yield of the four steps is 27.7%. It does not indicate the partial yield of the resolution with the chiral agent.

Application WO2008/062460 A2 discloses the resolution of racemic pregabalin in identical conditions as in the Organic Process Research & Development article. The salt obtained is purified also making use of an additional quantity of mandelic acid. The yield of the obtaining step of the diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (L) -(+) -mandelic acid and later purification thereof is 26.5% (example 5). The diastereoisomeric salt is released in a mixture of THF/water with a yield of 83% to obtain ( S ) -pregabalin which is later recrystallized in water/isopropanol with a yield of 90%.

Patent application US2006/0270871 Al discloses polymorfic form I of pregabalin and a process for its preparation which includes the resolution of racemic pregabalin with mandelic acid to obtain (S) -pregabalin which is later crystallized.

Bearing the aforementioned descriptions in mind and using the yields they report for each of the steps, we can calculate the yield that would be obtained on preparing the diastereoisomeric salt of pregabalin (III) from (±) -3- (carbamoylmethyl ) -5-methylhexanoic acid (I) .

Yield of the Hofmann reaction + salification with mandelic acid + purification of the diastereoisomeric salt

%

79.4% 26.5%

WO2006/122258 Al WO2008/062460 A2

We can also calculate the yield that would be obtained on preparing (S ) -pregabalin (IV) from (±) -3-

(carbamoylmethyl) -5-methylhexanoic acid (I) (using the yields reported in the state of the art for the different steps) . Overall yield of the process that consists of the Hofmann reaction + salification with mandelic acid + purification of the diastereoisomeric salt (with additional use of mandelic acid) + release of the salt + recrystallization of (S) -pregabalin :

1

79.4% 27.7%

WO2006/122258 Al Hoekstra et al.

2nd ossibility = 79.4 x 26.5 x 83 x 90 = 15.7%

79- % 26.5%

WO2006/122258 Al WO2008/062460 A2 release of the salt

(IV) (IV)

83% 90%

WO2008/062460 A2 WO2008/062460 A2 In summary, the existing methods to date to obtain

(S) -pregabalin (IV) from (±) -3- (carbamoylmethyl ) -5- methylhexanoic acid (I) :

a) provide total yields less than 23%

b) the initial steps of the Hofmann reaction and salification with mandelic acid are carried out separately c) the step of resolution with mandelic acid is performed in organic solvents or in aqueous mixtures thereof

d) the purification step of the diastereomeric salt is performed in the presence of mandelic acid.

Therefore, it would be desirable to have a simpler alternative method that allows doing without the use of organic solvents in the obtaining step of the diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (S) -(+) -mandelic acid and which provides a better yield.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an improved method for the synthesis of the (S) -stereoisomer of pregabalin starting from (±) -3- (carbamoylmethyl) -5- methylhexanoic acid that makes it possible to increase the yield in relation to that obtained following the methods described in the state of the art which makes it possible to decrease process costs.

In one aspect of the present invention, a method is provided for the preparation of a salt (III) of pregabalin and (S) -mandelic acid with a (S,S) diastereomer content greater than 80% which comprises the following steps:

(a) Hofmann reaction of (+) -3- (carbamoylmethyl) -5- methylhexanoic acid (I) to obtain racemic pregabalin (II), (b) addition of (S) -(+) -mandelic acid to obtain the corresponding diastereoisomeric salt (III) with a (S,S) diastereomer content greater than 80%

(c) optionally, purification of the salt obtained in step (b) ;

characterized in that step (b) is performed without isolating the product obtained in step (a) .

In one aspect of the invention, a method is provided for the obtaining of (S) -pregabalin (IV) which comprises the obtaining of a salt of pregabalin and (S) -mandelic (III) acid with a (S,S) diastereomer content greater than 80% as previously described, followed by the following steps :

(d) the conversion of the salt obtained in step (c) in (S)- pregabalin (IV); and

(e) optionally, purification of the (S ) -pregabalin . BRIEF DESCRIPTION OF THE FIGURES

Figure 1. Standard of XRPD obtained for the crystalline form of the salt of pregabalin and (S)-mandelic acid. Figure 2. Standard of XRPD obtained for the crystalline form of ( S ) -pregabalin, form I.

Figure 3. Standard of DSC obtained for the crystalline form of (S) -pregabalin, form I.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have developed a method of synthesis wherein a "one-pot" reaction is carried out in 2 steps which consists of a) the Hofmann reaction of racemic 3- (carbamoylmethyl) -5-methylhexanoic acid and b) the subsequent obtaining of a diastereomerically enriched salt (in the (S) diastereomer) of pregabalin and (S)-( + )- mandelic acid, without isolating the racemic pregabalin obtained in step a) . On avoiding the isolation or filtration of the racemic pregabalin it simplifies the process which is translated into greater profitability thereof. Furthermore, the method according to the invention has a yield greater than that obtained following the methods described in the state of the art.

Other advantages of the method developed in this invention are that the resolution with (S) -( + ) -mandelic acid can be carried out in aqueous medium and in the absence of organic solvents, and that the subsequent purification of the salt is performed without the need to add an additional quantity of a resolution agent.

In one aspect, the present invention provides a method for the preparation of a salt (III) of pregabalin and (S)- mandelic acid with a (S,S) diastereomer content greater than 80% which comprises the following steps:

(a) Hofmann reaction of (±) -3- (carbamoylmethyl) -5- methylhexanoic acid (I) to obtain racemic pregabalin (II) , (ID

(b) addition of (S) - ( +) -mandelic acid to obtain the corresponding diastereoisomeric salt (III) with a (S,S) diastereomer content greater than 80%

(c) optionally, purification of the salt obtained in step (b) ;

In an embodiment of the present invention the salt (III) of pregabalin and (S) -mandelic acid obtained after step (b) has a (S,S) diastereomer content greater than 85%, preferably greater than 90%, more preferably between 90% and 98% and even more preferably between 94.5% and 95.5%.

In an embodiment of the present invention, the preparation of a salt (III) of pregabalin and (S) -mandelic acid with a (S,S) diastereomer content greater than 80% comprises step (c) of purification.

In the first step of the reaction (step a) , racemic 3- ( carbamoylmethyl ) -5-methylhexanoic acid (I) is subjected to a Hofmann reaction to give racemic pregabalin (II), reaction intermediate which is not isolated, since then (+) - (S) -mandelic acid is added in aqueous medium (step b) in a same reaction to obtain the salt of pregabalin and (S) -mandelic acid (III) with a yield of 49.4% and with a (S,S) diastereomer content greater than 80%.

Hofmann reaction or reordering is understood as the reaction of a primary amide (R-CONH₂) to give an amine (R- NH₂) with one carbon atom less. The conditions of the Hofmann reaction are well known by persons skilled in the art. A suitable Hofmann agent is a hypohalite of alkaline metal, which may be prepared combining a base such as sodium hydroxide with a halogen, such as bromine. Other alkaline metals or alkaline earth metal bases or other halogens can also be used. Other Hofmann agents that can be used include, but are not limited to: bis ( trifluoroacetoxy) -iodobenzene , iodobenzene with formic acid, [hydroxy (tosyloxy) iodo] benzene, bis (acetoxy) iodobenzene, lead tetraacetate, benzyltrimethylammonium tribromide, N-bromosuccinimide in basic medium (such as a potassium hydroxide solution) , and N-bromosuccinimide in the presence of mercury II acetate or silver acetate. In a preferred embodiment, the Hofmann reaction of step (a) is performed with sodium hypobromite, preferably in aqueous medium which can also be prepared by the addition of bromine to a sodium hydroxide solution.

Racemic 3- (aminomethyl ) -5-methylhexanoic acid or racemic pregabalin (II) formed in step (a) can be resolved by selective crystallization with (S) -mandelic acid. In general, the S,S salt precipitates from the solution.

In step (b) of the reaction (S) -(+ ) -mandelic acid is added to the racemic pregabalin (II) formed in step (a) to obtain the diastereoisomeric salt of pregabalin and (S)- mandelic acid (III) which is enriched with the (S,S) diastereomer .

The salt enriched with (S,S) diastereomer can be preferably purified (step c) . Said purification is performed without the need to add an additional quantity of mandelic acid, and preferably in aqueous medium. More preferably, step (c) is performed in water containing NaCl. The purification methods that can be used are well known by persons skilled in the art and include, but are not limited to, recrystallization, filtration, etc. In a preferred embodiment of the invention, step (c) is carried out by recrystallization of the salt of pregabalin and -(S)- mandelic acid. In another embodiment of the invention, step

(c) is performed in water, more preferably in water containing NaCl. In yet another embodiment of the invention, step (c) is performed without the addition of

(S) - (+ ) -mandelic acid. The yield obtained by the inventors in step (c) is 64.9%.

In an embodiment of the invention, steps (a) and (b) of the reaction are performed in the absence of organic solvents. In another embodiment of the invention, steps (a) and (b) of the reaction are carried out in aqueous medium.

In another aspect of the invention, a method is provided for the obtaining of (S) -pregabalin (IV) which comprises the obtaining of a salt of pregabalin and (S)- mandelic acid (III) with a (S,S) diastereomer content greater than 80% as previously described, followed by the following steps:

(d) the conversion of the salt obtained in step (c) in (S)- pregabal (IV); and

(IV)

("I)

(e) optionally, purification of the (S) -pregabalin .

The first steps of this method consist, as previously described, of the reaction of (±) -3- (carbamoylmethyl) -5- methylhexanoic acid (I) to obtain racemic pregabalin which is not isolated (step a), and whereto (S) -(+) -mandelic acid is added to obtain the salt of pregabalin and (S) -mandelic acid (III) (step b) .

Step (d) of the reaction consists of the conversion of the salt of pregabalin and (S) -mandelic acid (III) in (S)- pregabalin (IV) . The release of (S) -pregabalin is performed by a hot extraction with water/isopropyl acetate or more preferably by using water/acetone. Alternatively, a base in aqueous medium can be used. Examples of bases include, but are not limited to, ammonium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate. In all cases the yield of the reaction to release the salt is 85.3% or more. In a preferred embodiment of the invention, step (d) is performed in water/isopropyl acetate. In another preferred embodiment of the invention, said step is performed in aqueous sodium hydroxide. In a more preferred embodiment of the invention, step (d) is performed in water/acetone .

Optionally, the ( S ) -pregabalin obtained in the previous step can be purified (step e) . The purification methods that can be used are well known by persons skilled in the art and include, but are not limited to, recrystallization, filtration, etc. In an embodiment of the invention, step (e) is performed by a recrystallization in a mixture of isopropanol/water, obtaining a yield of 91.5%. Alternatively, in another embodiment this purification can be performed by recrystallization only with water.

In another embodiment of the invention all steps are carried out in aqueous medium.

The "one-pot" reaction wherein steps (a) and (b) of the present invention are carried out simplifies the aforementioned method as the intermediate (II) is not isolated. Surprisingly, the method of the present invention provides a greater yield in comparison with those disclosed in the documents of the state of the art. The yield of steps (a), (b) and (c) is 32.1%, compared with 21.0% resulting from combining the yields previously described from documents WO2006/122258 Al and WO2008 /062460 A2. The overall yield for the preparation of (S) -pregabalin from a compound of formula (I) is of 25.0%, and therefore greater than those obtained from combining the yields from the different documents previously described, and which range between 15.7% and 22.0%.

The examples of embodiment included in the present specification describe in detail suitable processes to obtain a salt of pregabalin and (S)-mandelic acid and also for the obtaining of (S) -pregabalin according to the method of the invention. It is obvious for the person skilled in the art that these examples are only illustrative and should not be considered as limitation of the scope of the invention .

EXAMPLES

The compounds obtained in the examples described below are identified by their x-ray powder diffraction (XRPD) standards and differential scanning calorimetry (DSC) .

XRPD analyses were performed in an x-ray powder diffractometer , model Siemens D-500, equipped with a copper anode. Scanning parameters: 4-50 degrees 2Θ, continuous scanning, ratio: 1.2 degrees/minute.

The following abbreviations are used in the experimental part:

HPLC high performance liquid chromatography

EXAMPLE 1 : "One pot" synthesis of a salt of pregabalin and (S) -mandelic acid (steps a and b)

50.0 g of racemic 3- (carbamoylmethyl ) -5-methyl hexanoic acid (I) and 180 ml of water were loaded in a flask. It was stirred and cooled to 5-10°C. Then 38.4 g of 30% caustic soda were slowly loaded maintaining a temperature lower than 20°C and stirring until perfect dissolution .

135.0 g of 30% caustic soda were loaded in a 250 ml flask and it was cooled to 0/-5°C. 53.1 g of bromine were slowly added. It was stirred for a few minutes and the solution was loaded to a dropping funnel. The previously prepared solution was slowly added keeping the temperature between 20-40°C. It was heated to 45-50°C for a few minutes. It was cooled to 20-30°C and the pH was adjusted with 37% HC1 until pH = 4.5-5.5. 61.1 g of ( + ) - (S) -mande 1 i c acid were directly loaded on the suspension obtained. The suspension was heated until redissolution and it was then slowly cooled to 20-22°C. It was stirred for a few hours at 20-22°C and the solid obtained was filtered. It was dried at 55°C obtaining 41.0 g in the form of white crystalline solid (5% of isomer (R) ) . The XRPD standard obtained for the crystalline form of the salt of pregabalin and (S)-mandelic acid (III) is shown in Figure 1.

EXAMPLE 2 : Recrystallization of the salt of pregabalin and (S) -mandelxc acid (step c)

41.0 g of the crude salt of pregabalin and (S)- mandelic acid (III) and 160 ml of water were loaded in a 500 ml flask. They were heated to 65°C, obtaining a dissolution. It was gradually cooled to 60°C, remaining 30 minutes at this temperature and slowly cooling to 0-2°C. It was stirred for 2 hours at 0-5°C and filtered. After drying it, 26.6 g of the salt of pregabalin and (S)-mandelic acid (III) (<0.5% isomer R, 0% ash, 99% HPLC) were obtained.

EXAMPLE 3a: Release of pregabalin to obtain crude (S) - pregabalin (step d)

26.6 g of the salt of pregabalin and (S)-mandelic acid (III) (example 2), 53 ml of water and 105 ml of isopropyl acetate were loaded in a 500 ml flask. It was heated until redissolution and stirred for a few minutes. It was hot decanted and the phases were separated. A further two hot extractions were applied on the aqueous phase with 105 ml of isopropyl acetate each one. They were combined and the organic phases were kept for the later recovery of the mandelic acid.

The aqueous phase was loaded in a flask together with

66 ml of isopropanol. It was heated until redissolution and then cooled slowly to 0-2°C. It was stirred for 2 hours at 0-2°C. It was filtered and the solid washed with cold isopropanol. After drying it 11.6 g of crude ( S ) -pregabalin (IV) were obtained in the form of white crystalline solid (<0.2% isomer R, 0% ash, 99.2% HPLC, crystalline form I).

The organic phases were loaded in a flask and cooled to 20°C for a few hours. The solid was filtered and washed with isopropyl acetate. It was dried in an oven and 1.6 g of (S) -pregabalin were obtained with 3.8% of mandelic acid. This product can be recycled after start of the release.

EXAMPLE 3b: Release of pregabalin to obtain crude (S) - pregabalin (step d)

Alternatively, the release of pregabalin was performed by loading 20.0 g of the salt of pregabalin and (S)- mandelic acid (III), 40 ml of water (2 volumes) and 8.6 g of 30% caustic soda (1 equivalent) in a 250 ml flask. It was heated to 70 °C obtaining a suspension and it was stirred for 2 minutes. It was then gradually cooled to 20°C. It was then cooled to 0-5°C in an ice bath. It was then stirred at 0°C for a minimum of 2 hours. It was plate filtered and the flask was washed. The solid was compacted and drained. It was finally washed four times with 30 ml of acetone. The solid obtained was dried in an air oven at 55°C and 8.7 g of crude (S ) -pregabalin (IV) was obtained in the form of white crystalline solid.

EXAMPLE 3c: Release of pregabalin to obtain crude (S)- pregabalin (step d)

The release of pregabalin was performed by loading 50.0 g of the salt of pregabalin and (S) -mandelic acid (III), 100 ml of water and 1250 ml of acetone in a 2 L flask. The reaction mixture was heated to 56-57°C and stirred for 25 minutes at said temperature. The suspension obtained was cooled slowly to 20-22°C during 1 hour and it was kept at said temperature for approximately one more hour. The solid obtained was filtered and washed with acetone. After drying it 22.0 g of crude (S ) -pregabalin (IV) were obtained in the form of white crystalline solid (<0.2% isomer R, 0% ash, 99.1% HPLC, crystalline form I). EXAMPLE 4 : Recovery of mandelic acid

The filtered organic phases were concentrated to a minimum volume. It was cooled to 0°C and stirred for a few hours. It was filtered and dried and 10.4 g of (+)-(S)- mandelic acid were obtained at 99% purity.

EXAMPLE 5: Crystallization of crude (S) -pregabalin (step e)

20.0 g of crude ( S ) -pregabalin (example 3), 96 ml of isopropanol and 72 ml of water were loaded in a 500 ml flask and it was heated until redissolution . It was filtered and the resulting solution was gradually cooled to 0°C. It was kept for 2 hours at 0-3°C, it was filtered and the solid was washed with isopropanol. The filtered solid was dried to obtain 18.3 g of (S) -pregabalin (IV) in the form of white crystalline solid (<0.1% isomer R, 0% ash, 99.4% HPLC) . The product corresponds to the crystalline form, form I (equivalent to the crystalline form of the originator marketed under the Lyrica® brand) with the XRPD shown in Figure 2. The DSC standard is also shown in Figure 3.

Claims

1. Method for the preparation of a salt (III) of pregabalin and (S) -mandelic acid with a (S,S) diastereomer content greater than 80% which comprises the following steps :

(a) Hofmann reaction of (±) -3- (carbamoylmethyl) -5- methylhexanoic acid (I) to obtain racemic pregabalin (ID ,

(b) addition of (S) -(+) -mandelic acid to obtain the corresponding diastereoisomeric salt (III) with a (S,S) diastereomer content greater than 80%

(II) (ΙΠ)

(c) optionally, purification of the salt obtained in step (b) ;

2. Method according to claim 1, wherein the reaction of step (a) is performed with sodium hypobromite.

3. Method according to any of the preceding claims, wherein steps (a) and (b) of the reaction are performed in the absence of organic solvents.

4. Method according to any of the preceding claims, wherein steps (a) and (b) of the reaction are carried out in aqueous medium.

5. Method according to any of the preceding claims, wherein step (c) is performed in water.

6. Method according to any of the preceding claims, wherein step (c) is performed without the addition of (S)- (+)-mandelic acid.

7. Method for the obtaining of (S) -pregabalin (IV) which comprises the obtaining of a salt of pregabalin and (S)- mandelic acid (III) with a (S,S) diastereomer content greater than 80% according to any of claims 1 to 6, followed by the following steps:

(d) the conversion of the salt obtained in step (c) in (S) -pregabalin (IV); and

(III) (IV) (e) optionally, purification of the (S ) -pregabalin .

8. Method according to claim 7, wherein step (d) is performed in water/isopropyl acetate.

9. Method according to claim 7, wherein step (d) is performed in aqueous sodium hydroxide.

10. Method according to claim 7, wherein step (d) is performed in water/acetone.

11. Method according to any of claims 7 to 10, wherein step (e) is performed by recrystallization in a mixture of isopropanol /water .

12. Method according to any of claims 7 to 10, wherein step (e) is performed by recrystallization only in water.