ITMI20120137A1 - PROCEDURE AND INTERMEDIATE FOR THE PREPARATION OF RETIGABINE - Google Patents

Description

Description of the patent for industrial invention entitled:

â € œPROCESS AND INTERMEDIATES FOR THE PREPARATION OF RETIGABINAâ €

Field of invention

The invention relates to a new method for the preparation of Retigabine and new synthesis intermediates that can be used in said method.

Background of the invention

Retigabine is a new antiepileptic drug discovered by Asta Medica.

Its chemical name is ethyl N- [2-amino-4- (4-fluorobenzylamino) phenyl] -carbamate. The product has the following structural formula:

OO

NH

N NH

H2

F.

RETIGABINA

The preparation of Retigabine is described in DE4200259 where three synthesis procedures are reported starting from commercially available starting products, as shown in Scheme 1. Retigabine is isolated as a hydrochloride salt

NH2

Summary A N H N

O2N

NH2

<I> O2N II O2N III

NH2NH2Retigabine

F.

F F

F H N

Synthesis B H N H N

H2N

NO2

H2N H2N IV H2N

H N O

NO2NH2

O F F

NH2NH2

ON OO

Synthesis C N O

N H N

O2N

H N O H N O

O2N

O H N O H N O O O2N O2N

H N O H N O O O O O

Scheme 1

EP 0956281 claims three crystalline forms of Retigabine and methods for their preparation.

Patent application WO 03010134 claims the use of ethyl pyrocarbonate instead of ethyl chlorocarbonate in the presence of a tertiary amine for the preparation of Retigabine starting from benzotriamine IV (Scheme 1).

The evaluation of the synthesis methods described in the literature leads to consider the syntheses A and B reported in Scheme 1 as the most direct and efficient ones, since synthesis C is a multi-stage procedure having an unsatisfactory global yield and requiring the ™ use of a highly toxic reagent such as hydrazine.

Experimental tests carried out by the applicant of the present application on the syntheses A and B described above have highlighted two of their main critical points linked to benzenetriamine IV, namely its intrinsic poor stability and insufficient selectivity in the N-ethoxycarbonylation reaction both with chlorocarbonate of ethyl than with ethyl pyrocarbonate. As regards this last point, the patent application WO2011012659 reports that in some Retigabine preparations the formation of impurity V is observed, deriving from the bis-ethoxycarbonylation of benzenetriamine IV

OO

NH

N NH

H.

F <O> O

V.

The synthesis routes A, B and C therefore appear unsuitable for industrial processes.

The Chemcats database reports the compound (4-amino-3-nitrophenyl) - (4-fluorobenzyl) tert-butyl carbamate, having the register number CAS 1180526-23-1. The product corresponds to compound III protected to the secondary amino group with the tert-butoxycarbonyl group (BOC). However, the preparation and use of this product are not known.

An N-glucuronidation product of Retigabine to the secondary amino group, 1 - [[3-amino-4 - [(ethoxycarbonyl) -amino] phenyl] [(4-fluorophenyl) methyl] amino] -1-deoxy acid -β-D-glucopyranuronic acid, is described in Metabolism, Clinical and Experimental (2006), 55 (6), 721-721 and in Xenobiotica (1997), 27 (5), 431-441.

Description of the invention

It has been surprisingly found that by using the intermediate III, more stable than IV, it is possible to selectively protect its secondary amino group, thus allowing the selective N-ethoxycarbonylation of the primary amino group. The subsequent removal of the protective group on the secondary amine and the reduction of the nitro group, in whatever order they are performed, subsequently provide Retigabine. The synthetic sequence is illustrated in diagram 2

Scheme 2

The object of the present invention is therefore a process for the synthesis of Retigabine which includes the following steps:

i) protection of the secondary amine of III with a protecting group of secondary amino groups to give VI, in which P is a protecting group of secondary amino groups;

ii) N-ethoxycarbonylation of VI to give VII, where P is as defined above;

iii) removal of the protecting group P of VII to give VIII, followed by iv) reduction of the nitro group of VIII to give Retigabine; or

v) reduction of the nitro group of VII to give IX in which P is as defined above, followed by

vi) removal of the IX protecting group P to give Retigabine.

In one embodiment of the invention the Retigabina is prepared by carrying out in sequence the steps i), ii), iii) and iv).

In another embodiment of the invention the Retigabina is prepared by carrying out in sequence the steps i), ii), v) and vi).

In a preferred embodiment of the invention, when the protecting group P is removable under the same conditions used for the reduction of the nitro group, steps iii) and iv) or steps v) and vi) can be performed simultaneously, allowing the preparation of Retigabina in a single passage starting from intermediate VII, as reported in Scheme 3

Scheme 3

A further object of the invention is Retigabina obtained according to the process of the invention.

The compounds of formulas VI, VII, VIII and IX, with the exception of compound VI in which P is a tert-butoxycarbonyl group and with the exception of the acid 1 - [[3-amino-4- [(ethoxycarbonyl) amino] phenyl] [(4-fluorophenyl) methyl] -amino] -1-deoxy- β-D-glucopyranuronic, are new and therefore represent a further object of the invention.

Detailed description of the invention

The P group can be any protective group known for the protection of secondary amino groups. Examples of such groups are described in Philip Kocienski, â € œProtecting Groupsâ € third Edition, 2003, Georg Thieme Verlag, or in Theodora W. Greene and Peter G.M. Wuts in â € œProtective Groups in Organic Synthesisâ € fourth Edition, 2006, Wiley. Examples of protective groups include those in which P together with the nitrogen atom to which it is bonded forms an amide, for example acetyl, chloroacetyl, trifluoroacetyl, or a carbamate, for example tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trichloroethoxycarbonyl . Particularly preferred are tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl.

The reaction of III to give VI (step i)) can be carried out according to any of the various methods described in the literature for the protection of secondary amino groups. Generally the reaction is carried out by treating a solution of III in an aprotic organic solvent such as for example an ether, an ester, a carbonate, a hydrocarbon, or their mixtures, with an acylating agent in the presence of a base, typically a tertiary amine such as for example pyridine or diisopropylethylamine. Generally 1 to 2 molar equivalents of acylating agent are used per molar equivalent of III. The reaction is preferably carried out in a cyclic ether, for example dioxane, at a temperature between 0 ° C and 50 ° C for a time which can vary from 10 minutes to 24 hours.

The processing of the reaction mixture typically involves the partitioning of the reaction mass between water and an organic solvent, followed by washing of the organic phase with aqueous solutions, separation and concentration of the organic phase and optional isolation of VI by crystallization. Product VI is obtained in high yields, typically greater than 90%.

In some embodiments of the invention, when for example P is the tert-butoxycarbonyl group (BOC), conditions different from those described above can be used. If tert-butyl dicarbonate is used as acylating agent, protic solvents or aqueous mixtures can also be used in addition to the solvents described above, optionally in the presence of an organic or inorganic base.

The N-ethoxycarbonylation of VI to give VII (step ii)) is typically carried out in an aprotic organic solvent such as an ether, an ester, a carbonate, a hydrocarbon, or their mixtures, with ethyl chlorocarbonate in the presence of a base, preferably a tertiary amine such as pyridine or diisopropylethylamine. 1 to 2 molar equivalents of ethyl chlorocarbonate and base are used per equivalent of compound VI. The reaction is generally carried out at a temperature between 20 ° C and 100 ° C for a time that can vary from 1 hour to 24 hours. Preferably, ethyl chlorocarbonate is slowly added to the reaction mixture. Pyridine can be used both as a base and as a reaction solvent. The processing of the reaction mixture typically involves the partitioning of the reaction mass between water and an organic solvent, followed by washing of the organic phase with aqueous solutions, separation and concentration of the organic phase and optional isolation of VII by crystallization. Compound VII is obtained in high yields, typically greater than 90%.

The conditions for removing the protective group P from VII to give VIII (step iii)) or from IX to give Retigabine (step vi)) depend on the nature of P and are well known to those skilled in the art. We can use, for example, those described in Philip Kocienski, â € œProtecting Groupsâ € third Edition, 2003, Georg Thieme Verlag, or in Theodora W. Greene and Peter G. M. Wuts, â € œProtective Groups in Organic Synthesisâ € fourth Edition, 2006 , Wiley.

For the reduction of the nitro aromatic group of VII to give IX (step v)) or of VIII to give Retigabine (step iv)) various reaction conditions well known to those skilled in the art can be employed. These include catalytic hydrogenation using Raney nickel or palladium or platinum oxide on an inert support; metals in acid media; sodium sulfide; sodium hydrosulfite (dithionite) or sodium hypophosphite. In catalytic hydrogenation, both gaseous hydrogen and other sources of hydrogen, such as for example formic acid, cyclohexene, ammonium or triethylammonium formate, can be used. When using metals in acidic media, zinc or iron are preferably used.

The transformation of VII to Retigabine in a single step according to Scheme 3 can be achieved when the protective group P is labile under the conditions in which the nitro aromatic group is reduced, for example when the nitro group is reduced by catalytic hydrogenation and P Ã ̈ a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group. Hydrogenation can be carried out using gaseous hydrogen at a pressure of 1 to 3 bar in the presence of palladium on carbon in a solvent such as an alcohol, an ether or their mixtures at temperatures between 0 ° C and 50 ° C.

Reaction conditions that can be applied both to the reduction of the nitro group to amine and to the removal of the protective group P are, for example: sodium dithionite or sodium hypophosphite or sodium sulphide when P is p-nitrobenzyloxycarbonyl; zinc in acid solution when P is trichloroethoxycarbonyl or p-nitrobenzyloxycarbonyl.

Retigabine is generally isolated by crystallization in yields greater than> 90% and with HPLC purity greater than or equal to 99%. Its isolation can take place both as a free base and in the form of salt with inorganic acids, for example as described in example 1 of US patent 5,383,330.

The invention is now illustrated by the following examples.

Example 1 - Synthesis of VI (P = carbobenzyloxycarbonyl, CBZ) In a suitable reactor, inerted with nitrogen, 7.7 g of intermediate III are dissolved at room temperature in 150 ml of dioxane. 5.9 ml of diisopropylethylamine are added to the solution. It is cooled to 20 ° C and 4.8 ml of benzyl chloroformate are dropped into the solution, maintaining the temperature at 20 ° 30 ° C. The reaction is followed in HPLC until reagent III disappears.

The reaction is quenched in a mixture consisting of 500 ml of water / dichloromethane 1: 1. The phases are separated, the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water.

The organic phase is concentrated to obtain 11.0 g of VI (P = CBZ) as oil (Yield = 95%).

Example 2 - Synthesis of VII (P = CBZ)

In a suitable reactor, inerted with nitrogen, 7.4 g of intermediate VI (P = CBZ) are dissolved at room temperature in 170 ml of dioxane.

8.52 ml of diisopropylethylamine are added to the solution.

4.7 ml of ethyl chloroformate are dropped into the solution.

The mixture is heated to 60 ° 70 ° C and left under stirring for 8 ° 12 hours.

Once the conversion (control by HPLC) is completed, the reaction mixture is cooled to 25 ° C.

The reaction is quenched in a mixture consisting of 400 ml of water / dichloromethane 1: 1. The phases are separated, the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water.

The organic phase is concentrated to obtain 8.4 g of VII (P = CBZ) as oil (Yield = 92%).

Example 3 - Synthesis of Retigabina

In a suitable reactor, 11.3 g of intermediate VII (P = CBZ) are dissolved at room temperature in 200 ml of a 2: 1 dioxane / ethanol mixture.

5.1 g of 5% palladium on carbon are added. It is left under stirring under a hydrogen atmosphere (1 atm) for 8-12 hours following the course of the reaction by HPLC.

The catalyst is removed from the reaction mixture by filtration. The filtrate is evaporated to dryness to obtain crude retigabine which is purified by chromatography on silica using ethyl acetate / n-heptane mixtures as eluent. The product is isolated from acetate / n-heptane obtaining 6.6 g of Retigabine (yield 90%) with 99.5% purity.

Claims (7)

CLAIMS 1. Procedure for the preparation of Retigabina which includes the following steps: i) protection of the secondary amine of III F. H N O2N NH2 III with a protecting group of secondary amino groups to give VI, F. P. No. O2N NH2 YOU in which P is a protecting group of secondary amino groups; ii) N-ethoxycarbonylation of VI to give VII, F. P. No. O2N H N O OR VII where P is as defined above; iii) removal of the protecting group P of VII to give VIII, F. H N O2N H N O OR VIII followed by iv) reduction of the nitro group of VIII to give Retigabine; or, v) reduction of the nitro group of VII to give IX F. P. No. H2N H N O OR IX where P is as defined above, followed by vi) removal of the IX protecting group P to give Retigabine. 2. Process according to claim 1 wherein steps iii) and iv) or steps v) and vi) are performed simultaneously. 3. Process according to claim 1 wherein P, together with the nitrogen atom to which it is bonded, forms an amide or a carbamate 4. Process according to claim 3 wherein P is selected from the group of acetyl, chloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trichloroethoxycarbonyl. 5. Retigabine obtained according to the process of claims 1-4. 6. A compound of formula VI, VII, VIII or IX F F F F. P P N H N N P N O2N O2N H2N O N H N O H N O H N O 2 NH2O O O VI VII VIII IX in which P is a protecting group of secondary amino groups, with the exclusion of the compounds (4-amino-3-nitrophenyl) - (4-fluorobenzyl) -carbamate of tert-butyl and of the acid 1 - [[ 3-amino-4 - [(ethoxycarbonyl) -amino] phenyl] [(4-fluorophenyl) methyl] amino] -1-deoxy-β-D-glucopyranuronic. 7. A compound according to claim 6 wherein P is selected from the group of acetyl, chloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trichloroethoxycarbonyl. Milan, February 2, 2012