WO2013114315A1

WO2013114315A1 - Process and intermediates for the preparation of retigabine

Info

Publication number: WO2013114315A1
Application number: PCT/IB2013/050831
Authority: WO
Inventors: Davide Longoni; Samuele Frigoli; Marco Alpegiani
Original assignee: Olon S.P.A.
Priority date: 2012-02-02
Filing date: 2013-01-31
Publication date: 2013-08-08
Also published as: ITMI20120137A1

Abstract

A method for the preparation of retigabine starting with intermediate III is disclosed, comprising the step of protecting the secondary amine of III with a protecting group followed by N-ethoxycarbonylation of the primary amino group of the product obtained. The preparation of retigabine is completed by steps comprising removal of the protecting group and reduction of the nitro group to amino, which can be performed in any order or simultaneously. Novel intermediates usable with said method are also described.

Description

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF

RETIGABINE

Field of invention

The invention relates to a novel method of preparing retigabine and new synthetic intermediates usable with said method.

Background to the invention

Retigabine is a novel anticonvulsant discovered by Asta Medica.

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

RETIGABINE

The preparation of retigabine is described in DE4200259, which discloses three synthesis processes based on commercially available starting products, as shown in Scheme 1. Retigabine is isolated as the hydrochloride salt

EP0956281 claims three crystalline forms of retigabine and methods for their preparation.

Patent application WO03010134 claims the use of ethyl pyrocarbonate instead of ethyl chloroformate in the presence of a tertiary amine for the preparation of retigabine from benzotriamine IV (Scheme 1).

Evaluation of the synthesis methods described in the literature indicates that syntheses A and B shown in Scheme 1 are the most direct and efficient methods, as synthesis C is a multi-stage process with an unsatisfactory global yield which requires the use of a highly toxic reagent, namely hydrazine.

Experimental tests conducted by the present applicant on syntheses A and B described above have demonstrated two main critical factors associated with benzotriamine IV, namely its intrinsically low stability and poor selectivity in the N-ethoxycarbonylation reaction with either ethyl chloroformate or ethyl pyrocarbonate. As regards this last point, patent application WO201 1012659 states that the formation of impurity V, deriving from bis-ethoxycarbonylation of benzotriamine IV, is observed in some retigabine preparations

V

Synthesis routes A, B and C therefore seem unsuitable for industrial processes.

The Chemcats database reports the compound tert-butyl-N-(4-amino-3- nitrophenyl)-N-(4-fluorobenzyl)carbamate, having register number CAS 1 180525-23-1. The product corresponds to compound III being protected at the secondary amino group by the tert-butoxycarbonyl (BOC) group. However, the preparation and use of this product are unknown.

A product of N-glucuronidation of retigabine at the secondary amino group, l-[[3-amino-4-[(ethoxycarbonyl)-amino]phenyl][(4-fluorophenyl)- methyl]amino]-l-deoxy-p-D-glucopyranuronic acid, is described in Metabolism, Clinical and Experimental (2006), 55(6), 711-721 and in Xenobiotica (1997), 27(5), 431-441.

Description of the invention

It has surprisingly been found that by using intermediate III, which is more stable than intermediate IV, its secondary amino group can be selectively protected, thus allowing selective N-ethoxycarbonylation of the primary amino group. The subsequent removal of the protecting group on the secondary amine and the reduction of the nitro group, performed in any order, then provides retigabine. The synthesis sequence is illustrated in scheme 2

Scheme 2

The purpose of the present invention is therefore a process for the synthesis of retigabine which comprises the following steps:

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

ii) N-ethoxycarbonylation of VI to give VII, wherein P is as defined above; Hi) removal of 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 wherein P is as defined above, followed by

vi) removal of protecting group P of IX to give retigabine.

In one embodiment of the invention, retigabine is prepared by performing steps i), ii), Hi) and iv) in sequence.

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

In a preferred embodiment of the invention, when protecting group P is removable under the same conditions as used for the reduction of the nitro group, steps Hi) and iv) or steps v) and vi) can be performed simultaneously, enabling retigabine to be prepared in a single step starting with intermediate VII, as reported in Scheme 3

vn

Retigabine

Scheme 3

A further subject of the invention is retigabine obtained by the process according to the invention.

The compounds of formula VI, VII, VIII and IX, with the exception of compound VI, wherein P is a tert-butoxycarbonyl group, and with the exception of l-[[3-amino-4-[(ethoxycarbonyl)amino]phenyl][(4- fluorophenyl)methyl]-amino]- l-deoxy- β-D-glucopyranuronic acid, are novel, and therefore represent a further subject of the invention.

Detailed description of the invention

Group P can be any protecting group known to protect secondary amino groups. Examples of said groups are described by Philip Kocienski in "Protecting Groups", third edition, 2003, Georg Thieme Verlag, and by Theodora W. Greene and Peter G.M. Wuts in "Protective Groups in Organic Synthesis", fourth edition, 2006, Wiley. Examples of protecting groups comprise those wherein P, together with the nitrogen atom it is linked to, forms an amide, such as acetyl, chloroacetyl or trifluoroacetyl, or a carbamate, such as tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl or trichloroethoxycarbonyl. Tert-butoxycarbonyl, benzyloxycarbonyl and p- nitrobenzyloxycarbonyl are particularly preferred.

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

Processing of the reaction mixture typically involves partitioning 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 crystallisation. Product VI is obtained in high yields, typically exceeding 90%.

In some embodiments of the invention, such as when P is the tert- butoxycarbonyl (BOC) group, different conditions from those described above can be used. If tert-butyl dicarbonate is used as the 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 mixtures thereof, 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 conducted at a temperature of between 20°C and 100°C, for a time ranging from 1 to 24 hours. Ethyl chlorocarbonate is preferably added slowly to the reaction mixture. Pyridine can be used both as base and as reaction solvent. Processing of the reaction mixture typically involves partitioning 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 crystallisation. Compound VII is obtained with high yields, typically exceeding 90%.

The conditions for removal of protecting group P from VII to give VIII

(step Hi)) or from IX to give retigabine (step vi)) depend on the nature of P, and are well known to one skilled in the art. For example, those described by Philip Kocienski in "Protecting Groups", third edition, 2003, Georg Thieme Verlag, and by Theodora W. Greene and Peter G.M. Wuts in "Protective Groups in Organic Synthesis", fourth edition, 2006, Wiley, can be used.

Various reaction conditions well known to the skilled person can be used for the reduction of the aromatic nitro group of VII to give IX (step v)) or of VIII to give retigabine (step iv)). They include catalytic hydrogenation using Raney nickel or palladium or platinum oxide on an inert support; metals in acid media; sodium sulphide; sodium hydroxysulphite (dithionite) and sodium hypophosphite. Gaseous hydrogen or other hydrogen sources such as formic acid, cyclohexene, ammonium formate or triethylammonium formate can be used for the catalytic hydrogenation. When metals are used in acid media, zinc or iron is preferably employed.

VII can be converted to retigabine in a single step according to Scheme

3 when protective group P is labile under the conditions in which the aromatic nitro group is reduced, such as when the nitro group is reduced by catalytic hydrogenation and P is a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group. The hydrogenation can be conducted using gaseous hydrogen at the pressure of 1 to 3 bar in the presence of palladium on carbon in a solvent such as an alcohol, an ether or mixtures thereof, at temperatures of between 0°C and 50°C.

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

Retigabine is usually isolated by crystallisation, with yields exceeding

90% and HPLC purity greater than or equal to 99%. It can be isolated as free base or in the form of a salt with inorganic acids, for example as described in example 1 of US 5,383,330.

The invention will now be illustrated by the following examples.

Example 1 - Synthesis of VI (P = carbobenzoxy, CBZ)

In a suitable reactor, rendered inert with nitrogen, 7.7 g of intermediate III is dissolved at room temperature in 150 ml of dioxane and 5.9 ml of diisopropylethylamine is added. The solution is cooled to 20°C and 4.8 ml of benzyl chloroformate is dropped therein, maintaining the temperature at 20- 30°C. The reaction is monitored by HPLC until reagent III disappears.

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

The organic phase is concentrated to obtain 1 1.0 g of VI (P = CBZ) as oil (Yield = 95%).

Example 2 - Synthesis of VII (P = CBZ)

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

8.52 ml of diisopropylethylamine is added to the solution.

4.7 ml of ethyl chloroformate is dropped into the solution.

The solution is heated to 60-70°C and left under stirring for 8-12 hours. When the conversion has been completed (tested by HPLC), the reaction mixture is cooled to 25°C.

The reaction is quenched in a mixture consisting of 400 ml of 1 : 1 water/dichloromethane. The phases are separated and 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 retigabine

In a suitable reactor, 1 1.3 g of intermediate VII (P = CBZ) is dissolved at room temperature in 200 ml of a 2: 1 dioxane/ethanol mixture.

5.1 g of 5% palladium on carbon is added. The mixture is left under stirring in a hydrogen atmosphere (1 atm) for 8-12 hours, while the progress of the reaction is monitored by HPLC.

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

Claims

1. Process for the preparation of retigabine which comprises the following steps:

i) protection of the secondar amine of formula III

III

with a protecting group for secondary amino groups to give VI,

VI

wherein P is a protecting group for secondary amino groups;

ii) N-ethoxycarbonylation of VI to give VII,

VII wherein P is as defined above;

Hi) removal of the protecting group P from VII to give VIII,

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

IX

wherein P is as defined above, followed by

vi) removal of protecting group P of IX to give retigabine.

2. Process according to claim 1 wherein steps Hi) and iv) or steps v) and vi) are carried out at the same time.

3. Process according to claim 1 wherein P, together with the nitrogen atom which is linked to, forms an amide or a carbamate.

4. Process according to claim 3 wherein P is selected from the group consisting of acetyl, chloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trichloroethoxycarbonyl.

5. A compound of formula VI, VII, VIII or IX

VI VII VIII IX

wherein P is a protecting group for secondary amino groups, with the exception of the compounds tert-butyl-N-(4-amino-3-nitrophenyl)-N-(4- fluorobenzyl)carbamate and l-[[3-amino-4-[(ethoxycarbonyl)amino]- phenyl][(4-fluorophenyl)methyl]amino]-l-deoxy-B-D-glucopyranuronic acid.

6. A compound according to claim 5 wherein P is selected from the group consisting of acetyl, chloroacetyl, trifluoroacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and trichloroethoxycarbonyl.