MXPA06008333A - Method for producing a 2-(ethoxymethyl)tropane derivative - Google Patents

Abstract

The invention relates to a method for producing a 2-(ethoxymethyl)tropane derivative or a pharmaceutically acceptable salt thereof. The inventive is method is characterized by treating the corresponding 2-(hydroxymethyl)tropane derivative with ethyl bromide in the presence of a base, a phase transfer catalyst, and optionally a diluent and then optionally with an acid.

Description

PROCEDURE FOR THE PREPARATION OF A 2- (ETOXYMETHYL) TROPAN DERIVATIVE FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of a 2- (ethoxymethyl) -tropane derivative by reaction of a derivative of 2- ( hydroxymethyl) -tropane with ethyl bromide in the presence of a base and a phase transfer catalyst.

BACKGROUND OF THE INVENTION Derivatives of 2- (ethoxymethyl) -tropane are valuable pharmaceutical active ingredients for the treatment of various disorders of the central nervous system, such as, for example, Parkinson's or Alzheimer's disease. According to the teachings of the international patent application WO 97/30997, these compounds are prepared from a derivative of 2- (tosylmethyl) -tropane by reaction with ethoxide or by reaction of a derivative of 2- (hydroxyethyl) -tropane with sodium hydride as a base and diethyl sulfate. For safety reasons, it is hardly possible to carry out a production on a technical scale with the use of sodium hydride. Furthermore, this ethoxylation is hardly reproducible, runs with long reaction times and provides the active principle in the form of a solid which is difficult to isolate in unsatisfactory yields. Ref .: 173634 The underlying problem of the present invention, therefore, was proposed to indicate a procedure that would make it possible to prepare derivatives of 2- (ethoxymethyl) -tropane with good yields and at industrial scale and, thereby, avoid the drawbacks that appear in the known methods of the prior art.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly, it has now been found that 2- (ethoxymethyl) tropane derivatives of the formula (I) or a pharmaceutically acceptable salt thereof thereof. wherein R represents hydrogen or alkyl? -β, in particular methyl; and R2 represents phenyl optionally substituted once or several times with halogen, trifluoromethyl or cyano, in particular 3,4-dichlorophenyl; they can be prepared in good yields and on an industrial scale by reaction of a 2- (hydroxymethyl) tropane derivative of the formula (II), wherein R1 and R2 have the meaning indicated for formula (I), with ethyl bromide in the presence of a base, a phase transfer catalyst and optionally a diluent. The invention relates to an improved process for the preparation of a 2- (ethoxymethyl) -tropane derivative of the formula (I) or a pharmaceutically acceptable salt thereof, by reacting a 2- (hydroxymethyl) -tropane derivative of the formula (II) with ethyl bromide in the presence of a base, a phase transfer catalyst and, optionally, a diluent, and then optionally treated with an acid. Preferred embodiments of the process according to the invention are processes, in which: (A) as the base an alkali metal hydroxide is used, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, in particular potassium hydroxide in powder form; (B) the phase transfer catalyst (CTF) is used as a tetraalkylammonium or tetraalkylphosphonium salt, the respective alkyl groups being the same or different, such as, for example, tetraoctylammonium, methyltrioctylammonium, tetramethylammonium, tetraethylammonium, tetrahexylammonium salts, Aliquat 175, (tributylmethylammonium) or Aliquat 336 (methyltrioctylammonium). Preferably, the CTF is a tetraalkylammonium halide, a tetraalkylammonium sulfate, an acid tetraalkylammonium sulfate, a tetraalkylammonium nitrate or a tetraalkylammonium phosphate, in particular an acid tetraalkylammonium sulfate, very particularly preferably tetrahydric acid sulfate. n-butylammonium. The term "alkyl" as used above and below in relation to the phase transfer catalyst, embraces alkyl groups with 1 to 8, preferably 2 to 6., in particular 4 carbon atoms, straight chain and branched, Accordingly, as preferred alkyl groups can be mentioned the ethyl group, n-propyl, i-propyl, n-butyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, neo-pentyl, n-hexyl and 2-hexyl. The n-butyl group is very particularly preferred. Other preferred embodiments of the process according to the invention are processes, in which: (C) an aromatic hydrocarbon, preferably benzene, toluene or xylene, in particular toluene, or an optionally halogenated aliphatic hydrocarbon, preferably cyclohexane, is used as diluents. , methylcyclohexane, dichloromethane, chloroform, carbon tetrachloride or dichloroethane, in particular dichloromethane or an ether, preferably tetrahydrofuran (THF), diethyl ether, diisopropyl ether, tert-butyl methyl ether (TBME) or 1,2-dimethoxyethane (DME), in particular 1, 2-dimethoxyethane; (D) the reaction is carried out in a temperature range from -10 ° C to + 90 ° C, preferably from 0 ° C to 80 ° C, in particular from 20 to 65 ° C; (E) 0.75 to 100 equivalents, preferably 1.5 to 5.5 equivalents, in particular about 4 equivalents of ethyl bromide referred to 1 equivalent of a compound of the formula (II); (F) 2.5 to 100 equivalents are employed, preferably 3-8 to 10.5 equivalents, in particular 7.5 to 8.5, equivalents of base referred to 1 equivalent of a compound of the formula (II); (G) 0.01 to 0.5 equivalents are used, preferably 0.02 to 0.2 equivalents, in particular 0.05 to 0.15 equivalents of phase transfer catalyst referred to 1 equivalent of a compound of the formula (II); (H) After the reaction is complete, water is added to the reaction mixture, the phases are separated, the organic phase is washed with water, evaporated under reduced pressure and the. The residue is treated with an acid and the salt is isolated by addition of acids obtained; (I) the active ingredient of the formula is treated (I) obtained with a treated inorganic or organic acid. The resulting acid addition salts are, for example, hydrochlorides, hydrobromides, phosphates, nitrates, perchlorates, sulfates, citrates, lactates, tartrates, maleates, fumarates, mandelates, benzoates, ascorbates, cinnamates, benzenesulfonates, methanesulfonates, stearates, succinates. , glutamates, glucolates, toluene-p-sulfonates, formates, malonates, naphthalene-2-sulfonates, salicylates and acetates. Citrates are particularly preferred. Salts of this type are prepared in a manner corresponding to well-known preparation methods. In a particularly preferred embodiment, 4 equivivalents of ethyl bromide, optionally dissolved in 1,2-dimethoxyethane, are metered in with a stirring mixture, to a mixture based on 1 equivalent of a compound of the formula (II), approximately 20 times the amount by weight of 1,2-dimethoxyethane, referred to (II), about 8 equivalents of KOH and about 0.1 equivalents of tetra-n-butylammonium acid sulfate, in the space of 5 to 60 minutes at a temperature between 20 and 35 ° C.

Once the addition is complete, stirring is continued for 30 to 300, preferably approximately 45 to 180 minutes at a temperature between 40 and 80 ° C. Then water is added and stirred at the indicated temperature for another 30 to 300, preferably approximately 45 to 180 minutes, and then the organic phase is separated. The organic phase is concentrated and the residue is treated with acid, preferably citric acid. The acid addition salt of compounds of the formula (I) is isolated and dried. Other advantageous aspects of the procedure according to the invention are the high space-time yield in the present process, as well as the high yield and purity of the compound of the formula (I) or its salt obtained without further purification processes. The following Examples serve for the illustration of procedures, performed in an exemplary manner, for the preparation of a compound of the formula (I). They are to be understood only as possible ways of proceeding, represented in an exemplary manner, without limiting the scope of the invention to its content.

Example 1 Citrate (IR, 2R, 3S) -2-ethoxymethyl-3- (3,4-dicyanophenyl) -tropane To a mixture based on 10 g (0.0333 mol) of (1R, 2R, 3S) - 2-hydroxymethyl-3- (3,4-dichlorophenyl) -tropane prepared correspondingly to WO 97/30997), 14.92 g of powdered caustic potash (0.266 mol of KOH), 1.16 g (0, 00334 mol) of tetra-n-butylammonium hydrogen sulfate and 200 ml of DME are added, at a temperature between 20 and 31 ° C, and with stirring, 14.6 g (0.134 mol) of ethyl bromide in the space 15 minutes. After the addition is complete, stirring is continued for 1.5 hours at a temperature between 58 and 62 ° C. Then, 76 ml of water are added, the mixture is stirred for another hour at this temperature and the organic phase is separated. The organic phase is evaporated under reduced pressure in the rotary evaporator. The residue is dissolved with 90 ml of acetone at 55 ° C, filtered and continued to be washed with 10 ml of acetone. The solution obtained is treated with a mixture of 6.4 g (0.0333 mol) of citric acid and 20 ml of methanol at 40 ° C. The crystal suspension is cooled to 20 ° C and stirring is continued for one hour at 15 to 20 ° C. The crystals obtained are isolated and washed with 33 ml of acetone. After drying in the vacuum drying oven at 40 ° C, 14.55 g (83.6% of theory) are obtained with a purity of more than 99.4% of the title compound in the form of yellowish crystals.

Example 2 Citrate (IR, 2R, 3S) -2-ethoxymethyl-3- (3,4-dichlorophenyl) -tropane To a mixture based on 12 g (0.0400 mol) of (1R, 2R, 3S) - 2-hydroxymethyl-3- (3,4-dichlorophenyl) -tropane prepared correspondingly to WO 97/30997), 17.9 g of powdered caustic potash (0.320 mol of KOH), 1.39 g (0, 00409 mol) of tetra-n-butylammonium acid sulfate and 220 ml of DME are metered in, at a temperature between 20 and 31 ° C and with stirring, 17.5 g (0.161 mol) of ethyl bromide, dissolved in 20 ml of 1,2-dimethoxyethane, in the space of 15 minutes. After the addition is complete, stirring is continued for 1.5 hours at a temperature between 58 and 62 ° C. Subsequently, 76 ml of water are added, the mixture is stirred for another hour at this temperature and the organic phase is separated. The organic phase is evaporated under reduced pressure in the rotary evaporator. The residue is dissolved with 108 ml of acetone at 55 ° C, filtered and continued to be washed with 40 ml of acetone.

The solution obtained is treated with a mixture of 7.68 g (0.0400 mol) of citric acid and 24 ml of methanol at 40 ° C. The crystal suspension is cooled to 20 ° C and stirring is continued for one hour at 15 to 20 ° C. The obtained crystals are isolated and washed with at least 80 ml of acetone. After drying in the vacuum drying oven at 40 ° C, 17.44 g (83.85% of theory) are obtained with a purity of more than 99.5% of the title compound in the form of yellowish crystals. Comparative Example 1 Citrate of (IR, 2R, 3S) -2-ethoxymethyl-3- (3, -dichlorophenyl) tropane. (according to WO 97/30997) To a mixture based on (IR, 2R, 3S) -2-hydroxymethyl-3- (3,4-dichlorophenyl) tropane (26.9 g, 0.09 mol) and THF (200 ml) is added 60% sodium hydride in oil (4.6 g, 0.12 mol) and sulfate, ethyl (15.7 ml, 0.12 mol) and heated for half an hour to 30- 40 ° C. The reaction mixture is continued stirring at room temperature overnight, then heated for one hour at 30-40 ° C and poured into 500 mL of water. The mixture is extracted twice with TBDME, the organic phases are washed with water and dried over MgSO4. 32.82 g of the base are obtained. To a solution of (IR, 2R, 3S) -2-ethoxymethyl-3- (3, -dichloropheni) tropane, thus obtained, in 96% ethanol (275 ml) is added citric acid (19.2 g, 0, 1 mol). The solution is heated to reflux and allowed to stand for 3 hours at room temperature until crystallization. The mixture is placed half an hour on an ice bath, the crystalline product is filtered off and washed with 96% ethanol (50 ml and 25 ml). After drying 32.85 g (70% of theory) of the title compound having a melting point of 153-155 ° C are obtained. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (13)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Process for the preparation of a 2- (ethoxymethyl) -tropane derivative of the formula (I) or a pharmaceutically acceptable salt thereof. wherein R1 represents hydrogen or C6_6alkyl; and R2 represents phenyl optionally substituted one or more times with halogen, trifluoromethyl or cyano, characterized in that a derivative of 2- (hydroxymethyl) tropane of the formula (II), (ll) wherein R1 and R2 have the meaning indicated for formula (I), is reacted with ethyl bromide in the presence of a base, a phase transfer catalyst and optionally a diluent, and then , it is optionally treated with acid.

2. Process according to claim 1, characterized in that R1 represents methyl, and R2 represents 3,4-dichlorophenyl.

3. Method according to claim 1 or 2, characterized in that powdered potassium hydroxide is used as the base. .

Process according to one of claims 1 to 3, characterized in that a tetraalkylammonium or tetraalkylphosphonium salt is used as the phase transfer catalyst. 5. .

Process according to claim 4, characterized in that tetraalkylammonium acid sulfate is used as a phase transfer catalyst.

Method according to one of Claims 1 to 5, characterized in that an aromatic hydrocarbon and an optionally halogenated aliphatic hydrocarbon or an ether are used as the diluent.

7. Process according to claim 6, characterized in that toluene, dichloromethane or 1,2-dimethoxyethane are used as the diluent.

Method according to one of claims 1 to 7, characterized in that the reaction is carried out in a temperature range from -10 ° C to + 90 ° C- 9.

Method according to one of claims 1 to 8, characterized in that the ethyl bromide is metered in over a period of 5 to 180 minutes and the stirred mixture is stirred for a further 30 minutes. 180 minutes.

Method according to one of claims 1 to 9, characterized in that 0.75 to 100 equivalents of ethyl bromide are used, based on 1 equivalent of the formula (II).

Method according to one of claims 1 to 10, characterized in that 2.5 to 100 equivalents of base are used, based on 1 equivalent of formula (II).

Method according to one of claims 1 to 11, characterized in that 0.01 to 0.5 equivalents of phase transfer catalyst are used, based on 1 equivalent of formula (II).

13. Process for the preparation of a salt of a 2- (ethoxymethyl) -tropane derivative of the formula (I) according to one of claims 1 to 12, characterized in that after the reaction of the compound of the formula (II) has ended with ethyl bromide, water is added to the reaction mixture, the phases are separated, the organic phase is washed with water, concentrated under reduced pressure and the residue is treated with further purification, with the corresponding acid.