HK1097845B

HK1097845B - Method for producing a 2-(ethoxymethyl)tropane derivative

Info

Publication number: HK1097845B
Application number: HK07104270.6A
Authority: HK
Inventors: R．厄伦茨; O.梅尔; S.瓦格纳
Original assignee: 神经研究公司
Priority date: 2004-01-31
Filing date: 2005-01-20
Publication date: 2010-12-31

Description

Process for the preparation of 2- (ethoxymethyl) -tropane derivatives

The present invention relates to an improved process for the preparation of 2- (ethoxymethyl) -tropane derivatives by reacting a 2- (hydroxymethyl) -tropane derivative with bromoethane in the presence of a base and a phase transfer catalyst.

Background

2- (ethoxymethyl) -tropane derivatives are valuable pharmaceutical active substances for the treatment of various central nervous disorders, such as paralysis agitans or Alzheimer's disease.

This derivative is obtained either from a 2- (tosylmethyl) -tropane derivative by reaction with ethoxide or from a 2- (hydroxymethyl) -tropane derivative by reaction with sodium hydride and diethyl sulfate as bases, according to the teaching of international patent application WO 97/30997. From a safety point of view, the production using sodium hydride on an industrial scale is almost impossible. Furthermore, the ethylation is hardly reproducible because longer reaction times are experienced and the active substance is obtained in unsatisfactory yields as a solid which is difficult to separate.

It was therefore an object of the present invention to provide a process which makes it possible to prepare 2- (ethoxymethyl) -tropane derivatives in good yields on a large industrial scale and avoids the disadvantages of the processes known from the prior art.

Detailed Description

It has surprisingly been found that 2- (ethoxymethyl) -tropane derivatives of the formula (I), or a pharmaceutically acceptable salt thereof,

wherein

R¹Represents hydrogen or C_1-6Alkyl, especially methyl; and

R²represents phenyl optionally substituted one or more times by halogen, trifluoromethyl or cyano, in particular 3, 4-dichlorophenyl; by means of the 2- (hydroxymethyl) -tropane derivatives of the formula (II),

wherein R is¹And R²Having the definition as described for formula (I),

with bromoethane in the presence of a base, a phase transfer catalyst and optionally a diluent.

The subject of the present invention is therefore an improved process for the preparation of 2- (ethoxymethyl) -tropane derivatives of formula (I) or of pharmaceutically acceptable salts thereof, in which 2- (hydroxymethyl) -tropane derivatives of formula (II) are reacted with bromoethane in the presence of a base, a phase transfer catalyst and optionally a diluent, and are subsequently optionally treated with an acid.

A preferred embodiment of the process of the invention is a process wherein:

(A) as the base, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, particularly powdered potassium hydroxide;

(B) as phase transfer catalysts (PTK), tetraalkylammonium salts or tetraalkylphosphonium salts are used, where the individual alkyl groups can be identical or different, such as, for example, tetraoctylammonium, methyltrioctylammonium, tetramethylammonium, tetraethylammonium, tetrahexylammonium, Aliquat 175 (tributylmethylammonium) or Aliquat 336 (methyltrioctylammonium) salts. PTK is preferably a tetraalkylammonium halide, a tetraalkylammonium sulfate, a tetraalkylammonium hydrogen sulfate, a tetraalkylammonium nitrate or a tetraalkylammonium phosphate, in particular a tetraalkylammonium hydrogen sulfate, more particularly tetra-n-butylammonium hydrogen sulfate. The term "alkyl", as used above and below in relation to the phase transfer catalyst, includes straight and branched alkyl groups containing from 1 to 8, preferably from 2 to 6, especially 4, carbon atoms. Thus, mention may be made, as preferred alkyl groups, of ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, neopentyl, n-hexyl and 2-hexyl groups. N-butyl is more particularly preferred.

Another preferred embodiment of the process of the invention is a process wherein:

(C) as diluent, use is made of an aromatic hydrocarbon, preferably benzene, toluene or xylene, in particular toluene, or an optionally halogenated aliphatic hydrocarbon, preferably cyclohexane, 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 at a temperature in the range from-10 ℃ to +90 ℃, preferably from 0 ℃ to 80 ℃, in particular from 20 to 65 ℃;

(E) from 0.75 to 100 equivalents, preferably from 1.5 to 5.5 equivalents, in particular about 4 equivalents, of bromoethane are used, based on 1 equivalent of the compound of the formula (II);

(F) from 2.5 to 100 equivalents, preferably from 3.8 to 10.5 equivalents, in particular from 7.5 to 8.5 equivalents, of base are used, based on 1 equivalent of the compound of the formula (II);

(G) from 0.01 to 0.5 equivalent, preferably from 0.02 to 0.2 equivalent, in particular from 0.05 to 0.15 equivalent, of phase transfer catalyst, based on 1 equivalent of the compound of the formula (II);

(H) after the reaction, adding water to the reaction mixture, separating the phases, washing the organic phase with water, concentrating under reduced pressure, treating the residue with an acid, and isolating the resulting acid addition salt;

(I) treating the resulting active substance of formula (I) with an inorganic or organic acid. The resulting acid addition salts are, for example, the hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycolate, toluene-p-sulfonate, formate, malonate, naphthalene-2-sulfonate, salicylate and acetate salts. Citrate salts are particularly preferred. Such salts are prepared by corresponding well-known preparation methods.

In a particularly preferred embodiment, 4 equivalents of bromoethane, optionally dissolved in 1, 2-dimethoxyethane, are metered in with stirring into a mixture consisting of 1 equivalent of the compound of the formula (II), about 20 times the weight of 1, 2-dimethoxyethane, about 8 equivalents of KOH and about 0.1 equivalent of tetra-n-butylammonium hydrogensulfate, at a temperature of between 20 and 35 ℃ within 5 to 60 minutes. After the end of the addition, stirring is carried out at a temperature of between 40 and 80 ℃ for 30 to 300 minutes, preferably about 45 to 180 minutes. Subsequently water is added and stirring is carried out at said temperature for a further 30 to 300 minutes, preferably about 45 to 180 minutes, and the organic phase is then separated. The organic phase is concentrated and the residue is treated with an acid, preferably citric acid.

Isolating and drying the acid addition salt of the compound of formula (I).

Another advantageous aspect of the practice according to the invention is the high space-time yield and high yield and purity of the process, which leads to the compound of formula (I) or a salt thereof without further purification procedures.

The following examples serve to illustrate the processes carried out for the preparation of the compounds of formula (I). It should be understood that they have been presented by way of example only, and not limitation.

Example 1(1R, 2R, 3S) -2-ethoxymethyl-3- (3, 4-dichlorophenyl) -tropane citrate

14.6g (0.134Mol) of ethyl bromide are metered in, with stirring, over 15 minutes at a temperature of between 20 and 31 ℃ into a mixture of 10g (0.0333Mol) (1R, 2R, 3S) -2-hydroxymethyl-3- (3, 4-dichlorophenyl) -tropane (prepared according to WO 97/30997), 14.92g of powdered (0.266Mol KOH) caustic potash, 1.16g (0.00334Mol) tetra-n-butylammonium hydrogen sulfate and 200ml of DME.

After the end of the addition, the mixture was stirred for 1.5 hours at a temperature between 58 and 62 ℃. 76ml of water are subsequently added, stirring is carried out for a further 1 hour at this temperature and the organic phase is separated off. The organic phase is concentrated under reduced pressure in a rotary evaporator. The residue is dissolved in 90ml of acetone at 55 ℃, filtered and rinsed with 10ml of acetone. The resulting solution was treated with a mixture of 6.4g (0.0333Mol) citric acid and 20ml methanol at 40 ℃. The crystal suspension was cooled to 20 ℃ and stirred at 15 to 20 ℃ for 1 hour. The resulting crystals were separated and washed with 33ml of acetone. After drying at 40 ℃ in a vacuum drying oven, 14.55g (83.6% of theory) of the title compound are obtained in a purity of over 99.4% as yellow crystals.

Example 2(1R, 2R, 3S) -2-ethoxymethyl-3- (3, 4-dichlorophenyl) -tropane citrate

17.5g (0.161Mol) of bromoethane dissolved in 20ml of 1, 2-dimethoxyethane are metered into a mixture of 12g (0.0400Mol) (1R, 2R, 3S) -2-hydroxymethyl-3- (3, 4-dichlorophenyl) -tropane (prepared according to WO 97/30997), 17.9g of powdered (0.320Mol KOH) caustic potash, 1.39g (0.00409Mol) tetra-n-butylammonium hydrogen sulfate and 220ml of DME at a temperature between 20 and 31 ℃ over 15 minutes with stirring.

After the end of the addition, the mixture was stirred for 1.5 hours at a temperature between 58 and 62 ℃. 76ml of water are subsequently added, stirring is carried out for a further 1 hour at this temperature and the organic phase is separated off. The organic phase is concentrated under reduced pressure in a rotary evaporator. The residue was dissolved in 108ml of acetone at 55 ℃, filtered and washed with 40ml of acetone. The resulting solution was treated with a mixture of 7.68g (0.0400Mol) citric acid and 24ml methanol at 40 ℃. The crystal suspension was cooled to 20 ℃ and stirred at 15 to 20 ℃ for 1 hour. The resulting crystals were isolated and washed with at least 80ml of acetone. After drying at 40 ℃ in a vacuum drying oven, 17.44g (83.85% of theory) of the title compound are obtained in a purity of more than 99.5% as yellow crystals.

Comparative example 1(1R, 2R, 3S) -2-ethoxymethyl-3- (3, 4-dichlorophenyl) -tropane citric acid

(according to WO 97/30997)

To a mixture consisting of (1R, 2R, 3S) -2-hydroxymethyl-3- (3, 4-dichlorophenyl) tropane (26.9g, 0.09Mol) and THE (200ml) was added 60% sodium hydride in oil (4.6g, 0.12Mol) and ethyl sulfate (15.7ml, 0.12Mol) and heated at 30-40 ℃ for half an hour. The reaction mixture was stirred at room temperature overnight, then heated at 30-40 ℃ for 1 hour and poured into 500ml of water. The mixture was extracted twice with TBDME and the organic phase was washed with water and MgSO₄And (5) drying. 32.82g of base were obtained.

To a solution of the thus obtained (1R, 2R, 3S) -2-ethoxymethyl-3 (3, 4-dichlorophenyl) tropane in 96% ethanol (275ml) was added citric acid (19.2g, 0.1 mol). The solution was heated under reflux and left to stand at room temperature for 3 hours to crystallize. The mixture was placed on an ice bath for half an hour and the crystalline product was filtered and washed with 96% ethanol (50ml and 25 ml). After drying, 32.85g (70% of theory) of the title compound are obtained, melting point 153-155.5 ℃.

Claims

1. A process for the preparation of 2- (ethoxymethyl) -tropane derivatives of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

R¹Represents hydrogen or C_1-6An alkyl group; and

R²represents optionally substituted one or more times by halogen, trifluoromethyl or cyanoA phenyl group;

characterized in that 2- (hydroxymethyl) -tropane derivatives of formula (II)

Wherein R is¹And R²Having the definition as described for formula (I),

with bromoethane in the presence of a base which is lithium hydroxide, sodium hydroxide or potassium hydroxide and a phase transfer catalyst.

2. A process according to claim 1, characterized in that the 2- (hydroxymethyl) -tropane derivative of formula (II) is reacted with bromoethane in the presence of a base, a phase transfer catalyst and a diluent.

3. A process according to claim 1, characterized in that the compound of formula (II) is reacted with bromoethane and then treated with an acid.

4. A process according to any one of claims 1 to 3, wherein R is¹Represents a methyl group, and R²Represents 3, 4-dichlorophenyl group.

5. A process according to any one of claims 1 to 3, characterized in that powdered potassium hydroxide is used as the base.

6. A process according to any one of claims 1 to 3, characterized in that a tetraalkylammonium salt or a tetraalkylphosphonium salt is used as phase transfer catalyst.

7. A process according to claim 6, characterized in that tetraalkylammonium hydrogen sulfate is used as phase transfer catalyst.

8. A process according to any one of claims 1 to 3, characterized in that an aromatic hydrocarbon, optionally halogenated aliphatic hydrocarbon or an ether is used as diluent.

9. The process according to claim 8, characterized in that toluene, dichloromethane or 1, 2-dimethoxyethane is used as diluent.

10. A process according to any one of claims 1 to 3, characterized in that the reaction is carried out at a temperature in the range of-10 ℃ to +90 ℃.

11. A process according to any one of claims 1 to 3, characterized in that bromoethane is metered in over a period of from 5 to 180 minutes and the resulting reaction mixture is stirred for a further 30 to 180 minutes.

12. A process according to any one of claims 1 to 3, characterized in that from 0.75 to 100 equivalents of bromoethane are used, based on 1 equivalent of formula (II).

13. A process according to any one of claims 1 to 3, characterized in that 2.5 to 100 equivalents of base are used, based on 1 equivalent of formula (II).

14. A process according to any one of claims 1 to 3, characterized in that from 0.01 to 0.5 equivalents of phase transfer catalyst are used, based on 1 equivalent of formula (II).

15. Process for the preparation of salts of 2- (ethoxymethyl) -tropane derivatives of formula (I) according to any one of claims 1 to 3, characterized in that, after the end of the reaction of the compound of formula (II) with bromoethane, water is added to the reaction mixture, the phases are separated, the organic phase is washed with water and concentrated under reduced pressure, and the residue is treated with an acid without further purification.