HK1161587B - Piperazine salt and a process for the preparation thereof - Google Patents

Description

Piperazine salts and process for their preparation

Technical Field

The present invention relates to novel trans {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate and a process for its preparation.

Background

Trans {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl according to the invention]-Ethyl } -cyclohexylamine dihydrochloride monohydrate prepared by the process of the invention₃/D₂Key intermediates for a number of compounds of the receptor. Similar compounds are described in hungarian patent specifications nos. P0103988 and P0302451 and bioorg.med.chem.lett.en; 7; 18; 19972403-.

Hungarian patent specification No. P0103988 discloses a reaction route for the preparation of trans {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride. According to the preparation described in example 1, 2, 3-dichlorophenyl-piperazine and trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetaldehyde were dissolved and coupled in dichloromethane in the presence of sodium triethoxyborohydride to give trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexyl } -carbamic acid tert-butyl ester. The protecting group was then removed with hydrochloric acid in ethyl acetate according to the method described in example 2. The yield data for trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexyl } -carbamic acid tert-butyl ester or trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexyl } -amine dihydrochloride are not described.

A disadvantage of the above process is that when trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetaldehyde is prepared from the corresponding trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetic acid ester, the reaction can be carried out at temperatures below 70 ℃ with only 55% yield (Stemp et al, J.Med.chem.2000.Vol.43, No.9, p.7878-7885). However, the use of the above-mentioned operating temperatures and the very dangerous diisobutylaluminium hydride means that there are technical problems on an industrial scale, and therefore the reaction can only be carried out in additional equipment and under extreme conditions.

Disclosed in bioorg.med.chem.lett.en; 7; 18; the method in 19972403-2408 consists of eight reaction steps, the compounds are mentioned only in general, without any characterizing features. The eight step process appears to be cumbersome, costly and dangerous, especially when performed on an industrial scale.

Our aim was to provide a safe and easily controlled industrial scale process for the preparation of trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine key intermediate, by which it can be prepared in good yield via simple reaction steps without the use of extreme reaction conditions and additional equipment.

Summary of The Invention

During our experiments we have surprisingly found that starting from trans 2- {1- (4-N- [ tert-butoxycarbonyl ] -amino) -cyclohexyl } -acetate and using the economical process according to the invention, trans 4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate can be prepared in high purity on an industrial scale in four easily carried out and economical synthetic steps, all of which are carried out in good yield.

Trans 2- {1- (4- [ N-tert-butoxycarbonyl ] -amino) -cyclohexyl } -acetic acid ester was quantitatively converted into trans-2- {1- [4- (N-tert-butoxycarbonyl ] ] -amino ] -cyclohexyl } -ethanol by using sodium borohydride and aluminum trichloride in the first reaction step in the next reaction step, trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol obtained in step 1 was reacted with methanesulfonyl chloride to give a methanesulfonyl ester (mesylester), which was then reacted with 2, 3-dichlorophenyl piperazine in the presence of an acid-binding agent in the last step, the protecting group is removed in a mixture of water/hydrochloric acid/methanol under simple reaction conditions at a temperature of 40-100 ℃ to give trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate in very high purity and good yield.

Detailed Description

In a first reaction step trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetic acid ester was converted into trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol. It is well known to those skilled in the art that the above reaction can be carried out only at low temperatures (-40 ℃) and in the presence of very dangerous lithium aluminium hydride. In our experiments we have surprisingly found that trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol is obtained in almost quantitative yield when the reaction is carried out in the presence of sodium borohydride and aluminium trichloride in an ether solvent, such as THF, at a temperature of 0-30 ℃, preferably 5-25 ℃.

In a second reaction step, trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol obtained in step 1 was treated with methanesulfonyl chloride in the presence of an acid-binding agent to give a methanesulfonyl ester. Optionally, the reaction can be carried out without isolation of the starting trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol. Suitable acid binders that can be used in this reaction step include inert organic bases, preferably inert organic amines, more preferably triethylamine. Suitable solvents which may be used include inert water-immiscible solvents such as toluene, dichloromethane, chlorobenzene or xylene, preferably dichloromethane. The efficiency of the reaction is almost quantitative.

In the next step, trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethyl methanesulfonate was reacted with 2, 3-dichlorophenyl-piperazine in the presence of an acid binding agent to give trans {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -carbamic acid tert-butyl ester. As an optional route, the reaction can be carried out without isolation of the starting trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethyl methanesulfonate. As the acid-binding agent, an alkali metal base such as an alkali metal carbonate (alkalicarbonate), preferably potassium carbonate, is used. Suitable solvents that may be used in this reaction step include inert water-immiscible solvents such as toluene, dichloromethane, chlorobenzene or xylene, preferably dichloromethane. The yield is higher than 80%.

In a preferred embodiment of the present invention, the above three reaction steps are reduced to one step, and the reaction is carried out in one reaction vessel without isolating the intermediate compound. In this case, it is not necessary to clean the apparatus in the costly separation step. In this way, the overall yield is higher than 70% based on the starting materials, thus increasing the economic efficiency of the process.

In the last reaction step, the N-tert-butoxycarbonyl protecting group is removed in a mixture of aqueous hydrochloric acid and methanol at a temperature of 40-400 c, preferably 45-50 c, to give a crystalline product which is identified as the novel dihydrochloride monohydrate of trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexyl } -amine. We have surprisingly found that carrying out the reaction in the presence of water gives trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexyl } -amine dihydrochloride monohydrate in almost quantitative yield of more than 99% in high purity.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetic acid ester

A500 ml four-necked flask was charged with 40g (0,18mol) of trans 2- [1- (4-amino group)]-cyclohexyl) -acetic acid ethyl ester and 160ml dichloromethane, then 18,2g (0,18mol) triethylamine are added. The resulting reaction mixture was cooled to a temperature of 5-10 ℃ and then a solution of 40,0g (0,18mol) of di (tert-butyl) dicarbonate in 100ml of dichloromethane was added under nitrogen for 1 hour while stirring. The reaction mixture was then warmed to room temperature and stirred until the reaction proceeded. After the reaction was complete, 100g of 5% aqueous sodium carbonate were added and the phases were separated. Washing with 50ml of waterOrganic layer, after separation, with Na₂SO₄The organic layer was dried and the filtrate was concentrated in vacuo to 40 ml. The resulting concentrated crystalline suspension was poured into a large tray and dried under infrared lamp at up to 35 ℃.

In this way 47,9g of the title compound are obtained.

Yield: 93 percent

Melting point: 73-74 ℃.

Example 2

Preparation of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } ethanol

A500 ml four-necked flask was charged with 40g (0,18mol) of trans 2- [1- (4-amino group)]-cyclohexyl) -acetic acid ethyl ester hydrochloride and 160ml dichloromethane. To the resulting suspension 18,2g (0,18mol) of triethylamine were added. The resulting reaction mixture was cooled to a temperature of 8-10 ℃ and a solution of 40,0g (0,185mol) of di (tert-butyl) dicarbonate in 100ml of dichloromethane was added under nitrogen for 1 hour while stirring. The reaction mixture is then heated to a temperature of 22-25 ℃ and stirred until the reaction has proceeded. After the reaction was complete, 100g of 5% aqueous sodium carbonate were added and the phases were separated. The organic layer was extracted with 50ml of water and after separation, Na was added₂SO₄The organic layer was dried and the filtrate was concentrated in vacuo. The resulting trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino group]-cyclohexyl } -acetic acid ethyl ester was dissolved in 460ml of tetrahydrofuran and 13,68g (0,36mol) of sodium borohydride were added at 25 ℃ under nitrogen. To this reaction mixture was added dropwise, under nitrogen and at a temperature of 18-22 ℃ under stirring, a solution of 24,0g (0,18mol) of aluminum chloride in 250ml of anhydrous tetrahydrofuran for 1 hour, and the mixture was then stirred for a further 2 hours. After the reaction was complete, the mixture was cooled to a temperature of 5-10 ℃ and 650ml of water and 600ml of toluene were added. Then, the pH is adjusted to 3-4 by adding 40-45ml of concentrated hydrochloric acid and continuously stirring at a temperature of 20-25 ℃After stirring for 1 hour, the phases were separated, the aqueous layer was extracted with 50ml of toluene, the combined organic layers were washed with 3 × 150ml of water and dried in vacuo.

In this way, 41,1g of the title compound are obtained.

Yield: 94 percent of

Melting point: 101-103 ℃.

Example 3

Preparation of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } ethyl methanesulfonate

37g (0,15mol) of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol are dissolved in 360ml of dichloromethane at a temperature of 20-25 ℃ with stirring and 19,6g (0,19mol) of triethylamine are added. The resulting solution was cooled to a temperature of 0-5 ℃ and a solution of 40,0g (0,185mol) of di (tert-butyl) dicarbonate in 100ml of dichloromethane was added dropwise for 1 hour. Stirring was then continued for a further 1 hour while maintaining the temperature at 0-5 ℃ and the pH at 8-9 by addition of triethylamine. After completion of the reaction, 450ml of water was added and after stirring for 15 minutes, the phases were separated. The aqueous phase is extracted with 30ml of dichloromethane, then the combined organic phases are washed with 3X 300ml of water and the dichloromethane solution is concentrated in vacuo.

In this way, 46,2g of the title compound are obtained.

Yield: 90 percent of

Melting point: 112 ℃ and 113 ℃.

Example 4

Preparation of trans-N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine

48g (0,15mol) of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethyl methanesulfonate were suspended in 800ml of acetonitrile. To the resulting suspension were added 75g (0,28mol) of 1-2, 3-dichlorophenyl) piperazine hydrochloride and 71,8g (0,56mol) of potassium carbonate, and the reaction mixture was heated under reflux and stirred for 15 to 17 hours. After the reaction was complete, the mixture was cooled to a temperature of 45-50 ℃ and 900ml of water was added. The temperature was allowed to reach room temperature with stirring and stirring was continued for a further 1,5 hours. The isolated product was filtered and washed with water until neutral pH. Then, 400ml of water and 7ml of concentrated hydrochloric acid solution were added, and the mixture was stirred at a temperature of 20-25 ℃ for 2 hours, filtered, and then washed with 15-20ml of water. To the crude product obtained 540ml of acetonitrile were added and the reaction mixture was heated under reflux and stirred for 15 minutes. The mixture was cooled to a temperature of 0-5 ℃ and stirring was continued for 1 hour while maintaining the temperature at that level. The precipitated product was filtered, washed with 10ml of cold acetonitrile and dried.

In this way 54,7g of the title compound are obtained.

Yield: 80 percent of

Melting point: 150 ℃ and 154 ℃.

Example 5

Preparation of trans-N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine

A1 l four-necked round-bottomed flask was charged with 42,9g (0,15mol) of trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetic acid ethyl ester and 400ml of tetrahydrofuran under nitrogen at a temperature of 25 ℃ and to the resulting solution was added 11,4g (0,3mol) of sodium borohydride. To the stirred reaction mixture was added dropwise a solution of 20,0g (0,15mol) of aluminum chloride in 225ml of anhydrous tetrahydrofuran at a temperature of 18-22 ℃ under nitrogen for 1 hour, and then stirring was continued for a further 2 hours. After the reaction is complete, the mixture is cooled to a temperature of 5-10 ℃, 650ml of water are added, followed by 450ml of toluene, and the pH is adjusted to 3-4 by adding 30-40ml of concentrated hydrochloric acid. Stirring was continued for 1 hour at a temperature of 20-25 ℃. The phases were separated, the aqueous layer was extracted with 50ml of toluene, the combined organic layers were washed with 3X 150ml of water and concentrated in vacuo to a volume of about 50 ml. To this concentrated stirred solution 360ml of dichloromethane and 19,6g (0,19mol) of triethylamine are added at a temperature of 20-20 ℃. The solution is then cooled to a temperature of 0-5 ℃ and a solution of 19,7g (0,17mol) of methanesulfonyl chloride in 90ml of dichloromethane is added dropwise over 1 hour and the reaction mixture is stirred for a further 1 hour. The pH was maintained at 8-9 by addition of triethylamine. After the reaction was completed, 450ml of water was added and the mixture was stirred for 15 minutes, after which the phases were separated. The aqueous layer was extracted with 30ml of dichloromethane and then the combined organic layers were washed with 3X 300ml of water. The dichloromethane solution was concentrated under vacuum to a volume of about 70ml, then 900ml of acetonitrile was added and under vacuum, about 80-100ml of solvent was distilled off. The resulting residue is cooled to a temperature of 20-25 ℃ and 75g (0,28mol) of 1- (2, 3-dichlorophenyl) -piperazine hydrochloride and 71,8g (0,56mol) of potassium carbonate are added, after which the mixture is heated under reflux and stirred for 15-16 hours. After the reaction was complete, the mixture was cooled to a temperature of 45-50 ℃, 900ml of water was added, and the stirred mixture was then cooled to room temperature. Stirring was continued for a further 1.5 hours, during which time the temperature was maintained at this level. The resulting product was filtered off, washed with water until the pH was neutral, and then a solution of 400ml of water and 7ml of concentrated hydrochloric acid was added. After stirring at a temperature of 20-25 ℃ for 2 hours, the resulting product was filtered and washed with water. To the crude product obtained 540ml of acetonitrile was added and the mixture obtained was heated under reflux and stirred for 15 minutes and then cooled to a temperature of 0-5 ℃. Stirring was continued for another 1 hour, maintaining the temperature at 0-5 ℃. The precipitated product was filtered off and washed with 10ml of cold acetonitrile before drying.

In this way, 51,3g of the title compound are obtained.

Yield: 75 percent of

Melting point: 150 ℃ and 154 ℃.

Example 6

Preparation of trans-N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine

A500 ml four-necked round-bottomed flask was charged with 40g (0.18mol) of trans 2- [1- (4-aminocyclohexyl) -acetic acid ethyl ester hydrochloride and 160ml of dichloromethane, and to the resulting suspension was added 18.2g (0.18mol) of triethylamine. The resulting mixture was cooled to a temperature of 0-10 ℃ and a solution of 40.0g (0.185mol) of di (tert-butyl dicarbonate) in 100ml of dichloromethane was added under nitrogen and stirring for 1 hour. The reaction mixture is then heated to a temperature of 20-25 ℃ and stirring is continued until the reaction has proceeded. After the reaction was completed, 100g of a 5% aqueous sodium carbonate solution was added, and thereafter, the phases were separated. The organic layer was extracted with 50ml of water and, after separation, over Na₂SO₄The organic layer was dried and the solvent was removed under vacuum.

The resulting trans 2- {1- [ N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -acetic acid ethyl ester was dissolved in 468ml of tetrahydrofuran and 13.68g (0,36mol) of sodium borohydride were added at a temperature of 25 ℃ under nitrogen. To the stirred reaction mixture was added dropwise a solution of 24.0g (0.18mol) of aluminum chloride in 270ml of anhydrous tetrahydrofuran at a temperature of 18-22 ℃ over a period of 1 hour, and stirring was continued for about 2 hours. The reaction mixture is then cooled to a temperature of 5-10 ℃, 650ml of water and 600ml of toluene are added and the pH is adjusted to 3-4 by adding concentrated hydrochloric acid. After stirring at a temperature of 20-25 ℃ for 1 hour, the phases were separated and the aqueous layer was extracted with 50ml of toluene. The combined organic extracts were washed with 3 × 150ml of water and the mixture was concentrated to a volume of 60ml under vacuum. To the stirred concentrated solution, 430ml of dichloromethane and 23.5g (0.23mol) of triethylamine are added at a temperature of 20-25 ℃. The resulting solution is cooled to a temperature of 0-5 ℃ and a solution of 23.6g (0.2mol) of methanesulfonyl chloride in 110ml of dichloromethane is added dropwise over 1 hour. The reaction mixture was stirred for 1 hour while maintaining the temperature at 0-5 ℃. The pH was maintained at 8-9 by addition of triethylamine. After the reaction was complete, 500ml of water were added and after stirring for 15 minutes the phases were separated. The aqueous layer was extracted with 50ml of water and the combined organic layers were washed with 3X 300ml of water. The dichloromethane solution was concentrated to a volume of about 80ml under vacuum, 1l of acetonitrile was added, and then about 80-100ml of the solvent was distilled under vacuum. The resulting mixture is cooled to a temperature of 20-25 ℃ and 80g (0.3mol) of 1- (2, 3-dichlorophenyl) -piperazine and 82.8g (0.6mol) of potassium carbonate are added. The reaction mixture was heated to reflux and stirred for 15-17 hours. The mixture was then cooled to 45-50 ℃, 1l of water was added with stirring, the mixture was cooled to room temperature and stirring was continued for 1.5 hours. The precipitated product was filtered, washed with water until the pH was neutral, and a solution of 400ml of water and 7ml of concentrated hydrochloric acid was added. The resulting mixture was stirred at a temperature of 20-25 ℃ for 2 hours, the product was filtered and washed with water. To the crude product obtained 600ml of acetonitrile was added and the mixture obtained was stirred under reflux for 15 minutes, then cooled to 0-5 ℃ and stirred for a further 1 hour. The precipitated product was filtered, washed with 10ml of cold acetonitrile and dried.

In this way 57,5g of the title compound are obtained.

Yield: 70 percent of

Melting point: 150 ℃ and 154 ℃.

Example 7

Preparation of trans 4- {2- [ - (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate

A500 ml 3-neck round-bottom flask was charged with 22g (0,05m01) of trans N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine and 150ml ethanol. To this stirred mixture, a solution of 37,2ml of concentrated hydrochloric acid in 113ml of water was added and the mixture was heated to a temperature of 45-50 ℃ and stirring was continued for 2 hours while maintaining the same temperature. After the reaction was completed, 120-140ml of aqueous methanol was distilled off, and the resulting mixture was cooled to room temperature and further cooled to a temperature of 5-10 ℃ with stirring, and stirring was continued at the same temperature for 1 hour. The precipitated product was filtered and dried.

In this way, 21,5g of the title compound are obtained.

Yield: 94 percent of

Melting point: above 310 deg.C (decomposition).

Claims (6)

1. Process for the preparation of trans N- {4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate, characterised in that

a) Reacting trans 2- {1- [4- (N-tert-butoxycarbonyl) amino ] -cyclohexyl } -acetic acid ester with sodium borohydride and aluminum trichloride to give trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol;

b) reacting the resulting trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethanol with methanesulfonyl chloride in the presence of an acid binding agent to give trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethyl methanesulfonate;

c) reacting the resulting trans 2- {1- [4- (N-tert-butoxycarbonyl) -amino ] -cyclohexyl } -ethyl methanesulfonate with 2, 3-dichlorophenyl-piperazine in the presence of an acid binding agent to give trans N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine;

d) the resulting trans N-tert-butoxycarbonyl-4- {2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl } -cyclohexylamine was heated to a temperature of 40-100 ℃ in an aqueous hydrochloric acid/methanol mixture to give trans N- {4- {2- [4- (2, 3-dichlorophenyl) piperazin-1-yl ] -ethyl } -cyclohexylamine dihydrochloride monohydrate.

2. Process according to claim 1, characterized in that steps a) and b) are carried out without isolation of the resulting intermediate compound.

3. The process according to claim 1, characterized in that in step b) an organic amine is used as acid binder.

4. A process according to claim 3, characterized in that in step b) triethylamine is used as acid binding agent.

5. The process according to claim 1, characterized in that in step c) alkali metal carbonates are used as acid binding agents.

6. The process according to claim 1, characterized in that in step d) the heating is carried out at a temperature of 45-50 ℃.