HUP0900790A2 - A new process for the preparation of piperazine and their hydrochloric salts - Google Patents

Description

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New process for the preparation of piperazine compounds and their hydrochloric acid salts

Subject of the invention ZZÉTE1 E14

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The invention relates to a new process for the synthesis of trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl}-urea compounds of general formula (I)

^R 2 (I) where R 1 and R 2 independently mean:

- hydrogen atom or

- a straight-chain or branched alkyl group having 1 to 6 carbon atoms, optionally substituted with an aryl group, or

- R1 and R2 together with the intervening nitrogen atom may form a saturated or unsaturated, optionally substituted monocyclic or bicyclic heterocyclic ring, which may contain further heteroatoms such as oxygen, nitrogen or sulfur, or

- a C2-C7 alkenyl group containing 1-3 double bonds, or

- a monocyclic, bicyclic or tricyclic aryl group, which may optionally be substituted with one or more C1-6 alkoxy groups, C1-6 trifluoro-(C1-6)-alkoxy groups, C1-6 alkoxycarbonyl groups, C1-6 alkanoyl groups, aryl groups, C1-6 alkylthio groups, halogen atoms or cyano groups, or

- for the preparation of an optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group and their hydrochloric acid salts and/or hydrates and/or solvates.

Description of the state of the art

The base form of the compounds of general formula (I) is described in Hungarian patent application No. P0302451. The document describes the salts of these compounds in general terms, and does not provide physical data for the individual salts.

Application P0302451 describes three methods for preparing the base form of compounds of general formula (I). According to method (A), the reaction of the appropriate amines with (thio)carbamoyl chloride results, among others, in the target compound family characterized by the general formula. According to the example of method (A), its efficiency is only 65% with a very long reaction time. The major disadvantage of the described method (B) is that only those compounds from the target compound family characterized by the general formula can be prepared in which one of the R1 or _R2 groups is definitely a hydrogen atom. According to method (C), the appropriate amine is converted with a phosgene derivative into an isocyanate compound, from which the target compounds can be obtained by addition of another amine compound. The efficiency of the method is also very low, only 52%.

The common disadvantage of both methods (A) and (C) is that they require a long reaction time (48 and 20 hours, respectively), low yield (65% and 52%), and additional purification steps (recrystallization) to obtain the product of appropriate quality.

Brief description of the invention

Our goal was to develop a process that would be equally suitable for the production of di-, mono- or unsubstituted urea compounds of general formula (I) in high yield.

Surprisingly, we found that if the compound of formula (III) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine

or its salt and/or hydrate and/or solvate with a carbonic acid derivative of the general formula (VI)

R-O-CO-Z (VI) where R is a straight or branched alkyl group having 1-6 carbon atoms, a partially or fully halogenated alkyl group having 1-2 carbon atoms or a phenyl group, Z is a -O-R or -X group, where R is as above, X is halogen, is reacted, then the compound of general formula (IV) is obtained

where R has the same meaning as above, which is obtained by reacting with the amine compound of general formula (V) ^R i 'nh /

^R 2 (V) where R 1 and R 2 independently mean:

- hydrogen atom or

- a straight-chain or branched alkyl group having 1-6 carbon atoms, optionally substituted with an aryl group, or

- Rt and _R2 together with the intervening nitrogen atom may form a saturated or unsaturated, optionally substituted monocyclic or bicyclic heterocyclic ring, which may contain further heteroatoms such as oxygen, nitrogen or sulfur, or

- a C2-C7 alkenyl group containing 1-3 double bonds, or

- a monocyclic, bicyclic or tricyclic aryl group, which may optionally be substituted with one or more C1-6 alkoxy groups, C1-6 trifluoro-(C1-6)-alkoxy groups, C1-6 alkoxycarbonyl groups, C1-6 alkanoyl groups, aryl groups, C1-6 alkylthio groups, halogen atoms or cyano groups, or

- optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group, which can be converted into a compound of general formula (I) with very good efficiency,

where R1 and _R2 have the same meanings as described above.

Detailed description of the invention

The present invention relates to a new process for the preparation of compounds of general formula (I)

where R1 and _R2 independently mean:

- hydrogen atom or

- a straight-chain or branched alkyl group having 1-6 carbon atoms, optionally substituted with an aryl group, or

- R1 and _R2 together with the intervening nitrogen atom may form a saturated or unsaturated, optionally substituted monocyclic or bicyclic heterocyclic ring, which may contain further heteroatoms such as oxygen, nitrogen or sulfur, or

- a C2-C7 alkenyl group containing 1-3 double bonds, or

- a monocyclic, bicyclic or tricyclic aryl group, which may optionally be substituted with one or more C1-6 alkoxy groups, C1-6 trifluoro-(C1-6)-alkoxy groups, C1-6 alkoxycarbonyl groups, C1-6 alkanoyl groups, aryl groups, C1-6 alkylthio groups, halogen atoms or cyano groups, or

- for the preparation of an optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group having 3-14 carbon atoms, and their hydrochloric acid salts and/or hydrates and/or solvates.

In the meaning of R1 and R2 _, the aryl group can mean, for example, a phenyl, tolyl, naphthyl, phenanthryl group.

In the process, the compound of formula (III) frans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}cyclohexylamine or its salt or hydrate or solvate is

Cl

H ₂ N' (III) is dissolved or suspended in an indifferent solvent in the presence of a base. Then, a carbonic acid derivative of the general formula (VI) is reacted with

R-O-CO-Z (VI) where R is a straight or branched chain alkyl group having 1-6 carbon atoms, a partially or fully halogenated alkyl group having 1-2 carbon atoms or a phenyl group, Z is a -O-R or -X group, where R is as defined above, X is halogen, reacting to obtain the compound of general formula (IV) o (IV) where R is as defined above.

The resulting compound of general formula (IV) is reacted with the amine compound of general formula (V) ^R i

NH where R1 and R2 have the same meanings as described above, or its solution in an indifferent solvent can be converted into a compound of general formula (I).

In the process according to the invention, indifferent, water-immiscible solvents can be used as solvents, such as toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention, dichloromethane is used as the solvent.

In the process according to the invention, organic bases can be used as bases, preferably tertiary amines, such as triethylamine.

In the process according to the invention, in the carbonic acid derivative of the general formula (VI), the partially halogenated alkyl group in the meaning of R may be chloromethyl or chloroethyl, and the fully halogenated alkyl group may be trichloromethyl or pentachloroethyl. In a preferred embodiment of the invention, chloroformic acid ester or bis-trichloromethyl carbonate is used as the carbonic acid derivative.

The process can be carried out by isolating the urethane compound of general formula (IV) and then reacting it with the amine of general formula (V). The urethane compounds of general formula (IV) are formed quantitatively, but due to their poor isolation efficiency, in a preferred embodiment of the process they are not isolated but are further reacted with the amine of general formula (V). In this case, the efficiency of the conversion of the compound of formula (III) via the urethane compound of general formula (IV) to the compound of general formula (I) is above 90%.

The advantages of the process according to the invention compared to the methods known from the literature are manifested in the fact that, on the one hand, the yield has been significantly improved from 52-65% to 95%, and on the other hand, not only N-monosubstituted compounds can be produced by the process.

During our work, we prepared the base of the compounds characterized by general formula (I) and their hydrochloric acid salts.

According to one embodiment of the process according to the invention, the reaction mixture is worked up by extraction with an organic solvent after dilution with water, from which the base of the compound of general formula (I) can be isolated by known methods, for example, it is preferably isolated by solvent removal.

According to a more preferred embodiment of the process according to the invention, the base is not isolated, but after dilution with water, instead of extraction, the reaction mixture is acidified with hydrochloric acid to pH=2-4, and then converted into an aqueous suspension by distillation. From the suspension, the hydrochloric acid salt of the compound of general formula (I) is isolated with high purity and with an efficiency of over 90%.

Examples

The invention is illustrated by the following examples without limiting our claims in any way to them.

Example 1

7-trans-N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-ylethyl)cyclohexyl)carbamic acid methyl ester

6.45 g (0.015 mol) of the dihydrochloride of the compound of formula (III) is mixed in a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 2.3 ml (0.03 mol) of methyl chloroformate prepared in 25 ml of dichloromethane at 5-10 °C. The reaction mixture is stirred at 20-25 °C for 3 hours, then extracted with 3x150 ml (150 g) of dist. water. The organic phase is evaporated in vacuo, the evaporation residue is crystallized from methanol

This procedure afforded 4.5 g of the title compound. Yield: 72%. Melting point: 143-147 °C

Example 2

7trans-N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yn-ethyl)cyclohexyl)carbamic acid isopropyl ester

6.45 g (0.015 mol) of the dihydrochloride of the compound of formula (III) is mixed in a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate prepared in 30 ml of toluene at 5-10 °C. The reaction mixture is stirred at 20-25 °C for 3 hours, then extracted with 3x150 ml (150 g) of dist. water. The organic phase is evaporated in vacuo, the evaporation residue is crystallized from isopropanol.

This procedure afforded 4.4 g of the title compound (yield: 67%).

Melting point: 128-13ΓΟ

Example 3

Trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yn-ethyl}-N,N-dimethylcarbamoylcyclohexylamine

6.45 g (0.015 mol) of the dihydrochloride of compound (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 40 ml (13 g/100 ml concentration) of dimethylamino IPA (0.12 mol) cooled to 0-(10) °C so that the temperature remains below 0 °C. After stirring for 30 minutes at 0-(-5) °C, 100 ml of dist. water is added to the reaction mixture while stirring, then cc. The pH of the aqueous phase is adjusted to 7-8 using HCl. The reaction mixture is evaporated to 130 ml in vacuo, another 70 ml of dist. water is added to the mixture and the volume is reduced to 170 ml in vacuo. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 6.6 g of the title compound. Yield: 95% Melting point: 208-211 °C

Example 4

Trans-4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl-ethyl)-N,N-dimethylcarbamoylcyclohexylamine

4.4 g (0.011 mol) of francs-N-(4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)carbamic acid methyl ester are dissolved in 120 ml of dichloromethane, the solution thus obtained is added to 100 ml (13 g/100 ml concentration) of dimethylamino IPA (0.3 mol) cooled to 0-(-10) °C so that the temperature remains below 0 °C. After stirring at 0-(-5) “Ορη for 30 minutes, 100 ml of dist. water is added to the reaction mixture while stirring, then the pH of the aqueous phase is adjusted to 7-8 using cc. HCl. The reaction mixture is evaporated to 100 ml in vacuo, an additional 70 ml of dist. Water is added to the mixture and the volume is reduced to 120 ml under vacuum. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 4.3 g of the title compound. Yield: 95% Melting point: 208-211 °C

Example 5

Trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl1-ethyl}-N,N-dimethylcarbamoylcyclohexylamine hydrochloride

6.45 g (0.015 mol) of the dihydrochloride of compound (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 40 ml (13 g/100 ml concentration) of dimethylamino IPA (0.12 mol) cooled to 0-(10) °C so that the temperature remains below 0 °C. After stirring for 30 minutes at 0-(-5) °C, 100 ml of dist. water is added to the reaction mixture while stirring, then cc. The pH of the aqueous phase is adjusted to 2-3 using HCl. The reaction mixture is evaporated to 130 ml in vacuo, another 70 ml of dist. water is added to the mixture and the volume is reduced to 170 ml in vacuo. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 6.7 g of the title compound.

Yield: 96 %

Example 6

Trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yn-ethyl)-N,N-dimethylcarbamoylcyclohexylamine hydrochloride

6.72 g (0.015 mol) of the dihydrochloride monohydrate of the compound of formula (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 40 ml (13 g/100 ml concentration) of dimethylamino IPA (0.12 mol) cooled to 0-(10) °C so that the temperature remains below 0 °C. After stirring for 30 minutes at 0-(-5) °C, 100 ml of distilled water is added to the reaction mixture while stirring. water is added, then the pH of the aqueous phase is adjusted to 2-3 using cc. HCl. The reaction mixture is evaporated to 130 ml in vacuo, another 70 ml of dist. water is added to the mixture and the volume is reduced to 170 ml in vacuo. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 6.7 g of the title compound. Yield: 96%. Melting point: 221-224 °C

Example 7

1-Trans-(4-{2-{4-(2,3-dichlorophenyl)piperazin-1-yne-ethyl}cyclohexyl}urea

6.45 g (0.015 mol) of the dihydrochloride of the compound of formula (III) is mixed in a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 75 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 110 ml (17 g/100 ml concentration) of ammonia in methanol cooled to 0-(-10) °C so that the temperature remains below 0 °C. After stirring for 30 minutes at 0(-5) °C, the reaction mixture is evaporated to 100 ml in vacuo, then 800 ml of dist. water is added to the reaction mixture. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 5.6 g of the title compound (yield: 94%).

Melting point: 221-224 °C

Example 8

Trans-N-{4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yn-ethyl}cyclohexyl)-N'-methylurea hydrochloride

6.45 g (0.015 mol) of the dihydrochloride of compound (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 60 ml (12.5 g/100 ml concentration) of methylamine IPA cooled to 0-(-10) °C so that the temperature remains below 0 °C. After stirring at 0(-5) °C for 30 minutes, 130 ml of dist. water is added to the reaction mixture while stirring, then cc. The pH of the aqueous phase is adjusted to 2-3 using HCl. The reaction mixture is evaporated to 120 ml in vacuo, an additional 70 ml of dist. water is added to the mixture. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 6.6 g of the title compound. Yield: 95%. Melting point: 230-255°C.

Example 9

Trans-N-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl1-ethyl}cyclohexylurea hydrochloride

6.45 g (0.015 mol) of the dihydrochloride of the compound of formula (III) is mixed in a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 75 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 110 ml (17 g/100 ml concentration) of ammonia in methanol cooled to 0-(-10) °C so that the temperature remains below 0 °C. After stirring for 30 minutes at 010 °C, the reaction mixture is evaporated to 20 ml in vacuo, then 140 ml of dist. water is added to the reaction mixture, then the pH of the aqueous phase is adjusted to 2-3 with cc. HCl. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 5.86 g of the title compound (yield: 90%).

Melting point: 250-253 °C (decomposes).

Example 10

Trans-N-{4-(2-[4-(2,3-dichlorophenyl)-DIDerazin-1-yl-ethyl}-cyclohexyl}-morpholine-4-carboxylic acid amide

6.45 g (0.015 mol) of the dihydrochloride of compound (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 10.44 g of morpholine (0.12 mol) prepared in 70 ml of IPA, cooled to 0-(-10) °C, so that the temperature remains below 0 °C. After stirring for 30 minutes at 010 °C, 100 ml of dist. water is added to the reaction mixture while stirring, then cc. The pH of the aqueous phase is adjusted to 7-8 with HCl. The reaction mixture is concentrated in vacuo to 130 ml, a further 100 ml of distilled water is added to the mixture and the volume is reduced in vacuo to 150 ml. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 6.55 g of the title compound. Yield: 93%. Melting point: 204-206°C (decomposition).

Example 11

Trans-N-f 4-(244-(2,3^ΐΗ0Γί6ηίΙ)-ρίρ6Γ3ζίη-1-ίΙ1-θΐΐΙ}-οϊΜοΐΊ6ΧΐΙ}-ΓηοΓίοΙίη-4carboxylic acid hydrochloride

6.45 g (0.015 mol) of the dihydrochloride of compound (III) is mixed in 125 ml of dichloromethane and 12.25 ml of triethylamine, the thick suspension is stirred at 20-25 °C for 1 hour. The suspension is added to a solution of 4.9 g of bis-(trichloromethyl)carbonate prepared in 50 ml of dichloromethane at -5-(-10) °C over 1 hour. The reaction mixture thus obtained is added to a solution of 10.44 g of morpholine (0.12 mol) prepared in 70 ml of IPA, cooled to 0-(-10) °C, so that the temperature remains below 0 °C. After stirring for 30 minutes at 010 °C, 100 ml of dist. water is added to the reaction mixture while stirring, then cc. The pH of the aqueous phase is adjusted to 2-3 using HCl. The reaction mixture is evaporated to 130 ml in vacuo, another 100 ml of dist. water is added to the mixture and the volume is reduced to 150 ml in vacuo. The suspension is stirred at 20-25 °C for 1 hour and the product is isolated by filtration.

This procedure afforded 7.1 g of the title compound (yield: 94%).

Melting point: 197 °C (decomposes).

Claims (3)

Requirements 1. Process (I) compounds where R1 and R2 independently mean: - hydrogen atom or - a straight-chain or branched alkyl group having 1-6 carbon atoms, optionally substituted with an aryl group, or - R1 and R2 together with the intervening nitrogen atom may form a saturated or unsaturated, optionally substituted monocyclic or bicyclic heterocyclic ring, which may contain further heteroatoms such as oxygen, nitrogen or sulfur, or - a C2-C7 alkenyl group containing 1-3 double bonds, or - a monocyclic, bicyclic or tricyclic aryl group, which may optionally be substituted with one or more C1-6 alkoxy groups, C1-6 trifluoro-(C1-6)-alkoxy groups, C1-6 alkoxycarbonyl groups, C1-6 alkanoyl groups, aryl groups, C1-6 alkylthio groups, halogen atoms or cyano groups, or - for the preparation of an optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group having 3-14 carbon atoms, and their hydrochloric acid salts and/or hydrates and/or solvates, characterized in that the compound of formula (III) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}cyclohexylamine or its salt or hydrate or solvate (III) dissolved or suspended in an indifferent solvent in the presence of a base with a carbonic acid derivative of the general formula (VI) R-O-CO-Z (VI) where R is a straight or branched alkyl group having 1-6 carbon atoms, a partially or fully halogenated alkyl group having 1-2 carbon atoms or a phenyl group, Z is a -O-R or -X group, where R is as above, X is halogen, reacting to obtain the compound of general formula (IV) where R has the same meaning as above, which is combined with the amine compound of general formula (V) ^{as R} i YlH / R ₂ where R 1 and R ₂ have the same meanings as described above, or by reacting with a solution thereof prepared in an indifferent solvent, the compound of general formula (I) is obtained. 2. The process according to claim 1, characterized in that the carbonic acid derivative of general formula (VI) is chloroformic acid ester or bis-trichloromethyl carbonate. 3. The process according to claim 1, characterized in that the compound of general formula (IV) is not isolated before reacting with the compound of general formula (V).