CA1038866A - Process for the production of 4-(3-(10-(2-trifluoromethyl)-phenothiazinyl)propy)-1-piperazineethanol, 1-adamantane carboxylic acid ester - Google Patents
Process for the production of 4-(3-(10-(2-trifluoromethyl)-phenothiazinyl)propy)-1-piperazineethanol, 1-adamantane carboxylic acid esterInfo
- Publication number
- CA1038866A CA1038866A CA237,358A CA237358A CA1038866A CA 1038866 A CA1038866 A CA 1038866A CA 237358 A CA237358 A CA 237358A CA 1038866 A CA1038866 A CA 1038866A
- Authority
- CA
- Canada
- Prior art keywords
- phenothiazinyl
- trifluoromethyl
- piperazineethanol
- propyl
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PROCESS FOR THE PRODUCTION OF
4-[3-[10-(2-TRIFLUOROMETHYL)PHENOTHIAZINYL]-PROPYL]-1-PIPERAZINEETHANOL, 1-ADAMANTANE
CARBOXYLIC ACID ESTER
Abstract of the Disclosure An improved process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazineethanol, 1-adamantane carboxylic acid ester, a long acting ataractic agent, which yields the compound directly as the free base in crystalline form, comprises reacting 4-[3-[10-(2-trifluoro-methyl)phenothiazinyl]propyl]-1-piperazineethanol with a 1-adamantoyl halide in the presence of an organic amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the reactants are soluble but in which the organic amine hydrochloride by-product is insoluble.
4-[3-[10-(2-TRIFLUOROMETHYL)PHENOTHIAZINYL]-PROPYL]-1-PIPERAZINEETHANOL, 1-ADAMANTANE
CARBOXYLIC ACID ESTER
Abstract of the Disclosure An improved process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazineethanol, 1-adamantane carboxylic acid ester, a long acting ataractic agent, which yields the compound directly as the free base in crystalline form, comprises reacting 4-[3-[10-(2-trifluoro-methyl)phenothiazinyl]propyl]-1-piperazineethanol with a 1-adamantoyl halide in the presence of an organic amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the reactants are soluble but in which the organic amine hydrochloride by-product is insoluble.
Description
.
.
~0~8866 This invention relates to an improved process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, directly as the base in crystalline form. This process comprises esterifying 4-[3-[10-(2-trifluoromethyl~-phenothiazinyl]propyl]-l-piperazineethanol with a l-adamantoyl halide, preferably the chloride or bromide, at an elevated témperature, in the presence of an organic amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the two reactants and organic tertiary amine acid acceptor are soluble but in which the amine halide by-product is insoluble. The organic tertiary amine acid acceptor includes, for example, lower alkylamines, aniline derivatives or alkylated nitrogen heterocyclics. The aromatic hydro-carbon solvents include benzene or lower alkyl benzenes.
.' .
..
4-[3-~10-(2-trifluoromethyl)phenothiazinyl]propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester is a long acting ataractic agent derived from fluphenaæine and ~038866 described in U.S. Patent 3,320,248, issued May 16, 1967.
According to that patent, 4-[3-[10-(2-trifluoromethyl)-phenothiazinyl]propyl]-l-piperazineethanol is made to react with l-adamantoyl chloride in dry chloroform. The chloroform solution is then treated with ethereal hydrogen chloride to obtain as the crystalline product the hydro-chloride salt (Example 2A). In order to form the free base, the hydrochloride is neutraliæed with aqueous potassium carbonate solution ln ether and the product, as the base, is obtained from the ether solution as a viscous oil.
Since the long acting effects of the compound are best obtained by parenteral administration, preerred compositions are solutions in a parenterally acceptable liquid vehicle, e.g., in a vegetable oil like peanut oil, cottonseed oil, sesame oil or the like or a synthetic vehicle such as ethyl oleate or other fatty acid ester.
The 4-[3-~10-(2-trifluoromethyl)phenothiazinyl]propylJ-l-piperazineetha~ol, l-adamantanecarboxylic acid ester, hydrochloride, obtained by the method o~ the cited patent, though crystalline, is not soluble in the oily vehicle and must be formulated as a suspension which is less desirable.
The product, in the form of the base, is obtained by the method of the patent, by first isolating the hydrochloride salt and then neutralizing it to obtain the base. By this method, the base is obtained as a viscous oil.
It is clearly preferable to obtain the desired oil soluble base in pure crystalline form and without having to go through the hydrochloride salt. The method of this ~03~866 invention produces the desired product as the base in crystalline form directly without the need for the additional steps of forming and isolating the crystalline hydrochloride salt and converting it back to the base.
According to this invention, 4-[3-[10-(2-trifluoro-methyl)phenothiazlnyl]propyl]-l-piperazineethanol is reacted with about an equivalent amount, e.g., about 1:0.9 to 1.3, preferably 1:0.95 to 1.1 e~uivalents of a l-adamantoyl halide, preferably the chloride or bromide and especially the chloride. The reaction with fluphenazine is carried out at an elevated temperature in the presence of an organic tertiary amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the two reactants and the organic amine acid acceptor are soluble but in which the organic amine halide formed as a byproduct from the acid acceptor is insoluble.
The temperature at which the reaction is efected can be within the range of about 60 to 150C, preferably about 80 to 135C. According to the preferred modification, the acid acceptor is added slowly to a solution of the two reactants and heat is applied after completing the addi-tion. The reaction is carried out u~der anhydrous conditions. About 2 to 10 hours is sufficient for the reaction to be completed.
The easily formed l-adamantanecarboxylic acid chloride is preferred as reactant.
, ~38~66 . The organic amine acid acceptor can be selected from lower alkylamines such as triethylamine, which is preferred, trimethylamine, ethyl diiso]propylamine, etc., other tertiary amines such as aniline derivatives, e.g.
N-lower alkylanilines like N,N-dimethylaniline, or alkylated nitrogen heterocyclics like ~-ethylmorpholine, ~-methylpiperidine, bis 1,4-dimethylpiperazine, N-(n-propyl) pyrrolidine or the like.
The solvent which functions as the reaction medium 0 i9, a~ aromatic hydrocarbon including benzene, toluene, xylene, which constitute preferred members, as well as other lower alkylbenzenes like cumene, p-cymene, mesitylene, diethylbenzene, durene, o-cymene or the like.
It is essential that the aromatic solvent is one in which the 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol and the l-adamantoyl halide reactants, as well as the acid acceptor are soluble and one in which the amine halide salt formed during the . reaction, e.g., triethylamine hydrochloride, is insoluble.
The separation of this salt from the reaction mixture tends to drive the reaction to completion. Thus a non-aromàtic organic solvent such as tetrahydrofuran, in which an amine halide like triethylamine hydrochloride is soluble, is unsuitable for obtaining the desired product as the base. The use of chloroform, as described in the patent, is not desirable since the three dimensional structure of the adamantane ring permits the entry of proton dQnor solvents like chloroform to produce solvates which are extremely stable, such solvated 3~66 molecules are generally unacceptable as-a pharmaceutical agent.
The aromatic solvents described above are excellent solvents for the two reactants and the acid acceptor, but very poor solvents f~r the amine salt which is formed as by product. Under these conditions, a quantitative yield ,:
of the amine salt is obtained and it is easily filtered from the reaction mixture. The filtrate is then concen-trated to give the crystalline base in high yield. The `~ 10 crystalline base glves a non-hygroscopic dihydrochloride upon treatment with hydrochloric acid, which is useful or analytical purposes.
The following examples are illustrative of the invention. All temperatures are in degrees Celsius.
.
Example 1 A solution of 9.~1 g. of 4-[3-[10-(2-trifluoromethyl~-phenothiazinyl]propyl]-l-piperazineethanol and 5.0 g. of l-adamantoyl chloride in 200 ml. of anhydrous benzene is treated dropwise and with stirring, with 2.1 g. of triethylamine dissolved in 10 ml. oE anhydrous benzene.
A precipitate forms during the addition. Subsequently, the mixture is heated and stirred under reflux for six hours. During this time, the original curdy white precipi-tate changes into a dense, white powder. The mixture is cooled and filtered to give 2.9 g. of triethylamine hydro-chloride, m.p. 256-257 (dec.). The benzene filtrate is concentrated in vacuo on a rotary evaporator. The residue weighs about 14.0 g. and, when cooled, crystallizes ~38866 spontaneously to give the product, m.p. 96-98. ~ecrystal-lization from 222 mL. of hexane gives 11.0 g of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazine-ethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
Anal. calc'd. for C33H40F3~3o2s Found C, 66.32; H, 6.90; ~, 7.01 Example 2 ; To a solution of 21.9 g. of 4-[3-[10-t2-trifluoro-methyl)phenothiazinyl]propyl]-l-piperazineethanol and 12.1 g. of l-aqamantoyl chloride in 425 ml. of anhydrous toluene is added 5.1 g. of triethylamine in 25 ml. of anhydrous toluene. The flocculent precipitate that forms during the addition changes to a dense white powder in the subsequent four hour reflux period. The product is worked up as in Example 1 to obtain 26.5 g. of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl}propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
ExamPle 3 A solution of 7.3 g. of 4-[3-[10-(2--trifluoromethyl)-phenothiazinyl]propyl]-l-piperazineethanol and 4.0 g of l-adamantoyl chloride in 160 ml. of anhydrous xylene is treated dropwise with stirring with 1.7 g. of triethylamine.
The mixture i9 stirred and then heated under xeflux for two hours. The product is then worked up as in Example 1 to give 8.8 g of 4-[3-[10-t2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
.
~0~8866 This invention relates to an improved process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, directly as the base in crystalline form. This process comprises esterifying 4-[3-[10-(2-trifluoromethyl~-phenothiazinyl]propyl]-l-piperazineethanol with a l-adamantoyl halide, preferably the chloride or bromide, at an elevated témperature, in the presence of an organic amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the two reactants and organic tertiary amine acid acceptor are soluble but in which the amine halide by-product is insoluble. The organic tertiary amine acid acceptor includes, for example, lower alkylamines, aniline derivatives or alkylated nitrogen heterocyclics. The aromatic hydro-carbon solvents include benzene or lower alkyl benzenes.
.' .
..
4-[3-~10-(2-trifluoromethyl)phenothiazinyl]propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester is a long acting ataractic agent derived from fluphenaæine and ~038866 described in U.S. Patent 3,320,248, issued May 16, 1967.
According to that patent, 4-[3-[10-(2-trifluoromethyl)-phenothiazinyl]propyl]-l-piperazineethanol is made to react with l-adamantoyl chloride in dry chloroform. The chloroform solution is then treated with ethereal hydrogen chloride to obtain as the crystalline product the hydro-chloride salt (Example 2A). In order to form the free base, the hydrochloride is neutraliæed with aqueous potassium carbonate solution ln ether and the product, as the base, is obtained from the ether solution as a viscous oil.
Since the long acting effects of the compound are best obtained by parenteral administration, preerred compositions are solutions in a parenterally acceptable liquid vehicle, e.g., in a vegetable oil like peanut oil, cottonseed oil, sesame oil or the like or a synthetic vehicle such as ethyl oleate or other fatty acid ester.
The 4-[3-~10-(2-trifluoromethyl)phenothiazinyl]propylJ-l-piperazineetha~ol, l-adamantanecarboxylic acid ester, hydrochloride, obtained by the method o~ the cited patent, though crystalline, is not soluble in the oily vehicle and must be formulated as a suspension which is less desirable.
The product, in the form of the base, is obtained by the method of the patent, by first isolating the hydrochloride salt and then neutralizing it to obtain the base. By this method, the base is obtained as a viscous oil.
It is clearly preferable to obtain the desired oil soluble base in pure crystalline form and without having to go through the hydrochloride salt. The method of this ~03~866 invention produces the desired product as the base in crystalline form directly without the need for the additional steps of forming and isolating the crystalline hydrochloride salt and converting it back to the base.
According to this invention, 4-[3-[10-(2-trifluoro-methyl)phenothiazlnyl]propyl]-l-piperazineethanol is reacted with about an equivalent amount, e.g., about 1:0.9 to 1.3, preferably 1:0.95 to 1.1 e~uivalents of a l-adamantoyl halide, preferably the chloride or bromide and especially the chloride. The reaction with fluphenazine is carried out at an elevated temperature in the presence of an organic tertiary amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the two reactants and the organic amine acid acceptor are soluble but in which the organic amine halide formed as a byproduct from the acid acceptor is insoluble.
The temperature at which the reaction is efected can be within the range of about 60 to 150C, preferably about 80 to 135C. According to the preferred modification, the acid acceptor is added slowly to a solution of the two reactants and heat is applied after completing the addi-tion. The reaction is carried out u~der anhydrous conditions. About 2 to 10 hours is sufficient for the reaction to be completed.
The easily formed l-adamantanecarboxylic acid chloride is preferred as reactant.
, ~38~66 . The organic amine acid acceptor can be selected from lower alkylamines such as triethylamine, which is preferred, trimethylamine, ethyl diiso]propylamine, etc., other tertiary amines such as aniline derivatives, e.g.
N-lower alkylanilines like N,N-dimethylaniline, or alkylated nitrogen heterocyclics like ~-ethylmorpholine, ~-methylpiperidine, bis 1,4-dimethylpiperazine, N-(n-propyl) pyrrolidine or the like.
The solvent which functions as the reaction medium 0 i9, a~ aromatic hydrocarbon including benzene, toluene, xylene, which constitute preferred members, as well as other lower alkylbenzenes like cumene, p-cymene, mesitylene, diethylbenzene, durene, o-cymene or the like.
It is essential that the aromatic solvent is one in which the 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol and the l-adamantoyl halide reactants, as well as the acid acceptor are soluble and one in which the amine halide salt formed during the . reaction, e.g., triethylamine hydrochloride, is insoluble.
The separation of this salt from the reaction mixture tends to drive the reaction to completion. Thus a non-aromàtic organic solvent such as tetrahydrofuran, in which an amine halide like triethylamine hydrochloride is soluble, is unsuitable for obtaining the desired product as the base. The use of chloroform, as described in the patent, is not desirable since the three dimensional structure of the adamantane ring permits the entry of proton dQnor solvents like chloroform to produce solvates which are extremely stable, such solvated 3~66 molecules are generally unacceptable as-a pharmaceutical agent.
The aromatic solvents described above are excellent solvents for the two reactants and the acid acceptor, but very poor solvents f~r the amine salt which is formed as by product. Under these conditions, a quantitative yield ,:
of the amine salt is obtained and it is easily filtered from the reaction mixture. The filtrate is then concen-trated to give the crystalline base in high yield. The `~ 10 crystalline base glves a non-hygroscopic dihydrochloride upon treatment with hydrochloric acid, which is useful or analytical purposes.
The following examples are illustrative of the invention. All temperatures are in degrees Celsius.
.
Example 1 A solution of 9.~1 g. of 4-[3-[10-(2-trifluoromethyl~-phenothiazinyl]propyl]-l-piperazineethanol and 5.0 g. of l-adamantoyl chloride in 200 ml. of anhydrous benzene is treated dropwise and with stirring, with 2.1 g. of triethylamine dissolved in 10 ml. oE anhydrous benzene.
A precipitate forms during the addition. Subsequently, the mixture is heated and stirred under reflux for six hours. During this time, the original curdy white precipi-tate changes into a dense, white powder. The mixture is cooled and filtered to give 2.9 g. of triethylamine hydro-chloride, m.p. 256-257 (dec.). The benzene filtrate is concentrated in vacuo on a rotary evaporator. The residue weighs about 14.0 g. and, when cooled, crystallizes ~38866 spontaneously to give the product, m.p. 96-98. ~ecrystal-lization from 222 mL. of hexane gives 11.0 g of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazine-ethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
Anal. calc'd. for C33H40F3~3o2s Found C, 66.32; H, 6.90; ~, 7.01 Example 2 ; To a solution of 21.9 g. of 4-[3-[10-t2-trifluoro-methyl)phenothiazinyl]propyl]-l-piperazineethanol and 12.1 g. of l-aqamantoyl chloride in 425 ml. of anhydrous toluene is added 5.1 g. of triethylamine in 25 ml. of anhydrous toluene. The flocculent precipitate that forms during the addition changes to a dense white powder in the subsequent four hour reflux period. The product is worked up as in Example 1 to obtain 26.5 g. of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl}propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
ExamPle 3 A solution of 7.3 g. of 4-[3-[10-(2--trifluoromethyl)-phenothiazinyl]propyl]-l-piperazineethanol and 4.0 g of l-adamantoyl chloride in 160 ml. of anhydrous xylene is treated dropwise with stirring with 1.7 g. of triethylamine.
The mixture i9 stirred and then heated under xeflux for two hours. The product is then worked up as in Example 1 to give 8.8 g of 4-[3-[10-t2-trifluoromethyl)phenothiazinyl]-propyl]-l-piperazineethanol, l-adamantanecarboxylic acid ester, m.p. 96-98.
Claims (9)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazine-ethanol, 1-adamantane carboxylic acid ester which comprises reacting 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl-1-piperazineethanol with a 1-adamantoyl halide at an elevated temperature in the presence of an organic amine acid acceptor in an anhydrous aromatic hydrocarbon solvent in which the two reactants and acid acceptor are soluble but in which the amine halide by product is insoluble and separating 4-[3-[10-(2-trifluoromethyl)-phenothiazinyl]propyl]-1-piperazineethanol, 1-adamantane-carboxylic acid ester from the reaction medium.
2. A process as in Claim 1 wherein the acid acceptor is a lower alkylamine and the solvent is benzene, toluene or xylene.
3. A process as in Claim 1 wherein the acid acceptor is triethylamine and the solvent is benzene.
4. A process as in Claim 1 wherein the acid acceptor is triethylamine and the solvent is toluene.
5. A process as in Claim 1 wherein the acid acceptor is triethylamine and the solvent is xylene.
6. A process for the production of 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazineethanol, 1-adamantane carboxylic acid ester which comprises esteri-fying 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazineethanol with 1-adamantoyl chloride in anhydrous benzene, toluene or xylene in the presence of triethylamine, filtering off the triethylamine hydrochloride formed during the reaction and separating crystalline 4-[3-[10-(2-trifluoromethyl)phenothiazinyl]propyl]-1-piperazine-ethanol, 1-adamantanecarboxylic acid ester from the solvent.
7. A process as in Claim 6 wherein the solvent is benzene.
8. A process as in Claim 6 wherein the solvent is toluene.
9. A process as in Claim 6 wherein the solvent is xylene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA237,358A CA1038866A (en) | 1975-10-09 | 1975-10-09 | Process for the production of 4-(3-(10-(2-trifluoromethyl)-phenothiazinyl)propy)-1-piperazineethanol, 1-adamantane carboxylic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA237,358A CA1038866A (en) | 1975-10-09 | 1975-10-09 | Process for the production of 4-(3-(10-(2-trifluoromethyl)-phenothiazinyl)propy)-1-piperazineethanol, 1-adamantane carboxylic acid ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038866A true CA1038866A (en) | 1978-09-19 |
Family
ID=4104232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA237,358A Expired CA1038866A (en) | 1975-10-09 | 1975-10-09 | Process for the production of 4-(3-(10-(2-trifluoromethyl)-phenothiazinyl)propy)-1-piperazineethanol, 1-adamantane carboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1038866A (en) |
-
1975
- 1975-10-09 CA CA237,358A patent/CA1038866A/en not_active Expired
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