CA1038391A - Piperidinobutyrophenone derivatives - Google Patents
Piperidinobutyrophenone derivativesInfo
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- CA1038391A CA1038391A CA232,325A CA232325A CA1038391A CA 1038391 A CA1038391 A CA 1038391A CA 232325 A CA232325 A CA 232325A CA 1038391 A CA1038391 A CA 1038391A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
PIPERIDINOBUTYROPHENONE DERIVATIVES
Abstract of the Disclosure:
Novel piperidinobutyrophenone derivatives of the formula:
wherein R1 and R3 are halogen, R2 is amino or C1-4 acylamino and R4 is halogen, C1-4 alkyl or trifluoromethyl, which are useful as psychotropic and analgesic agents and can be prepared by oxidative cleavage of the corresponding indole derivatives of the formula:
Abstract of the Disclosure:
Novel piperidinobutyrophenone derivatives of the formula:
wherein R1 and R3 are halogen, R2 is amino or C1-4 acylamino and R4 is halogen, C1-4 alkyl or trifluoromethyl, which are useful as psychotropic and analgesic agents and can be prepared by oxidative cleavage of the corresponding indole derivatives of the formula:
Description
103~91 The present invention relates to piperidinobutyro-phenone derivatives, and their production and use. More particularly, it relates to novel piperidinobutyrophenone compounds which are useful as psychotropic agents as well as analgesic agents, and their production and use.
There is a growing demand for new psychotropic agents, though a large number of agents has been developed in this field. As the result of the extensive study, it has now been found that piperidinobutyrophenone compounds of the formula:
R1 ~ COC~2C~2C~2 W ~ R3 (I) wherein Rl and R3 are halogen, R2 is amino or Cl 4 acylamino and R4 is halogen, Cl_4 alkyl or trifluoromethyl, and their non-toxic pharmaceutically acceptable salts have excellent pharmacological properties such as as psychotropic (par-ticularly neuroleptic and sedative) and analgesic activities and are useful as psychotropic and analgesic agents.
Accordingly, a main object of the present inven-tion is to provide the piperidinobutyrophenone compounds (I) 20 and their non-toxic pharmaceutically acceptable salts.
Another object of this invention is to provide a pharma-ceutical composition containing at least one of the piperidino-butyrophenone compounds (I) and their non-toxic pharma-ceutically acceptable salts as an active ingredient. A
further object of the invention is to provide a process for '~
There is a growing demand for new psychotropic agents, though a large number of agents has been developed in this field. As the result of the extensive study, it has now been found that piperidinobutyrophenone compounds of the formula:
R1 ~ COC~2C~2C~2 W ~ R3 (I) wherein Rl and R3 are halogen, R2 is amino or Cl 4 acylamino and R4 is halogen, Cl_4 alkyl or trifluoromethyl, and their non-toxic pharmaceutically acceptable salts have excellent pharmacological properties such as as psychotropic (par-ticularly neuroleptic and sedative) and analgesic activities and are useful as psychotropic and analgesic agents.
Accordingly, a main object of the present inven-tion is to provide the piperidinobutyrophenone compounds (I) 20 and their non-toxic pharmaceutically acceptable salts.
Another object of this invention is to provide a pharma-ceutical composition containing at least one of the piperidino-butyrophenone compounds (I) and their non-toxic pharma-ceutically acceptable salts as an active ingredient. A
further object of the invention is to provide a process for '~
- 2 - ~ I
preparation of the piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts. These and other objects of the invention will be apparent from the foregoing and subsequent descriptions.
As used herein, the term "Cl 4 alkyl" means straight or branched alkyl having one to four carbon atoms.
The term "Cl 4 acylamino" means acylamino having one to four carbon atoms, and it preferably includes formylamino and alkanoylamino such as acetamino. The term "halogen"
1~ includes fluorine, chlorine, bromine and iodine, and it preferably includes fluorine when used with respect to R
and chlorine when used with respect to R3 and R4.
Among the piperidinobutyrophenone compounds (I), preferred are those wherein R3 and R4 are present re spectively at the 3- and 4-positions of the phenyl group linked to the piperidino ring or vice versa. In such compounds, those wherein Rl is fluorine, R2 is amino, formylamino or acetamino, R3 is chlorine and R4 is chlorine, methyl or trifluoromethyl are particularly preferable.
2-0 The piperidinobutyrophenone compound (I) of this invention or its salt can be prepared by oxidative cleavage of the corresponding indole compound of the formula:
Rl)~. R5 ~R3 ~II) wherein R5 is hydrogen or Cl 3 alkyl and Rl, R3 and R4 are
preparation of the piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts. These and other objects of the invention will be apparent from the foregoing and subsequent descriptions.
As used herein, the term "Cl 4 alkyl" means straight or branched alkyl having one to four carbon atoms.
The term "Cl 4 acylamino" means acylamino having one to four carbon atoms, and it preferably includes formylamino and alkanoylamino such as acetamino. The term "halogen"
1~ includes fluorine, chlorine, bromine and iodine, and it preferably includes fluorine when used with respect to R
and chlorine when used with respect to R3 and R4.
Among the piperidinobutyrophenone compounds (I), preferred are those wherein R3 and R4 are present re spectively at the 3- and 4-positions of the phenyl group linked to the piperidino ring or vice versa. In such compounds, those wherein Rl is fluorine, R2 is amino, formylamino or acetamino, R3 is chlorine and R4 is chlorine, methyl or trifluoromethyl are particularly preferable.
2-0 The piperidinobutyrophenone compound (I) of this invention or its salt can be prepared by oxidative cleavage of the corresponding indole compound of the formula:
Rl)~. R5 ~R3 ~II) wherein R5 is hydrogen or Cl 3 alkyl and Rl, R3 and R4 are
- 3 --l03sasl each as defined above, or its salt to give the corresponding acylamino compound of the formula:
1 ~ CCN2C~2C~2 N ~ ~ R3 (IA) r NHCOR5 ~
\ R4 wherein Rl, R3, R4 and R5 are each as defined above and, if necessary, hydrolytic deacylation of the latter to give the corresponding amino compound of the formula:
1 ~ COC~2C~2C~2-N ~ R
2 ~ 3 (IB) wherein Rl, R3 and R4 are each as defined above.
For the oxidative cleavage, it is preferable to use an oxidizing agent such as ozone, chromic anhydride, chromic acid, chromates, periodic acid, periodates, per-acetic acid or permanganates. Among them, the use of ozone, chromic anhydride, chromic acid or periodates is particularly preferred. The reaction is usually effected in the pre-sence of a solvent. The choice of the solvent depends on the oxidizing agent employed, and it may be selected from water, acetone, carbon tetrachloride, acetic acid, sulfuric acid, pyridine and the like. The oxidizing agent is used in a stoichiometric amount or more. The reaction temper-ature varies depending on the oxidizing agent employed.
The most preferred oxidizing agent is ozone and - 103~391 chromic acid. When the oxidation is effected using ozone, the reaction is preferably carried out at room temperature or below. The indole compound (II) is dissolved or suspended in a solvent such as formic acid, acetic acid or carbon tetrachloride and then ozonized oxygen is intro-duced therein with stirring.
When the oxidation is performed with chromic acid in the presence o acetic acid, it is preferable to use the chromic acid in 2 - 10 times the equimolar amount and to effect the reaction at a temperature between 15 to 60C.
The indole compound (II) is dissolved or suspended in a solvent, and the oxidizing agent is added thereto with stirring. Generally, the reaction terminates within about 24 hours.
; The produced acylamino compound (IA) can be separated from the reaction mixture in a crude form by extraction with or without prior neutralization and evapo-ration to dryness. The product may be further purified, for instance, by recrystallization from a suitable solvent ~0 system in a conventional manner.
Hydrolytic deacylation of the thus obtained amino compound (IA) may be accomplished by a conventional hydro-lysis procedure, e.g. under an acidic or alkaline condition.
The recovery of the produced amino compound (IB) from the reaction mixture, if necessary, followed by purification may be performed in any manner conventionally adopted for separation.
The thus obtained piperidinobutyrophenone com-pound (I) can be converted into its non-toxic pharmaceu-S0 tically acceptable salts by treatment with inorganic or ., 10~8391 1 organic acids or esters in a conventional manner. When treatment is made with inorganic or organic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic/ acetic, benzoic, gluconic and ascorbic acids, there are formed acid addition salts. When treatment is made with inorganic or organic acid esters such as alkyl sulfates, alkyl halides and alkyl alkylbenzenesulfonates, there are formed quaternary ammonium salts.
The indole compound (II) used as the starting material in the above process may be prepared, for instance, according to the following scheme:
.
10383gl W
U~
, I
N H ~N ~ ~N H
U --' .~ U
~ U ~ U ~
V
S~
C) U~
103839~. ;
wherein X is a reactive ester residue such as halogen or arylsulfonyloxy and Rl, R3, R4 and R5 are each as defined above.
Specific examples of the piperidinobutyrophenone compound (I~ obtained by the present invention are as follows:
~ -[4-(4'-Chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidino]-2-formylamino-4-fluorobutyrophenone;
y-~4-(4'-Chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidinol-2-propylamino-4-fluorobutyrophenone;
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-formylamino-4-fluorobutyrophenone;
y-[4-(4'-Chloro-3'-trifluoromethylphenyl)-~-hydroxypiperidino]-2-isopropionylamino-4-fluorobutyro-phenone;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-~-formylamino-4-fluorobutyrophenone, etc.
The piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts have ~ central nervous system depressant activity. When, for instance, orally applied to mice and rats at about 0.1 -50 mg/kg, they produce characteristic CNS-depressing effects, and their effe~ts are superior to that of the standard neuroleptics, e.g. chlorpromazine. Thus, they are useful as psychotropic agents, particularly as neuroleptic and sedative agents. They are also useful as analgesic agents.
Besides, the piperidinobutyrophenone compounds (I) wherein Rl is amino are useful as synthetic intermediates for known psychotropic and neuroleptic agents.
The piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts may be administered to mammals orally or parenterally. For this purpose, these compounds may be utilized as sterile solu-tions or suspensions in water, polyethylene glycol, vege-table oils or other pharmaceutically acceptable vehicles.
The compounds may also be administered in tablets, capsules and suppositories and for this purpose may be combined with conventional, pharmaceutically acceptable binders and ex-cipients such as gelatin, sugars (e.g. lactose, glucose, sucrose), starches, stearic acid or salts thereof (e.g.
magnesium stearate, calcium stearate), talc, vegetable fats or oils, etc. The usual oral dosage is 0.3 - 100 mg per os daily.
The following examples illustrate the present invention in more details but do not limit its scope. In these examples, % is by weight.
Example 1 Oxygen containing 1 - 2 ~ of ozone was introduced into a solution of 10.8 g of 1-~y-(6-fluoro-2-methyl-3-20 indolyl)propyl]-4~(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine in 120 ml of acetic acid at a temperature of 15 - 20C until the starting compound was not detected in thin layer chromatogram (silica gel; n-hexane - ethyl acetate - methanol - ammonia). After acetic acid was distilled off under reduced pressure, the residual oil was diluted with water, made alkaline and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual free base was converted to the hydrochloride with ~0 hydrogen chloride in ethanol and recrystallized from ethanol ~038~91 to yield y-[4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone hydrochloride. M.P. 232 - 233C.
In the same manner as above, the following com-pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone, M.P. 104 - 109C (hydrate);
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-2-acetamino-4-fluorobutyrophenone, M.P. 91 - 101C
(hydrate).
Example 2 A mixture of 2.0 g of y-[4-(4'-chloro-3'-tri-fluoromethylphenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone hydrochloride, 3 ml of concentrated hydrochloric acid and 25 ml of ethanol was refluxed for 2 hours. After diluting with water, the resulting mixture was made alkaline with 10 % sodium hydroxide and extracted with ethyl acetate. The extract was concentrated to dryness, and the residue was crystallized from aqueous methanol-isopropyl ether to yield y-[4-(4'-chloro-3'-tri-fluoromethylphenyl)-4-hydroxypiperidino]-2-amino-4-fluoro butyrophenone. M.P. 166 - 167C.
In the same manner as above, the following com-pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-amino-4-fluorobutyrophenone hydrochloride, M.P. 214 -214.5C;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-2-amino-4-fluorobutyrophenone hydrochloride, M.P.
207 - 210C.
Example 3 Preparation of the starting indole compounds:-(1) To a stirred solution of 11.1 g of ~-(6-fluoro-2-methyl-3-indolyl)propionic acid and 5.1 g of triethylamine in 70 ml of tetrahydrofuran was added dropwise 5.5 g of ethyl chloroformate at a temperature below 0C.
Stirring was continued for additional 20 minutes and thereto was added dropwise a solution of 14.0 g of 4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine in 200 ml of tetrahydrofuran. After addition was completed, the reaction mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed successively with water, diluted hydrochloric acid, diluted sodium hydroxide, water and finally saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol to yield 1-[~-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine as crystalline powder. M.P. 172.5 - 174.0C.
(2) To a stirred mixture of 1.0 g of lithium aluminium hydride in 15 ml of anhydrous ether was added dropwise a solution of 4.55 g of crude 1-[~-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-trifluoro methylphenyl)-4-hydroxypiperidine in 50 ml of anhydrous tetrahydrofuran at room temperature. After the addition was completed, the reaction mixture was heated under refluxing for 2.5 hours and hydrolyzed by addition of water-tetra-S hydrofuran mixture under cooling. The resulting suspension 10383~ j was filtered, and the filtrate was concentrated and ex-tracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to yield l-[y-(6-fluoro-2-methyl-3-indolyl)propyl~-4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine as amorphous powder, which was converted to the hydrochloride by a conventional procedure to give crystals. M.P. 225 -228C (decomp.).
In the same manner as above, the following com-pounds were obtained:
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-(3',4'-dichlorophenyl)-4-hydroxypiperidine;
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-(3'-chloro-4'-methylphenyl)-4-hydroxypiperidine.
. ,,: .,
1 ~ CCN2C~2C~2 N ~ ~ R3 (IA) r NHCOR5 ~
\ R4 wherein Rl, R3, R4 and R5 are each as defined above and, if necessary, hydrolytic deacylation of the latter to give the corresponding amino compound of the formula:
1 ~ COC~2C~2C~2-N ~ R
2 ~ 3 (IB) wherein Rl, R3 and R4 are each as defined above.
For the oxidative cleavage, it is preferable to use an oxidizing agent such as ozone, chromic anhydride, chromic acid, chromates, periodic acid, periodates, per-acetic acid or permanganates. Among them, the use of ozone, chromic anhydride, chromic acid or periodates is particularly preferred. The reaction is usually effected in the pre-sence of a solvent. The choice of the solvent depends on the oxidizing agent employed, and it may be selected from water, acetone, carbon tetrachloride, acetic acid, sulfuric acid, pyridine and the like. The oxidizing agent is used in a stoichiometric amount or more. The reaction temper-ature varies depending on the oxidizing agent employed.
The most preferred oxidizing agent is ozone and - 103~391 chromic acid. When the oxidation is effected using ozone, the reaction is preferably carried out at room temperature or below. The indole compound (II) is dissolved or suspended in a solvent such as formic acid, acetic acid or carbon tetrachloride and then ozonized oxygen is intro-duced therein with stirring.
When the oxidation is performed with chromic acid in the presence o acetic acid, it is preferable to use the chromic acid in 2 - 10 times the equimolar amount and to effect the reaction at a temperature between 15 to 60C.
The indole compound (II) is dissolved or suspended in a solvent, and the oxidizing agent is added thereto with stirring. Generally, the reaction terminates within about 24 hours.
; The produced acylamino compound (IA) can be separated from the reaction mixture in a crude form by extraction with or without prior neutralization and evapo-ration to dryness. The product may be further purified, for instance, by recrystallization from a suitable solvent ~0 system in a conventional manner.
Hydrolytic deacylation of the thus obtained amino compound (IA) may be accomplished by a conventional hydro-lysis procedure, e.g. under an acidic or alkaline condition.
The recovery of the produced amino compound (IB) from the reaction mixture, if necessary, followed by purification may be performed in any manner conventionally adopted for separation.
The thus obtained piperidinobutyrophenone com-pound (I) can be converted into its non-toxic pharmaceu-S0 tically acceptable salts by treatment with inorganic or ., 10~8391 1 organic acids or esters in a conventional manner. When treatment is made with inorganic or organic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic/ acetic, benzoic, gluconic and ascorbic acids, there are formed acid addition salts. When treatment is made with inorganic or organic acid esters such as alkyl sulfates, alkyl halides and alkyl alkylbenzenesulfonates, there are formed quaternary ammonium salts.
The indole compound (II) used as the starting material in the above process may be prepared, for instance, according to the following scheme:
.
10383gl W
U~
, I
N H ~N ~ ~N H
U --' .~ U
~ U ~ U ~
V
S~
C) U~
103839~. ;
wherein X is a reactive ester residue such as halogen or arylsulfonyloxy and Rl, R3, R4 and R5 are each as defined above.
Specific examples of the piperidinobutyrophenone compound (I~ obtained by the present invention are as follows:
~ -[4-(4'-Chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidino]-2-formylamino-4-fluorobutyrophenone;
y-~4-(4'-Chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidinol-2-propylamino-4-fluorobutyrophenone;
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-formylamino-4-fluorobutyrophenone;
y-[4-(4'-Chloro-3'-trifluoromethylphenyl)-~-hydroxypiperidino]-2-isopropionylamino-4-fluorobutyro-phenone;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-~-formylamino-4-fluorobutyrophenone, etc.
The piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts have ~ central nervous system depressant activity. When, for instance, orally applied to mice and rats at about 0.1 -50 mg/kg, they produce characteristic CNS-depressing effects, and their effe~ts are superior to that of the standard neuroleptics, e.g. chlorpromazine. Thus, they are useful as psychotropic agents, particularly as neuroleptic and sedative agents. They are also useful as analgesic agents.
Besides, the piperidinobutyrophenone compounds (I) wherein Rl is amino are useful as synthetic intermediates for known psychotropic and neuroleptic agents.
The piperidinobutyrophenone compounds (I) and their non-toxic pharmaceutically acceptable salts may be administered to mammals orally or parenterally. For this purpose, these compounds may be utilized as sterile solu-tions or suspensions in water, polyethylene glycol, vege-table oils or other pharmaceutically acceptable vehicles.
The compounds may also be administered in tablets, capsules and suppositories and for this purpose may be combined with conventional, pharmaceutically acceptable binders and ex-cipients such as gelatin, sugars (e.g. lactose, glucose, sucrose), starches, stearic acid or salts thereof (e.g.
magnesium stearate, calcium stearate), talc, vegetable fats or oils, etc. The usual oral dosage is 0.3 - 100 mg per os daily.
The following examples illustrate the present invention in more details but do not limit its scope. In these examples, % is by weight.
Example 1 Oxygen containing 1 - 2 ~ of ozone was introduced into a solution of 10.8 g of 1-~y-(6-fluoro-2-methyl-3-20 indolyl)propyl]-4~(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine in 120 ml of acetic acid at a temperature of 15 - 20C until the starting compound was not detected in thin layer chromatogram (silica gel; n-hexane - ethyl acetate - methanol - ammonia). After acetic acid was distilled off under reduced pressure, the residual oil was diluted with water, made alkaline and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual free base was converted to the hydrochloride with ~0 hydrogen chloride in ethanol and recrystallized from ethanol ~038~91 to yield y-[4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone hydrochloride. M.P. 232 - 233C.
In the same manner as above, the following com-pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone, M.P. 104 - 109C (hydrate);
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-2-acetamino-4-fluorobutyrophenone, M.P. 91 - 101C
(hydrate).
Example 2 A mixture of 2.0 g of y-[4-(4'-chloro-3'-tri-fluoromethylphenyl)-4-hydroxypiperidino]-2-acetamino-4-fluorobutyrophenone hydrochloride, 3 ml of concentrated hydrochloric acid and 25 ml of ethanol was refluxed for 2 hours. After diluting with water, the resulting mixture was made alkaline with 10 % sodium hydroxide and extracted with ethyl acetate. The extract was concentrated to dryness, and the residue was crystallized from aqueous methanol-isopropyl ether to yield y-[4-(4'-chloro-3'-tri-fluoromethylphenyl)-4-hydroxypiperidino]-2-amino-4-fluoro butyrophenone. M.P. 166 - 167C.
In the same manner as above, the following com-pounds were obtained:
y-[4-(3',4'-Dichlorophenyl)-4-hydroxypiperidino]-2-amino-4-fluorobutyrophenone hydrochloride, M.P. 214 -214.5C;
y-[4-(3'-Chloro-4'-methylphenyl)-4-hydroxypiperi-dino]-2-amino-4-fluorobutyrophenone hydrochloride, M.P.
207 - 210C.
Example 3 Preparation of the starting indole compounds:-(1) To a stirred solution of 11.1 g of ~-(6-fluoro-2-methyl-3-indolyl)propionic acid and 5.1 g of triethylamine in 70 ml of tetrahydrofuran was added dropwise 5.5 g of ethyl chloroformate at a temperature below 0C.
Stirring was continued for additional 20 minutes and thereto was added dropwise a solution of 14.0 g of 4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine in 200 ml of tetrahydrofuran. After addition was completed, the reaction mixture was stirred for 3 hours at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed successively with water, diluted hydrochloric acid, diluted sodium hydroxide, water and finally saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol to yield 1-[~-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine as crystalline powder. M.P. 172.5 - 174.0C.
(2) To a stirred mixture of 1.0 g of lithium aluminium hydride in 15 ml of anhydrous ether was added dropwise a solution of 4.55 g of crude 1-[~-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-(4'-chloro-3'-trifluoro methylphenyl)-4-hydroxypiperidine in 50 ml of anhydrous tetrahydrofuran at room temperature. After the addition was completed, the reaction mixture was heated under refluxing for 2.5 hours and hydrolyzed by addition of water-tetra-S hydrofuran mixture under cooling. The resulting suspension 10383~ j was filtered, and the filtrate was concentrated and ex-tracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to yield l-[y-(6-fluoro-2-methyl-3-indolyl)propyl~-4-(4'-chloro-3'-trifluoromethylphenyl)-4-hydroxypiperidine as amorphous powder, which was converted to the hydrochloride by a conventional procedure to give crystals. M.P. 225 -228C (decomp.).
In the same manner as above, the following com-pounds were obtained:
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-(3',4'-dichlorophenyl)-4-hydroxypiperidine;
l-[y-(6-Fluoro-2-methyl-3-indolyl)propyl]-4-(3'-chloro-4'-methylphenyl)-4-hydroxypiperidine.
. ,,: .,
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing piperidinobutyro-phenone compounds of the formula:
wherein R1 and R3 are each chlorine, bromine, fluorine or iodine, R2 is amino or C1-4 acylamino and R4 is chlorine, bromine, fluorine or iodine, C1-4 alkyl or trifloromethyl, and their salts, which comprises oxidising a compound of the formula:
wherein R5 is hydrogen or C1-3 alkyl and R1, R3 and R4 are each as defined above or its salt to give a compound of the formula:
wherein R1, R3, R4 and R5 are each as defined above or its salt and, if necessary, hydrolyzing the latter to give a compound of the formula:
wherein R1, R3 and R4 are each as defined above or its salt.
wherein R1 and R3 are each chlorine, bromine, fluorine or iodine, R2 is amino or C1-4 acylamino and R4 is chlorine, bromine, fluorine or iodine, C1-4 alkyl or trifloromethyl, and their salts, which comprises oxidising a compound of the formula:
wherein R5 is hydrogen or C1-3 alkyl and R1, R3 and R4 are each as defined above or its salt to give a compound of the formula:
wherein R1, R3, R4 and R5 are each as defined above or its salt and, if necessary, hydrolyzing the latter to give a compound of the formula:
wherein R1, R3 and R4 are each as defined above or its salt.
2. The process according to claim 1, wherein R
is fluorine.
is fluorine.
3. The process according to claim 1, wherein R2 is amino, formylamino or acetamino.
4. The process according to claim 1, wherein R3 is chlorine and R4 is chlorine, methyl or trifluoromethyl.
5. The process according to claim 1, wherein R1 is fluorine and R2 is amino, formylamino or acetamino.
6. The process according to claim 1, wherein R3 is chlorine and R4 is chlorine, methyl or trifluoromethyl, one of R3 and R4 being present at the 3-position of the benzene ring and the other at the 4-position of the benzene ring.
7. The process according to claim 1, wherein the starting compound is a compound of the formula:
wherein R5 is hydrogen or C1-2 alkyl and R4 is chlorine, methyl or trifluoromethyl.
wherein R5 is hydrogen or C1-2 alkyl and R4 is chlorine, methyl or trifluoromethyl.
8. The process according to claim 7, wherein R4 is methyl.
9. The process according to claim 7, wherein R4 is chlorine.
10. The process according to claim 1, wherein the starting material is a compound of the formula:
wherein R5 is hydrogen or C1-2 alkyl and R4 is chlorine, methyl or trifluoromethyl.
wherein R5 is hydrogen or C1-2 alkyl and R4 is chlorine, methyl or trifluoromethyl.
11. The process according to claim 10, wherein R4 is trifluoromethyl.
12. A compound of the formula:
wherein R1 and R3 are each halogen, R2 is amino or C1-4 acylamino and R4 is halogen, C1-4 alkyl or trifluoromethyl, and its non-toxic pharmaceutically acceptable salts, whenever produced by the process of claim 1 or an obvious chemical equivalent.
wherein R1 and R3 are each halogen, R2 is amino or C1-4 acylamino and R4 is halogen, C1-4 alkyl or trifluoromethyl, and its non-toxic pharmaceutically acceptable salts, whenever produced by the process of claim 1 or an obvious chemical equivalent.
13. A compound of the formula:
wherein R2 is amino, formylamino or acetamino and R4 is chlorine, methyl or trifluoromethyl whenever produced by the process of claim 7 or an obvious chemical equivalent.
wherein R2 is amino, formylamino or acetamino and R4 is chlorine, methyl or trifluoromethyl whenever produced by the process of claim 7 or an obvious chemical equivalent.
14. A compound or the formula:
wherein R2 is amino, formylamino or acetamino and R4 is chlorine, methyl or trifuloromethyl whenever produced by the process of claim 10 or an obvious chemical equivalent.
wherein R2 is amino, formylamino or acetamino and R4 is chlorine, methyl or trifuloromethyl whenever produced by the process of claim 10 or an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8729574A JPS5116677A (en) | 1974-07-29 | 1974-07-29 | SHINKINABUCHIROFUENONJUDOTAI OYOBI SONOSANFUKAENNOSEIHO |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038391A true CA1038391A (en) | 1978-09-12 |
Family
ID=13910811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA232,325A Expired CA1038391A (en) | 1974-07-29 | 1975-07-28 | Piperidinobutyrophenone derivatives |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5116677A (en) |
| BE (1) | BE831818A (en) |
| CA (1) | CA1038391A (en) |
| DE (1) | DE2533865A1 (en) |
| FR (1) | FR2280378A1 (en) |
| GB (1) | GB1501475A (en) |
| NL (1) | NL7508870A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04116411U (en) * | 1991-03-28 | 1992-10-19 | セントラル硝子株式会社 | Glass antenna connection structure |
| JP2638715B2 (en) * | 1992-07-31 | 1997-08-06 | セントラル硝子株式会社 | Glass antenna connection structure |
| DE10153346A1 (en) * | 2001-10-29 | 2004-04-22 | Grünenthal GmbH | Substituted indoles |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI52216C (en) * | 1969-07-16 | 1977-07-11 | Sumitomo Chemical Co | Process for the preparation of gamma-piperidinobutyrophenone derivatives. |
| US3850935A (en) * | 1971-10-16 | 1974-11-26 | Sumitomo Chemical Co | Process for producing piperidine derivatives by degrading quaternary piperidinium salts |
| BE792906A (en) * | 1971-12-18 | 1973-06-18 | Sumitomo Chemical Co | ARYL-KETONES AND THEIR PREPARATION |
| SE419441B (en) * | 1972-03-18 | 1981-08-03 | Sumitomo Chemical Co | PROCEDURE FOR PREPARING BUTYROPHENON DERIVATIVES |
-
1974
- 1974-07-29 JP JP8729574A patent/JPS5116677A/en active Pending
-
1975
- 1975-07-24 NL NL7508870A patent/NL7508870A/en not_active Application Discontinuation
- 1975-07-28 FR FR7523504A patent/FR2280378A1/en active Granted
- 1975-07-28 BE BE158686A patent/BE831818A/en unknown
- 1975-07-28 GB GB3147075A patent/GB1501475A/en not_active Expired
- 1975-07-28 CA CA232,325A patent/CA1038391A/en not_active Expired
- 1975-07-29 DE DE19752533865 patent/DE2533865A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2280378B1 (en) | 1979-04-06 |
| JPS5116677A (en) | 1976-02-10 |
| DE2533865A1 (en) | 1976-02-19 |
| NL7508870A (en) | 1976-02-02 |
| FR2280378A1 (en) | 1976-02-27 |
| BE831818A (en) | 1976-01-28 |
| GB1501475A (en) | 1978-02-15 |
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