CA1244020A - Basic esters of benzoic acids and 2-thio- phencarboxylic acids, processes for their preparation and a pharmacological composition containing these esters - Google Patents
Basic esters of benzoic acids and 2-thio- phencarboxylic acids, processes for their preparation and a pharmacological composition containing these estersInfo
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- CA1244020A CA1244020A CA000435456A CA435456A CA1244020A CA 1244020 A CA1244020 A CA 1244020A CA 000435456 A CA000435456 A CA 000435456A CA 435456 A CA435456 A CA 435456A CA 1244020 A CA1244020 A CA 1244020A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides novel basic esters of the formula I
(1) wherein R is a group of the formulae or
The present invention provides novel basic esters of the formula I
(1) wherein R is a group of the formulae or
Description
The present invention relates to a novel basic esters of benzoic acids and of 2-thiophencarboxylic acids, their pharmaceutically acceptable salts with acids, to processes for their preparatlon and to a pharmaceutical composition, containing these novel esters.
Thus, the present invention provides novel compounds which e.g. may be used as agents in local anaesthesia, and which show a lower toxicity and an improved effectiveness over conven-tional compounds.
The present invention also provid~s processes for preparing the novel compounds which are easy to carry out and which are economical.
According to the present invention there are provided novel basic esters having the formula I
~ ,Il 2--CI~ 2 3 wherein R is a group of the formulae 1~l ~$
~
l~l s ~
wherein Rl is hydrogen or Cl-C4 alkyl, and R2 is Cl-C4 alkyl, halogen, a C1-C4 alkoxy, Cl-C4 alkylthio, nitro, amino or a Cl-C4 alkylamino, Rl and R2 being the same or different, and R3 is a ~.
basic group selected from di(Cl-C4) alkylamino or a 6-membered nitrogen containlng aromatic heterocyclic group which may contain a further oxygen atom, and their pharmacologlcally useful salts with acids.
~2~
The first process of this invention for preparing the ncvel basic esters of formula I
R-~-O-CH2-CH2-R3 (I) wherein R and R3 are defined above, and their pharmacologically useful salts, is characterized in that benzoic acids or thiophencarboxylic acids or their acid halides of the formulae 1 . Rl ~ - COR' alld ~ COR' - J~2 wherein R' is a hydroxyl group or halogen, and Rl and R2 are defined above, are reacted with an alcohol of formula II
Hoo-cH2-cH2-R3 (II) wherein R3 is defined above, and that the obtained compounds occasionally are transformed into their pharmacologically useful salts.
The second process of this inventi.on for preparing the novel basic esters of formula I
o R-~-o-c~2-cH2-R3 (I) wherein R and R3 are defined above, and their pharmacologically useful salts, is characterized ln that salts of benzoi.c acids or thiophencarboxylic acids of the formulae ~1 - COOI~I and l ~ i ~ ' COO;~I
~2 wherein M is a metal salt, and Rl and R2 are defined above, are reacted with a halide of formula III
Hal-cH2-c~2-R3 ~III) wherein ~Ial is a halogen atom, and R3 is defined above, and that the obtained compounds occasionally are transformed into their pharmacologically useful salts.
The compounds of the general formula I, wherein R2 is amino, may be prepared by reducing the nitro compounds.
Both processes of this invention may also be realized in the presence of at least ona solvent. Occasionally also cata-lysts may be used. Somebody skilled in the art may easily deter-mine the suitable reactlon temperatures and reaction times. Usu-ally one works at standard pressure, whereby also excess pressure and underpressure ~vacuum) are not excluded.
The administration of the novel compounds of formula I
according to this invention is realized in an usual way, as this is known in the art for the known compounds, The preferred embodimen-ts are illustrated in the set of Examples, wherein also some novel starting materials and interme-diates are described.
A. Exam~les for benzoic acid esters Example 1 To a solution of sodium me-thylate, prepared of 2.34 g (o.l mol) sodiurn in 100 ml absolute ethanol, are added 13.6 g (o.l mol) 2-methylbenzoic acid and then 15 g (O.ll mol) N-(2-chloroethyl)-piperidine are added slowly drop by drop. The mix-ture ~as stirred and heated for 5 hours. After cooling, the pre-cipitated sodium chloride was filtered with suction and then washed with ethanol. The filtrate was evaporated in the vacuum of a water jet pump, the residue was diluted with water and extracted with ether. The base was extracted with diluted hydrochloric acid. The acidic solution was made alkaline and was extracted with ether. After the evaporation of the ether the base was reacted with etheric hydrochloric acid lnto the hydrochloride of the 2-methyl-benzoic acid-2-piperidino ethyl ester. Mp. 164-165C.
ExamPle 2 In the same way as described in Example 1 the hydrochloride of 2,6-dlmethylbenzoic acid-2-piperidino-ethyl ester having an mp. 211-213C was obtained, when 26,-dimethyl-benzoic acid is used instead of 2-methyl-benzoic acid.
Example 3 To a solution of 805 mg (0.035 mol~ sodium in 40 rnl absolute ethanol are added 5.4 g ~0.035 mol) 2-fluoro-6-methyl-benzoic acid, and then 6.1 g (0.045 mol) 2-diethyl-amino-ethylchloride are added drop by drop, and this mixture is reacted, as described in Example 1, to yield the hydrochloride of
Thus, the present invention provides novel compounds which e.g. may be used as agents in local anaesthesia, and which show a lower toxicity and an improved effectiveness over conven-tional compounds.
The present invention also provid~s processes for preparing the novel compounds which are easy to carry out and which are economical.
According to the present invention there are provided novel basic esters having the formula I
~ ,Il 2--CI~ 2 3 wherein R is a group of the formulae 1~l ~$
~
l~l s ~
wherein Rl is hydrogen or Cl-C4 alkyl, and R2 is Cl-C4 alkyl, halogen, a C1-C4 alkoxy, Cl-C4 alkylthio, nitro, amino or a Cl-C4 alkylamino, Rl and R2 being the same or different, and R3 is a ~.
basic group selected from di(Cl-C4) alkylamino or a 6-membered nitrogen containlng aromatic heterocyclic group which may contain a further oxygen atom, and their pharmacologlcally useful salts with acids.
~2~
The first process of this invention for preparing the ncvel basic esters of formula I
R-~-O-CH2-CH2-R3 (I) wherein R and R3 are defined above, and their pharmacologically useful salts, is characterized in that benzoic acids or thiophencarboxylic acids or their acid halides of the formulae 1 . Rl ~ - COR' alld ~ COR' - J~2 wherein R' is a hydroxyl group or halogen, and Rl and R2 are defined above, are reacted with an alcohol of formula II
Hoo-cH2-cH2-R3 (II) wherein R3 is defined above, and that the obtained compounds occasionally are transformed into their pharmacologically useful salts.
The second process of this inventi.on for preparing the novel basic esters of formula I
o R-~-o-c~2-cH2-R3 (I) wherein R and R3 are defined above, and their pharmacologically useful salts, is characterized ln that salts of benzoi.c acids or thiophencarboxylic acids of the formulae ~1 - COOI~I and l ~ i ~ ' COO;~I
~2 wherein M is a metal salt, and Rl and R2 are defined above, are reacted with a halide of formula III
Hal-cH2-c~2-R3 ~III) wherein ~Ial is a halogen atom, and R3 is defined above, and that the obtained compounds occasionally are transformed into their pharmacologically useful salts.
The compounds of the general formula I, wherein R2 is amino, may be prepared by reducing the nitro compounds.
Both processes of this invention may also be realized in the presence of at least ona solvent. Occasionally also cata-lysts may be used. Somebody skilled in the art may easily deter-mine the suitable reactlon temperatures and reaction times. Usu-ally one works at standard pressure, whereby also excess pressure and underpressure ~vacuum) are not excluded.
The administration of the novel compounds of formula I
according to this invention is realized in an usual way, as this is known in the art for the known compounds, The preferred embodimen-ts are illustrated in the set of Examples, wherein also some novel starting materials and interme-diates are described.
A. Exam~les for benzoic acid esters Example 1 To a solution of sodium me-thylate, prepared of 2.34 g (o.l mol) sodiurn in 100 ml absolute ethanol, are added 13.6 g (o.l mol) 2-methylbenzoic acid and then 15 g (O.ll mol) N-(2-chloroethyl)-piperidine are added slowly drop by drop. The mix-ture ~as stirred and heated for 5 hours. After cooling, the pre-cipitated sodium chloride was filtered with suction and then washed with ethanol. The filtrate was evaporated in the vacuum of a water jet pump, the residue was diluted with water and extracted with ether. The base was extracted with diluted hydrochloric acid. The acidic solution was made alkaline and was extracted with ether. After the evaporation of the ether the base was reacted with etheric hydrochloric acid lnto the hydrochloride of the 2-methyl-benzoic acid-2-piperidino ethyl ester. Mp. 164-165C.
ExamPle 2 In the same way as described in Example 1 the hydrochloride of 2,6-dlmethylbenzoic acid-2-piperidino-ethyl ester having an mp. 211-213C was obtained, when 26,-dimethyl-benzoic acid is used instead of 2-methyl-benzoic acid.
Example 3 To a solution of 805 mg (0.035 mol~ sodium in 40 rnl absolute ethanol are added 5.4 g ~0.035 mol) 2-fluoro-6-methyl-benzoic acid, and then 6.1 g (0.045 mol) 2-diethyl-amino-ethylchloride are added drop by drop, and this mixture is reacted, as described in Example 1, to yield the hydrochloride of
2-fluoro-6-methyl-benzoic acid-2-diethyl-aminoethyl ester having an mp. of 136.7.
`'.~
The starting material was obtained as follows:
18.75 g (0.1 mol) of 2-amino-6-methyl-benzoic acid-hydrochloride are diazotized in 55 ml water and 9 ml concentrated hydrochloric acid with sodium nitrite, and at a temperature of -5C 50 ml hexafluorophosphoric acid are added. The precipitated salt was filtered with suction and decomposed in xylene at a tem-perature of 125C. After cooling, the acid is extracted in a sodium carbonate solution, acidified and extracted in ether.
After dryiny and evaporating the e-ther, the substance contains as a by-product 2-hydroxy-6-methyl-benzoic acid. After the esteri-fication to the ethyl ester, the 2-hydroxy-6-methyl-benzoic acid ester is extracted in sodium carhonate solution, the 2-fluoro-6-methyl-benzoic acid-ethyl ester is distilled and saponified with alcoholic potassium hydroxide. Mp. 124.6~.
Exam~le 4 As described in Example 3, the hydrochloride of 2-bromo-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-pared from 2-bromo-6-methyl-benzoic acid. Mp. 183.5-18~.5.
Example_5 AS described in Example 3, the hydrochloride of 2-iodo-6-methyl-benzoic acid-2-diethylamino-ethyl ester is prepared from the sodium salt of 2-iodo-6-methyl-benzoic acid and 2-diethy-lamino-ethylchloride and etheric hydrochloric acid. Mp. 192.8.
Exam~le 6 As described in Example 1, the hydrochloride of 2-ethoxy-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-pared from 2-ethoxy-6-methyl-benzoic acid and 2-diethylamino-ethylchloride. Mp. 125-127.
~2~
Example 7 When using N--(2-chloroethyl)-piperidine instead of 2-diethylamino-ethylchloride, then, as described in Example 6, the hydrochloride of 2-ethoxy-6-methyl-benzoic acid-2-piperidino-ethyl ester is obtained. Mp. 154.6.
The 2-ethoxy-6-methyl-benzoic acid is synthesized in a two-step synthesis of 2-chloro-6-methyl-1-benzonitrile.
2-ethoxy-6-methyl-benzonitri]e:
To a sodium methylate solution, prepared of 5.3 g sodium in 75 ml absolute ethanol, are added 20 g (0.132 mol) 2-chloro-6-methyl-benzonitrile and this mixture is heated in an autoclave having a glass insertion for 40 hours at a temperature of 130. After cooling the precipitated sodium salt is flltered with suction, the filtrate is evaporated in the vacuum of the water ~et pump, and the residue is dilute with ether. After washi.ng, drying and evaporating the ether, a produce having an mp. of 36-37.5 is obt,ained.
2-ethoxy-6-methyl-benzoic acid:
The nitrile is saponified either in ethanolic potassium hydroxide under pressure or in glycerine at a temperature of 210C. Mp. 86-38.
_xamPle 8 When 2-ethyl-thio-6-methyl-benzoic acid is used instead of 2-ethoxy-6-methyl-benzoic acid, then, as in Example 7, the hydrochloride of 2-ethylthio-6-methyl-benzoic acid-2-diethy-lamino-ethyl ester is obtained. Mp. 104.3.
Example 8a When 2.3 g ~0.02 mol) fumaric acid in ethanol are added to 6 g (0.02 mol~ base of 2-ethylthio-5-methyl-benzoic acid-2-diethylamino-ethyl ester in ether, then the fumarate crystal-lizes. Mp. 116.4.
Ex amPl e 9 As in Example 1, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-diethylamino-ethyl ester is prepared from the sodium salt of 2-methyl-6-nitro-benzoic acid, 2-diethylamino-ethylchloride and etheric hydrochloric acid. Mp. 159-160.5.
Exam~le 10 ~ s in Example 1, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-piperidino-ethyl ester is prepared from 2-methyl-6-nitro-benzoic acid. Mp. 181.6.
Example 11 As in Example 10, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-morpholino-ethyl ester is prepared when 4-(2-chloroethyl)-morpholine is used instead of N-(2-chloroethyl)-piperidine. ~p. 186.9.
Example 12 .
As described in Example 1, the dihydrochloride of 2-ethylamino-6-methyl-benzoic acid-2-diethylaminoethyl ester is prepared from 2-ethylamino-6-methyl-benzoic acid, 2-diethylamino-ethylchloride and etheric hydrochloric acid. Mp. 129.2.
Example 13 AS described ln Example 1, 2-butylamino-6-methyl-ben-zoic acid and 2-diethyl-amino-ethylchloride are reacted to the base (2-butylamino-6-methyl-benzoic acid-2-diethylamino-ethyl ester). When an eg~limolar amount fumaric acid, as described in Example 8a, is added to the base, then the fumarate having an mp.
of 99.7 is obtained.
The starting materials are prepared as follows:
The mixture of 10.5 g (0.058 mol) 2-amino-6-methyl-ben-zoic acid-ethyl ester in 87 ml benzene and 14.5 ml acetic acid and 1~.5 g zinc powder are heated to reflux temperature. Then 6.6 g acetaldehyde in 14.5 ml benzene are added slowly drop by drop, and the mixture is heated for 2.5 hours under reflux.
After cooling, the mixture is filtered with suction, washed with benzene, and the filtrate is made alkaline. The benzene layer is separated, the al~aline aqueous solution is extracted with ben-zene, the combined benzene layers are washed and dried, and after the evaporation of the benzene the 2-ethylamino-6-methyl-benzoic acid-ethyl ester is distilled. Bp. 136-139/min.
~.1 g (0.02 mol) of the ethyl ester in 50 ml ethanol are saponified with 3.25 g potassium hydroxide in 21.5 ml water by refluxing for 8 hours. The ethanol is evaporated, to the residue water is added, the neutral compounds, which may be pre-sen-t, are extracted with ether, the aqueous solution is acidified to a pH of 6.5 and extracted with ether. After washing, drying and evaporating the ether, 2-ethylamino-6-methyl-benzoic acid is obtained. Mp. 97 . 6.
When butyraldehyde is used instead of acetaldehyde, then as described above, 2-butylamino-6-methyl-benzoic acid-ethyl ester is obtained. Bp. 156-158/0.65 mm.
~S
After saponification, 2-butylamino-6-methyl-benzoic acid is obtained. Mp. 87.9.
Example 14 To 25.5 g (0.92 mol) 2-methyl-6-nitro-benzoic acid-2-diethylamino-ethyl ester in 500 ml concentrated hydrochloric acid are added during one hour 100 g tin (II)-chloride, and then the mixture is heated for one hour on the boiling water bath. After cooling, the mixture is made alkaline with 35 percent sodium hydroxide and extracted with ether. After washing the etherical solution, drying and evaporating the ether, the base is reacted with etheric hydrogen chloride in the dihydrochloride of 2-amino-6-methyl-benzoic acid-2-diethylamino-ethyl-ester. Mp. 186-188.
Example 15 ~ s described in Example 14, the dihydrochloride of 2-amino-6-methyl-benzoic acid-N-(2-piperidino)-ethyl ester is pre-pared, when 2-methyl-6-nitro-benzoic acid-N-(2-piperidino)-ethyl ester ls used. Mp. 199.8.
B. Examples for 2-thiophencarboxvlic acid esters Example 1 In the same way as with the benzoic acid esters the hydrochloride of 3-methylthiophen-2-carboxylic acid-2-diethy-lamino-ethyl ester is prepared from the sodium sal-t of 3-methylthiophen-2-carboxylic acid, 2-diethylaminoethylchloride and etheric hydrochloric acid. Mp. 145.7.
Example 2 ~s described in Example 1, the hydrochloride of 5-methylthiophen-2-carboxylic acid-2-diethylamino-ethyl ester is prepared, Mp. 145.7, when 5-methylthiophen-2-carboxylic acid is used.
`'.~
The starting material was obtained as follows:
18.75 g (0.1 mol) of 2-amino-6-methyl-benzoic acid-hydrochloride are diazotized in 55 ml water and 9 ml concentrated hydrochloric acid with sodium nitrite, and at a temperature of -5C 50 ml hexafluorophosphoric acid are added. The precipitated salt was filtered with suction and decomposed in xylene at a tem-perature of 125C. After cooling, the acid is extracted in a sodium carbonate solution, acidified and extracted in ether.
After dryiny and evaporating the e-ther, the substance contains as a by-product 2-hydroxy-6-methyl-benzoic acid. After the esteri-fication to the ethyl ester, the 2-hydroxy-6-methyl-benzoic acid ester is extracted in sodium carhonate solution, the 2-fluoro-6-methyl-benzoic acid-ethyl ester is distilled and saponified with alcoholic potassium hydroxide. Mp. 124.6~.
Exam~le 4 As described in Example 3, the hydrochloride of 2-bromo-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-pared from 2-bromo-6-methyl-benzoic acid. Mp. 183.5-18~.5.
Example_5 AS described in Example 3, the hydrochloride of 2-iodo-6-methyl-benzoic acid-2-diethylamino-ethyl ester is prepared from the sodium salt of 2-iodo-6-methyl-benzoic acid and 2-diethy-lamino-ethylchloride and etheric hydrochloric acid. Mp. 192.8.
Exam~le 6 As described in Example 1, the hydrochloride of 2-ethoxy-6-methyl-benzoic acid-2-diethylamino-ethyl ester is pre-pared from 2-ethoxy-6-methyl-benzoic acid and 2-diethylamino-ethylchloride. Mp. 125-127.
~2~
Example 7 When using N--(2-chloroethyl)-piperidine instead of 2-diethylamino-ethylchloride, then, as described in Example 6, the hydrochloride of 2-ethoxy-6-methyl-benzoic acid-2-piperidino-ethyl ester is obtained. Mp. 154.6.
The 2-ethoxy-6-methyl-benzoic acid is synthesized in a two-step synthesis of 2-chloro-6-methyl-1-benzonitrile.
2-ethoxy-6-methyl-benzonitri]e:
To a sodium methylate solution, prepared of 5.3 g sodium in 75 ml absolute ethanol, are added 20 g (0.132 mol) 2-chloro-6-methyl-benzonitrile and this mixture is heated in an autoclave having a glass insertion for 40 hours at a temperature of 130. After cooling the precipitated sodium salt is flltered with suction, the filtrate is evaporated in the vacuum of the water ~et pump, and the residue is dilute with ether. After washi.ng, drying and evaporating the ether, a produce having an mp. of 36-37.5 is obt,ained.
2-ethoxy-6-methyl-benzoic acid:
The nitrile is saponified either in ethanolic potassium hydroxide under pressure or in glycerine at a temperature of 210C. Mp. 86-38.
_xamPle 8 When 2-ethyl-thio-6-methyl-benzoic acid is used instead of 2-ethoxy-6-methyl-benzoic acid, then, as in Example 7, the hydrochloride of 2-ethylthio-6-methyl-benzoic acid-2-diethy-lamino-ethyl ester is obtained. Mp. 104.3.
Example 8a When 2.3 g ~0.02 mol) fumaric acid in ethanol are added to 6 g (0.02 mol~ base of 2-ethylthio-5-methyl-benzoic acid-2-diethylamino-ethyl ester in ether, then the fumarate crystal-lizes. Mp. 116.4.
Ex amPl e 9 As in Example 1, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-diethylamino-ethyl ester is prepared from the sodium salt of 2-methyl-6-nitro-benzoic acid, 2-diethylamino-ethylchloride and etheric hydrochloric acid. Mp. 159-160.5.
Exam~le 10 ~ s in Example 1, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-piperidino-ethyl ester is prepared from 2-methyl-6-nitro-benzoic acid. Mp. 181.6.
Example 11 As in Example 10, the hydrochloride of 2-methyl-6-nitro-benzoic acid-2-morpholino-ethyl ester is prepared when 4-(2-chloroethyl)-morpholine is used instead of N-(2-chloroethyl)-piperidine. ~p. 186.9.
Example 12 .
As described in Example 1, the dihydrochloride of 2-ethylamino-6-methyl-benzoic acid-2-diethylaminoethyl ester is prepared from 2-ethylamino-6-methyl-benzoic acid, 2-diethylamino-ethylchloride and etheric hydrochloric acid. Mp. 129.2.
Example 13 AS described ln Example 1, 2-butylamino-6-methyl-ben-zoic acid and 2-diethyl-amino-ethylchloride are reacted to the base (2-butylamino-6-methyl-benzoic acid-2-diethylamino-ethyl ester). When an eg~limolar amount fumaric acid, as described in Example 8a, is added to the base, then the fumarate having an mp.
of 99.7 is obtained.
The starting materials are prepared as follows:
The mixture of 10.5 g (0.058 mol) 2-amino-6-methyl-ben-zoic acid-ethyl ester in 87 ml benzene and 14.5 ml acetic acid and 1~.5 g zinc powder are heated to reflux temperature. Then 6.6 g acetaldehyde in 14.5 ml benzene are added slowly drop by drop, and the mixture is heated for 2.5 hours under reflux.
After cooling, the mixture is filtered with suction, washed with benzene, and the filtrate is made alkaline. The benzene layer is separated, the al~aline aqueous solution is extracted with ben-zene, the combined benzene layers are washed and dried, and after the evaporation of the benzene the 2-ethylamino-6-methyl-benzoic acid-ethyl ester is distilled. Bp. 136-139/min.
~.1 g (0.02 mol) of the ethyl ester in 50 ml ethanol are saponified with 3.25 g potassium hydroxide in 21.5 ml water by refluxing for 8 hours. The ethanol is evaporated, to the residue water is added, the neutral compounds, which may be pre-sen-t, are extracted with ether, the aqueous solution is acidified to a pH of 6.5 and extracted with ether. After washing, drying and evaporating the ether, 2-ethylamino-6-methyl-benzoic acid is obtained. Mp. 97 . 6.
When butyraldehyde is used instead of acetaldehyde, then as described above, 2-butylamino-6-methyl-benzoic acid-ethyl ester is obtained. Bp. 156-158/0.65 mm.
~S
After saponification, 2-butylamino-6-methyl-benzoic acid is obtained. Mp. 87.9.
Example 14 To 25.5 g (0.92 mol) 2-methyl-6-nitro-benzoic acid-2-diethylamino-ethyl ester in 500 ml concentrated hydrochloric acid are added during one hour 100 g tin (II)-chloride, and then the mixture is heated for one hour on the boiling water bath. After cooling, the mixture is made alkaline with 35 percent sodium hydroxide and extracted with ether. After washing the etherical solution, drying and evaporating the ether, the base is reacted with etheric hydrogen chloride in the dihydrochloride of 2-amino-6-methyl-benzoic acid-2-diethylamino-ethyl-ester. Mp. 186-188.
Example 15 ~ s described in Example 14, the dihydrochloride of 2-amino-6-methyl-benzoic acid-N-(2-piperidino)-ethyl ester is pre-pared, when 2-methyl-6-nitro-benzoic acid-N-(2-piperidino)-ethyl ester ls used. Mp. 199.8.
B. Examples for 2-thiophencarboxvlic acid esters Example 1 In the same way as with the benzoic acid esters the hydrochloride of 3-methylthiophen-2-carboxylic acid-2-diethy-lamino-ethyl ester is prepared from the sodium sal-t of 3-methylthiophen-2-carboxylic acid, 2-diethylaminoethylchloride and etheric hydrochloric acid. Mp. 145.7.
Example 2 ~s described in Example 1, the hydrochloride of 5-methylthiophen-2-carboxylic acid-2-diethylamino-ethyl ester is prepared, Mp. 145.7, when 5-methylthiophen-2-carboxylic acid is used.
Claims (64)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a basic ester of formula I
(I) wherein R is a group of the formulae or wherein R1 is hydrogen or C1-C4 alkyl, and R2 is C1-C4 alkyl, halogen, a C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino or a C1-C4 alkylamino, R1 and R2 being the same or different, and R3 is a basic group selected from di(C1-C4) alkylamino or a 6-membered nitrogen containing aromatic heterocyclic group which may contain a further oxygen atom or a pharmacoloyically useful salt thereof with an acid in which (a) a benzoic acid or a thiophencarboxylic acid or an acid halide thereof of the formula or wherein R' is a hydroxyl group or halogen, and R1 and R2 are as above, are reacted with an alcohol of formula II
HO-CH -CH2-R3 (II) wherein R3 is as above, or (b) a salt of a benzoic acid or a thiophencarboxylic acid of the formulae or wherein M is a metal atom, and R1 and R2 are defined above, is reacted with a halide of formula III
Hal-CH2-CH2-R3 wherein Hal is a halogen atom, and R3 is defined above and when required the free base obtained is converted into a pharmacolo-gically useful salt with an acid.
(I) wherein R is a group of the formulae or wherein R1 is hydrogen or C1-C4 alkyl, and R2 is C1-C4 alkyl, halogen, a C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino or a C1-C4 alkylamino, R1 and R2 being the same or different, and R3 is a basic group selected from di(C1-C4) alkylamino or a 6-membered nitrogen containing aromatic heterocyclic group which may contain a further oxygen atom or a pharmacoloyically useful salt thereof with an acid in which (a) a benzoic acid or a thiophencarboxylic acid or an acid halide thereof of the formula or wherein R' is a hydroxyl group or halogen, and R1 and R2 are as above, are reacted with an alcohol of formula II
HO-CH -CH2-R3 (II) wherein R3 is as above, or (b) a salt of a benzoic acid or a thiophencarboxylic acid of the formulae or wherein M is a metal atom, and R1 and R2 are defined above, is reacted with a halide of formula III
Hal-CH2-CH2-R3 wherein Hal is a halogen atom, and R3 is defined above and when required the free base obtained is converted into a pharmacolo-gically useful salt with an acid.
2. The process of claim 1, in which the acid halide in (a) is an acid chloride.
3. The process of claim 1, in which the halide of formula III is a chloride.
4. The process according to claim 1 or 3, in which the salt of the benzoic acid or the thiophencarboxylic acid is an alkali metal salt.
5. A basic ester of the formula I
(I) wherein R is a group of the formulae or wherein R1 is hydrogen or C1-C4 alkyl, and R2 is C1-C4 alkyl, halogen, a C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino or a C1-C4 alkylamino, R1 and R2 being the same or different, and R3 is a basic group selected from di(C1-C4) alkylamino or a 6-membered nitrogen containing aromatic heterocyclic group which may contain a further oxygen atom or a pharmacologically useful salt thereof.
(I) wherein R is a group of the formulae or wherein R1 is hydrogen or C1-C4 alkyl, and R2 is C1-C4 alkyl, halogen, a C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino or a C1-C4 alkylamino, R1 and R2 being the same or different, and R3 is a basic group selected from di(C1-C4) alkylamino or a 6-membered nitrogen containing aromatic heterocyclic group which may contain a further oxygen atom or a pharmacologically useful salt thereof.
6. A process according to claim 1, in which R1 is hydrogen or methyl, R2 is methyl, fluorine, bromine, iodine, ethoxy, ethylthio, nitro, amino, ethylamino, or butylamino, and R3 is diethylamino, piperidino or morpholino.
7. A compound of formula I given in claim 1 or a pharmacologically useful salt thereof with an acid in which R1, R2 and R3 are as in claim 6.
8. A process according to claim 6, in which R is a group of the formula wherein R1 and R2 are as in claim 6.
9. A compound of formula I given in claim 1 or a pharmacologically useful salt thereof with an acid In which R is as in claim 8 and R1, R2 and R3 are as in claim 8.
10. A process according to claim 6, in which R is a group of the formula wherein R1 is as in claim 6.
11. A compound of formula I given in claim 1 or a pharmacologically useful salt thereof with an acid in which R is as in claim 10 and R1 and R3 are as in claim 6.
12. A process according to claim 1, in which the free base is reacted with an acid selected from hydrochloric, hydro-bromic, fumaric or maleic acid.
13. A salt of a basic ester of the formula I given in claim 1, wherein R and R3 are as in claim 1 which is a hydro-chloride, hydrobromide, fumarate, maleate, hydrogenfumarate or hydrogenmaleate.
14. A process according to claim 1, in which R is wherein R1 Is hydrogen and R2 is methyl and R3 is piperldino.
15. A process according to claim 1, which comprises reacting 2-methylbenzoic in an ethanolic sodium methylate solution with N-(2-chloroethyl)-piperldine.
16. 2-methylbenzoic acid-2-piperldino ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
17. A process according to claim 1, In which R is wherein R1 and R2 are methyl and R3 is piperldino.
18. A process according to claim 1, which comprises reacting 2,6-dimethylbenzoic acid in an ethanolic sodium methy-late solution with N-(2-chloroethyl)-piperldine.
19. 2,6-dimethylbenzoic acid-2-piperldino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
20. A process according to claim 1, In which R Is wherein R1 is methyl, R2 is fluoro and R3 is diethylamino.
21. A process according to claim 1, which comprises reacting 2-fluoro-6-methylbenzoic acid in an ethanolic sodium ethylate solution with 2-diethylamino-ethylchloride.
22. 2-fluoro-6-methylbenzoic acid-2-diethylaminoethyl ester or a pharmaceutically acceptable acid addition salt there-of.
23. A process according to claim 1, in which R is wherein R1 is methyl, R2 is bromo and R3 is diethylamino.
24. A process according to claim 1, which comprises reacting 2-bromo-6-methyl-benzoic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchloride.
25. 2-bromo-6-methylbenzoic acid-2-diethylamino ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
26. A process according to claim 1, In which R is wherein R1 is methyl, R2 is lodo and R3 is diethylamino.,
27. A process according to claim 1, which comprises reacting 2-lodo-6-methylbenzoic acid in ethanolic sodium methy-late solution with 2-diethylamino-ethylchloride.
28. 2-lodo-6-methylbenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
29. A process according to claim 1, In which R is wherein R1 is methyl, R2 is ethoxy and R3 is diethylamino.
30. A process according to claim 1, which comprises reacting 2-ethoxy-6-methylbenzoic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchloride.
31. 2-ethoxy-6-methylbenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
32. A process according to claim 1, in which R Is wherein R1 is methyl, R2 is ethoxy and R3 is piperldino.
33. A process according to claim 1, which comprises reacting 2-ethoxy-6-methylbenzoic acid in an ethanolic sodium methylate solution with 2-ethoxy-6-methyibenzoic acid-2-piper-idino-ethyl ester.
34. 2-ethoxy-6-methylbenzoic acid-2-piperldino-ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
35. A process according to claim 1, in which R is wherein R1 is methyl, R2 is ethylthio and R3 is diethylamino.
36. A process according to claim 1, which comprises reacting 2-ethylthio-6-methylbenzoic acid in an ethanolic sodium methylate with 2-diethylamino-ethylchloride.
37. 2-ethylthio-6-methylbenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
38. A process according to claim 1, in which R is wherein R1 is methyl, R2 is nitro and R3 is diethylamino.
39. A process according to claim 1, which comprises reacting 2-methyl-6-nitrobenzoic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchloride.
40. 2-methyl-6-nitrobenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
41. A process according to claim 1, In which R Is wherein R1 is methyl, R2 is nitro and R3 is piperldino.
42. A process according to claim 1, which comprises reacting 2-methyl-6-nitrobenzoic acid in an ethanolic sodium methylate solution with N-(2-chloroethyl)-piperldine.
43. 2-methyl-6-nitrobenzoic acid-2-piperldino-ethyl ester or a pharmaceutically acceptable acid addition salt there-of,
44. A process according to claim 1, in which R is wherein R1 is methyl, R2 is nitro and R3 is morpholino.
45. A process according to claim 1, which comprises reacting 2-methylbenzoic acid in an ethanolic sodium methylate solution with 4-(2-chloroethyl)-morpholine.
46. 2-methyl-6-nitrobenzoic acid-2-moropholino ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
47. A process according to claim 1, in which R is wherein R1 is methyl, R2 is ethylamino and R3 is diethylamino.
48. A process according to claim 1, which comprises reacting 2-ethylamino-6-methylbenzoic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchoride.
49. 2-ethylamino-6-methylbenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
50. A process according to claim 1, in which R is wherein R1 is methyl, R2 is butylamino and R3 is diethylamino.
51. A process according to claim 1, which comprises reacting 2-butylamino-6-methylbenzoic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchloride.
52. 2-butylamino-6-methylbenzoic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
53. A process according to claim 1, in which R is wherein R1 is methyl, R2 is amino and R3 is diethylamino.
54. A process which comprises heating 2-methyl-6-nitrobenzoic acid-2-diethylamino-ethyl ester in concentrated hydrochloric acid with tin(II)-chloride.
55. 2-amino-6-methylbenzoic acid-2-diethylamino-ethyl-ester or a pharmaceutically acceptable acid addition salt there-of.
56. A process according to claim 1, in which R is wherein R1 is methyl, R2 is amino and R3 is piperldino.
57. A process which comprises heating 2-methyl-6-nitrobenzoic acid-N-(2-piperldino)-ethyl ester in concentrated hydrochloric acid with tint(II)-chloride.
58. 2-amino-6-methylbenzoic acid-N-(2-piperldino)-ethyl ester or a pharmaceutically acceptable acid addition salt there-of.
59. A process according to claim 1, in which R is wherein R1 is methyl in the 3-position and hydrogen in the 5-position.
60. A process according to claim 1, which comprises reacting 3-methylthiophen-2-carboxylic acid in an ethanolic sodium methylate solution with 2-diethylamino-ethylchloride.
61. 3-methylthiophen-2-carboxylic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
62. A process according to claim 1, in which R is wherein R1 is methyl un the 5-position and R1 is hydrogen in the 3-position.
63. A process according to claim 1, which comprises reacting 5-methylthiophen-2-carboxylic acid in an ethanolic sodium solution with 2-diethylamino-ethylchloride.
64. 5-methylthiophen-2-carboxylic acid-2-diethylamino-ethyl ester or a pharmaceutically acceptable acid addition salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5115/82-6 | 1982-08-27 | ||
| CH5115/82A CH651014A5 (en) | 1982-08-27 | 1982-08-27 | BASIC ESTERS OF BENZOESIC ACIDS AND OF 2-THIOPHENIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ESTERS. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1244020A true CA1244020A (en) | 1988-11-01 |
Family
ID=4288176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000435456A Expired CA1244020A (en) | 1982-08-27 | 1983-08-26 | Basic esters of benzoic acids and 2-thio- phencarboxylic acids, processes for their preparation and a pharmacological composition containing these esters |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5998044A (en) |
| CA (1) | CA1244020A (en) |
| CH (1) | CH651014A5 (en) |
| DE (1) | DE3328494A1 (en) |
| FR (1) | FR2532304B1 (en) |
| GB (1) | GB2126219B (en) |
| IT (1) | IT1168211B (en) |
| SE (1) | SE8304457L (en) |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL19578C (en) * | 1925-01-15 | |||
| US2173827A (en) * | 1936-10-26 | 1939-09-26 | Pitman Moore Company | Alkyl thio-substituted benzoic acid alkamine ester salts, intermediate and process of preparing same |
| GB525199A (en) * | 1939-02-15 | 1940-08-23 | Novocol Chemical M F G Co Inc | Improvements in or relating to local anaesthetic bases and process of preparing same |
| US2372116A (en) * | 1942-03-24 | 1945-03-20 | Pierce | Amino alcohol esters |
| US2383074A (en) * | 1942-04-16 | 1945-08-21 | American Cyanamid Co | Alkamine derivatives of o-alkoxymethyl benzoic acid |
| US2404691A (en) * | 1944-08-30 | 1946-07-23 | Squibb & Sons Inc | Chemical compounds |
| US2831016A (en) * | 1954-05-27 | 1958-04-15 | Univ Missouri | beta-substituted aminoalkyl 2,6-dialkylsubstituted benzoates and method of making the same |
| US3047574A (en) * | 1960-03-28 | 1962-07-31 | Searle & Co | 2-cyclohexyl-4-(2-hydroxyethyl)-3-methylmorpholine esters of substituted benzoic acids |
| FR2432516A1 (en) * | 1978-08-01 | 1980-02-29 | Synthelabo | 4-Phenyl-piperazino-ethanol derivs. - having CNS activity, useful for treating anxiety and depression |
-
1982
- 1982-08-27 CH CH5115/82A patent/CH651014A5/en not_active IP Right Cessation
-
1983
- 1983-08-06 DE DE19833328494 patent/DE3328494A1/en not_active Ceased
- 1983-08-15 GB GB08321954A patent/GB2126219B/en not_active Expired
- 1983-08-17 SE SE8304457A patent/SE8304457L/en not_active Application Discontinuation
- 1983-08-26 CA CA000435456A patent/CA1244020A/en not_active Expired
- 1983-08-26 FR FR838313762A patent/FR2532304B1/en not_active Expired
- 1983-08-26 IT IT48885/83A patent/IT1168211B/en active
- 1983-08-27 JP JP58157049A patent/JPS5998044A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CH651014A5 (en) | 1985-08-30 |
| IT8348885A0 (en) | 1983-08-26 |
| FR2532304A1 (en) | 1984-03-02 |
| FR2532304B1 (en) | 1989-05-19 |
| SE8304457D0 (en) | 1983-08-17 |
| SE8304457L (en) | 1984-02-28 |
| JPS5998044A (en) | 1984-06-06 |
| GB2126219B (en) | 1987-05-28 |
| IT1168211B (en) | 1987-05-20 |
| DE3328494A1 (en) | 1984-03-01 |
| GB2126219A (en) | 1984-03-21 |
| GB8321954D0 (en) | 1983-09-14 |
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