CA1099719A - Process for the preparation of n-(1-benzylpiperid-4- yl)-benzamides - Google Patents
Process for the preparation of n-(1-benzylpiperid-4- yl)-benzamidesInfo
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- CA1099719A CA1099719A CA317,711A CA317711A CA1099719A CA 1099719 A CA1099719 A CA 1099719A CA 317711 A CA317711 A CA 317711A CA 1099719 A CA1099719 A CA 1099719A
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- group
- carbon atoms
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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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
Therapeutically useful N-(1-benzylpiperid-4-yl)-benzamides of the formula:
(wherein X represents a chlorine or bromine atom, R1 represents an alkyl group containing up to 6 carbon atoms, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions) are prepared by a new process which comprises reacting a thiobenzoic acid derivative of the formula:
V
(wherein R4 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms as substituents) with an alkyl chlorofonmate containing up to 6 carbon atoms in the alkyl moiety in an organic solvent and in the presence of triethylamine at a temperature between -15°C and 0°C, and reacting the resulting VI
(wherein R5 represents an alkyl group containing up to 6 carbon atoms) in situ with a 1-benzyl-4-aminopiperidine of the formula:
IV
at a temperature between 0°C and 20°C, and - when R4 in the compound so obtained of the formula:
VII
is the formyl group or an alkanoyl radical as hereinbefore mentioned - subjecting the compound to acid hydrolysis to remove the acyl group and give an N-(1-benzylpiperid-4-yl)-benzamide of general formula I.
Therapeutically useful N-(1-benzylpiperid-4-yl)-benzamides of the formula:
(wherein X represents a chlorine or bromine atom, R1 represents an alkyl group containing up to 6 carbon atoms, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions) are prepared by a new process which comprises reacting a thiobenzoic acid derivative of the formula:
V
(wherein R4 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms as substituents) with an alkyl chlorofonmate containing up to 6 carbon atoms in the alkyl moiety in an organic solvent and in the presence of triethylamine at a temperature between -15°C and 0°C, and reacting the resulting VI
(wherein R5 represents an alkyl group containing up to 6 carbon atoms) in situ with a 1-benzyl-4-aminopiperidine of the formula:
IV
at a temperature between 0°C and 20°C, and - when R4 in the compound so obtained of the formula:
VII
is the formyl group or an alkanoyl radical as hereinbefore mentioned - subjecting the compound to acid hydrolysis to remove the acyl group and give an N-(1-benzylpiperid-4-yl)-benzamide of general formula I.
Description
9~
THIS I~VENTION relates to a new process for the preparation of N~ benzylpiperid-4~yl)-benzamides of the general formula:
X
H2N ~ CONH ~ -CH~
ORl wherein X represents a chlorine or bromine atom, Rl repxesents a straight- or branched-chain alkyl group containing up to six carbon atoms~ for example methyl, ethyl, propyl, butyl, pentyl or hexyl, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions, and pharmaceutically acceptable salts thereof. The invention is more particularly -15~ concerned with the preparation of such benzamides wherein X
is as hereinbefore defined, especially a chlorine atom, R
is an alkyl group containing up to~five carbon atoms (preferably methyl), R2 is a hydrogen atom, or a halogen atom or a methyl or methoxy group in the 4-position (preferably hydrogen), and pharmaceutically acceptable salts thereof.
Benæamide derivatives of general formula I can be prepared b~ various processes which have been described ~97~
inter alia in, for example, the specification of British Patent No. 1507463. Of the proce~ses hithert~ described for their preparation that which involve~ the reaction of a 2-alkoxy-4-amino-5-halobenzoic acid of the general formula: `
H2N ~ COOH II
ORl ~ , ~ .
(wherein X and Rl are as hereinbefore defined), the amino group of which is optionally protected by an acyl group ~uch as acetyl, rifluoroacetyl, chloroacetyl or phthaloyl~ with an alkyl chloroformate and the subsequent reaction of the intermediate mixed anhydride of the general formula:
I
H2N ~ O ~ C0-0-Co-o-Y III
(wherein X and Rl are as hereinbefore defined and Y
15 represents an alkyl group), or N-acylated derivative ~`
thereof, with an appropriate l-benzyl-4-aminopiperidine of the general formula~-
THIS I~VENTION relates to a new process for the preparation of N~ benzylpiperid-4~yl)-benzamides of the general formula:
X
H2N ~ CONH ~ -CH~
ORl wherein X represents a chlorine or bromine atom, Rl repxesents a straight- or branched-chain alkyl group containing up to six carbon atoms~ for example methyl, ethyl, propyl, butyl, pentyl or hexyl, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions, and pharmaceutically acceptable salts thereof. The invention is more particularly -15~ concerned with the preparation of such benzamides wherein X
is as hereinbefore defined, especially a chlorine atom, R
is an alkyl group containing up to~five carbon atoms (preferably methyl), R2 is a hydrogen atom, or a halogen atom or a methyl or methoxy group in the 4-position (preferably hydrogen), and pharmaceutically acceptable salts thereof.
Benæamide derivatives of general formula I can be prepared b~ various processes which have been described ~97~
inter alia in, for example, the specification of British Patent No. 1507463. Of the proce~ses hithert~ described for their preparation that which involve~ the reaction of a 2-alkoxy-4-amino-5-halobenzoic acid of the general formula: `
H2N ~ COOH II
ORl ~ , ~ .
(wherein X and Rl are as hereinbefore defined), the amino group of which is optionally protected by an acyl group ~uch as acetyl, rifluoroacetyl, chloroacetyl or phthaloyl~ with an alkyl chloroformate and the subsequent reaction of the intermediate mixed anhydride of the general formula:
I
H2N ~ O ~ C0-0-Co-o-Y III
(wherein X and Rl are as hereinbefore defined and Y
15 represents an alkyl group), or N-acylated derivative ~`
thereof, with an appropriate l-benzyl-4-aminopiperidine of the general formula~-
2 ~ -CH2 ~ RR3 IV
.~, .
.
7 ~ 9 (whexein R2 and R3 are as hereinbefore defined) to give ~:
`~ a benzamide derivative of general formula I, or a corresponding N-acylated compound which can be converted - by methods known per se into such a derivative, i5 the 5 most facile (cf. Examples 2 and 3 of British Patent No.
1507463). A disadvantage of that process arises from ; the fact that the benzoic acid reactants of general formula II are relatively insoluble in common, cheap commercially available solvents, and therefore in such 10 a process an expensive solvent such as anhydrous tetrahydrofuran is required for the process to be carried out successfully on a commercial scale and then - even so -because of the low solubility of the initial benzoic acid reactant~ yields of the desired benzamide derivatives of general formula I in excess of 80% of the theoretical are difficult to attain. ~:
It has now unexpectedly been found after research and experimentation that benzamide derivatives of general formula I can be obtained in extremely high 20 yield, viz. about 95% of the theoretical, when a thiobenzoic acid derivative of the general formula:-R4_NH~COSH V
~1 ~wherein X and Rl are as herelnbefore defined, and R4 ... /~
'' : ' ' ~ ' ' ' ': :, . " ' ... .
:
,, ' ~ .:
: ~
~9~19 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms, e.g.
chlorine, as substituents) is utiliæed as starting .
material. Moreover, as the thiobenzoic acid derivatives of general fonmula V are soluble in common commercially ~:~
available solvents, solvents such as acetone, methylene chloride and chloroform, which are much cheaper than tetrahydrofuran, can be employed.
According to the present invention, benz~mide derivatives of general formula I are prepared by the process which comprises reacting a thiobenzoic acid derivative of general formula V with an alkyl chloroformate containing up to 6 carbon atoms in the alkyl moiety ~:
(preferably ethyl chloroformate) in an organic solvent (preferably acetone) and in the presence of triethylamine at a temperature between -15C and 0C, and reacting the resulting thioanhydride of the general formula~
X
O O
R4-NH ~ ~ B-S-CO-R5 VI
OR
(wherein X, Rl and R4 are as hereinbefore defined, and R5 represents an alkyl group containin~ up to 6 carbon atoms) in situ with a l-benzyl-4-aminopiperidine of general formula IV at a temperature between 0C and 20C, and - when R4 in the compotlnd so obtained of the general '.,:, :, . , . ~ ~ . : , ~ , , : , -; , :., ~ : : - , ::.: . . . . . : .
. :
~399719 formula:
X
2 ~ ~ R VII
:, ~
(wherein the various symbols are as herei~before defined) is the formyl group or an alkanoyl radical as hereinbefore S mentioned - subjecting the compound to acid hydrolysis to remove the acyl group and give an N~ benzylpiperid-4-: `
yl)-benzamide of general formula I.
The products of general formula VII, obtainable in yields of about 95% of the theoretical by the process of the present invention, may be isolated from the reaction mixture by removing the organic solvent in:vacuo, dissolving the residue in chloroform, washing the chloroform solution with water and an aqueous solution of sodium hydroxide, drying the solution of the product, e.g. with ~a2SO4, evaporating lS the chloroform in vacuo and recrystallizing the product of formula VII from a suitable solvent, for example diethyl ether, ethanol or methanol.
When R4 in the product of general formula VII
is the formyl group or an alkanoyl radical, the said group or radical is preferably hydrolysed by heating the product in an aqueous alcoholic solution oE hydrochloric acid at the boiling point of the mixture. The resulting ~' amino compound of general formula I is then isolated by .
~ - 6 ~95~7~ :
diluting the mixture with water, making the solution alkaline by addition of aqueous sodium hydroxide and extracting the product with a suitable solvent, for example methylene chloride or chloroform. The pure product can then be obtained by evaporating the solvent and recrystallizing it from a suitable solvent,~ for example diethyl ether, ethanol or methanol.
The bases of general formula I thus obtained may be converted by methods known per se into ;~
pharmaceutically acceptable salts, e.g. malates.
fumarates or hydrochlorides,by treatment with an organic acid such as malic~ or fumaric acid or an inorganic acid such as hydrochloric acid in ethanol.
The thiobenzoic acids of general formula V
may be prepared from an amide of the general fonmula:
X :
R4-NH ~ O ~ CONH2 VIII ~
: ~ ORl : ~
(wherein X, Rl and R4 are as hereinbefore defined) by reaction with sodium hydride and carbon disulphide (I. Shaha]c and Y. Sasson, J. Amer. Chem. Soc. 95, 3440, 1973).
The following Examples illustrate the preparation of benzamide derivatlves of general formula I by the process of the present invention.
(a) To a cold stirred solution of 2-methoxy-4-acetamido-5-chlorothiobenzolc acid (7.79 g; 0~03 moles) in acetone (80 ml) was added a solution of triethylamine (4.2 ml, 0.03 moles3 in acetone (10 ml). Whilst maintaining the temperature between -15 and -10C, a solution of ethyl chloroformate (2~85 ml; 0.03 moles) in acetone (10 ml) was slowly added, the reactlon mixture was stirred at that temperature for one hour, and then 1-benzyl-4-aminopiperidine (5.7 g, 0.03 moles) dissolved in acetone (10 ml) was added. The temperatur~ of the reaction mixture was allowed to rise to room temperature and the mixture was stirred overnight at that temperature.
The solvent was then removed in vacuo, the residue was treated with water, extracted with chloroform and then washed successively with aqueous lN sodium hydroxide solution and water~ The chlorofo~rm solution was dried (Na2S04), evaporated to dryness and the residue dissolved in diethyl ether. The soIution was filtered and on 20 cooling, 11.6 g (93% yield) of N~ benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide, m.p. 134-135C, were obtained.
(b3 A mixture of the above-mentioned product (11 g, 0.026 moles), water (30 ml)~and concentrated hydrochloric acid (9 ml) was boiled under reflux for 1.5 hours. The ; solution was then cooled, dlluted with water and made alkaline with a concentrated aqueous solution of sodium ~.
- ~ _ : , :: ;~: .: : - :, 7~-hydroxide, extracted with chloroform and the chloroform layer washed with water and dried (Na2SO4). I'he solvent was evaporated in vacuo to give N~ benzylpiperid-4-yl) 2-methoxy-4-amino-5-chlorobenzamide which was dissolved in ho~ ethanol and the stoichiometric amount of d,l-malic acid was added. On cooling, N-(l-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide acid malate (11.26 g; 85.3% yield), m.p. 168-170C (dec.), was obtained. ;~
~ ~, By a similar procedure to that described in Example 1, ~ benzylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide was obtained and converted into its hydrochloride, mOp. 219-221C. Yield in step (a~
: 93.5%.
By a similar procedure to that described in Example 1, ~-(1-~-methylbenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide was obtained and converted into its hydrochloride, m.p. 234-235C. Yield in step (a) : g8%.
EX~IPLE 4 By a similar procedure to that described in Example 1, ~ luorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide was obtained and converted into its hydrochloride monohydrate, m.p. 256-258C (dec.).
Yield in step (a) : 96%.
g _ .', ..
., ; - . . ..
*~9 To a cold solution of 2-methoxy-4-amino-5-chlorothiobenzoic acid ~8.7 g, 0.04 mole) in acetone ~120 ml), triethylamine (5.6 ml, 0.04 moles) was added.
The mixture was stirred and cooled to -15C to -10C
and ethyl chloroformate (3.8 ml; 0.04 moles) was slowly added. Stirring was continued at that temperature for 1 hour. A solution of l-benzyl-4-aminopiperidine (7.6 g 0.04 moles) in acetone (20 ml) was then slowly added and the mixture was stirred for 1 hour at -15C to -10C. The temperature was then allowed to rise to room temperature and the mixture was stirred at that temperature overnight.
The solvent was then evaporated ln vacuo and the residue treated with a mixture of chloroform and water. The chloroform layer was separated, washed with a dilute solution of sodium hydroxide and then with~water. The chloroform solution was dried, (Na2S04) and the solvent evaporated in vacuo to give a solid residue which was dissolved in hot diethyl ether, filtered and allowed to crystallize. N-(l-Benzylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide (14.1 g, 94.2%), m.p. 193-195C was thus obtained.
Its hydrochloride monohydrate, m.p. 217-219C, was prepared by treating the base with aqueous-ethanolic hydrochloric acid solution.
~y a similar procedure to that described in :, , :. .: , :
.~ " :
~: : : ' .' ` : :
: ~ , , . . : :: ::
,, ~ ~: . , 7~ ~
Example 5, N-(l-p-methoxybenzylpiperid~4-yl~-2-methoxy-4-amino-5-chlorobenæamide hydrochloride, m.p.
238~-239C, was prepared. Yield 94.8%.
By a similar proceduxe to that described in Example 5, N-tl-p-chlorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 253-256C, was prepared. Yield 96.3%.
By a similar procedure to that described in Example 5, ~ (l-benzylpiperid-4-yl)-2-methoxy-ll-amin 5-chlorobenzamide hydrochloride, m.p. 271-273C, was prepared. Yield 97.5%.
EXAMPLE 9`
By a similar procedure to that deecribed in Example 5, N-~l-p-bromobenzylpiperid-4-yl) 2-methoxy-4-~lino-5-chlorobenzamide hydrochloride, mOp. 242-243C
was prepared. Yield 96~1%.
There can also be prepared by the procedure of Example 5 the following products of general formula I
using appropriate starting materials of general formula V and IV:-N-tl-m-chloro~enzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 249-251C, and N (l-piperonylpiperid-4-yl)-2-methoxy 4-amino-S-chlorobenzamide hydrochloride, m.p. 264-266Co : -: : :. - ."
~ ~, The N~ benzyl'piperid-4-yl)-henzamides of general formula I have pharmacological properties, principally the ability to antagonize the effects of dopamine or dopaminergic agents of endogenous or ~xogenous origin. 'rhey may be used for the treatment of various ailments as mentionedon the first page of British Patent Specification 1507463 hereinbe~ore referred to.
.
. .
:. .:.: ,, . . , . :,.:
-.: :, ::
.~, .
.
7 ~ 9 (whexein R2 and R3 are as hereinbefore defined) to give ~:
`~ a benzamide derivative of general formula I, or a corresponding N-acylated compound which can be converted - by methods known per se into such a derivative, i5 the 5 most facile (cf. Examples 2 and 3 of British Patent No.
1507463). A disadvantage of that process arises from ; the fact that the benzoic acid reactants of general formula II are relatively insoluble in common, cheap commercially available solvents, and therefore in such 10 a process an expensive solvent such as anhydrous tetrahydrofuran is required for the process to be carried out successfully on a commercial scale and then - even so -because of the low solubility of the initial benzoic acid reactant~ yields of the desired benzamide derivatives of general formula I in excess of 80% of the theoretical are difficult to attain. ~:
It has now unexpectedly been found after research and experimentation that benzamide derivatives of general formula I can be obtained in extremely high 20 yield, viz. about 95% of the theoretical, when a thiobenzoic acid derivative of the general formula:-R4_NH~COSH V
~1 ~wherein X and Rl are as herelnbefore defined, and R4 ... /~
'' : ' ' ~ ' ' ' ': :, . " ' ... .
:
,, ' ~ .:
: ~
~9~19 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms, e.g.
chlorine, as substituents) is utiliæed as starting .
material. Moreover, as the thiobenzoic acid derivatives of general fonmula V are soluble in common commercially ~:~
available solvents, solvents such as acetone, methylene chloride and chloroform, which are much cheaper than tetrahydrofuran, can be employed.
According to the present invention, benz~mide derivatives of general formula I are prepared by the process which comprises reacting a thiobenzoic acid derivative of general formula V with an alkyl chloroformate containing up to 6 carbon atoms in the alkyl moiety ~:
(preferably ethyl chloroformate) in an organic solvent (preferably acetone) and in the presence of triethylamine at a temperature between -15C and 0C, and reacting the resulting thioanhydride of the general formula~
X
O O
R4-NH ~ ~ B-S-CO-R5 VI
OR
(wherein X, Rl and R4 are as hereinbefore defined, and R5 represents an alkyl group containin~ up to 6 carbon atoms) in situ with a l-benzyl-4-aminopiperidine of general formula IV at a temperature between 0C and 20C, and - when R4 in the compotlnd so obtained of the general '.,:, :, . , . ~ ~ . : , ~ , , : , -; , :., ~ : : - , ::.: . . . . . : .
. :
~399719 formula:
X
2 ~ ~ R VII
:, ~
(wherein the various symbols are as herei~before defined) is the formyl group or an alkanoyl radical as hereinbefore S mentioned - subjecting the compound to acid hydrolysis to remove the acyl group and give an N~ benzylpiperid-4-: `
yl)-benzamide of general formula I.
The products of general formula VII, obtainable in yields of about 95% of the theoretical by the process of the present invention, may be isolated from the reaction mixture by removing the organic solvent in:vacuo, dissolving the residue in chloroform, washing the chloroform solution with water and an aqueous solution of sodium hydroxide, drying the solution of the product, e.g. with ~a2SO4, evaporating lS the chloroform in vacuo and recrystallizing the product of formula VII from a suitable solvent, for example diethyl ether, ethanol or methanol.
When R4 in the product of general formula VII
is the formyl group or an alkanoyl radical, the said group or radical is preferably hydrolysed by heating the product in an aqueous alcoholic solution oE hydrochloric acid at the boiling point of the mixture. The resulting ~' amino compound of general formula I is then isolated by .
~ - 6 ~95~7~ :
diluting the mixture with water, making the solution alkaline by addition of aqueous sodium hydroxide and extracting the product with a suitable solvent, for example methylene chloride or chloroform. The pure product can then be obtained by evaporating the solvent and recrystallizing it from a suitable solvent,~ for example diethyl ether, ethanol or methanol.
The bases of general formula I thus obtained may be converted by methods known per se into ;~
pharmaceutically acceptable salts, e.g. malates.
fumarates or hydrochlorides,by treatment with an organic acid such as malic~ or fumaric acid or an inorganic acid such as hydrochloric acid in ethanol.
The thiobenzoic acids of general formula V
may be prepared from an amide of the general fonmula:
X :
R4-NH ~ O ~ CONH2 VIII ~
: ~ ORl : ~
(wherein X, Rl and R4 are as hereinbefore defined) by reaction with sodium hydride and carbon disulphide (I. Shaha]c and Y. Sasson, J. Amer. Chem. Soc. 95, 3440, 1973).
The following Examples illustrate the preparation of benzamide derivatlves of general formula I by the process of the present invention.
(a) To a cold stirred solution of 2-methoxy-4-acetamido-5-chlorothiobenzolc acid (7.79 g; 0~03 moles) in acetone (80 ml) was added a solution of triethylamine (4.2 ml, 0.03 moles3 in acetone (10 ml). Whilst maintaining the temperature between -15 and -10C, a solution of ethyl chloroformate (2~85 ml; 0.03 moles) in acetone (10 ml) was slowly added, the reactlon mixture was stirred at that temperature for one hour, and then 1-benzyl-4-aminopiperidine (5.7 g, 0.03 moles) dissolved in acetone (10 ml) was added. The temperatur~ of the reaction mixture was allowed to rise to room temperature and the mixture was stirred overnight at that temperature.
The solvent was then removed in vacuo, the residue was treated with water, extracted with chloroform and then washed successively with aqueous lN sodium hydroxide solution and water~ The chlorofo~rm solution was dried (Na2S04), evaporated to dryness and the residue dissolved in diethyl ether. The soIution was filtered and on 20 cooling, 11.6 g (93% yield) of N~ benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide, m.p. 134-135C, were obtained.
(b3 A mixture of the above-mentioned product (11 g, 0.026 moles), water (30 ml)~and concentrated hydrochloric acid (9 ml) was boiled under reflux for 1.5 hours. The ; solution was then cooled, dlluted with water and made alkaline with a concentrated aqueous solution of sodium ~.
- ~ _ : , :: ;~: .: : - :, 7~-hydroxide, extracted with chloroform and the chloroform layer washed with water and dried (Na2SO4). I'he solvent was evaporated in vacuo to give N~ benzylpiperid-4-yl) 2-methoxy-4-amino-5-chlorobenzamide which was dissolved in ho~ ethanol and the stoichiometric amount of d,l-malic acid was added. On cooling, N-(l-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide acid malate (11.26 g; 85.3% yield), m.p. 168-170C (dec.), was obtained. ;~
~ ~, By a similar procedure to that described in Example 1, ~ benzylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide was obtained and converted into its hydrochloride, mOp. 219-221C. Yield in step (a~
: 93.5%.
By a similar procedure to that described in Example 1, ~-(1-~-methylbenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide was obtained and converted into its hydrochloride, m.p. 234-235C. Yield in step (a) : g8%.
EX~IPLE 4 By a similar procedure to that described in Example 1, ~ luorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide was obtained and converted into its hydrochloride monohydrate, m.p. 256-258C (dec.).
Yield in step (a) : 96%.
g _ .', ..
., ; - . . ..
*~9 To a cold solution of 2-methoxy-4-amino-5-chlorothiobenzoic acid ~8.7 g, 0.04 mole) in acetone ~120 ml), triethylamine (5.6 ml, 0.04 moles) was added.
The mixture was stirred and cooled to -15C to -10C
and ethyl chloroformate (3.8 ml; 0.04 moles) was slowly added. Stirring was continued at that temperature for 1 hour. A solution of l-benzyl-4-aminopiperidine (7.6 g 0.04 moles) in acetone (20 ml) was then slowly added and the mixture was stirred for 1 hour at -15C to -10C. The temperature was then allowed to rise to room temperature and the mixture was stirred at that temperature overnight.
The solvent was then evaporated ln vacuo and the residue treated with a mixture of chloroform and water. The chloroform layer was separated, washed with a dilute solution of sodium hydroxide and then with~water. The chloroform solution was dried, (Na2S04) and the solvent evaporated in vacuo to give a solid residue which was dissolved in hot diethyl ether, filtered and allowed to crystallize. N-(l-Benzylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide (14.1 g, 94.2%), m.p. 193-195C was thus obtained.
Its hydrochloride monohydrate, m.p. 217-219C, was prepared by treating the base with aqueous-ethanolic hydrochloric acid solution.
~y a similar procedure to that described in :, , :. .: , :
.~ " :
~: : : ' .' ` : :
: ~ , , . . : :: ::
,, ~ ~: . , 7~ ~
Example 5, N-(l-p-methoxybenzylpiperid~4-yl~-2-methoxy-4-amino-5-chlorobenæamide hydrochloride, m.p.
238~-239C, was prepared. Yield 94.8%.
By a similar proceduxe to that described in Example 5, N-tl-p-chlorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 253-256C, was prepared. Yield 96.3%.
By a similar procedure to that described in Example 5, ~ (l-benzylpiperid-4-yl)-2-methoxy-ll-amin 5-chlorobenzamide hydrochloride, m.p. 271-273C, was prepared. Yield 97.5%.
EXAMPLE 9`
By a similar procedure to that deecribed in Example 5, N-~l-p-bromobenzylpiperid-4-yl) 2-methoxy-4-~lino-5-chlorobenzamide hydrochloride, mOp. 242-243C
was prepared. Yield 96~1%.
There can also be prepared by the procedure of Example 5 the following products of general formula I
using appropriate starting materials of general formula V and IV:-N-tl-m-chloro~enzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 249-251C, and N (l-piperonylpiperid-4-yl)-2-methoxy 4-amino-S-chlorobenzamide hydrochloride, m.p. 264-266Co : -: : :. - ."
~ ~, The N~ benzyl'piperid-4-yl)-henzamides of general formula I have pharmacological properties, principally the ability to antagonize the effects of dopamine or dopaminergic agents of endogenous or ~xogenous origin. 'rhey may be used for the treatment of various ailments as mentionedon the first page of British Patent Specification 1507463 hereinbe~ore referred to.
.
. .
:. .:.: ,, . . , . :,.:
-.: :, ::
Claims (12)
1. A process for the preparation of N-(1-benzylpiperid-4-yl)-benzamides of the general formula:
I
(wherein X represents a chlorine or bromine atom, R1 represents a straight- or branched-chain alkyl group containing up to 6 carbon atoms, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions) which comprises reacting a thiobenzoic acid derivative of the general formula:- V
(wherein X and Rl are as hereinbefore defined, and R4 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms as substituents) with an alkyl chloroformate containing up to 6 carbon atoms in the alkyl moiety in an organic solvent and in the presence of triethylamine at a temperature between -15°C and 0°C, and reacting the resulting thioanhydride of the general formula:
VI
(wherein X, R1 and R4 are as hereinbefore defined, and R5 represents an alkyl group containing up to 6 carbon atoms) in situ with a 1-benzyl-4-aminopiperidine of the general formula:- IV
(wherein R2 and R3 are as hereinbefore defined) at a temperature between 0°C and 20°C, and - when R4 in the compound so obtained of the general formula:
VII
(wherein the various symbols are as hereinbefore defined) is the formyl group or an alkanoyl radical as hereinbefore mentioned subjecting the compound to acid hydrolysis to remove the acyl group and give an N-(1-benzylpiperid-4-yl)-benzamide of general formula I.
I
(wherein X represents a chlorine or bromine atom, R1 represents a straight- or branched-chain alkyl group containing up to 6 carbon atoms, R2 and R3 represent hydrogen atoms or one of those symbols represents a chlorine atom in the 3- or 4-position or a methyl or methoxy group in the 4-position and the other symbol represents a hydrogen atom, or R2 and R3 together represent a methylenedioxy group attached to the 3- and 4-positions) which comprises reacting a thiobenzoic acid derivative of the general formula:- V
(wherein X and Rl are as hereinbefore defined, and R4 represents a hydrogen atom, the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying one to three halogen atoms as substituents) with an alkyl chloroformate containing up to 6 carbon atoms in the alkyl moiety in an organic solvent and in the presence of triethylamine at a temperature between -15°C and 0°C, and reacting the resulting thioanhydride of the general formula:
VI
(wherein X, R1 and R4 are as hereinbefore defined, and R5 represents an alkyl group containing up to 6 carbon atoms) in situ with a 1-benzyl-4-aminopiperidine of the general formula:- IV
(wherein R2 and R3 are as hereinbefore defined) at a temperature between 0°C and 20°C, and - when R4 in the compound so obtained of the general formula:
VII
(wherein the various symbols are as hereinbefore defined) is the formyl group or an alkanoyl radical as hereinbefore mentioned subjecting the compound to acid hydrolysis to remove the acyl group and give an N-(1-benzylpiperid-4-yl)-benzamide of general formula I.
2. A process according to claim 1 in which the thiobenzoic acid derivative of general formula V is reacted with ethyl chloroformate.
3. A process according to claim 1 or 2 in which the reactions are carried out in acetone, methylene chloride or chloroform as the organic sol-vent.
4. A process according to claim 1 wherein R4 in the reactant of ge-neral formula V depicted in claim 1 represents the formyl group, or an alkanoyl radical containing from 2 to 5 carbon atoms optionally carrying 1 to 3 halogen atoms as substituents, and the resulting product of general formula VII depicted in claim 1 is hydrolysed by treatment with an aqueous alcoholic solution of hydrochloric acid at the boiling point of the mixture to give an N-(1-benzyl-piperid-4-yl)-benzamide of general formula I depicted in claim l.
5. A process according to claim 1 wherein in the general formulae de-picted in claim 1 X is as defined in claim 1, R1 represents a straight- or branched-chain alkyl group containing up to 5 carbon atoms, R2 is attached to the para-position of the benzene ring and represents a hydrogen or chlorine atom or a methyl or methoxy group, and R3 represents a hydrogen atom.
6. A process according to claim 1 or 5 wherein X represents a chlorine atom.
7. A process according to claim 1 wherein in the general formulae de-picted in claim 1 X represents a chlorine atom, R1 represents the methyl group, R2 is attached to the para-position of the benzene ring and represents a hydro-gen or chlorine atom or a methyl or methoxy group, and R3 represents a hydrogen atom.
8. A process according to claim 1 wherein R2 and R3 in general formulae I, IV and VII depicted in claim 1 represent hydrogen atoms.
9. A process according to claim 1 where m in the general formulae de-picted in claim 1 X represents a chlorine atom, R1 represents the methyl group and R2 and R3 represent hydrogen atoms.
10. A process according to claim 1 followed by the step of converting the N-(1-benzylpiperid-4-yl)-benzamide of general formula I depicted in claim 1 thus obtained into a pharmaceutically acceptable salt.
11. N-(1-benzylpiperid-4-yl)-benzamides of general formulae I depicted in claim I when prepared by the process claimed in claim 1.
12. The N-(1-benzylpiperid-4-yl)-benzamide of general formula I de-picted in claim 1 wherein X represents a chlorine atom, R1 represents the methyl group and R2 and R3 represent hydrogen atoms, when prepared by the pro-cess claimed in claim 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES470772 | 1978-06-14 | ||
| ES470772A ES470772A1 (en) | 1978-06-14 | 1978-06-14 | Novel manufacture of nn*11benzylpiperidoo44** benzamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1099719A true CA1099719A (en) | 1981-04-21 |
Family
ID=8476283
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA317,711A Expired CA1099719A (en) | 1978-06-14 | 1978-12-11 | Process for the preparation of n-(1-benzylpiperid-4- yl)-benzamides |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS54163584A (en) |
| AR (1) | AR224620A1 (en) |
| BE (1) | BE872641A (en) |
| CA (1) | CA1099719A (en) |
| ES (1) | ES470772A1 (en) |
| FR (1) | FR2428631A1 (en) |
| IL (1) | IL56146A (en) |
| NZ (1) | NZ189085A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5822232U (en) * | 1981-08-04 | 1983-02-10 | 相生精機株式会社 | Clamp pallet exchange device for machine tools |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1507463A (en) * | 1975-03-10 | 1978-04-12 | Gallardo Antonio Sa | N-(1-benzylpiperid-4-yl)-benzamides methods for their preparation and pharmaceutical compositions containing them |
-
1978
- 1978-06-14 ES ES470772A patent/ES470772A1/en not_active Expired
- 1978-12-04 NZ NZ189085A patent/NZ189085A/en unknown
- 1978-12-07 IL IL56146A patent/IL56146A/en unknown
- 1978-12-08 BE BE192227A patent/BE872641A/en not_active IP Right Cessation
- 1978-12-08 FR FR7835285A patent/FR2428631A1/en active Granted
- 1978-12-11 JP JP15297578A patent/JPS54163584A/en active Granted
- 1978-12-11 CA CA317,711A patent/CA1099719A/en not_active Expired
- 1978-12-13 AR AR274784A patent/AR224620A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| ES470772A1 (en) | 1979-01-16 |
| IL56146A0 (en) | 1979-03-12 |
| JPS612063B2 (en) | 1986-01-22 |
| BE872641A (en) | 1979-06-08 |
| NZ189085A (en) | 1981-04-24 |
| JPS54163584A (en) | 1979-12-26 |
| AR224620A1 (en) | 1981-12-30 |
| IL56146A (en) | 1982-07-30 |
| FR2428631A1 (en) | 1980-01-11 |
| FR2428631B1 (en) | 1982-12-31 |
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