WO2003055857A1 - A process for synthesis of heterocyclic aminoalkyl benzamides - Google Patents
A process for synthesis of heterocyclic aminoalkyl benzamides Download PDFInfo
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- WO2003055857A1 WO2003055857A1 PCT/YU2002/000029 YU0200029W WO03055857A1 WO 2003055857 A1 WO2003055857 A1 WO 2003055857A1 YU 0200029 W YU0200029 W YU 0200029W WO 03055857 A1 WO03055857 A1 WO 03055857A1
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- aminosulphonyl
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- 0 COc(ccc(S(N)(=O)=O)c1)c1C(NCC(CCC1)N1C1*[*+]1)=O Chemical compound COc(ccc(S(N)(=O)=O)c1)c1C(NCC(CCC1)N1C1*[*+]1)=O 0.000 description 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Definitions
- the suggested invention is related to the area of organic chemical technology, specificly to the process for obtainig of compounds belonging to the group of heterocyclic aminoalkyl benzamides, of general formula I, salts and/or hydrates and/or optical isomers thereof:
- Ri and R 2 denote Ci - C alkyl group
- R denotes amino-sulphonyl group
- R 4 denotes a hydrogen atom or an amino group
- R 5 denotes a hydrogen or a halogen atom
- the coefficients m and n have value of 1 and/or 2.
- sulpiride (RS, R+ or S-)-5-(Aminosulphonyl)-N-/(l-ethyl-2- pyrrolidinyl)methyl/-2-metoxybenzamide) of formula II
- sulmepride (RS, R+ or S-)-5- (Aminosulphonyl)-2-methoxy-N-/(l-methyl-2-pyrrolidinyl)methyl/benzamide
- the compounds belonging to the group of heterocyclic aminoalkyl benzamides of general formula I are also used in treatment of parkinsonism, for contraceptive mixtures, in treacment of sterility, as fungicides, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins.
- the suggested original invention solves the problem of obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides using cheaper starting substances, by reaction of 2-alcoxy-5-sulphamoyl-alkyl benzoate with (RS, R+ or S-) heterocyclic amine, with higher degree of their exploitation, which enables obtaining of the entire pallet of pharmaceutically acceptable compounds.
- Advantages of the present invention are: simple procedure of performing, lower reaction temperature and work at atmospheric pressure, without use of catalysts, performing of the reaction in cheaper and safer organic solvents, with obtaining of final product without subsequent purification, achieving of good yield and high quality of the final product, which makes the procedure cheaper for industrial use.
- French patent Fr 73 35 601 describes the procedure, according to which, the reaction between 2-methoxy-5-sulphamidobenzoic acid with N-ethyl-2- aminomethylpirrolidon in dioxane, in the presence of catalyst PhSiCh, gives sulpiride of formula II.
- Yugoslav patent YU 35 118 describes the procedure according to which 2-methoxy- 5-sulphamoylbenzoic acid ester in presence of hydrazin hydrate at 60°C in aqueous medium, is converted into 2-methoxy-5-sulphamoylbenzoyl hydrazid, and it is in aqueous medium, in presence of sodium nitrite converted into 2-methoxy-5- sulphamoylbenzoylazi.de, which is in presence of l-ethyl-2-aminomethyl pirrolidon in dioxane at temperature of 10°C gives sulpiride of formula II.
- Yugoslav patent YU 35 119 describes the procedure according to which l-ethyl-2- aminomethyl pyrrolidon in presence of phosphorous oxychloride in pyridine, is converted into N, N',N"-(l-ethyl-2-aminomethyl)phosphorous amide, which in reaction with 2- methoxy-5-sulphamoyl methylbenzoic acid in pyridine gives sulpiride of formula II.
- German patent DE 27 21 643 describes the procedure for obtaining of sulpiride of formula II, starting with 5-chlorosulphonyl-2-metoxybenzoyl chloride in chloroform at temperature of 10°C, N-ethyl-2-aminomethylpyrrolidon is instillated, and afterwards, that solution is added to the ammonium solution, and heated under reflux.
- the acylating agent N-acyl imidazole has priority, and it is obtained by reaction of an acid with 1, 1 '-sulphinyldiimidazole, but, also with 1, 1 '-carbonyldiimidazole.
- the suggested invention is related to the procedure of obtaining of the compounds of high pharmacopoeic purity, belonging to the group of heterocyclic aminoalkyl benzamides of general formula I and/or salts and/or hydrates and/or optical isomers thereof:
- Ri and R 2 denote C ⁇ - C 4 an alkyl group
- R 3 denotes amino-sulphonyl group
- R 4 denotes a hydrogen atom or an amino group
- R 5 denotes a hydrogen or a halogen atom
- the coefficients m and n have value of 1 and/or 2.
- Obtained compound is afterwards transformed into form of a tablet, pill, dragee, capsule, or ampulla, using usual pharmaceutical additives.
- the reactant of general formula VIII that is (RS, R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative has an asymmetric C atom, which does not alter the configuration during the synthesis.
- optically pure reactant of general formula VIII is used for the synthesis, ie, (R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative
- the mentioned procedure gives the compound belonging to the group of heterocyclic aminoalkyl benzamides of general formula I in the form of optical isomer R+ or S-.
- the present invention provides a completely new, original procedure for obtaining of heterocyclic aminoalkyl benzamides, using cheaper starting substances, with higher degree of their exploitation.
- the advantage of the present invention is in the just the way of synthesis of heterocyclic aminoalkyl benzamides, by synthesis of 2-alcoxy-5-sulphamoyl- alkyl benzoates and their reaction with the corresponding heterocyclic amine, which avoids the disadvantages of the procedures stated in already existing patents (use of catalysts, high temperatures of reaction, use of expensive and dangerous organic solvents, as well as obtaining of product which must be additionally purified, which reduces the yield and increases the costs of the very production).
- Basicly new procedure is described, which, in contrast to the already known procedures, has number of advantages, such as simplicity of the procedure of performing, lower temperature of reaction and work at atmospheric pressure, without using of catalysts, performing of the reaction in the cheaper and safer organic solvents, with obtaining of the final product without subsequent purification, achieving good yield and high quality of the final procuct, which makes the procedure cheaper for industrial use.
- the invention is primarily related to the synthesis of sulpiride (RS, R+ or S-) 5- (Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl)methyl/-2-methoxybenzamide, of formula II,
- the compounds processed in such way can be used in pharmaceutical form of tablets, pills, dragees, capsules, or ampullas, using usual pharmaceutical additives, for obtaining of pharmaceutical preparations used in therapy as antipsychotics, antidepressives and antiemetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism, obtained in usual manner.
- reaction mixture Into cooled reaction mixture, gradually is added 15% aqueous solution of HCl to pH 3, precipitate of 2-methoxy-5-sulphamoyl benzoic acid is separated by filtration, rinsed with water and suspended in 240 cm 3 of methanol, in which previously, 60 cm of sulphuric acid was disolved, and refluxed for 6 hours. Reaction mixture is effluxed into 900 cm of 15% aqueous solution of sodium carbonate, filtered, rinsed with water, then with methanol, well dried on filter funnel, and 2-methoxy-5-sulphamoyl methyl benzoate is obtained.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The simple, new, original and convenient for use, procedure for obtaining of compounds, belonging to the group of $i(heterocyclic aminoalkyl benzamides) of general formula 1, is developed, and/or salts and/or hydrates and/or optical isomers thereof, wherein R1 and R2 denote C1-C4 $i(alkyl) group, R3 denotes an $i(aminosulphonyl) group, denotes a $i(hydrogen) atom or an $i(amino) group, R5 denotes a $i(hydrogen) or a $i(halogen) atom, and and the coefficients $i(m )and $i(n) have value of 1 and/or 2. Of a particular interest in clinical practice are: $i(sulpiride )(RS, R+ or S-)-(5-$i(aminosulphonyl))-N-/(1-$i(ethyl)-2-$i(pyrrolidinyl))$i(methyl)/-2-$i(methoxybenzamide)) and sulmepride (RS, R+ or S-)-(5-($i(aminosulphonyl))-2-$i(methoxy)-N-/-(1-$i(methyl-)2-$i(pyrrolidinyl)methyl/benzamide)). The compounds belonging to this group are used in therapy as: antipsychotics, anti depressives and anti emetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism. The advantage of the present invention is in its completely new and simple way to carry out the synthesis of $i(heterocyclic aminoalkyl benzamides )and/or salts and/or hydrates thereof, through reaction of $i(2-alcoxy-5-suiphamoyl-alkyl benzoate )with the corresponding (RS R+ or S-) heterocyclic amine. )Lower temperature of rection and work at atmospheric pressure without catalysts, performing the reaction in cheaper and safer organic solvents, i obtaining the final product which does not require any additional purification, achieving of I good yield and high quality of the final product, cheaper procedure for industrial use and obtaining of the product of high pharmacopeic purity.
Description
A PROCESS FOR SYNTHESIS OF HETEROCYCLIC AMINOALKYL BENZAMIDES
The field of technique
The suggested invention is related to the area of organic chemical technology, specificly to the process for obtainig of compounds belonging to the group of heterocyclic aminoalkyl benzamides, of general formula I, salts and/or hydrates and/or optical isomers thereof:
(I) wherein Ri and R2 denote Ci - C alkyl group, R denotes amino-sulphonyl group, R4 denotes a hydrogen atom or an amino group, R5 denotes a hydrogen or a halogen atom, and the coefficients m and n have value of 1 and/or 2. Of special interest, concerning clinical practice, are: sulpiride (RS, R+ or S-)-5-(Aminosulphonyl)-N-/(l-ethyl-2- pyrrolidinyl)methyl/-2-metoxybenzamide) of formula II and sulmepride (RS, R+ or S-)-5- (Aminosulphonyl)-2-methoxy-N-/(l-methyl-2-pyrrolidinyl)methyl/benzamide of formula III,
(II) (III)
These compounds are used in therapy as antipsychotics, antidepressives and antiemetics.
The compounds belonging to the group of heterocyclic aminoalkyl benzamides of general formula I are also used in treatment of parkinsonism, for contraceptive mixtures, in treacment of sterility, as fungicides, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins.
According to international patent classification (Int.Cl.5) the invention can be classified into classes: C 07D 207/00, C 07D 207/06 and C 07D 207/08.
Technical problem
There was a need to come to the new, technically more perfect process for obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides and/or salts and/or hydrates and/or optical isomers thereof, which are used in human medicine as antipsychotics, antidepressives and antiemetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism. The suggested invention of the synthesis procedure is technically more convenient, more ecconomical, with higher yield and purity. Contemporary pharmaceutical technology sets the more strict demands for increasingly higher purity of the products, in comparison with already existing patents from the eighties, which had lower criteria.
The suggested original invention, in completely new way, solves the problem of obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides using cheaper starting substances, by reaction of 2-alcoxy-5-sulphamoyl-alkyl benzoate with (RS, R+ or S-) heterocyclic amine, with higher degree of their exploitation, which enables obtaining of the entire pallet of pharmaceutically acceptable compounds. Advantages of the present invention are: simple procedure of performing, lower reaction temperature and work at atmospheric pressure, without use of catalysts, performing of the reaction in cheaper and safer organic solvents, with obtaining of final product without subsequent purification, achieving of good yield and high quality of the final product, which makes the procedure cheaper for industrial use. In this way, disadvantages of the procedures mentioned in known patents, are avoided, for example: use of catalysts, high reaction temperatures, use of expensive and unsafe dangerous organic solvents, as well as obtaining of the product which requires an additional purification, which lowers the yield and raises the costs of the production.
Background of the invention
In professional and patent literature, there are number of ways for obtaining of compounds belonging to the group of heterocyclic aminoalkyl benzamides and/or salts and/or hydrates and/or optical isomers thereof.
It is known from before that the compounds belonging to the group of heterocyclic aminoalkyl benzamides of general formula I, possess antipsychotic, antidepressive and antiemetic properties (Annals of the New York Academy of Science, 96, 315, (1962)).
French patent Fr 73 35 601 describes the procedure, according to which, the reaction between 2-methoxy-5-sulphamidobenzoic acid with N-ethyl-2- aminomethylpirrolidon in dioxane, in the presence of catalyst PhSiCh, gives sulpiride of formula II.
In another French patent Fr 22 45 628, synthesis is carried out at temperature of 165°C, and as a catalyst, P2O5 is used.
Yugoslav patent YU 35 118 describes the procedure according to which 2-methoxy- 5-sulphamoylbenzoic acid ester in presence of hydrazin hydrate at 60°C in aqueous medium, is converted into 2-methoxy-5-sulphamoylbenzoyl hydrazid, and it is in aqueous medium, in presence of sodium nitrite converted into 2-methoxy-5- sulphamoylbenzoylazi.de, which is in presence of l-ethyl-2-aminomethyl pirrolidon in dioxane at temperature of 10°C gives sulpiride of formula II.
Yugoslav patent YU 35 119 describes the procedure according to which l-ethyl-2- aminomethyl pyrrolidon in presence of phosphorous oxychloride in pyridine, is converted into N, N',N"-(l-ethyl-2-aminomethyl)phosphorous amide, which in reaction with 2- methoxy-5-sulphamoyl methylbenzoic acid in pyridine gives sulpiride of formula II.
German patent DE 27 21 643 describes the procedure for obtaining of sulpiride of formula II, starting with 5-chlorosulphonyl-2-metoxybenzoyl chloride in chloroform at temperature of 10°C, N-ethyl-2-aminomethylpyrrolidon is instillated, and afterwards, that solution is added to the ammonium solution, and heated under reflux.
German patents DE 15 95 925 and DE 17 95 723, as well as Yugoslav patent YU 29 097, describe the procedures for obtaining of heterocyclic aminoalkyl benzamides by reaction of 2-alcoxybenzoic acid with suitable amines using various ways of converting of carboxylic group into active acylating agent. As the acylating agent, N-acyl imidazole has
priority, and it is obtained by reaction of an acid with 1, 1 '-sulphinyldiimidazole, but, also with 1, 1 '-carbonyldiimidazole.
Common disadvantages of the procedures described in the mentioned patents are: use of catalysts, high temperatures of reactions, use of expencive and dangerous organic solvents, as well as obtaining of a product which requires an additional purification, which lowers the yield and increases costs of the production.
Description of the invention with examples
The suggested invention is related to the procedure of obtaining of the compounds of high pharmacopoeic purity, belonging to the group of heterocyclic aminoalkyl benzamides of general formula I and/or salts and/or hydrates and/or optical isomers thereof:
Accoring to the new, original invention, the synthesis is carried out through the following series of reactions, and it starts when 2-alcoxy benzoic acid of formula IV:
(IV) in presence of chlorosulphonic acid, at temperature of reaction mixture in the range between 30-80°C, for 1-4 hours, at atmosperic pressure, is converted into 2-alcoxy-5- chlorosulphonyl benzoic acid of formula V:
(V) which is afterwards, in presence of ammonium hydroxide, with. heating at temperature in range between 20-50°C, for 1-5 hours, at atmospheric pressure, as well as, with neutralization with HCl aqueous solution, converted into 2-alcoxy-5-sulphamoyl benzoic acid of formula VI,
which is, afterwards, in presence of alcohol, for example methanol, ethanol, at temperature of reflux of reaction mixture for 2-9 hours, at atmosperic pressure, is converted into 2- alcoxy-5-sulphamoyl alkyl benzoate of formula VII:
(VII)
The synthetized 2-alcoxy-5-sulphamoyl benzoate of formula VII and (R, R+ or S-) 1-alkyl-
2-aminoalkyl heterocyclic derivative of formula VIII
Obtained compound is afterwards transformed into form of a tablet, pill, dragee, capsule, or ampulla, using usual pharmaceutical additives.
The reactant of general formula VIII, that is (RS, R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative has an asymmetric C atom, which does not alter the configuration during the synthesis. When optically pure reactant of general formula VIII is used for the synthesis, ie, (R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative, the mentioned procedure gives the compound belonging to the group of heterocyclic aminoalkyl benzamides of general formula I in the form of optical isomer R+ or S-.
The present invention provides a completely new, original procedure for obtaining of heterocyclic aminoalkyl benzamides, using cheaper starting substances, with higher degree of their exploitation. The advantage of the present invention is in the just the way of synthesis of heterocyclic aminoalkyl benzamides, by synthesis of 2-alcoxy-5-sulphamoyl- alkyl benzoates and their reaction with the corresponding heterocyclic amine, which avoids the disadvantages of the procedures stated in already existing patents (use of catalysts, high temperatures of reaction, use of expensive and dangerous organic solvents, as well as obtaining of product which must be additionally purified, which reduces the yield and increases the costs of the very production). Basicly new procedure is described, which, in contrast to the already known procedures, has number of advantages, such as simplicity of the procedure of performing, lower temperature of reaction and work at atmospheric pressure, without using of catalysts, performing of the reaction in the cheaper and safer organic solvents, with obtaining of the final product without subsequent purification, achieving good yield and high quality of the final procuct, which makes the procedure cheaper for industrial use.
The invention is primarily related to the synthesis of sulpiride (RS, R+ or S-) 5- (Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl)methyl/-2-methoxybenzamide, of formula II,
(II) sulmepride (RS, R+ or S-) (5-(Aminosulphonyl)-2-methoxy-N-/(l-methyl-2- pyrrolidinyl)methyl/benzamide), of formula III
The compounds processed in such way, can be used in pharmaceutical form of tablets, pills, dragees, capsules, or ampullas, using usual pharmaceutical additives, for obtaining of pharmaceutical preparations used in therapy as antipsychotics, antidepressives
and antiemetics, fungicides, for contraceptive mixtures, in treatment of sterility, as radiopharmaceutical compositions in nuclear medicine, in treatment of migraine of various origins, as well as in treatment of parkinsonism, obtained in usual manner.
In order to make understanding of the procedure, which is the subject of the present invention, easier, examples of different phases of the procedure are given, but should not be considered as restrictive.
EXAMPLE 1: Synthesis of sulpiride (RS, R+ or S-) (5-(Aminosulphonyl)-N-/(l- ethyl-2-pyrrolidinyl)methyl/methoxybenzamide) of formula II
Into 284 cm3 of chlorosulphonic acid, 100 gr of 2-methoxy benzoic acid is added, with constant stirring and cooling, the syntesis is being carried out for 1 hour at 50°C, and then, for half an hour at 70°C, and afterwards, the reaction mixture is effluxed into 1000 cm3 of cooled distillated water, filtered, rinsed with water, and obtained precipitate of 2- methoxy-5-chlorosulphonly benzoic acid is added, with constant stirring, to 500 cm3 of ammonium hydroxide, heated for 2 hours at 30°C. Into cooled reaction mixture, gradually is added 15% aqueous solution of HCl to pH 3, precipitate of 2-methoxy-5-sulphamoyl benzoic acid is separated by filtration, rinsed with water and suspended in 240 cm3 of methanol, in which previously, 60 cm of sulphuric acid was disolved, and refluxed for 6 hours. Reaction mixture is effluxed into 900 cm of 15% aqueous solution of sodium carbonate, filtered, rinsed with water, then with methanol, well dried on filter funnel, and 2-methoxy-5-sulphamoyl methyl benzoate is obtained. Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwards suspended in 215 cm3 of ethylene glycol, to which 62 gr of (RS) l-ethyl-2-aminomethylpyrrolidine was previously added. After heating at 62-65°C for 36 hours, filtering, rinsing with cooled distilled water and drying at 45°C, 138,6 g of sulpiride (RS) 5-(Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl)methyl/-2-methoxybenzamide of formula II is obtained, 90%) yield.
Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwards suspended in 215cm of etylene glycol to which 62 gr of (R+) 1 -ethyl-2-aminomethylpyrrolidin was previously added. After heating at 62-65°C for 36 hours, rinsing with cooled distilled water
and drying at 45°C, 138,6 g of sulpiride (R+) 5-(Aminosulphonyl)-N-/(l-ethyl-2- pyrrolidinyl)methyl/-2-methoxybenzamide of formule II is obtained, 90%» yield.
Obtained 2-methoxy-5-sulphamoyl methyl benzoate is afterwords suspended in 215 cm3 of etylene glycol to which 62 gr of (S-) l-ethyl-2-aminomethylpyrrolidin was previously added. After heating at 62-65°C for 36 hours, rinsing with cooled distilled water and drying at 45°C, 138,6 g of sulpiride (S-) 5-(Aminosulphonyl)-N-/(l-ethyl-2- pyrrolidinyl)methyl/-2-methoxybenzamide of formule II is obtained, 90% yield.
EXAMPLE 2: Synthesis of sulmepride (RS, R+ or S-) (5-(Aminosulphonyl)-2-methoxy-N- /(l-methyl-2-pyrrolidinyl)methyl/benzamide) of formula III
The synthesis is carried out analogously to the procedure described in Example 1, with the difference that instead of the compound (RS) l-ethyl-2-aminomethyl pyrrolidin, (RS) l-methyl-2-aminomethyl pyrrolidin is used, and sulmepride (RS) (5- (Aminosulphonyl)-2-methoxy-N-/(l-methyl-2-pyrrolidinyl)methyl/benzamide) of formula III is obtained, 75 % yield.
The synthesis is carried out analogously to the procedure described in Example 1, with the difference that instead of the compound (R+) l-ethyl-2-aminomethyl pyrrolidin, (R+) l-methyl-2-aminomethyl pyrrolidin is used, and sulmepride (R+) (5- (Aminosulphonyl)-2-methoxy-N-/(l-methyl-2-pyrrolidinyl)methyl/benzamide) of formula III is obtained, 75% yield.
The synthesis is carried out analogously to the procedure described in Example 1 , with the difference that instead of the compound (S-) l-ethyl-2-aminomethyl pyrrolidin, (S-) l-methyl-2-aminomethyl pyrrolidin is used, and sulmepride (S-) (5-(Aminosulphonyl)- 2-methoxy-N-/(l-methyl-2-pyrrolidinyl)methyl/benzamide) of formula III is obtained, 75% yield.
Claims
1. The procedure for obtainig of pharmaceutical compounds, belonging to the group of heterocyclic aminoalkyl benzamides, of general formula I, and/or salt and/or hydrates and/or optical isomers thereof:
(V) which is, afterwards, converted, with heating at temperature in the range between 20- 50°C, in presence of ammonium hydroxide, into 2-alcoxy-5-sulphamoyl benzoic acid of formula VI: 
(VI) and it is, in presence of an alcohol, for example methanol, ethanol, at temperature of reflux of reaction mixture, converted into 2-alcoxy-5-sulphamoyl alkyl benzoate of formula VII:
(VII) which reacts with (RS, R+ or S-) l-alkyl-2 -aminoalkyl heterocyclic derivative of formula VIII:
(VIII) in an organic solvent, belonging to the group of alcohols, such as: methanol, ethanol, ethylene glycol, for 10 to 90 hours, at atmospheric pressure and temperature of the reaction mixture in the range between 20 and 100°C, primarily at temperature in the range between 35 and 85°C, and the compound of general formula I is obtained, in the form of pharmaceutically acceptable salt and/or hydrate of pharmacological purity, which is afterwards converted into the form of tablets, pills, dragees, capsules, or ampullas, using usual pharmaceutical additives.
2. The procedure, according to the patent claim 1, denoted by the fact, that 0,8 to 2,5 mol of (RS, R+ or S-) l-alkyl-2-aminoalkyl heterocyclic derivative of general formula VIII reacts with a single mol of 2-methoxy-5-sulphamoyl-methylbenzoate of formule VII, and heterocyclic aminoalkyl benzamide, of general formula I is obtained.
3. The compound sulpiride (RS) (5-(Aminosulphonyl)rN-/(l-ethyl-2-pyrrolidinyl)methyl/- 2-methoxy benzamide), obtained according to the procedure described in the patent claims 1 and 2, in the form of a salt and/or a hydrate.
4. The compound sulpiride (R+) (5-(Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl)methyl/- 2-methoxy benzamide), obtained according to the procedure described in the patent claims 1 and 2, in the form of a salt and/or a hydrate.
5. The compound sulpiride (S-) (5-(Aminosulphonyl)-N-/(l-ethyl-2-pyrrolidinyl)methyl/- 2-methoxy benzamide), obtained according to the procedure described in the patent claims 1 and 2, in the form of a salt and/or a hydrate.
6. The compound sulmepride (RS) (5-(Aminosulphonyl)-2-methoxy-N-/(l-methyl-2- pyrrolidinyl)methyl/benzamide), obtained according to the procedure described in the patent claims 1 and 2 in the form of a salt and/or a hydrate.
7. The compound sulmepride (R+) (5-(Aminosulphonyl)-2-methoxy-N-/(l-methyl-2- pyrrolidinyl)methyl/benzamide) , obtained according to the procedure described in the patent claims 1 and 2 in the form of a salt and/or a hydrate.
8. The compound sulmepride (S-) (5-(Aminosulphonyl)-2-methoxy-N-/(l-methyl-2- pyrrolidinyl)methyl/benzamide) , obtained according to the procedure described in the patent claims 1 and 2 in the form of a salt and/or a hydrate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420887A (en) * | 2013-08-30 | 2013-12-04 | 孙威 | Levosulpiride compound and preparation method thereof |
| CN103772256A (en) * | 2012-10-24 | 2014-05-07 | 天士力控股集团有限公司 | Preparation method for high-purity sulpiride or optical isomers thereof |
| CN103804265A (en) * | 2012-11-08 | 2014-05-21 | 江苏天士力帝益药业有限公司 | Synthesis and post-processing method of sulpiride or optical isomer thereof |
| CN105601544A (en) * | 2015-12-30 | 2016-05-25 | 苏州诚和医药化学有限公司 | Synthesis method of 2-methoxyl-5-amino sulfanoylmethyl benzoate |
| CN112441960A (en) * | 2020-12-14 | 2021-03-05 | 常州康普药业有限公司 | Synthetic method of sulpiride |
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| US3342826A (en) * | 1964-01-13 | 1967-09-19 | Ile De France | Heterocyclic aminoalkyl benzamides |
| DE2212340A1 (en) * | 1972-03-15 | 1973-09-20 | Troponwerke Dinklage & Co | 5-sulphamoyl-o-anisamide deriv prodn via 5-sulphamoyl-o-anisic - acid 3,5-dimethylpyrazolide |
| DE2305632A1 (en) * | 1972-04-10 | 1973-10-18 | Microsules Argentina Sociedad | N-(1-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl - -benzamides - prepd from salicylic acid cpds |
| DE2459221A1 (en) * | 1973-12-21 | 1975-06-26 | Italfarmaco Spa | 1-Ethyl-2-(2-methoxy-5-sulphamoylbenzamidomethyl)-pyrrolidine - prepd. from methyl 2-methoxy-5-sulphamoyl-benzoate |
| GB1447329A (en) * | 1973-09-28 | 1976-08-25 | Deteudes Scintifiques Et Ind D | Preparation of sulphonyl-benzamide derivatives |
| GB2014990A (en) * | 1978-02-16 | 1979-09-05 | Ravizza Spa | Process for preparing an optically active benzamide, the optically active benzamide so obtained and pharmaceutical compositions containing it |
-
2002
- 2002-12-27 AU AU2002364553A patent/AU2002364553A1/en not_active Abandoned
- 2002-12-27 WO PCT/YU2002/000029 patent/WO2003055857A1/en not_active Application Discontinuation
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| US3342826A (en) * | 1964-01-13 | 1967-09-19 | Ile De France | Heterocyclic aminoalkyl benzamides |
| DE2212340A1 (en) * | 1972-03-15 | 1973-09-20 | Troponwerke Dinklage & Co | 5-sulphamoyl-o-anisamide deriv prodn via 5-sulphamoyl-o-anisic - acid 3,5-dimethylpyrazolide |
| DE2305632A1 (en) * | 1972-04-10 | 1973-10-18 | Microsules Argentina Sociedad | N-(1-ethyl-2-pyrrolidylmethyl)-2-methoxy-5-sulphamoyl - -benzamides - prepd from salicylic acid cpds |
| GB1447329A (en) * | 1973-09-28 | 1976-08-25 | Deteudes Scintifiques Et Ind D | Preparation of sulphonyl-benzamide derivatives |
| DE2459221A1 (en) * | 1973-12-21 | 1975-06-26 | Italfarmaco Spa | 1-Ethyl-2-(2-methoxy-5-sulphamoylbenzamidomethyl)-pyrrolidine - prepd. from methyl 2-methoxy-5-sulphamoyl-benzoate |
| GB2014990A (en) * | 1978-02-16 | 1979-09-05 | Ravizza Spa | Process for preparing an optically active benzamide, the optically active benzamide so obtained and pharmaceutical compositions containing it |
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| "ZHONGGUO YIYAO GONGYE ZAZHI - CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN, SHANGHAI,, CN", ZHONGGUO YIYAO GONGYE ZAZHI - CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN, SHANGHAI,, CN, vol. 27, no. 11, 1996, pages 487 - 489, XP009008935, ISSN: 1001-8225 * |
| JIANG Z-L ET AL: "SYNTHESIS OF LEVOSULPIRIDE", ZHONGGUO YIYAO GONGYE ZAZHI - CHINESE JOURNAL OF PHARMACEUTICALS, SHANGHAI YIYAO GONGYE YANJIUYUAN, SHANGHAI,, CN, vol. 27, no. 11, 1996, pages 485 - 486, XP009008934, ISSN: 1001-8225 * |
| VALENTA V ET AL: "POTENTIAL NEUROLEPTICS OF THE ORTHOPRAMIDE SERIES;SYNTHESIS OF N-SUBSTITUTED 5-(AMINOSULFONYL)-2-METHOXYBENZAMIDES", COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, ACADEMIC PRESS, LONDON, GB, vol. 52, no. 8, 1987, pages 2095 - 2106, XP009008918, ISSN: 0010-0765 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772256A (en) * | 2012-10-24 | 2014-05-07 | 天士力控股集团有限公司 | Preparation method for high-purity sulpiride or optical isomers thereof |
| CN103804265A (en) * | 2012-11-08 | 2014-05-21 | 江苏天士力帝益药业有限公司 | Synthesis and post-processing method of sulpiride or optical isomer thereof |
| CN103420887A (en) * | 2013-08-30 | 2013-12-04 | 孙威 | Levosulpiride compound and preparation method thereof |
| CN105601544A (en) * | 2015-12-30 | 2016-05-25 | 苏州诚和医药化学有限公司 | Synthesis method of 2-methoxyl-5-amino sulfanoylmethyl benzoate |
| CN112441960A (en) * | 2020-12-14 | 2021-03-05 | 常州康普药业有限公司 | Synthetic method of sulpiride |
| CN112441960B (en) * | 2020-12-14 | 2022-03-01 | 常州康普药业有限公司 | Synthetic method of sulpiride |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002364553A1 (en) | 2003-07-15 |
| WO2003055857A8 (en) | 2003-10-30 |
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