CA1055926A - Arginine salt of amoxycillin - Google Patents
Arginine salt of amoxycillinInfo
- Publication number
- CA1055926A CA1055926A CA233,612A CA233612A CA1055926A CA 1055926 A CA1055926 A CA 1055926A CA 233612 A CA233612 A CA 233612A CA 1055926 A CA1055926 A CA 1055926A
- Authority
- CA
- Canada
- Prior art keywords
- amoxycillin
- arginine
- mixture
- salt
- propyleneglycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cephalosporin Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT
The present invention relates to the arginine salt of amoxycillin, to a process for the preparation thereof and to pharmaceutical compositions containing said salt, which has antibiotic properties.
The present invention relates to the arginine salt of amoxycillin, to a process for the preparation thereof and to pharmaceutical compositions containing said salt, which has antibiotic properties.
Description
The pre~ent invention relates to a salt. More particularly, the invention is concerned with a salt of a penicillanic acid derivative, a proces-s for the manufacture thereof and pharmaceutical preparations containing same.
The salt provided by the present invention is the salt of 6-l(R)-a-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginine.
6-[(R)-a-Amino-p-hydroxyphenylacetamido]-penicillanic acid is an antibiotic which is known under the name amoxycillin and which ha~ a wide spectrum of activity. Amoxycillin, which is practically in~oluble in water and aqueous solutions, as well a it3 hitherto known salts, can not be administered parenterally.
There has accordingly been a need for a new, non-toxic, parenterally admini~trable form of amoxycillin while retaining the antibiotic propertiea thereof.
It has now been found in accordance with the present invention that the arginine ~alt of amoxycillin satisfies the foregoing requirements.
According to the process provided by the pre~ent invention, the arginine salt of amoxycillin is manufactured by reacting 6-[(R)-a-amino-p-hydroxyphenylacetamido]--penicillanic acid or a hydrated form thereof, the amino group Me/26.6.1975 - 2 -being optionally present in protected form, with arginine and cleaving off a protecting group which may be present.
The 6-[(R)--amino-p-hydroxyphenylacetamido]-penicillanic acid used as the starting material can contain an amino group provided with a protecting group instead of a free amino group, Such a protected amino group is then converted, following the reaction of the 6-[tR)-~-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginlne, into a free amino group in a manner known per se. Thus, for example, an optionally sub-stituted benzyloxycarbonylamino group can be re-converted into a free amino group by catalytical hydrogenation.
In the reaction of amoxycillin or a hydrated form thereof with arginine there are preferably used equivalent amounts of both reactants. ~owever, an excess of up to about 10% of arginine can be used if desired. The reaction can be carried out in the presence of water, methanol, dimethyl sulphoxide, dlmethylformamide or the like, or in the presence of a mixture of propyleneglycol and methanol or of a mixture of water or propyleneglycol on the one side and ethanol, propanol or iso-propanol on the other side, as a solvent, there being prefer-ably used methanol, a mixture of propyleneglycol and methanol or a mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side. Most preferred ls the use of a mixture of propyleneglycol and ethanol. The reaction i5 conveniently carried out at a temper~
ture between about 0C and 30C. The reaction is preferably carried out at room temperature or, when water is used as the solvent, at 5C.
When the reaction of amoxycillin or a hydrated form thereof with arginine ls carried out in the presence of water as a solvent, the isolation of the arginlne salt of amoxycillin from the reaction mixture can be carried out by lyophilisation.
When the reaction of amoxycillin of a hydrated form thereof with arginine is carried out in the presence of a solvent other than water, e.g. methanol, dimethyl sulphoxide or dimethylformamide, the lsolation of the arginine salt of amoxy-clllin from the reaction mixture can be carried out by stirring the reaction mixture in a second solvent, e.g. diethyl ether, ethyl acetate or the llke, in which the arginine salt of amoxy-cillin is insoluble. In thls case, at least 2 volumes of the second solvent are conveniently used per volume of the first solvent.
When the reactlon of axginine with amoxycillin or a hydrated form thereof is carried out in the presence of a mixture of water and ethanol, propanol or isopropanol, as a solvent, there are conveniently used 15-25 volumes, preferably 20 volumes, of water per 100 volumes of ethanol and 40-60 volumes, preferably 50 volumes, of water per 100 volumes of propanol or isopropanol. When the reaction of arginine with amoxycillin or a hydrated form thereof is carried out in the presence of a mixture of propyleneglycol and methanol, ethanol, propanol or isopropanol, as a solvent, there are conveniently used 30-50 volumes, preferably 40 volumes, of propyleneglycol per 100 volumes of methanol or ethanol and 60-100 volumes, preferably 75 volumes, of propyleneglycol per 100 volumes of propanol or isopropanol. When a mixture of propyleneglycol and methanol or a mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side is used as a solvent, the arginine salt of amoxycillin can be isolated from the reaction mixture by stirring the reaction mixture in a solvent, conveniently ethanol, propanol or iso-propanol, in which the arglnine salt of amoxycillin is insoluble.
In order to precipitate the arginine salt of amoxycillin, there are conveniently used 3 volumes of one of these three solvents per volume of the mixture of propyleneglycol and methanol or per volume of the mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side, used as solvent in the reaction of arginine with amoxy-clllin.
The arginine salt of amoxycillin has an antibioticactivity in the order of that of amoxycillin. It possess a wide spectrum of activity against gram-positive and gram--negative microorganisms.
The salt provided by the present invention can be used for the treatment and prophylaxis of infectious diseases and as disinfection agents. Individual dosages of ca 0.25 g to
The salt provided by the present invention is the salt of 6-l(R)-a-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginine.
6-[(R)-a-Amino-p-hydroxyphenylacetamido]-penicillanic acid is an antibiotic which is known under the name amoxycillin and which ha~ a wide spectrum of activity. Amoxycillin, which is practically in~oluble in water and aqueous solutions, as well a it3 hitherto known salts, can not be administered parenterally.
There has accordingly been a need for a new, non-toxic, parenterally admini~trable form of amoxycillin while retaining the antibiotic propertiea thereof.
It has now been found in accordance with the present invention that the arginine ~alt of amoxycillin satisfies the foregoing requirements.
According to the process provided by the pre~ent invention, the arginine salt of amoxycillin is manufactured by reacting 6-[(R)-a-amino-p-hydroxyphenylacetamido]--penicillanic acid or a hydrated form thereof, the amino group Me/26.6.1975 - 2 -being optionally present in protected form, with arginine and cleaving off a protecting group which may be present.
The 6-[(R)--amino-p-hydroxyphenylacetamido]-penicillanic acid used as the starting material can contain an amino group provided with a protecting group instead of a free amino group, Such a protected amino group is then converted, following the reaction of the 6-[tR)-~-amino-p-hydroxyphenylacetamido]-penicillanic acid with arginlne, into a free amino group in a manner known per se. Thus, for example, an optionally sub-stituted benzyloxycarbonylamino group can be re-converted into a free amino group by catalytical hydrogenation.
In the reaction of amoxycillin or a hydrated form thereof with arginine there are preferably used equivalent amounts of both reactants. ~owever, an excess of up to about 10% of arginine can be used if desired. The reaction can be carried out in the presence of water, methanol, dimethyl sulphoxide, dlmethylformamide or the like, or in the presence of a mixture of propyleneglycol and methanol or of a mixture of water or propyleneglycol on the one side and ethanol, propanol or iso-propanol on the other side, as a solvent, there being prefer-ably used methanol, a mixture of propyleneglycol and methanol or a mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side. Most preferred ls the use of a mixture of propyleneglycol and ethanol. The reaction i5 conveniently carried out at a temper~
ture between about 0C and 30C. The reaction is preferably carried out at room temperature or, when water is used as the solvent, at 5C.
When the reaction of amoxycillin or a hydrated form thereof with arginine ls carried out in the presence of water as a solvent, the isolation of the arginlne salt of amoxycillin from the reaction mixture can be carried out by lyophilisation.
When the reaction of amoxycillin of a hydrated form thereof with arginine is carried out in the presence of a solvent other than water, e.g. methanol, dimethyl sulphoxide or dimethylformamide, the lsolation of the arginine salt of amoxy-clllin from the reaction mixture can be carried out by stirring the reaction mixture in a second solvent, e.g. diethyl ether, ethyl acetate or the llke, in which the arginine salt of amoxy-cillin is insoluble. In thls case, at least 2 volumes of the second solvent are conveniently used per volume of the first solvent.
When the reactlon of axginine with amoxycillin or a hydrated form thereof is carried out in the presence of a mixture of water and ethanol, propanol or isopropanol, as a solvent, there are conveniently used 15-25 volumes, preferably 20 volumes, of water per 100 volumes of ethanol and 40-60 volumes, preferably 50 volumes, of water per 100 volumes of propanol or isopropanol. When the reaction of arginine with amoxycillin or a hydrated form thereof is carried out in the presence of a mixture of propyleneglycol and methanol, ethanol, propanol or isopropanol, as a solvent, there are conveniently used 30-50 volumes, preferably 40 volumes, of propyleneglycol per 100 volumes of methanol or ethanol and 60-100 volumes, preferably 75 volumes, of propyleneglycol per 100 volumes of propanol or isopropanol. When a mixture of propyleneglycol and methanol or a mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side is used as a solvent, the arginine salt of amoxycillin can be isolated from the reaction mixture by stirring the reaction mixture in a solvent, conveniently ethanol, propanol or iso-propanol, in which the arglnine salt of amoxycillin is insoluble.
In order to precipitate the arginine salt of amoxycillin, there are conveniently used 3 volumes of one of these three solvents per volume of the mixture of propyleneglycol and methanol or per volume of the mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side, used as solvent in the reaction of arginine with amoxy-clllin.
The arginine salt of amoxycillin has an antibioticactivity in the order of that of amoxycillin. It possess a wide spectrum of activity against gram-positive and gram--negative microorganisms.
The salt provided by the present invention can be used for the treatment and prophylaxis of infectious diseases and as disinfection agents. Individual dosages of ca 0.25 g to
2 g up to four times per day can be administered to adults.
On the basis of its excellent water-solubility (more than 10%) and of its excellent local tolerability, the salt provided by the present invention is particularly suitable for parenteral administration.
The acute toxicity (LD 50) of the arginine salt of amoxycillin amounts to 2500-5000 mg/kg upon intraveneous administration and to more than 5000 mg/kg upon subcutaneous administration to mice. The activity (CD 50) of the arginine salt of amoxycillin against Escherichia coli upon subcutaneous administration to mice amounts to 4.5 mg/kg.
Pharmaceutical preparations provided by the present invention can contain the arginine salt of amoxycillin in association with a compatible pharmaceutical carrier material.
Such a carrier material can be an organic or inorganic inert carrier material suitable for enteral or, especially, parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate and the like. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées, suppositories or capsules) or, especially, in a liquid form (e.g. as aqueous solutions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emul~ifying agents, salts for varying the osmotic pressure or buffers. The pharmaceutical preparations may also contain therapeutically valuable materials other than the salt provided by the present invention. Preferably, the arginine salt of amoxycillin ls contained as active substance in a dry ampoule.
10559~6 The following Examples illustrate the process provided by the present invention:
Example 1 1.70 g of L-arginine are added portionwise within 10 S minutes to a suspension of 4.20 g of amoxycillin trihydrate in 200 ml of water stirred at 5C. After stirring for a further 10 minutes, undissolved material is filtered off under suction and the filtrate is lyophilised. There are obtained 5.2 g of lyophilisate. Melting point: decomposition above 200C. [a]25 = +175.0 (c = 1.0 in water).
Example 2 A suspension of 184 g of L-arginine in 4 litres of absolute methanol, stirred at room temperature, is treated within 3 minutes with 429 g of amoxycillin trihydrate and the lS mixture is vigorously stirred for a further 15 minutes.
Insoluble material is filtered off under suction and the filtrate is introduced into 10 litres of diethyl ether. The precipitate is filtered off under suction, washed with 6 litres of diethyl ether and dried. There are obtained 491 g of the arginine salt of amoxycillin. Melting point: decomposition above 200C. []25 = +174.7 (c = 1.0 in water).
Example 3 To a suspension of 12 g of L-arginine in 21 ml of water, stirred at room temperature, are added 100 ml of absolute ethanol and immediately thereafter 24 g of amoxycillin 1~559Z6 trihydrate. After stirring for 5 minutes, the mixture is filtered clear under suction and the syrupy solution allowed to flow into 1.2 litres of vigorously stirred absolute ethanol cooled to -5C. The precipitated product is filtered off under suction and washed with 400 ml of absolute ethanol.
After drying in vacuo, there are obtained 20.5 g of the arginine salt of amoxycillin. Melting point: decompo~ition above 200C. [~]25 = +165.9 (c = 1.0 in water).
Example 4 42 g of amoxycillin trihydrate are added to a suspension of 21 g of L-arginine in 70 ml of propyleneglycol and 180 ml of absolute ethanol and the mixture is intensively stirred for 45 minutes at room temperature. The mixture is then filtered and the fi~trate introduced into 1.4 litres of absolute ethanol at -5C while stirring. The precipitated salt is filtered off under suction, washed four times with 50 ml of absolute ethanol each time and dried in vacuo. There are obtained 40.4 g of the arginine salt of amoxycillin. Melting point: decompo-sition above 200C. [a]25 = +157 (c = 1 in water).
Example 5 8.2 g of amoxycillin trihydrate are added to a sl~spension of 4.2 g of L-arginine in 60 ml of propyleneglycol and 80 ml of isopropanol and the mixture is intensively stirred for 60 minutes at room temperature. The mixture is then filtered and the filtrate introduced into 500 ml of isopropanol at 5C
while stirring. The precipitated salt is filtered off under suction, washed four times with 30 ml of isopropanol each time and dried in vacuo. There are obtained 8.2 g of the arginine salt of amoxycillin. Melting point: decomposition above 200~C. [~]D5 ' +168.7 (c = 1 in water).
Example 6 To a suspension of 20 g of L-arginine in a mixture of 70 ml of propyleneglycol and 180 ml of methanol are added 40 g of amoxycillln trihydrate and the mixture is stirred at 20C for 15 minutes. The mixture is then filtered, washed wlth a mixture of 28 ml of propyleneglycol and 72 ml of methanol and added to 1,4 1 of isopropanol stirred at 5C. After stirring at 5C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times wlth 50 ml of i~opropanol. After drying in vacuo, there are obtained 50,2 g of the arginine salt of amoxycillin. Melting point: decomposition above 210C.
[]D5= ~159 (c = 1,493 in water).
Example 7 To a suspension of 20 g of L arginine in a mixture of 70 ml of propyleneglycol and 180 ml of absolute ethanol, vigorously stirred at 20C, are added 40 g of amoxycillin trihydrate and the mixture is stirred for a further 30 minutes at 20C. Insoluble material in then filtered off, washed with a mixture of 14 ml of propyleneglycol and 36 ml of absolute ethanol and the viscous solution is added to 1,4 1 of isopro-panol stirred a 5C. After stirring at 5C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times with 50 ml of ~0559Z6 isopropanol and then flve times wlth 50 ml of diethyl ether.
After drying in vacuo, there are obtalned 45,7 g of the arginine salt of amoxyclllin. Melting point: decomposition above 210 C. [~]D = +172,2 (c = 1,5 in water).
The following Examples illustrate typical pharmaceutical preparations containing the arginine salt of amoxycillin provided by this invention:
Example A
A lyophilisate of the following composition, based on 4 ml of ready-for-use injection solution, is manufactured in the usual manner:
Arginine salt of amoxycillin370 mg Methyl p-hydroxybenzoate 1.1 mg Propyl p-hydroxybenzoate 0.135 mg Example B
740 mg of the arginine salt of amoxycill~n are filled into a dry ampoule in the usual manner. In order to prepare a ready-for-use injection solution, 5 ml of sterile water or 5 ml of a sterile physiological sodium chloride solution are added to thi salt.
On the basis of its excellent water-solubility (more than 10%) and of its excellent local tolerability, the salt provided by the present invention is particularly suitable for parenteral administration.
The acute toxicity (LD 50) of the arginine salt of amoxycillin amounts to 2500-5000 mg/kg upon intraveneous administration and to more than 5000 mg/kg upon subcutaneous administration to mice. The activity (CD 50) of the arginine salt of amoxycillin against Escherichia coli upon subcutaneous administration to mice amounts to 4.5 mg/kg.
Pharmaceutical preparations provided by the present invention can contain the arginine salt of amoxycillin in association with a compatible pharmaceutical carrier material.
Such a carrier material can be an organic or inorganic inert carrier material suitable for enteral or, especially, parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate and the like. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées, suppositories or capsules) or, especially, in a liquid form (e.g. as aqueous solutions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preserving, stabilising, wetting or emul~ifying agents, salts for varying the osmotic pressure or buffers. The pharmaceutical preparations may also contain therapeutically valuable materials other than the salt provided by the present invention. Preferably, the arginine salt of amoxycillin ls contained as active substance in a dry ampoule.
10559~6 The following Examples illustrate the process provided by the present invention:
Example 1 1.70 g of L-arginine are added portionwise within 10 S minutes to a suspension of 4.20 g of amoxycillin trihydrate in 200 ml of water stirred at 5C. After stirring for a further 10 minutes, undissolved material is filtered off under suction and the filtrate is lyophilised. There are obtained 5.2 g of lyophilisate. Melting point: decomposition above 200C. [a]25 = +175.0 (c = 1.0 in water).
Example 2 A suspension of 184 g of L-arginine in 4 litres of absolute methanol, stirred at room temperature, is treated within 3 minutes with 429 g of amoxycillin trihydrate and the lS mixture is vigorously stirred for a further 15 minutes.
Insoluble material is filtered off under suction and the filtrate is introduced into 10 litres of diethyl ether. The precipitate is filtered off under suction, washed with 6 litres of diethyl ether and dried. There are obtained 491 g of the arginine salt of amoxycillin. Melting point: decomposition above 200C. []25 = +174.7 (c = 1.0 in water).
Example 3 To a suspension of 12 g of L-arginine in 21 ml of water, stirred at room temperature, are added 100 ml of absolute ethanol and immediately thereafter 24 g of amoxycillin 1~559Z6 trihydrate. After stirring for 5 minutes, the mixture is filtered clear under suction and the syrupy solution allowed to flow into 1.2 litres of vigorously stirred absolute ethanol cooled to -5C. The precipitated product is filtered off under suction and washed with 400 ml of absolute ethanol.
After drying in vacuo, there are obtained 20.5 g of the arginine salt of amoxycillin. Melting point: decompo~ition above 200C. [~]25 = +165.9 (c = 1.0 in water).
Example 4 42 g of amoxycillin trihydrate are added to a suspension of 21 g of L-arginine in 70 ml of propyleneglycol and 180 ml of absolute ethanol and the mixture is intensively stirred for 45 minutes at room temperature. The mixture is then filtered and the fi~trate introduced into 1.4 litres of absolute ethanol at -5C while stirring. The precipitated salt is filtered off under suction, washed four times with 50 ml of absolute ethanol each time and dried in vacuo. There are obtained 40.4 g of the arginine salt of amoxycillin. Melting point: decompo-sition above 200C. [a]25 = +157 (c = 1 in water).
Example 5 8.2 g of amoxycillin trihydrate are added to a sl~spension of 4.2 g of L-arginine in 60 ml of propyleneglycol and 80 ml of isopropanol and the mixture is intensively stirred for 60 minutes at room temperature. The mixture is then filtered and the filtrate introduced into 500 ml of isopropanol at 5C
while stirring. The precipitated salt is filtered off under suction, washed four times with 30 ml of isopropanol each time and dried in vacuo. There are obtained 8.2 g of the arginine salt of amoxycillin. Melting point: decomposition above 200~C. [~]D5 ' +168.7 (c = 1 in water).
Example 6 To a suspension of 20 g of L-arginine in a mixture of 70 ml of propyleneglycol and 180 ml of methanol are added 40 g of amoxycillln trihydrate and the mixture is stirred at 20C for 15 minutes. The mixture is then filtered, washed wlth a mixture of 28 ml of propyleneglycol and 72 ml of methanol and added to 1,4 1 of isopropanol stirred at 5C. After stirring at 5C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times wlth 50 ml of i~opropanol. After drying in vacuo, there are obtained 50,2 g of the arginine salt of amoxycillin. Melting point: decomposition above 210C.
[]D5= ~159 (c = 1,493 in water).
Example 7 To a suspension of 20 g of L arginine in a mixture of 70 ml of propyleneglycol and 180 ml of absolute ethanol, vigorously stirred at 20C, are added 40 g of amoxycillin trihydrate and the mixture is stirred for a further 30 minutes at 20C. Insoluble material in then filtered off, washed with a mixture of 14 ml of propyleneglycol and 36 ml of absolute ethanol and the viscous solution is added to 1,4 1 of isopro-panol stirred a 5C. After stirring at 5C for a further 15 minutes, the precipitated arginine salt of amoxycillin is filtered off under suction and washed five times with 50 ml of ~0559Z6 isopropanol and then flve times wlth 50 ml of diethyl ether.
After drying in vacuo, there are obtalned 45,7 g of the arginine salt of amoxyclllin. Melting point: decomposition above 210 C. [~]D = +172,2 (c = 1,5 in water).
The following Examples illustrate typical pharmaceutical preparations containing the arginine salt of amoxycillin provided by this invention:
Example A
A lyophilisate of the following composition, based on 4 ml of ready-for-use injection solution, is manufactured in the usual manner:
Arginine salt of amoxycillin370 mg Methyl p-hydroxybenzoate 1.1 mg Propyl p-hydroxybenzoate 0.135 mg Example B
740 mg of the arginine salt of amoxycill~n are filled into a dry ampoule in the usual manner. In order to prepare a ready-for-use injection solution, 5 ml of sterile water or 5 ml of a sterile physiological sodium chloride solution are added to thi salt.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of the arginine salt of amoxycillin, which process comprises reacting 6-[(R)-.alpha.-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated from thereof, the amino group being option-ally present in protected form, with arginine and cleaving off a protecting group which may be present.
2. A process according to claim 1 wherein the reaction of 6-[(R)-.alpha.-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of methanol or of a mixture of water or propyleneglycol on the one side and ethanol, propanol or isopropanol on the other side as a solvent.
3. A process according to claim 1 or 2 wherein the reaction of 6-[(R)-.alpha.-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propyleneglycol and ethanol as a solvent.
4. A process according to claim 1 wherein the reaction of 6-[(R)-.alpha.-amino-p-hydroxyphenylacetamido]-penicillanic acid or a hydrated form thereof with arginine is carried out in the presence of a mixture of propyleneglycol and methanol as a solvent.
5. The arginine salt of amoxycillin, when manufactured by the process claimed in claim 1 inclusive, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1143374 | 1974-08-21 | ||
| CH658075 | 1975-05-22 | ||
| CH817675 | 1975-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055926A true CA1055926A (en) | 1979-06-05 |
Family
ID=27175528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA233,612A Expired CA1055926A (en) | 1974-08-21 | 1975-08-18 | Arginine salt of amoxycillin |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5148418A (en) |
| AR (1) | AR208560A1 (en) |
| AT (1) | AT338975B (en) |
| AU (1) | AU8364775A (en) |
| BR (1) | BR7505337A (en) |
| CA (1) | CA1055926A (en) |
| DD (1) | DD121325A5 (en) |
| DE (1) | DE2536949A1 (en) |
| DK (1) | DK375775A (en) |
| ES (1) | ES440337A1 (en) |
| FI (1) | FI752193A (en) |
| FR (1) | FR2282270A1 (en) |
| GB (1) | GB1464065A (en) |
| IE (1) | IE41514B1 (en) |
| IL (1) | IL47712A0 (en) |
| LU (1) | LU73220A1 (en) |
| NL (1) | NL7509698A (en) |
| NO (1) | NO752889L (en) |
| PH (1) | PH13527A (en) |
| SE (1) | SE7509219L (en) |
| YU (1) | YU188375A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2319338A1 (en) | 1975-08-01 | 1977-02-25 | Synthelabo | NEW A-PHENYL BENZYLIDENIC DERIVATIVES OF AMINO ACIDS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| JP6746378B2 (en) | 2016-05-27 | 2020-08-26 | 東洋電装株式会社 | Magnetic rotation detector |
-
1975
- 1975-07-15 IL IL7547712A patent/IL47712A0/en unknown
- 1975-07-24 YU YU01883/75A patent/YU188375A/en unknown
- 1975-07-31 FI FI752193A patent/FI752193A/fi not_active Application Discontinuation
- 1975-08-04 AU AU83647/75A patent/AU8364775A/en not_active Expired
- 1975-08-08 AR AR259948A patent/AR208560A1/en active
- 1975-08-13 PH PH17466A patent/PH13527A/en unknown
- 1975-08-14 NL NL7509698A patent/NL7509698A/en unknown
- 1975-08-18 SE SE7509219A patent/SE7509219L/en unknown
- 1975-08-18 CA CA233,612A patent/CA1055926A/en not_active Expired
- 1975-08-19 JP JP50099886A patent/JPS5148418A/ja active Pending
- 1975-08-19 DD DD187936A patent/DD121325A5/xx unknown
- 1975-08-19 DE DE19752536949 patent/DE2536949A1/en active Pending
- 1975-08-19 FR FR7525629A patent/FR2282270A1/en not_active Withdrawn
- 1975-08-19 LU LU73220A patent/LU73220A1/xx unknown
- 1975-08-20 GB GB3460775A patent/GB1464065A/en not_active Expired
- 1975-08-20 BR BR7505337*A patent/BR7505337A/en unknown
- 1975-08-20 IE IE1832/75A patent/IE41514B1/en unknown
- 1975-08-20 AT AT645275A patent/AT338975B/en active
- 1975-08-20 ES ES440337A patent/ES440337A1/en not_active Expired
- 1975-08-20 NO NO752889A patent/NO752889L/no unknown
- 1975-08-20 DK DK375775A patent/DK375775A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU188375A (en) | 1982-02-28 |
| BR7505337A (en) | 1976-08-03 |
| AU8364775A (en) | 1977-02-10 |
| ES440337A1 (en) | 1977-03-16 |
| PH13527A (en) | 1980-06-19 |
| IE41514L (en) | 1976-02-21 |
| FR2282270A1 (en) | 1976-03-19 |
| IL47712A0 (en) | 1975-10-15 |
| AT338975B (en) | 1977-09-26 |
| DK375775A (en) | 1976-02-22 |
| AR208560A1 (en) | 1977-02-15 |
| ATA645275A (en) | 1977-01-15 |
| NL7509698A (en) | 1976-02-24 |
| DE2536949A1 (en) | 1976-03-04 |
| FI752193A (en) | 1976-02-22 |
| NO752889L (en) | 1976-02-24 |
| JPS5148418A (en) | 1976-04-26 |
| LU73220A1 (en) | 1977-04-15 |
| IE41514B1 (en) | 1980-01-16 |
| GB1464065A (en) | 1977-02-09 |
| DD121325A5 (en) | 1976-07-20 |
| SE7509219L (en) | 1976-02-23 |
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