GB1594997A - Process for the preparation of amoxicillin - Google Patents
Process for the preparation of amoxicillin Download PDFInfo
- Publication number
- GB1594997A GB1594997A GB1311178A GB1311178A GB1594997A GB 1594997 A GB1594997 A GB 1594997A GB 1311178 A GB1311178 A GB 1311178A GB 1311178 A GB1311178 A GB 1311178A GB 1594997 A GB1594997 A GB 1594997A
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- United Kingdom
- Prior art keywords
- solution
- temperature
- reaction
- condensing
- carried out
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
(54) PROCESS FOR THE PREPARATION OF
AMOXICILLIN
(71) GALENIKA FARMACEUTSKA-HEMIJSKA INDUSTRIJA, a body corporate organised under the laws of Yugoslavia, of Senski Trg 7, 11080
Zemun, Yugoslavia, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a process for the preparation of amoxicillin, i.e. p hydroxy - a - aminobenzyl - penicillin, which is one of the recently developed semi-synthetic penicillins.
It has now been found that the preparation of this semi-synthetic antibiotic is particularly simple if p-oxyphenylglycine and 6-amino-penicillinic acid (6 APA) or derivatives thereof are used as reactants and certain carbodiimides are used as condensing agents, according to the following scheme:
HOCH--COOH + H2NCl N--CHH-CH/3(CH3)2 100H I I C1 (OH3 2 R3N=C=NR3 NH-R1 OC-N CH-COOR2 (f) (tut) --CHH-CCO--NHH-CH-CH/S'c(CH3), hydrolysis NH-R1 OCN OH HO CO--NHH-CCH-CH/C(CH sFC(CH 3)2 H0-- I NH2 OO-N CH-COOH wherein:
R, representsH or CH3-C=CH-COOC2H 5; and R2 represents -H or -Si(CH,)2-.
(The group -Si(CH3)2- bonds two molecules of the compounds corresponding to the above general formula (II) and also serves to protect the carboxylic group.)
The present invention provides a process for the preparation of amoxicillin which comprises condensing
(a) a compound corresponding to the following general formula (1):
wherein R1 represents H or CH3-C=CH-COOC2H5; and (b) a compound corresponding to the following general formula (ill):
wherein R2 represents H or -Si(CH3)2-; in the presence of a solvent and in the presence of at least one condensing agent which is dicyclohexylcarbodiimide or diisopropylcarbodiimide; subjecting the solution to a first evaporation stage; dissolving the residue in distilled water; extracting the solution at least once; cooling the solution; and subjecting the solution to a second evaporation stage under vacuum.
In order to avoid the possibility of establishing an inverse bonding sequence of p-oxyphenylglycine and 6-APA, which is possible when non-equivalent aminoacids are condensed, the reaction is carried out using protected reactants.
Dicyclohexylcarbodiimide or diisopropylcarbodiimide are chosen as condensing agents specific for establishing amide bonds.
To protect the p-oxyphenylglycine amino group, a residue of acetoacetic ester in enolic form is used, while to protect the 6-APA carboxyl group, a dimethyldichlorosilane residue is used.
This interesting semi-synthetic penicillin may be produced, according to the prior art, in many ways, for example as follows:- 1. Acylation of 6-aminopenicillanic acid using p-oxyphenylglycinechloride in an acid medium, similar to the preparation of ampicillin;
2. Acylation of 6-APA using a mixed anhydride of p-oxyphenylglycine, wherein the amino group of the acylating agent is blocked with a protecting group;
3. Acylation of 6-APA using a mixed anhydride of p-oxy-a-chloro-phenylacetic acid, and then treating the reaction product with sodiumazide and subsequently reducing the introduced azide groups into amide groups;
4. Treating the iminoether, obtained from benzylpenicillin esters, with poxyphenylglycine chloride, and then treating with sodiumthiophenolate to cleave the protecting ester bound and in that way to set free newly produced semisynthetic penicillin with changed acyl residue.
The acylation of 6-APA using p-oxyphenylglycine chloride is the simplest of the above methods. With the other methods it is necessary to prepare the reactants separately and to carry out other reactions as well, in order to cleave the protecting groups or introduce the amino groups.
One advantage of the present invention is that common and commercially available products may be used as reactants which are neither harmful nor sensitive, particularly to environmental factors (for example, p-oxyphenylglycine, p-oxyphenylglycine-Dane salt, i.e. the p-oxyphenyglycine derivatives wherein R; represents CH3-C--CHCOOCH3 or CH3-C=CHCOOC2H5, 6-APA and carbodiimide), and of all the necessary reactants, it is necessary to prepare only the silyl ester of 6-aminopenicillanic acid. The most important advantage of the present invention is that p-oxyphenylglycine-Dane salt is used directly in the condensing reaction itself with 6-APA, while in known methods it must be prepared and isolated before being used in the reaction with 6-APA.
More particularly according to the present invention, the condensation of poxyphenylglycine with 6-APA may be carried out in an appropriate solvent, in the presence of a minimum quantity of water, generally at a temperature of from 10 to 15"C. The pH of the reaction medium is preferably from 2 to 2.5. The reaction is generally completed in approximately 3 hours of continuous mixing. After the reaction is completed, the solvent is evaporated off, for example, in a rotary vacuum evaporator at a temperature of not greater than 30"C. When the solvent is evaporated off, say about 30 ml of distilled water are added to the residue, the pH of the solution may be adjusted to 1 and then the aqueous solution may be extracted twice with 25 ml each of methylisobutyl ketone or chloroform. After the extraction, the pH of the aqueous solution may be adjusted to 5.2 by adding an appropriate quantity of a 10% aqueous NaOH solution, and then the solution is evaporated at a temperature of 5"C in a rotary vacuum evaporator, for example.
During the evaporation of the solution, a pale yellowish precipitate of crude amoxicillin trihydrate separates.
The following may be used as reactants in the process according to the present invention: 1. p-oxyphenylglycine, as well as p-oxyphenylglycine-Dane salt, the amino group of which is protected with the residue of acetoacetic ester in enol form (potassium D (-) - N - ( - ethoxy - carbonyl - propan - 2 - ol)a - amino - p oxyphenylacetate), consequently providing two ways for carrying out the procedure;
2. 6-aminopenicillanic acid (6-APA) and the silyl ester of 6-APA obtained by the reaction of 6-APA with dimethyldichloro-silane, thus increasing the number of ways for carrying out the procedure to four;
3. Dicyclohexylcarbodiimide and diisopropylcarbodiimide as condensing
agents;
4. Dioxane and acetone as solvents for carrying out the condensing reaction between p-oxyphenyglycine and 6-APA;
5. Methylisobutyl ketone and chloroform as solvents for the extraction after the condensation reaction is completed.
The following Examples illustrate the present invention.
EXAMPLE 1
0.01 M p-oxyphenylglycine, 0.01 M 6-APA and 50 ml. dioxane are introduced
into a 250 ml. four-necked reaction flask which is equipped with a stirrer, reflux
condenser and thermometer. 0.012 M of dicyclohexylcarbodiimide and from 1 to 3
ml. of distilled water are added to this mixture. The pH of the reaction mixture is adjusted to from 2 to 2.5 by the addition of conc. HCI and vigorous stirring. The temperature of the reaction mixture is maintained at from 10 to 150C. After vigorous stirring for three hours, the separated white precipitate of dicyclohexylcarbamide is filtered off and the clear solution is evaporated under vacuum at a temperature of 30"C. 30 ml. of distilled water are added to the residue
and the pH value is adjusted to 1. The solution is extracted twice using methyl
isobutyl ketone. After separation of the ketonic layer, the pH value of the aqueous
solution is adjusted to 5.2 by the addition of a 10% NaOH solution. The solution is cooled at 50C and the thus-cooled solution is subjected to evaporation under vacuum. The pale yellowish coloured precipitate of amoxicillintrihydrate is separated. The yield is 1.17 g.
EXAMPLE 2
The reaction is carried out as described in Example 1, except that diisopropylcarbodiimide is used as the condensing agent. The yield of crude amoxicillintrihydrate precipitate is 1.24 g.
EXAMPLE 3
The reaction is carried out as described in Example 1, except that, during the condensation of p-oxyphenylglycine and 6-APA, acetone is used. Crude pale yellowish amoxicillin trihydrate is separated. The yield is 1.85 g.
EXAMPLE 4
The reaction Is carried out as described in Example 1, except that 4.12 g of dicyclohexylcarbodiimide are used. 2.14 g. of the pale yellowish amoxicillintrihydrate precipitate is separated from the aqueous solution.
EXAMPLE 5
The reaction is carried out using 0.023 M p-oxyphenylglycine-Dane salt and 0.01 M 6-APA in 50 ml of acetone and from 1 to 3 ml of water. 0.02 M of dicyclohexylcarbodiimide is used as the condensing agent and the pH of the reaction medium is maintained between 2 and 2.5. The temperature of the reaction mixture is maintained at from 10 to 150C. After stirring the reaction mixture for three hours, the separated white precipitate of dicyclohexylcarbamide is filtered off and the clear solution is evaporated under vacuum at a temperature of 30"C. 30 ml of distilled water and 30 ml of methyl-isobutyl ketone is added to the evaporated residue and the pH of the solution is adjusted to 1. The solution is then cooled to about 5"C and this temperature is maintained for an hour, under continuous stirring. Then, the ketone solution is separated and the extraction is repeated using the same quantity of methyl-isobutyl ketone. After adjusting the pH of the aqueous solution to 5.2, the aqueous solution is cooled and subjected to evaporation under vacuum, to separate the amoxicillintrihydrate. The yield is 1.76 g.
EXAMPLE 6
The reaction is carried out as described in Example 5, except that 0.02 M diisopropylcarbodiimide is used as the condensing agent. The yield of crude amoxicillintrihydrate is 1.60 g.
EXAMPLE 7
The reaction is carried out as described in Example 5, but using 5 ml of dioxane as solvent, The yield of amoxicillintrihydrate is 1.22 g.
EXAMPLE 8
The reaction is carried out using 0.01 M of the dimethylsilylester of 6-APA, which is prepared by treating 6-APA with the corresponding quantity of dimethylchlorosilane and 0.01 M of p-oxyphenylglycine. To the reaction mixture in 50 ml of acetone, from I to 3 ml of distilled water and 0.02 M of dicyclohexylcarbodiimide are added. The pH of the solution is adjusted to from 2 to 2.5. The reaction mixture is stirred intensively for 3 hours at a temperature of from 10 to 150C. Then, the separated white precipitate is filtered off, the solvent is evaporated under vacuum at room temperature and the residue is dissolved in 30 ml of distilled water. The aqueous solution, the pH of which is adjusted to 1, is extracted twice with 25 ml of methyl-isobutyl ketone, and then the pH of the solution is adjusted to 5.2 by the addition of a 10% solution of NaOH. The solution is cooled and evaporated under vacuum at 50C to separate the pale yellowish precipitate of amoxicillintrihydrate. The yield is 1.50 g.
EXAMPLE 9
The reaction is carried out as described in Example 8, except that extraction is carried out using 25 ml of chloroform, twice, instead of methyl-isobutyl ketone.
The yield of amoxicillintrihydrate is 1.38 g.
EXAMPLE 10
The reaction is carried out using 0.011 M of p-oxyphenylglycineDane salt and 0.01 M of the dimethylsilylester of 6-APA, which is prepared by treating 6-APA with dimethyldichlorosilane. 60 ml of acetone, from 1 to 3 ml of distilled water and 0.012 M of dicyclohexylcarbodiimide are added to the reactants, and the pH of the reaction mixture is adjusted to from 2 to 2.5. After stirring for three hours, the separated dicyclohexylcarbamide is filtered off using a Buchner funnel and the solution evaporated under vacuum at room temperature, 50 ml of distilled water are added to the reaction residue after the evaporation and the pH of the solution obtained is adjusted to 1. The solution is then cooled at 5"C and maintained at this temperature, while being stirred continuously for 1 hour. Then, the solution is extracted, twice, with 25 ml of methyl-isobutyl ketone. By adding NaOH solution, the pH of the aqueous solution is adjusted to 5.2. The solution is then evaporated under vacuum at a temperature of 5"C. The pale yellowish precipitate of amoxicillintrihydrate is separated in a quantity of 1.47 g.
EXAMPLE 11
The reaction is carried out as described in Example 10, except that 0.012 M of diisopropylcarbodiimide is used as the condensing agent. The yield of amoxicillintrihydrate is 1.52 g.
EXAMPLE 12
The reaction is carried out as described in Example 10, except that the extraction is performed, twice, using 25 ml of chloroform. The yield of amoxicillintrihydrate is 1.38 g.
WHAT WE CLAIM IS:
1. A process for the preparation of amoxicillin which comprises condensing
(a) a compound corresponding to the following general formula (I):
wherein R1 represents H or CH3-C=CH-COOC2H5; and
(b) a compound corresponding to the following general formula (II):
wherein R2 represents H or -Si(CH3)2-; in the presence of a solvent and in the presence of at least one condensing agent which is dicyclohexylcarbodiimide or diisopropylcarbodiimide, subjecting the solution to a first evaporation stage; dissolving the residue in distilled water; extracting the solution at least once; cooling the solution; and subjecting the solution to a second evaporation stage under vacuum.
2. A process as claimed in claim I in which dioxane and acetone are used as solvents in the condensing reaction.
3. A process as claimed in claim I or claim 2 in which the condensing reaction is carried out in a medium the pH of which is from 2 to 2.5 and at a temperature of from 10 to 150C.
4. A process as claimed in any of claims I to 3 in which the condensing reaction is carried out under vigorous stirring for 3 hours.
5. A process as claimed in any of claims 1 to 4, in which the first evaporation stage is carried out at a temperature of from room temperature to 30cm.
6. A process as claimed in any of claims I to 5 in which methylisobutyl ketone and chloroform are used as the extracting solvents.
7. A process as claimed in any of claims 1 to 7, wherein the solution is cooled to a temperature of 5"C before the second evaporation stage.
8. A process for the preparation of amoxicillin which comprises condensing a mixture of a compound corresponding to the following general formula (I):
wherein R, represents H or CH3-C=CH-COOC2H ; and a compound corresponding to the following general formula (II):
wherein R2 represents H or -Si(CH3)2-- in a solvent under vigorous stirring for 3 hours and in the presence of a condensing agent which is dicyclohexylcarbodiimide or diisopropylcarbodiimide and distilled water, at a constant pH value and temperature, evaporating the thus-obtained clear solution at a temperature of
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (11)
1. A process for the preparation of amoxicillin which comprises condensing
(a) a compound corresponding to the following general formula (I):
wherein R1 represents H or CH3-C=CH-COOC2H5; and
(b) a compound corresponding to the following general formula (II):
wherein R2 represents H or -Si(CH3)2-; in the presence of a solvent and in the presence of at least one condensing agent which is dicyclohexylcarbodiimide or diisopropylcarbodiimide, subjecting the solution to a first evaporation stage; dissolving the residue in distilled water; extracting the solution at least once; cooling the solution; and subjecting the solution to a second evaporation stage under vacuum.
2. A process as claimed in claim I in which dioxane and acetone are used as solvents in the condensing reaction.
3. A process as claimed in claim I or claim 2 in which the condensing reaction is carried out in a medium the pH of which is from 2 to 2.5 and at a temperature of from 10 to 150C.
4. A process as claimed in any of claims I to 3 in which the condensing reaction is carried out under vigorous stirring for 3 hours.
5. A process as claimed in any of claims 1 to 4, in which the first evaporation stage is carried out at a temperature of from room temperature to 30cm.
6. A process as claimed in any of claims I to 5 in which methylisobutyl ketone and chloroform are used as the extracting solvents.
7. A process as claimed in any of claims 1 to 7, wherein the solution is cooled to a temperature of 5"C before the second evaporation stage.
8. A process for the preparation of amoxicillin which comprises condensing a mixture of a compound corresponding to the following general formula (I):
wherein R, represents H or CH3-C=CH-COOC2H ; and a compound corresponding to the following general formula (II):
wherein R2 represents H or -Si(CH3)2-- in a solvent under vigorous stirring for 3 hours and in the presence of a condensing agent which is dicyclohexylcarbodiimide or diisopropylcarbodiimide and distilled water, at a constant pH value and temperature, evaporating the thus-obtained clear solution at a temperature of
from room temperature to 30"C, dissolving the residue in distilled water and extracting it twice, cooling the solution to a temperature of 5"C and evaporating it under vacuum.
9. A process as claimed in claim 1 substantially as herein described.
10. A process as claimed in claim 1 substantially as herein described with reference to any one of the Examples.
11. Amoxicillin when prepared by a process as claimed in any of claims 1 to 10.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
YU88377A YU40474B (en) | 1977-04-04 | 1977-04-04 | Process for obtaining amoxicillin |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1594997A true GB1594997A (en) | 1981-08-05 |
Family
ID=25551844
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB1311178A Expired GB1594997A (en) | 1977-04-04 | 1978-04-04 | Process for the preparation of amoxicillin |
Country Status (4)
Country | Link |
---|---|
JP (1) | JPS53149992A (en) |
CS (1) | CS204027B2 (en) |
GB (1) | GB1594997A (en) |
YU (1) | YU40474B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0439096A2 (en) * | 1990-01-22 | 1991-07-31 | Biochemie Gesellschaft M.B.H. | Improvements in or relating to beta lactam production |
ES2050621A1 (en) * | 1992-11-06 | 1994-05-16 | Antibioticos Sa | An improved procedure for the preparation of 6-[alpha]- aminopenicillins |
-
1977
- 1977-04-04 YU YU88377A patent/YU40474B/en unknown
-
1978
- 1978-04-04 JP JP3888078A patent/JPS53149992A/en active Pending
- 1978-04-04 GB GB1311178A patent/GB1594997A/en not_active Expired
- 1978-04-04 CS CS218178A patent/CS204027B2/en unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0439096A2 (en) * | 1990-01-22 | 1991-07-31 | Biochemie Gesellschaft M.B.H. | Improvements in or relating to beta lactam production |
EP0439096A3 (en) * | 1990-01-22 | 1992-06-10 | Biochemie Gesellschaft M.B.H. | Improvements in or relating to beta lactam production |
EP0976755A1 (en) * | 1990-01-22 | 2000-02-02 | BIOCHEMIE Gesellschaft m.b.H. | Improvements in or relating to beta lactam production |
ES2050621A1 (en) * | 1992-11-06 | 1994-05-16 | Antibioticos Sa | An improved procedure for the preparation of 6-[alpha]- aminopenicillins |
Also Published As
Publication number | Publication date |
---|---|
YU88377A (en) | 1982-06-30 |
YU40474B (en) | 1986-02-28 |
JPS53149992A (en) | 1978-12-27 |
CS204027B2 (en) | 1981-03-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |