AN IMPROVED PROCESS FOR THE SYNTHESIS OF AMOXICILLIN TRIHYDRATE
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of provisional specification no. 1399/DEL/2010 filed on dated 16th June, 2010, filed by the present inventors, which is incorporated herein by reference.
FIELD OF INVENTION
This invention relates to a novel process for the production of highly pure penicillin such as amoxicillin trihydrate with reduced concentration of halogen-containing solvents.
BACKGROUND OF INVENTION
Amoxicillin is a well known representative of the class of 6-alpha-aminoacyl-penicillins and widely prescribed for the treatment of bacterial infections caused by susceptible microorganisms.
Many processes in the prior art have been investigated for the production of amoxicillin which involve the acylation of 6-amino penicillanic acid (6-APA) with D-N-(1 -ethoxycarbonylpropen-2-yl)-α-aminophenylacetate, commonly known as dane salt in the presence of a halogen containing solvent. Generally, methylene chloride is a preferred halogen containing solvent since the final product is obtained in high yield. Even though methylene chloride is a health and environment hazard it is still being widely used as a solvent since the end product is obtained in high yield.
The use of methylene chloride and other halogen containing solvents has been criticized for years. Environmental problems arise in its use since methylene chloride is not biologically degradable. Emission controls on manufacturing plants using chlorinated hydrocarbons are contemplated. Various Pharmacopeia Commissions are considering the possibility of reducing methylene chloride residues in pharmaceuticals. The problem is especially acute for pharmaceuticals where the concentration level of such solvents should be carefully monitored.
Furthermore, the common prior art methods used to reduce the methylene chloride concentration within permissible limits in the final product involve the use of an additional solvent such as Butyl acetate. Amoxicillin trihydrate obtained after acylation step is treated in an ester such as butyl acetate and thereafter purified and crystallized to obtain amoxicillin trihydrate having lower concentration of methylene chloride.
The major disadvantage of this process is the presence of an additional solvent impurity in the final product. Consequently, use of another solvent such as butyl acetate for reducing methylene chloride concentration further lowers the purity of the final product. Other drawbacks of this process include additional cost incurred due to cost associated with the inventory, consumption and handling of the additional solvent. Moreover, use of an additional solvent require further infrastructure for storage, movement and solvent distillation system thereby increasing the cost of industrial scale production. As a result, these prior art processes are not economical and efficient for an industrial scale production.
There was thus a clear need to find alternative industrially viable syntheses of amoxicillin trihydrate. An improved process has been developed which aids in the lowering of methylene chloride content and also gives high yield of the final product. It also obviates the need for extra equipment and infrastructure required for an additional solvent such as butyl acetate. Furthermore it is economical in operation and complicated purification techniques are avoided.
SUMMARY
It is an object of the invention to provide a process for preparation of amoxicillin trihydrate of formula (I).
(Formula Removed)
It is still another object of the invention to provide a process for the preparation of amoxicillin trihydrate, wherein the process comprises the purification of amoxicillin trihydrate in the presence of an alcohol-water solution in vacuum and simultaneous purging of inert gas.
It is another object of the invention to provide a process for preparation of amoxicillin trihydrate of high purity.
It is still another object of the invention to provide a process for preparation of amoxicillin trihydrate having low concentration of solvent impurity.
DETAILED DESCRIPTION OF THE INVENTION
The various aspects of the present invention leading to an improved process intended to reduce methylene chloride concentration in amoxicillin trihydrate within permissible limits is detailed below.
The term "pure" amoxicillin trihydrate means amoxicillin trihydrate with residual solvents with in limit prescribed in ICH guidelines e.g. alcohol or methylene chloride.
In an embodiment of the present invention, the process for the synthesis of highly pure amoxicillin trihydrate, comprises of the following steps:
a. condensation of 6-amino penicillanic acid with derivative dane salt in the presence of
a halogen containing solvent;
b. hydrolysis of the reaction solution from step a) in presence of an acid;
c. purification of the product from step (b) in vacuum and inert atmosphere;
d. crystallization.
In another embodiment of the invention, halogen containing solvent is selected from the group comprising but not limited to methylene chloride, chloroform or carbon tetrachloride.
In an embodiment of the invention, the inert gas used can be used from other members of the inert gas family without departing from the spirit and scope of the invention
In an embodiment of the invention, 6APA is suspended in a halogen containing organic solvent such as methylene chloride and an alcohol, preferably but not limited to isopropyl alcohol. A tertiary organic base selected from the group comprising trialkylamines preferably but not limited to triethylamine is added to the 6-APA solution. This 6-APA solution is then condensed with a reaction mixture of dane salt, dimethylamide and pivaloyl chloride in the presence of methylene chloride and pyridine. Subsequently, the hydrolysis of the product so obtained is carried out in the presence of an acid preferably hydrochloric acid.
The reaction mixture obtained after condensation and hydrolysis is diluted with water and isopropanol is added. The reaction is carried out in a reaction vessel in the presence of an inert gas and vacuum at a defined temperature ranging from 0 °C to 25 °C. Thereafter, the solution is crystallized to obtain a highly pure product.
After the hydrolysis step, pH of solution reaches about 1.0. At this pH, Amoxicillin tends to separate as its hydrochloride salt, thus resulting in loss of yield and increasing impurity profile. This may result in reprocessing of the entire batch and hence further increasing the capital cost of the industrial scale process. To overcome the salt separation, an alcohol preferably but not limited to isopropanol is added with water which helps in avoiding the separation of Amoxicillin as its hydrochloride salt.
In a preferred embodiment of the invention, amoxicillin trihydrate having low solvent impurity is prepared under vacuum with simultaneous purging of nitrogen gas in the presence of isopropanol-water solution. Consequently, the boiling point of methylene chloride is lowered in vacuum coupled with an inert atmosphere and as a result, methylene chloride escapes from the reaction medium. The final product is characterized by a lower concentration of methylene chloride. Furthermore, this process also leads to evaporation of a small quantity of isopropyl alcohol from the reaction solution.
Moreover, purging of nitrogen gas simultaneously in vacuum enables a higher rate of evaporation of methylene chloride from the reaction solution. Such a situation is achieved keeping in view that methylene chloride has a boiling point of 39 °C which is lowered in the vacuum. Purging of nitrogen gas aids in a further increase in rate of evaporation of methylene chloride from the reaction mixture. In addition, vacuum and simultaneous nitrogen gas atmosphere also facilitate the evaporation of isopropanol from the reaction mixture. Hence,
the final product has reduced contents of residual solvents such as methylene chloride and also isopropanol.
The process of preparation of pure amoxicillin trihydrate as embodied in the present invention has a markedly enhanced efficacy which is feasible at an industrial scale production and also renders an effective solution to the problem of methylene chloride content in pharmaceuticals which if of utmost importance in the medical industry.
The compounds and processes of the present invention will be better understood in connection with the following synthetic scheme I which illustrates the methods by which the compounds of the invention may be prepared.
(Scheme Removed)
Amoxicillin trihydrate obtained from the above process has shown to have low concentration of methylene chloride which is under the permissible limits in compliance with ICH guidelines.
The novel method for the production of amoxicillin trihydrate as described in various, embodiments of the present invention does not involve the use of an additional solvent which is used to reduce methylene chloride content in the final product. As a consequence, the cost is reduced considerably and highly pure Amoxicillin trihydrate is obtained.
The purity of Amoxicillin trihydrate obtained by process as described in various embodiments of the present invention is more than 95%, which is in coherence with processes as specified by all Pharmacopeia's.
While the present invention has been described in terms of their specific embodiments, certain modifications in the process and various crystalline forms of the subject compound including specially designed equipments used are intended to be included within the scope of the present invention.
The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention.
EXAMPLES:
Example 1
Preparation of Amoxicillin trihydrate
Dane salt (337.5 kg) is dissolved in pyridine (2.25 kg) and methylene dichloride (900 L) at a temperature of °C. The resultant solution is stirred for minutes at °C and then cooled to about -30 °C to -50 °C and pivaloyl chloride (136.35 kg) is added. The mixture is stirred for another minutes at °C and then cooled to °C. 6-APA (225 kg) is dissolved in methylene chloride (225 L), isopropyl alcohol (100 kg) and triethylamine (123.7 kg) in a reaction vessel. This mixture is then added to the earlier prepared dane salt solution at about -30 to -50 °C. The acylation is allowed to proceed for about 150 minutes at -20 to -50°C. The reaction mixture is hydrolysed with concentrated HCI (280 kg) and water (2000 L).
The aqueous phase containing the title compound is then mixed with water (1000 L) and isopropanol (500 L) and this resulting solution is transferred to a reaction vessel. The temperature is maintained at 5 to 25 °C -preferably 15 deg.C and vacuum is applied. Nitrogen gas is purged simultaneously by maintaining the temperature at 15 °C. After minutes of the reaction, the title compound is crystallized at 0-5 °C. Product is isolated, washed and dried. Purity: >95%

We Claim:-
1. A process for the preparation of amoxicillin trihydrate, having formula (I)
(Formula Removed)
comprising:
a) condensation of 6-amino penicillanic acid with dane salt in the presence of a halogen containing solvent followed by hydrolysis with an acid,
b) purification of the said product
i. dilution of the reaction solution obtained from step (a) with an alcohol;
ii. reaction in vacuum;
iii. purging of inert gas simultaneously; and
c) crystallization
2. A process according to claim 1, wherein said alcohol is selected from the group comprising of methanol, ethanol, iso-propanol, n-propanol, iso-butanol, n-butanol or t-butanol.
3. A process according to claim 1, wherein temperature in step (b) is maintained at a range of from about 0 °C to about 25 °C, preferably 15 °C.
4. A process according to claim 1, wherein said inert gas used is selected from the group comprising of nitrogen or other members from the inert gas family.
5. A process according to claim 1, wherein said halogen containing solvent is selected from the group comprising of methylene chloride, chloroform or carbon tetrachloride,
6. A process according to claim 1, wherein said end product is characterized by concentration of methylene dichloride within the range prescribed in ICH guidelines
7. A process according to claim 1, wherein said end product is characterized by concentration of isopropanol within the range prescribed in ICH guidelines
8. A process according to claim 1, wherein said crystallization is accomplished at temperature range of from about 0 °C to 20 °C -preferably 5 °C
9. A process according to claim 1, wherein said end product i.e. amoxicillin trihydrate is produced at a purity greater than about 95%.
10. A system for the purification of amoxicillin trihydrate which comprises:

a) a reactor adapted to receive a reaction solution containing amoxicillin trihydrate dissolved in an alcohol-water solution,
b) a first valve coupled to the said reactor for vacuum source,
c) a second valve coupled to the said reactor for inlet of an inert gas.

11. The system according to claim 10, wherein the said first valve and said second valve are operated simultaneously
12. The system of claim 10, wherein the said reactor is maintained at a temperature range of from about 0 °C to 25 °C, preferably 15 °C.
13. The system according to claim 10, wherein the said inert gas is nitrogen or other members from the inert gas family.
14. The system according to claim 10, wherein the said alcohol is isopropanol
15. The system according to claim 10, wherein amoxicillin trihydrate is produced at a purity greater than about 95%.