WO2019008594A1 - Continuous process for the preparation of 2-(1h-imidazol-4-yl) ethanamine and pharmaceutically acceptable salts thereof - Google Patents
Continuous process for the preparation of 2-(1h-imidazol-4-yl) ethanamine and pharmaceutically acceptable salts thereof Download PDFInfo
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- WO2019008594A1 WO2019008594A1 PCT/IN2017/050610 IN2017050610W WO2019008594A1 WO 2019008594 A1 WO2019008594 A1 WO 2019008594A1 IN 2017050610 W IN2017050610 W IN 2017050610W WO 2019008594 A1 WO2019008594 A1 WO 2019008594A1
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- histamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Definitions
- the present invention discloses a commercially viable, cost effective and energy efficient process for the preparation of 2-(lH-Imidazol-4-yl) ethanamine or pharmaceutically acceptable salts thereof in high purity and yield via application of continuous flow technology.
- 2-(lH-Imidazol-4-yl) ethanamine represented as compound of formula I, possesses significant biological activity and is used as standard in biological assays and as a component in certain allergy diagnostic kits. Histamine occurs widely in nature, but to take full advantage of its therapeutic properties, it is important to obtain large quantities of histamine of pharmaceutical grade by synthetic routes.
- Histamine in therapeutic applications is used as its dihydrochloride salt, which can be conveniently synthesized by decarboxylation of histidine. Using this synthetic process, histidine is decarboxylated and subsequently treated to form the dihydrochloride salt form of the molecule.
- Hashimoto et al in Chemistry Letters, 1986, 883-896 discussed the preparation of histamine, wherein histidine is decarboxylated using cyclohexanone as a catalyst in cyclohexanol solvent.
- the process disclosed involves the decarboxylation reaction being carried out in 26 hours and used toluene and HC1 gas for the preparation of dihydrochloride salt.
- the process disclosed is not industrially feasible as the reaction time is too long, which results in a lot of energy consumption and further the process fails in providing histamine dihydrochloride of pharmaceutical grade as it contains a number of impurities which makes the process unsuitable for large scale production.
- JPH05255204 discloses use of acetophenone catalyst and diethylene glycol as solvent for the decarboxylation of histidine to histamine.
- the said process is also reported to be inconsistent in providing histamine dihydrochloride in desired purity and yield.
- the process disclosed suffered the incompatibility in terms of removal of traces of diethylene glycol as histamine and its dihydrochloride salt are highly soluble in water and none of the isolation techniques worked efficiently to remove the diethylene glycol solvent from the product.
- it is rendered inapplicable on industrial scale.
- the principal object of the present invention is to provide an improved and efficient process for the preparation of histamine or pharmaceutically acceptable salts thereof which is simple, economic and alleviates one or more problems of the prior art disclosed processes.
- the present invention provide a process for the preparation of histamine or pharmaceutically acceptable salts thereof, comprising
- step (b) performing the decarboxylation reaction by feeding solution of step (a) to a continuous reactor to obtain histamine and optionally converting the histamine to its pharmaceutically acceptable salts.
- Chemical reactors are vessels, wherein chemical reactions are carried out; their performance determines the reliability and suitability of a process, its environment safety, the consumption of energy and the raw materials required.
- a continuous reactor is a reactor where there are no moving parts other than pumps that deliver the reactants. To achieve efficient mixing of reactants the addition of static mixing elements such as glass beads inside the reactor is done that provides ideal conditions of radial mixing and continuous flow necessary to perform reactions.
- One such example of a continuous reactor is plug flow reactor. In a plug flow reactor, the flow of reactants pumped in the reactor is laminar and the properties of the reaction medium i.e. pressure, temperature, reactant and product concentrations are the same throughout the entire cross section of flow.
- Plug flow reactors usually operate in adiabatic and non-isothermal conditions. Consequently, from the standpoint of kinetic parameters of a chemical reaction under isothermal conditions, plug flow reactors are more efficient than stirred tank reactors.
- the present invention provides an improved method for the preparation of histamine or pharmaceutically acceptable salts thereof using a continuous reactor.
- the process has distinct advantages in regard to cycle time, energy consumption, yield and product purity over traditional methods.
- the process employs application of continuous reactor technology for the preparation of desired product in high yield and high purity with enhanced in-process control on impurities with shorter reaction time.
- the present invention provides a process for the preparation of histamine or pharmaceutically acceptable salts thereof, comprising
- a solution of L-histidine is prepared using a solvent and a catalyst.
- the solvent used is selected from the group comprising of alcohols such as ethylene glycol and the like; aromatic hydrocarbon such as toluene, xylene and the like; aprotic polar solvents such as N-methyl pyrrolidone, N,N-dimethylformamide, dimethylsulphoxide and the like; water or mixtures thereof.
- the catalyst used is selected from the group comprising of acetophenone, 4-methylacetophenone, 4-nitroacetophenone, 4-bromoacetophenone, benzoyl peroxide, 2,2'-azobisisobutyronitrile, cyclohexanone and the like.
- the solution of L-histidine and the catalyst is prepared at room temperature.
- the catalyst is used in 0.5 to 1.5 mole equivalents of L-histidine.
- the decarboxylation reaction of L-histidine is carried out by feeding the solution prepared in step (a) at the flow rate of 20-80 ml/min at reflux temperature to a continuous reactor.
- the continuous reactor used is selected from the group comprising of plug flow reactor and the like.
- the reaction is optionally carried out under inert atmosphere or under an inert gas stream at reflux temperature of the solvent of the solution. Examples of the inert gas include nitrogen, helium, neon, argon and the like.
- the residence time necessary in the method according to the invention depends on various parameters, such as, for example, the temperature or reactivity of the starting materials.
- the term "residence time" refers to the internal volume of the reaction zone within the continuous reactor occupied by the reactant fluid flowing through the space, at the temperature and pressure being used.
- the residence time is between about 1 minute and about 10 minutes.
- the resulting reaction mixture is subjected to various isolation techniques to isolate histamine such as extraction, filtration, distillation etc.
- histamine obtained is optionally converted to its pharmaceutically acceptable salts selected from the group comprising of hydrochloride, hydrobromide, tartrate, oxalate and the like.
- the final product is optionally purified by a suitable recrystallization procedure known in the literature.
- the histamine hydrochloride obtained is having purity not less than 99 %.
- Example 2 Purification of histamine dihydrochloride: To histamine hydrochloride (100 g), added methanol (800 ml) and raised the temperature of reaction mass to 60-70 °C and stirred to get a clear solution. To the clear solution added carbon (5 g) at 50-55 °C and stirred for another 30 minutes. The solution was filtered and the solvent was partially distilled out. The resulting reaction mass, added isopropyl alcohol (300 ml) and raised the temperature of reaction mass to 60-70 deg C, stirred at this temperature for about 1 hour. The reaction mass was cooled slowly to 10-15 °C while stirring. The solid so obtained was filtered and dried to obtain histamine dihydrochloride .
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Abstract
of the invention The invention relates to a commercially viable, cost effective and energy efficient process for the preparation of 2-(1H-Imidazol-4-yl) ethanamine or pharmaceutically acceptable salts thereof in high purity and yield via application of continuous flow technology.
Description
CONTINUOUS PROCESS FOR THE PREPARATION OF 2-(lH-IMIDAZOL-4-YL) ETHAN AMINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
Field of the Invention
The present invention discloses a commercially viable, cost effective and energy efficient process for the preparation of 2-(lH-Imidazol-4-yl) ethanamine or pharmaceutically acceptable salts thereof in high purity and yield via application of continuous flow technology.
Background of the Invention
2-(lH-Imidazol-4-yl) ethanamine (histamine) represented as compound of formula I, possesses significant biological activity and is used as standard in biological assays and as a component in certain allergy diagnostic kits. Histamine occurs widely in nature, but to take full advantage of its therapeutic properties, it is important to obtain large quantities of histamine of pharmaceutical grade by synthetic routes.
I
Histamine in therapeutic applications is used as its dihydrochloride salt, which can be conveniently synthesized by decarboxylation of histidine. Using this synthetic process, histidine is decarboxylated and subsequently treated to form the dihydrochloride salt form of the molecule.
Hashimoto et al in Chemistry Letters, 1986, 883-896 discussed the preparation of histamine, wherein histidine is decarboxylated using cyclohexanone as a catalyst in cyclohexanol solvent. The process disclosed involves the decarboxylation reaction being carried out in 26 hours and used toluene and HC1 gas for the preparation of dihydrochloride salt. The process disclosed is not industrially feasible as the reaction time is too long, which results in a lot of energy consumption and further the process fails in providing histamine dihydrochloride of pharmaceutical grade as it contains a number of impurities which makes the process unsuitable for large scale production.
JPH05255204 discloses use of acetophenone catalyst and diethylene glycol as solvent for the decarboxylation of histidine to histamine. The said process is also reported to be inconsistent in providing histamine dihydrochloride in desired purity and yield. Further, the process disclosed suffered the incompatibility in terms of removal of traces of diethylene glycol as histamine and its dihydrochloride salt are highly soluble in water and none of the isolation techniques worked efficiently to remove the diethylene glycol solvent from the product. Thus, owing to various disadvantages of the disclosed process, it is rendered inapplicable on industrial scale.
Thus, there exists a need in the art for the development of an industrially feasible, cost effective, economic and simple process capable of controlling the impurities, for producing histamine or pharmaceutically acceptable salts thereof with high purity and high yield.
Accordingly, as an alternative to the prior art methods, in the present invention improved conditions have been optimized for the synthesis of histamine or pharmaceutically acceptable salts thereof by application of continuous flow reactor technology. The process has distinct advantages in regard to cycle time, energy consumption, and product purity over traditional methods.
Object and Summary of the Invention
The principal object of the present invention is to provide an improved and efficient process for the preparation of histamine or pharmaceutically acceptable salts thereof which is simple, economic and alleviates one or more problems of the prior art disclosed processes.
It is another object of the present invention to provide a cost effective and industrially feasible process for producing histamine or pharmaceutically acceptable salts thereof, wherein the process provides high yield and high purity of the desired product by reducing the formation of impurity, in a consistent and reproducible manner.
In accordance with an object, the present invention provide a process for the preparation of histamine or pharmaceutically acceptable salts thereof, comprising
(a) preparing a solution of L-histidine of Formula II and a catalyst in a solvent;
II
(b) performing the decarboxylation reaction by feeding solution of step (a) to a continuous reactor to obtain histamine and optionally converting the histamine to its pharmaceutically acceptable salts.
Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
Chemical reactors are vessels, wherein chemical reactions are carried out; their performance determines the reliability and suitability of a process, its environment safety, the consumption of energy and the raw materials required. A continuous reactor is a reactor where there are no moving parts other than pumps that deliver the reactants. To achieve efficient mixing of reactants the addition of static mixing elements such as glass beads inside the reactor is done that provides ideal conditions of radial mixing and continuous flow necessary to perform reactions. One such example of a continuous reactor is plug flow reactor. In a plug flow reactor, the flow of reactants pumped in the reactor is laminar and the properties of the reaction medium i.e. pressure, temperature, reactant and product concentrations are the same throughout the entire cross section of flow. Further, all the elemental volumes of the reaction medium remain in the reactor for the same period of time, and the change in concentration, temperature, and pressure with time are identical for each elemental volume. Plug flow reactors usually operate in adiabatic and non-isothermal conditions. Consequently, from the standpoint of kinetic parameters of a chemical reaction under isothermal conditions, plug flow reactors are more efficient than stirred tank reactors.
The present invention provides an improved method for the preparation of histamine or pharmaceutically acceptable salts thereof using a continuous reactor. The process has distinct advantages in regard to cycle time, energy consumption, yield and product purity over traditional methods. The process employs application of continuous reactor technology for the preparation of desired product in high yield and high purity with enhanced in-process control on impurities with shorter reaction time.
The present invention provides a process for the preparation of histamine or pharmaceutically acceptable salts thereof, comprising
(a) preparing a solution of L-histidine of Formula II and a catalyst in a solvent;
II
(b) performing the decarboxylation reaction by feeding solution of step (a) to a continuous reactor to obtain histamine and optionally converting the histamine to its pharmaceutically acceptable salts. According to the present invention, a solution of L-histidine is prepared using a solvent and a catalyst. The solvent used is selected from the group comprising of alcohols such as ethylene glycol and the like; aromatic hydrocarbon such as toluene, xylene and the like; aprotic polar solvents such as N-methyl pyrrolidone, N,N-dimethylformamide, dimethylsulphoxide and the like; water or mixtures thereof. The catalyst used is selected from the group comprising of acetophenone, 4-methylacetophenone, 4-nitroacetophenone, 4-bromoacetophenone, benzoyl peroxide, 2,2'-azobisisobutyronitrile, cyclohexanone and the like. The solution of L-histidine and the catalyst is prepared at room temperature. The catalyst is used in 0.5 to 1.5 mole equivalents of L-histidine.
According to present invention, the decarboxylation reaction of L-histidine is carried out by feeding the solution prepared in step (a) at the flow rate of 20-80 ml/min at reflux
temperature to a continuous reactor. The continuous reactor used is selected from the group comprising of plug flow reactor and the like. The reaction is optionally carried out under inert atmosphere or under an inert gas stream at reflux temperature of the solvent of the solution. Examples of the inert gas include nitrogen, helium, neon, argon and the like. The residence time necessary in the method according to the invention, depends on various parameters, such as, for example, the temperature or reactivity of the starting materials. The term "residence time" refers to the internal volume of the reaction zone within the continuous reactor occupied by the reactant fluid flowing through the space, at the temperature and pressure being used. The residence time is between about 1 minute and about 10 minutes.
After the reaction is complete, the resulting reaction mixture is subjected to various isolation techniques to isolate histamine such as extraction, filtration, distillation etc.
According to present invention, histamine obtained is optionally converted to its pharmaceutically acceptable salts selected from the group comprising of hydrochloride, hydrobromide, tartrate, oxalate and the like. The final product is optionally purified by a suitable recrystallization procedure known in the literature.
According to present invention, the histamine hydrochloride obtained is having purity not less than 99 %.
The major advantages realized in the present invention as compared to prior art batch processes are high yield, high purity, consistency, absence or least formation of impurities. These distinctively identified advantages of the reactions in continuous reactor results from minimized residency time and continuous flow nature of the reaction, which thereby reduces the contact time between desired product and unreacted starting materials.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of histamine. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Examples
Example 1: Preparation of histamine dihydrochloride:
To a solution of L-histidine (100 g) in N-methyl pyrrolidone (950 ml), added acetophenone (58.7 g) at room temperature under nitrogen. The reaction mixture was stirred for about 30 minutes at room temperature under nitrogen. The temperature of circulating oil on plug flow reactor was set to 200-210 °C. The plug flow feeding point was fed with solution prepared above at a flow rate of 40 ml/min at 200-210 °C under nitrogen. The resulting reaction mass from plug flow reactor was taken into another vessel at 20-30 °C and filtered. To the filtrate, added dichloromethane (50 ml) and slowly adjusted the pH of the reaction mixture to 1-2 using isopropanol-HCl solution. The resulting reaction mixture was stirred for about 2-4 hours for complete precipitation. The solid obtained was filtered and dried to obtain histamine dihydrochloride.
Yield: 80%
Example 2: Purification of histamine dihydrochloride: To histamine hydrochloride (100 g), added methanol (800 ml) and raised the temperature of reaction mass to 60-70 °C and stirred to get a clear solution. To the clear solution added carbon (5 g) at 50-55 °C and stirred for another 30 minutes. The solution was filtered and the solvent was partially distilled out. The resulting reaction mass, added isopropyl alcohol (300 ml) and raised the temperature of reaction mass to 60-70 deg C, stirred at this temperature for about 1 hour. The reaction mass was cooled slowly to 10-15 °C while stirring. The solid so obtained was filtered and dried to obtain histamine dihydrochloride .
Yield: 70%; Assay: 99.3%
Claims
1. A process for the preparation of histamine or pharmaceutically acceptable salts thereof, comprising
(a) preparing a solution of L-histidine of Formula II and a catalyst in a solvent;
II
(b) performing the decarboxylation reaction by feeding solution of step (a) to a continuous reactor to obtain histamine and optionally converting histamine to its pharmaceutically acceptable salts.
2. The process according to claim 1, wherein the catalyst used in step (a) is selected from the group comprising of acetophenone, 4-methylacetophenone, 4- nitroacetophenone, 4-bromoacetophenone, benzoyl peroxide, 2,2'- azobisisobutyronitrile and cyclohexanone.
3. The process according to claim 1, wherein the solvent used in step (a) is selected from the group comprising of alcohols, aromatic hydrocarbon, aprotic polar solvent, water and mixtures thereof.
4. The process according to claim 3, wherein the solvent used is selected from ethylene glycol, toluene, xylene, N-methyl pyrrolidone, Ν,Ν-dimethylformamide and dimethylsulphoxide.
5. The process according to claim 1, wherein the continuous reactor used is plug flow reactor.
6. The process according to claim 1, wherein the continuous reaction is having residence time of about 1 minute to about 10 minutes.
7. The process according to claim 1, wherein the reaction is performed under inert atmosphere.
8. The process according to claim 1, wherein the pharmaceutically acceptable salt of histamine formed is dihydrochloride.
9. The process according to claim 1, histamine dihydrochloride is prepared with purity not less than 99.9%.
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| Application Number | Priority Date | Filing Date | Title |
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| IN201711023282 | 2017-07-03 | ||
| IN201711023282 | 2017-07-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045500A (en) * | 2021-03-31 | 2021-06-29 | 苏州园方生物科技有限公司 | Preparation method of histamine dihydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6403806B1 (en) * | 1998-12-23 | 2002-06-11 | Maxim Pharmaceuticals, Inc. | Synthesis of histamine dihydrochloride |
| US7485756B2 (en) * | 2006-12-20 | 2009-02-03 | Evonik Degussa Gmbh | Continuous process for decarboxylating carboxylic acids |
-
2017
- 2017-12-22 WO PCT/IN2017/050610 patent/WO2019008594A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6403806B1 (en) * | 1998-12-23 | 2002-06-11 | Maxim Pharmaceuticals, Inc. | Synthesis of histamine dihydrochloride |
| US7485756B2 (en) * | 2006-12-20 | 2009-02-03 | Evonik Degussa Gmbh | Continuous process for decarboxylating carboxylic acids |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113045500A (en) * | 2021-03-31 | 2021-06-29 | 苏州园方生物科技有限公司 | Preparation method of histamine dihydrochloride |
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