Field of the Invention
The present invention discloses a commercially viable, cost effective and energy efficient
process for the preparation of 2-(l#-Imidazol-4-yl)ethanamine or pharmaceutical^
acceptable salts thereof in high purity and yield via application of continuous flow
technology.
Background of the Invention
2-(l#-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.
NH2
HN ]
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 HCI 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;
O
HN. 1 I
. 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
pharmaceutical^ 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;
O
HN I |
\ ^ N NH2
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
pharmaceutical^ 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 pharmaceutical^ acceptable salts
thereof, comprising
(a) preparing a solution of L-histidine of Formula II and a catalyst in a solvent;
O
HN ] J
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, N,N-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%.