Back ground of the invention
Almotriptan malate (Formula-II) is a new selective serotonin 5-HTlB/lD receptor agonist which is chemically related to sumatriptan and is used in the acute treatment of migraine
US Patent 5565447 describes the preparation of Almotriptan malate by decarboxylation of a carboxylic acid of the formula-Ill in presence of cuprous oxide catalyst. The base thus obtained was of 75-80% pure and was purified by column chromatography and isolated as oil. The hydrochloride salt was prepared in acetone using hydrochloric acid saturated dioxane. This patent further describes pharmaceutically acceptable salts of Almotriptan for example the hydrochloride salt.


Spanish Pat.No.2084560 describes the conversion of Almotriptan to its acid addition salts
for example malate, tartrate, succinate or hydrochloride.
The process for the preparation of Almotriptan was also disclosed in Tetrahedron, 57(2001)1041-1048 and is illustrated in scheme-I.

4-(l-pyrrolidinyl sulfonyl methyl)aniline on diazotization with sodium nitrite and reduction with stannous chloride in concentrated Hydrochloric acid yields 4-(l-Pyrrolidinyl sulfonyl methyl)phenyl hydrazine hydrochloride
STAGE-II


1 = 4-Chlorobutyraldehyde Diethyl acetal 2 = Sodium borohydride and formaldehyde
4-(l-Pyrrolidinyl sulfonyl methyl) phenyl hydrazine hydrochloride on Indolization with 4-Chloro butyraldehyde diethyl acetal followed by dimethyl ation with sodium borohydride and formaldehyde affords Almotriptan .
STAGE-III


Almotriptan on salt formation with malic acid yields Almotriptan malate.
When this process is implemented it yielded Almotriptan base of only 70-80% purity in our hands This on salt formation with malic acid resulted in Almotriptan malate of purity 90%. The drug substance Almotriptan malate, thus obtained is therefore not useful for pharmaceutical application.
Almotriptan base is the precursor of the salt form of Almotriptan malate. As such, there is a need for a process to generate Almotriptan base of high purity which may be conveniently used as a precursor in the preparation of highly pure Almotriptan malate directly suitable for therapeutic use.
It is observed that pharmaceutically acceptable salts of Almotriptan malate when prepared from Almotriptan of lower purity do not meet the pharmaceutically acceptable quality. There is therefore an unfulfilled need to provide industrially feasible process for the preparation of pharmaceutically acceptable salts of Almotriptan from less pure Almotriptan without employing column chromatography as described in the prior art.
To overcome the problem the present invention provides a process to prepare highly pure Almotriptan base through acid addition salts of Almotriptan . When the base is liberated from the acid addition salts, Almotriptan base of high purity results.

It is found that when the less pure Almotriptan is reacted with fumaric acid it selectively forms the corresponding acid addition salt, leaving behind the other related substances and impurities which are otherwise difficult to remove by the conventional methods. The fumaric acid salt of Almotriptan is further converted to highly pure Almotriptan base which in turn is converted into other pharmaceutically acceptable salts with higher purity.
Summary of the invention
The main object of the present invention is to provide an improved process for the preparation of highly pure (>99.7%) Almotriptan base and/or its pharmaceutically acceptable salts
Another object of the invention is to provide a process for preparation of highly pure (>99.7%) Almotriptan and/or its pharmaceutically acceptable salts using fumaric acid salt of Almotriptan
Accordingly in the present invention highly pure Almotriptan and its pharmaceutically acceptable salts are prepared by
1. Treatment of Almotriptan of 70-80% with hydrochloric acid and again liberation of Almotriptan of purity of 85.0%
2. Treating Almotriptan base of 85% purity with fumaric acid yielding fumaric acid addition salt of Almotriptan (Almotriptan fumarate)

3. neutralizing Almotriptan fumarate and isolating Almotriptan base of purity 99.7% and converting highly pure Almotriptan to other acceptable acid addition salts
Detailed description of the invention
Thus in accordance with the present invention preparation of Almotriptan and its pharmaceutically acceptable salts comprise the following steps :
i. Treatment of Almotriptan of purity 70-80% pure with hydrochloric acid again liberation of Almotriptan of purity 85%
ii. Treating crude Almotriptan thus obtained with fumaric acid yielding fumaric acid addition salt of Almotriptan (Almotriptan fumarate)
iii. Converting Almotriptan fumarateto highly pure(>99.7)Almotriptan base by treatment with base.
In a specific embodiment, the present invention provides a process for the preparation of highly pure Almotriptan base and its pharmaceutically acceptable salts, which involve
Reacting Almotriptan base prepared by the prior art processes (70-80% pure)with

furmaric acid by
i. Dissolving Almotriptan base (of purity 70-80% prepared by prior art processes) in acetone
ii. Adjusting pH with IPA-HCl to 2.0
iii. Maintaining under stirring for 2-3 hours at room temperature iv. Filtering and washing with acetone.
V. Neutralizing Almotriptan hydrochloride with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent
vi. Extracting with organic solvent and Separating the layers, vii. Washing the organic layer with water, followed by carbon treatment viii. Concentrating the organic layer under vacuum affording Almotriptan of purity 85% by HPLC
ix. Dissolving Almotriptan base of purity 85% in methanol X. Adding fumaric acid directly or as a suspension to the reaction mixture xi. Heating reaction mass to reflux temperature and maintaining at the same temperature for 1 -2 hours
xii. Cooling reaction mass to room temperature and maintaining at the same temperature for 2-3 hours
xiii. Filtering, washing with methanol and drying the product at 60-70 °C, affording pure Almotriptan fumaric acid addition salt
The prepared Almotriptan fumaric acid addition salt thus prepared is novel and was

identified and characterized by chemical analysis, IR, NMR & Mass spectrum. Almotriptan acid addition salt is further converted to Almotriptan by i. Neutralizing Almotriptan fumaric acid addition salt with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent
ii. Extracting with organic solvent and separating the layers, iii. Washing the organic layer with water, followed by carbon treatment iv. Concentrating the organic layer under vacuum affording Almotriptan of purity >99.7% HPLC
The details of the invention are given in the Examples which are provided for illustration only and therefore the Examples should not be construed to limit the scope of the invention.
EXAMPLES Example-1 : Process for the preparation highly pure Almotriptan of formula -I
Step -1: Preparation of Almotriptan fumarate :
Almotriptan base (1kg, purity 78%) was dissolved in acetone(lOL). Isopropanolic Hydrochloride(10%) was added slowly to pH 2.0 at room temperature and maintained over l-2hrs. The precipitated material was filtered and washed with 5L of acetone. The filtered wet product was suspended in DM water(15L) and stirred for 1hour. Aqueous 5% sodium hydroxide solution was added over a period of 30 minutes to a pH of 9-12 and

extracted with ethyl acetate. The organic layer was washed with DM water and was
distilled off completely under vacuum. The resultant Almotriptan base of 85% purity
was dissolved in 8L of methanol and stirred for 30 minutes. Fumaric acid (2.76kg) was
suspended in 6.5L methanol and added slowly to the reaction mass. Reaction mass was
heated to reflux temperature and maintained at the same temperature for 1hour. Reaction
mass was brought to room temperature and maintained at the same temperature for 3-4
hours. Filtered and washed with methanol. Resultant Almotriptan fumarate of 99.6%
purity was dried in oven at 50-60°C.
Dry weight of Almotriptan fumarate : 0.46kg
Step - II: Preparation of highly pure Almotriptan from Almotriptan fumarate:
Almotriptan fumarate (1.0kg) was suspended in DM water(15L)and stirred for 1 hour.
Aqueous 5% sodium hydroxide solution(3L) was added over a period of 30 min to a pH
of 9-12 and extracted with ethyl acetate(2x5L). The organic layer was washed with DM
water and treated with activated carbon. Ethyl acetate was distilled off under vacuum to
a residual volume of 4L and stirred for 1-2 hours by charging 4L heptane The
precipitated product is filtered and washed with ethyl acetate. The product is dried at
temperature of 60-70°C till constant weight.
Dry weight of Almotriptan : 0.45 kgs
Purity: 99.75% (by HPLC)
Step-III(Preparation of Almotriptan malate):
The resultant Almotriptan base of 99.75% purity was dissolved in 4.5L of methanol and
stirred for 30 minutes. DL-Malic acid (0.18kg) was dissolved in 1.8L methanol and
added slowly to the reaction mass at room temperature. Reaction mass was maintained at

the same temperature for 4hours. Filtered and washed with methanol. Resultant Almotriptan malate of 99.9% purity was dried in oven at 50-60'oC. Dry weight of Almotriptan malate : 0.36kg
Advantages of the invention
1) The Almotriptan base is produced in more than 99.7% purity.
2) The process can be used for commercial preparation of Almotriptan salts of pharmaceutical grade.
3) The process is suitable for operation on industrial scale runs.

We claim:
1. Novel process for the preparation of highly pure (>99.7%) Almotriptan and its
pharmaceutically acceptable acid addition salts comprising the following steps
i. Dissolving Almotriptan base (of purity 70-80% purity prepared by prior art processes)
in acetone
ii. Adjusting pH with Isopropanolic-HCl to 2.0
iii. Maintaining under stirring for 2-3 hours at room temperature
iv. Filtering and washing with acetone.
V. Neutralizing Almotriptan hydrochloride with a base such as organic amines, alkali
hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and
water immiscible solvent
vi. Extracting with organic solvent and separating the layers,
vii. Washing the organic layer with water, followed by carbon treatment
viii. Concentrating the organic layer under vacuum affording Almotriptan of purity
85% by HPLC
ix. Dissolving Almotriptan base of purity 85% in methanol
X. Adding fumaric acid directly or as a suspension to the reaction mixture
xi. Heating the reaction mass to reflux temperature and maintaining at the same
temperature for 1-2 hours
xii. Cooling reaction mass to room temperature and maintaining at the same temperature
for 2-3 hours

xiii. Filtering, washing with methanol and drying the product at 60-70 °C, aftording pure Almotriptan as an acid addition salt of fumaric acid.
xiv. Neutralizing Almotriptan fumaric acid addition salt with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent XV. Extracting with organic solvent and separating the layers, xvi. Washing the organic layer with water, followed by carbon treatment xvii. Concentrating the organic layer under vacuum affording Almotriptan of purity 99.7% by HPLC
2. The acid addition salt 'Almotriptan fumarate' as a novel pharmaceutically acceptable salt of Almotriptan
3. Almotriptan base of High purity (> 99.7%)
4. A novel method of preparing highly pure (> 99.7%) Almotriptan essentially as herein described with reference to example 1 .