FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for preparation of eletriptan of formula I,
(Formula Removed)
or pharmaceutically acceptable salts thereof.
The present invention also relates to novel process for the preparation of a-form of
eletriptan hydrobromide.
BACKGROUND OF THE INVENTION
Eletriptan of formula I, is a selective 5-hydrotryptamine IB/ID receptor antagonist
and is chemically known as (R)-3-((l-methylpyrrolidone-2-yl)methyl)-5-(2-
(phenylsulfonyl)ethyl) 1 H-indole.
(Formula Removed)
It is used for the acute treatment of migraine with or without aura in adults. Pfizer markets eletriptan tablets containing eletriptan hydrobromide under the name Relpax®. It belongs to the triptan class of drugs that includes sumatriptan, naratriptan, rizatriptan, almotriptan, zomitriptan and frovatriptan.
Eletriptan, and intermediates thereof, were first described in US patents 5,545,644 and equivalent patents US 5,607,951, and EP 0 592 438. Patent discloses process for preparation of eletriptan by acetylating (R)-5-bromo-3(N-methylpyrroldin-2-ylmethyl)-l H-indole using acetic anhydride in the presence of triethylamine and N,N-dimethylformamide which in situ undergoes Heck reaction with phenylvinyl sulfone using palladium acetate, tri-o-tolylphosphine and triethylamine to give N-acetylated
Heck coupled intermediate which is then hydrolysed using potassium carbonate in methanol followed by reduction to give eletriptan. The process is as shown below:
(Formula Removed)
It is observed that N-acetylation reaction does not undergo to completion and yields N-acetylated dehydro eletriptan intermediate with low yield and low purity. Other disadvantage of the process is use of strong base such as potassium carbonate for the hydrolysis reaction, which may result in undesired impurities in product. US patent 6,110,940 discloses two polymorphic forms of eletriptan hydrobromide namely α- form and ß-form. Patent discloses two processes for the preparation of α-form of eletriptan hydrobromide. According to first process, a solution of eletriptan in acetone is treated with an aqueous solution of hydrogen bromide and the resulting oil is crystallized from 2-propanol.
According to second process, a solution of eletriptan in acetone or ether solvent at 0-10 °C is treated with an aqueous solution of hydrogen bromide to give ß-form which is then crystallized from aqueous acetone and slurring give α-form of eletriptan hydrobromide. This process proceeds via P-form and adds an extra step to the synthesis of a- form.
In addition to above, when processes are repeated for the industrial scale synthesis, the yields of eletriptan hydrobromide using these processes are very low.
US patent 6,927,296 discloses a process for the preparation of a-form of eletriptan hydrobromide by reaction of eletriptan in 2-butanone with hydrobromic acid followed by distillation, α- Form prepared by the above process also requires polymorph annealing step to increase resistance to subsequent hydration, which is extra step to the process. In addition, 2-butanone is low boiling solvent so recovery losses are high which adds cost to the process.
US patent application 2008/028719 exemplified several processes for preparation of α-form of eletriptan hydrobromide. In one of processes α-form is prepared by dissolving p-form of eletriptan hydrobromide in ethanol at room temperature and then cooled at -19 °C for 3 days. The process takes lot of time i.e 3 days with stringent condition means low temperature for the generation of a-form of eletriptan hydrobromide, which makes the process unsuitable from industrial point of view. Another process discloses the synthesis of a-form of eletriptan hydrobromide by slurrying ß-form of eletriptan hydrobromide in a solvent selected from isobutanol, methyl acetate, mixture of tetrahydrofuran and water, and cyclohexane. All processes proceed through ß-form and adds extra step to the process that is unattractive for commercial synthesis.
US patent application 2009/299077 discloses a process for the preparation of eletriptan involving the purification of dihydro eletriptan intermediate and (R)-5-bromo-3-(N-methylpyrroldin-2-ylmethyl)-lH-indole intermediate by salt formation followed by neutralization to give purified intermediate which is further used for the synthesis of pure eletriptan. The disclosed process has more number of steps therefore not amenable for cost effective synthesis. The process described involves acetylation of (R)-5-bromo-3-(N-methylpyrroldin-2-ylmethyl)-lH-indole using acetic anhydride in the presence of triethylamine, DMAP and N,N-dimethylformamide which in situ undergoes reaction with phenylvinyl sulfone using palladium acetate, tri-o-tolylphosphine and diisopropyl amine as base to give N-acetylated heck coupled intermediate which is then hydrolyzed using potassium carbonate in methanol to give
dehydro eletriptan intermediate. Use of strong base such as potassium carbonate during hydrolysis result in product having impurities thus needs further purification. A recent PCT publication WO 2010/049952 discloses a process for the preparation of eletriptan by the reaction of bromo indole with phenyl vinyl sulfone which is then reduced to give 5-(2-(phenylsulfonyl)ethyl)-lH-indole. Above intermediate is then made to react with CBZ-proline in the presence of Grignard reagent and Lewis acid followed by reduction to provide eletriptan. Patent application also describes purification of eletriptan using salts formation such as oxalate, fumarate and malate, which adds extra step to the process. Moreover, patent is silent about the purity of eletriptan which is foremost requirement in pharmaceutical field. Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials, by-products of the reaction, products of side reactions, or degradation products. Similarly, synthetic strategy employed for the preparation of eletriptan is complex, therefore may results in the formation of several undesired by products due to competing side reactions. Impurities in eletriptan or any other active pharmaceutical ingredient are undesirable and in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. According to ICH guidelines, process impurities should be maintained below set limits by specifying the quality of raw materials, their stoichiometric ratios, controlling process parameters, such as temperature, pressure, time and including purification steps, such as crystallization, distillation and liquid-liquid extraction, in the manufacturing process. Typically, these limits are less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower, typically less than 0.10 % by weight. Therefore, in the manufacture of a drug substance, the purity of the products, such as eletriptan is
required before commercialization. Therefore, pharmaceutical active compounds
must be either free from these impurities or contain impurities in acceptable limits. In
addition to this, regulatory authorities worldwide require that drug manufacturers
should isolate, identify and characterize the impurities in their products.
In the view of the above, most of the prior art processes yield intermediates of low
purity as well as in low yield, which in turn have their effect on the purity, and yield
of the final API. In addition, the processes for the synthesis of a-form of eletriptan
hydrobromide does not produce consistent result and product obtained by the prior art
processes found to be mixture with other forms. Thus, there is an urgent need for the
development of a process which produces final API i.e. eletriptan and its
pharmaceutically acceptable salts of high purity and having impurities in either
acceptable amounts or free from the impurities. Present invention fulfills the need in
the art and provides an improved, industrially advantageous process for the synthesis
of eletriptan and its pharmaceutically acceptable salts thereof and produce the
consistency in results during polymorph preparation.
OBJECTIVE OF THE INVENTION
It is foremost objective of the invention is to provide an improved and industrially
advantageous process for the preparation of eletriptan and pharmaceutically
acceptable salts thereof.
Another objective of the invention is to provide a process for the preparation of
eletriptan and pharmaceutically salts thereof free from impurities or having impurities
less than 0.15%.
Another objective of the invention is to provide a process for preparation of eletriptan
and pharmaceutically acceptable salts thereof which involves isolation of the key
intermediate, (R)-1 -[5-bromo-3-( 1 -methyl-pyrrolidin-2-ylmethyl)-indol-1 -yl]-
ethanone (N-acetyl bromo indole intermediate).
Another objective of the invention is to provide a process for the preparation of pure
N-acetyl bromo indole intermediate.
Another objective of the invention is to provide process for the preparation of
eletriptan and pharmaceutically salts thereof using a mild base.
Still another objective of the invention is to provide a process for the preparation of
α-polymorphic form of eletriptan hydrobromide.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of eletriptan of
formula I,
(Formula Removed)
and pharmaceutically acceptable salts thereof.
The process comprises the steps of:
a), protecting amine group of bromo indole intermediate of formula II,
(Formula Removed)
using a suitable acetylating agent in a solvent to form N-acetylated bromo indole intermediate of formula HI,
(Formula Removed)
b). isolating N-acetylated bromo indole intermediate of formula III; c). reacting intermediate of formula III with phenyl vinyl sulfone to form acetylated dehydro intermediate of formula IV,
(Formula Removed)
d). deprotecting acetylated dehydro intermediate of formula IV using a mild base to form dehydro eletriptan of formula V, and
(Formula Removed)
e). converting dehydro eletriptan of formula V in to eletriptan or pharmaceutically
acceptable salts thereof. According to another embodiment, present invention provides isolated N-acetyl bromo indole intermediate of formula III.
According to still another embodiment, present invention provides a process for the preparation of eletriptan of formula I or pharmaceutically acceptable salts thereof, comprises the steps of: a), deprotecting acetylated dehydro intermediate of formula IV,
(Formula Removed)
using a mild base to form dehydro eletriptan of formula V,
(Formula Removed)
b). converting dehydro eletriptan of formula V to eletriptan or pharmaceutically acceptable salts thereof. According to another embodiment, present invention provides a process for preparation of α-form of eletriptan hydrobromide, comprises the steps of:
a), providing a solution of eletriptan free base in a solvent selected from glycols or glycerols or a mixture of glycols or glycerols with other solvent;
b). adding a suitable source of hydrogen bromide,
c). stirring for a time sufficient for salt formation;
d). removing the solvent from organic layer;
e). crystallizing from a second solvent;
f). isolating a-form of eletriptan hydrobromide. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: HPLC chromatogram of dehydro eletriptan intermediate prepared as per comparative Example 3
Figure 2: HPLC chromatogram of dehydro eletriptan intermediate prepared as per Example 3 Method B
Figure 3: HPLC chromatogram of pure dehydro eletriptan intermediate having impurities less than 0.15 % by HPLC
Figure 4: X-ray diffraction pattern of α-form of eletriptan hydrobromide. DETAILED DESCRIPTION OF THE INVENTION
As used herein term BIP refers to 5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole"
According to one embodiment, present invention provides a process for the preparation of eletriptan or pharmaceutically acceptable salts thereof starting from intermediate of formula II.
Generally, process involves acetylation of intermediate of formula II using a suitable acetylating agent in a suitable solvent at a temperature 0 to 150 °C for few minutes to few hours. Preferably, reaction can be carried out at reflux temperature of solvent for
1 to 12hours, more preferably till the completion of the reaction. The completion of reaction can be monitored by any one of the chromatographic techniques such as thin layer chromatography (TLC), ultra-pressure liquid chromatography (UPLC), High pressure liquid chromatography (HPLC) and the like. Suitable acetylating agent employed for the reaction can be selected from acetic anhydride, acetyl halide, a compound of general formula CH3COX (wherein X is selected from OCOR, OSOjR,
(Formula Removed)
and the like; R and R' are same or different and can be selected from alkyl, aryl, alkaryl, aralkyl and the like) and the like. Suitable solvent employed for the reaction includes aprotic solvent such as N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl pyrrolidone, sulfolane, dimethyl sulfoxide and the like. After the completion of the reaction, N-acetyl bromo indole intermediate of formula III can be isolated from the reaction mixture using suitable techniques known in the art.
Specifically, N-acetyl bromo indole intermediate of formula III can be isolated from reaction mixture by generation of biphasic system in reaction mixture. Biphasic system can be generated by the addition of water and water immiscible solvent to the reaction mixture. Water immiscible solvent includes ether such as methyl tertiary butyl ether; aliphatic or aromatic hydrocarbons, halogenated solvents, esters and the like or mixture thereof. After the layer separation, aqueous layer can optionally be washed with a water immiscible solvent as described above and/or charcoalized. Aqueous layer can be basified with a suitable base till the reaction mass attain pH 8, preferably between 8-9. Preferably basification of reaction mixture can be carried out at a temperature of -10 to 40 °C. Suitable base includes organic base such as ammonia, triethyl amine; or inorganic base such as sodium bicarbonate, sodium carbonate, lithium carbonate, lithium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
Intermediate of formula III can be extracted from the resulting reaction mixture using
a suitable solvent which includes halogenated solvent such as dichloromethane, chloroform; ethers such as methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran; aliphatic or aromatic hydrocarbon such as toluene, C3.10 esters such as ethyl acetate and the like or mixture thereof. Desired product i.e. N-acetyl bromo indole intermediate of formula III can be recovered from resulting solution by solvent removal using suitable techniques such as distillation, evaporation and the like. The isolated product can be optionally purified using solvent which include aliphatic or aromatic hydrocarbon solvent such as cyclohexane, n-hexane, n-heptane; toluene,; ethers such as isopropyl ether and the like or mixture thereof.
Above reaction is preferentially carried out in the absence of base. It is found by the present inventor that carrying out acetylation reaction in the presence of base, reaction does not go to completion. Whenever attempts are made to perform acetylation in presence of base, the starting material remain unreacted in the reaction mixture (monitored by chromatographic techniques) as shown in the example 1. It is highly advantageous to isolate the N-acetyl bromo indole intermediate of formula III from the reaction mixture to remove impurities that may be present in the starting material i.e. intermediate of formula II or generated during this reaction. Starting material of formula II can be prepared by any of the method known in the art or can be procured commercially from the market. Starting compound of formula II may be found to be contaminated with some identified as well as some unidentified impurities. Typically intermediate of formula II, as prepared by the prior art processes or procured from the market is contaminated mainly with three impurities as shown below:
(Formula Removed)
These impurities are difficult to remove by conventional purification methods. Except des bromo, other two impurities have potential group to react with phenyl vinyl sulfone in the next stage, which result in eletriptan with low yield as well low purity due to contamination of impurities.
Therefore present invention provides a method for the removal of impurities at the N-acetyl intermediate stage by isolating N-acetyl intermediate of formula III from the reaction mixture. Isolated N-acetyl intermediate of formula III is found to be either free from the above impurities or having these impurities in acceptable amounts. During acetylation above impurities also get acetylated to form respective acetylated products.
Isolated N-acetyl intermediate is found to contain impurities less than 0.15 % by HPLC. Preferably, N-acetyl intermediate is found to contain des bromo BIP acetate and/or hydroxy BIP acetate and/or keto BIP acetate less than 0.15 % by HPLC. More preferably, N-acetylated product is found to be free from hydroxy BIP acetate and/or keto BIP acetate impurities.
Pure and isolated N-acetyl intermediate of formula HI is made to react with phenyl vinyl sulfone to form intermediate of formula IV.
Generally, reaction of intermediate of formula III with phenyl vinyl sulfone can be carried out in the presence of a suitable base and a catalyst at a temperature of 0 to 150 °C for few minutes to few hours. Suitable base includes organic base which include amine of general formula NR1R2R3 (wherein R1, R2 and R3 can be same or different and can be selected independently from C1-10 alkyl group) such as diisopropyl ethyl amine; or inorganic base such as alkali metal carbonate, bicarbonates, hydroxides, alkoxides and the like. Catalyst includes palladium acetate, palladium chloride, or organometallic palladium as a complex with tri-o-tolylphosphine ligand or PR1R2R3 (wherein R1, R2 and R33 are same as defined above), and the like. Preferably, catalyst is palladium acetate as a complex with tri-o-tolylphosphine. The reaction can be carried out in a suitable solvent that includes
aprotic solvent such as N,N- dimethylformamide, N,N-dimethyl acetamide, N-methyl pyrrolidone and the like or mixture thereof. Usually, the reaction of acetyl intermediate of formula III and phenyl vinyl sulfone is carried out at a temperature of about 0 to 150 °C for 1 to 12 hours, most preferably till the completion of the reaction. Acetylated dehydro intermediate of formula IV can be recovered from the reaction mixture using a suitable method known in the art. Specifically, reaction mixture can be quenched wherever required to inhibit the unreacted catalyst, if any present in the reaction mixture. Suitable quenching agent employed is suitable acid in a solvent to obtain a suspension followed by filtration to obtain filtrate. Suitable acid includes inorganic acid, which can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; or organic acid which includes carboxylic acid such as formic acid, acetic acid; sulfonic acid such as p-toluene sulfonic acid and the like. Solvent used includes aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, cyclohexane, hexane, heptane; C3-10 ether such as isopropyl ether, methyl tertiary butyl ether, methyl cyclopentyl ether; ester such as ethyl acetate; halogenated solvents such as dichloromethane, chloroform and the like. Preferably, reaction mixture can be cooled prior to addition of acid to a temperature of -15 to 25 °C, more preferably to a temperature of 25 to 20 °C. The filtrate thus obtained can be optionally washed with another solvent and/or charcoalized. Solvent for washing purpose include aliphatic or aromatic hydrocarbon such as toluene, aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile; esters such as ethyl acetate; ether such as tetrahydrofuran and the like. The washing can be repeated with same or different solvent and can be done before or after the charcoalisation. Thereafter, suitable base is added to combined filtrate to form a second suspension comprising of a precipitate of intermediate of formula IV. Suitable Base used for the precipitation can be organic base such as ammonia, triethylamine, ethanolamines or inorganic base such as alkali or alkaline metal carbonate,
bicarbonates, hydroxides and the like. Reaction mixture can be optionally seeded with pure acetylated dehydro intermediate of formula IV. Addition of base to the reaction mixture neutralizes the acid and thus creates a basic solution. Preferably, the pH of the reaction mixture after the addition of base is 8 to 11, more preferably 9.0 to 9.5. Intermediate of formula IV can be isolated from the resulting suspension by suitable techniques such as filtration, centrifugation and the like. Acetyl dehydro intermediate of formula IV thus prepared can be optionally purified with a suitable solvent such as C 3-10 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; C 4-12 ether such as methyl tertiary butyl ether, isopropyl ether; C 1-10 alcohol such as methanol, ethanol, iso-propanol; xylene, ethyl benzene, cyclohexane, n-hexane, n-heptane; C 3-10 esters such as ethyl acetate; nitriles such as acetonitrile; aliphatic or aromatic hydrocarbon such as toluene, water and the like or mixture thereof.
Acetyl dehydro intermediate of formula IV thus prepared from isolated N-acetyl bromo indole intermediate of formula III is found to be free from impurities or having impurities in acceptable amounts. The main reason for the high purity of the intermediate of formula IV is removal of precursor of possible impurities at intermediate stage i.e. N-acetyl intermediate of formula III. Intermediate of formula IV found to have purity more than 92 % by HPLC, preferably more than 95 % by HPLC, more preferably 95 % by HPLC.
Acetyl dehydro intermediate of formula IV is then deprotected to form dehydro-eletriptan of formula V employing hydrolysis in the presence of mild base which also forms novel feature of the invention.
Generally, deprotection of acetyl dehydro intermediate of formula IV can be carried out using a suitable base in a solvent at a temperature of -15 to 120 °C for few minutes to few hours, preferably for 1 to 12 hours, more preferably till the completion of the reaction. Suitable base employed for the reaction can be selected from sodium carbonate, lithium carbonate; ammonia, primary amine such as ethylamine,
ethanolamine; secondary amine such as diethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene. H2O; 4-dimethylaminopyridine.H20 and the like. Solvent used for the reaction includes alcohol such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dimethoxy ethane and the like or mixture thereof. Preferably reaction can be carried out at a temperature of 20 to 60 °C for 1 to 3 hours, more preferably till completion of the reaction. After completion of reaction, reaction mixture can be optionally charcoalized to improve the color quality and/or filtered to remove any insoluble particulate present in the reaction mixture. Dehydro-eletriptan of formula V can be recovered from the reaction mixture by removal of solvent followed by addition of water and/or a solvent such as acetone to the reaction mixture. The product thus precipitated out can be isolated from reaction mixture by suitable techniques such as filtration, centrifugation and the like. Dehydro eletriptan intermediate of formula V thus prepared can be purified by employing any suitable purification method to enhance the purity of the product and/or to minimize the impurities present in the product. Intermediate of formula V can be washed with a suitable solvent. Suitable solvent includes water, C1-10 alcohol such as methanol, ethanol, isopropanol; C3-10 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile; C3-10 ester such a ethyl acetate; C 4-12 ethers such as tetrahydrofuran and the like or mixture thereof. It is highly advantageous to carry out deprotection reaction in the presence of mild base as compared to potassium carbonate. It is found by the present inventor, when reaction is carried out using potassium carbonate as a base, it yield dehydro eletriptan of formula V in low yields and low purity. Intermediate of formula V prepared by the prior art processes found to have purity less than 91 % by HPLC and contain certain impurities as shown in the Figure 1. As is known in the art, management of process impurities is greatly enhanced by understanding their chemical structures and by identifying the parameters that influence the amount of impurities in the final product. One of the identified impurities is found to have structure formula:
(Formula Removed)
wherein R is hydrogen or alkyl depending upon nature of alcohol used for the reaction
The amount of alkyl hydroxy impurity of formula VI depends upon the nature of base employed for the reaction. The amount of alkyl hydroxy impurity is more when reaction is carried out using potassium carbonate as base. Potassium carbonate being a strong base generate alkoxide ion of alcoholic solvent used for the reaction, alkoxide ion thus generated attack on the intermediate of formula V and result in the generation of alkyl hydroxy impurity. More strong is the base, more is the generation of above impurity. Present inventor employ the use of mild base as specified above which minimize the generation of alkoxide ion in the reaction mixture and thus result in dehydro eletriptan of formula V with high purity. One more impurity found which is found to be present in the intermediate of formula V is impurity at RRT 1.22 as shown in figure 1. Use of mild base during the reaction minimizes the generation of both impurities namely alkyl hydroxy impurity as well as impurity at RRT 1.22 along with some other impurities as shown in Figure 2.
Other impurity that may be present in intermediate of formula V is hydroxy dehydro-eletriptan impurity of formula VII,
(Formula Removed)
The precursor of this impurity is hydroxy BIP impurity that may present in the starting material or may generate during the reaction. As the present invention involves removal of BIP hydroxy impurity during isolation of N-acetyl intermediate of formula III in the form of their acetylated product, so chances of formation of
above impurity at this stage is minimized. Thus N-acetyl intermediate of formula III free from the hydroxy impurity or having less than 0.15% yields intermediate of formula V free of hydroxy dehydro-eletriptan impurity or may be present less than 0.15 %. Hence, present invention has added advantage of isolation of N-acetyl intermediate of formula III during synthesis of eletriptan.
One more impurity that may be present in dehydro eletriptan of formula V is bis phenyl sulfone impurity. Presence of above impurity in the product can be checked by mass analysis showing M+l peak at 535. Based upon the mass analysis and possible side reaction, bis phenyl sulfone impurity can have two structures as shown below:
(Formula Removed)
Main reason for generation of above impurity is demethylation reaction followed by
side reaction of phenyl vinyl sulfone with dehydro eletriptan intermediate of formula
V. Phenyl vinyl sulfone may react with pyrrolidine nitrogen to generate impurity of
formula Villa or with indole nitrogen to form impurity of formula VIIIb.
The intermediate of formula V thus prepared by the present invention is found to be
highly pure as having purity more than 96% by HPLC, preferably more than 97 % by
HPLC, more preferably 99.47% by HPLC. Intermediate of formula V is highly pure
and contain identified as well unidentified impurities less than 0.15 % by HPLC as
shown in figure 3.
Dehydro-eletriptan intermediate of formula V is then converted to eletriptan or its
pharmaceutically acceptable salts thereof.
Generally, process involves the reaction of intermediate of formula V with a suitable
reducing agent in a solvent at a temperature of 0 to 70 °C for few minutes to few
hours, preferably till the completion of reduction reaction. Reducing agent can be selected from any reagent known in the art that can effectively serve the purpose of reduction of double bond provided it does not have any effect on other functionality of intermediate of formula V. Specifically reducing agent includes a catalyst such as palladium (with or without carbon) and the like in combination with a suitable acid such as methanesulfonic acid or palladium hydroxide Pd(OH)2 and the like. Solvent includes C3-10 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogenated solvent such as dichloromethane; C1-10 alcohol; C3-10 esters; aliphatic or aromatic hydrocarbon such as toluene, cyclohexane and the like or mixture thereof. The reaction mixture can be stirred under hydrogen atmosphere till the completion of the reaction. After completion of reaction, catalyst is filtered off from the reaction mixture and catalyst can be washed with a suitable solvent. The eletriptan of formula I can be isolated from the reaction using suitable techniques or can be used as such for further step of salt formation.
Specifically, eletriptan can be isolated from the reaction by removal of solvent followed by addition of water to the reaction mixture followed by basification using a suitable base. Suitable base used for basification can be organic base such as ammonia or inorganic base that includes alkali or alkaline metal hydroxide carbonates, bicarbonate thereof, such as sodium hydroxide, sodium carbonate, sodium bicarbonate and the like. Preferably, suitable base can be added to the reaction mixture till the reaction pH of the reaction mixture reaches between 8 to 11, more preferably between 9 to 11. The desired product can be extracted from the resulting mixture by layer separation using a suitable solvent from the reaction mixture. The solvent used for the extraction includes C5-10 ether such as methyl tertiary butyl ether, isopropyl ether, 2-methyl tetrahydrofuran, methyl cyclopentyl ether; C5-10 aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, cyclohexane, n-heptane, n-hexane; C3-10 ester such as ethyl acetate; halogenated solvent such as chloroform, dichloromethane; and the like or mixture thereof.
Eletriptan can be recovered from the resulting solution by the removal of solvent using suitable techniques such as distillation or evaporation and the like. Eletriptan, thus prepared, can optionally be purified using suitable purification to enhance purity of product. Any suitable purification procedure like crystallization, slurry wash, solvent anti-solvent system or combination of these procedures, may be employed to get purified material. Solvent for purification can be chosen amongst water, alcohols, aliphatic ketones, aliphatic or aromatic hydrocarbons, aliphatic esters, ethers; nitriles, halogenated solvents, aprotic polar solvents and the like. Eletriptan is then converted to its pharmaceutically acceptable salts. Preferably, eletriptan or reaction mixture containing eletriptan can be converted to eletriptan hydrobromide by any of the methods known in the art.
Eletriptan hydrobromide can exist in different polymorphic forms mainly α- form and ß-form. Present invention provides a process for preparation of α-form of eletriptan hydrobromide, which form another novel part of the invention. Generally, salt formation can be carried out by the reaction of eletriptan in a suitable solvent with a source of bromide ion at a temperature -15 to 50 °C for a time sufficient for salt formation. Preferably, reaction can be carried out at a temperature below 15°C, more preferably at a temperature of 5 to 15 °C till completion of reaction. Usually, salt formation reaction completes in 3 hours. Suitable solvent employed for reaction can be selected amongst glycols such as monoethylene glycol; or glycerols or glycols or glycerols in combination with other solvents which includes water, halogenated solvent such as dichloromethane, chloroform and the like. Source of bromide ion can be selected amongst aqueous hydrobromic acid, gaseous hydrobromic acid, solvent saturated with gaseous hydrobromic acid, ammonium bromide, hydrobromide salt of amines such as trialkyl amine, dialkyl amine or alkyl amine and the like; solvent employed includes alcohol such as isopropanol, ethanol, methanol,; nitriles such as acetonitrile; ether such as isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran; esters such as ethyl acetate; halogenated solvents such as
dichloromethane, chloroform and the like. After completion of reaction,a suitable alcoholic solvent can be optionally added to mixture and charcoalised. Desired product can be isolated from the resulting organic layer by the removal of solvent followed by crystallization using a suitable solvent. Suitable solvent used for the crystallization purpose includes C1-8 alcohol such as isopropanol, ethanol, methanol, tertiary butanol, isobutanol; nitriles such as acetonitrile; ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, dimethoxy ethane; esters such as ethyl acetate; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; aliphatic or aromatic hydrocarbon such as n-hexane, cyclohexane, n-heptane, toluene, ethyl benzene, xylene and the like or mixture thereof.
Eletriptan hydrobromide thus obtained by the process of present invention displays powder X-ray diffraction pattern similar to a-form of eletriptan hydrobromide as shown in Figure 4.
Eletriptan hydrobromide thus prepared is found to be highly pure in nature and have impurities less than 0.15 %; more preferably less than 0.10 %. As per the recommendation of regulatory authorities, the impurities present in the final API must be identified and characterized. Therefore, final API i.e. eletriptan hydrobromide is analyzed for the presence of impurities and found to display the presence of following impurities less than 0.15 % by HPLC.
One of the impurities that may present in the final product i.e. eletriptan hydrobromide is N-oxide eletriptan having formula IX,
(Formula Removed)
or acid addition salts thereof.
Mass analysis of the sample shows the presence of impurity showing M+1 peak at
399. Above N-oxide impurity may be present in isomeric form.
Other organic impurity can be UK-120 impurity having formula X,
(Formula Removed)
or acid addition salts thereof.
Mass analysis of the sample shows the presence of impurity showing M+1 peak at 243.18. The identified impurities that may present in dehydro eletriptan of formula V as well as in final API i.e. eletriptan hydrobromide as described in the present invention may be isolated from the reaction mixture using suitable techniques such as column chromatography, preparative chromatography and the like or can be synthesized using suitable reaction conditions which enrich the presence of impurities.
Eletriptan hydrobromide can optionally be purified using suitable purification to enhance the purity of the product. Any suitable purification procedure such as, for example, crystallization, derivatisation, slurry wash, salt preparation, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material. However, other equivalent procedures such as acid-base treatment or acid-acid treatment could, also be used, to purify the intermediates as well as final product. Solvent for the purification can be chosen amongst water, C1-8 alcohols such as methanol, ethanol, isopropanol, aliphatic C3-8 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, C3.10 aliphatic or aromatic hydrocarbons, C3-10 aliphatic esters such as ethyl acetate, isopropyl acetate, C4-10 ethers such as isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, dimethoxyethane, 2-methyl tetrahydrofuran; nitriles such as acetonitrile, halogenated solvents such as dichloromethane, aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidinone, sulfolane and the like or mixtures thereof in suitable proportion. Preferably, eletriptan hydrobromide is crystallized from acetonitrile, dichloromethane: acetonitrile; dichloromethane: C3-8 ketones; dichloromethane: C3.10
esters; dichloromethane: C1-8 alcohols; dichloromethane: C4-10 ethers; acetonitrile: C3-8 ketones; or acetonitrile: C3-8 ester. Eletriptan hydrobromide used for purification can be any polymorphic form, it can be of α-form, ß-form, amorphous or monohydrate or mixture of various polymorphic form. Crystallization with nitrile solvent or its mixture with other solvent and mixture of dichloromethane with other solvent yield a-form of eletriptan hydrobromide.
Eletriptan hydrobromide prepared by the invention is highly pure in nature; it has purity more than 99%, preferably more than 99.5%, more preferably 99.57 % by HPLC. Eletriptan hydrobromide found to have impurities less than 0.15 % or free from impurities selected amongst UK-120, N-oxide eletriptan, dehydro eletriptan, acetyl dehydro eletriptan and/ or l-[5-(2-Benzenesulfonyl-ethyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone or hydrobromide salts thereof. Major advantage realized in the present invention is synthesis of eletriptan hydrobromide in high overall yield and high purity. Another advantage lies in the isolation of N-acetyl intermediate of formula III, as most of the possible impurities removed during its isolation. Still another advantage of the present invention is use of mild base during deprotection reaction which yield intermediate of formula V having impurities in acceptable amounts or free from impurities. The process of present invention is highly advantageous in the preparation of eletriptan hydrobromide having impurities in acceptable amounts or free from impurities. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. COMPARATIVE EXAMPLES
Example 1: Preparation of (R)-l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone as per US 5,545,644
A solution of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-lH-indole (50 g) in dimethylformamide (40 ml) and triethylamine (18.98 g) was treated with acetic
anhydride (19.15 g) for 10 minutes. Reaction mixture was heated to 90 -100°C for 2 hours and then cooled. Reaction was monitored using thin layer chromatographic analysis which indicates presence of 15-20% of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (50g) in dimethylformamide remained unacetylated. Example 2: Preparation of (R)-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone as per US 5,545,644 A Solution of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-lH-indole (50 g) in dimethylformamide (40 ml) and triethylamine (18.98 g) was treated with acetic anhydride (19.15 g) for 10 minutes. Reaction mixture was heated to 90-100 °C, for 2 hours and then cooled. The reaction mixture was poured to a solution of palladium acetate (1.91 g), tri-o-tolyphosphine (5.20 g), phenyl vinyl sulphone (35.86 g) and triethylamine (36.24 g) in dimethylformamide (90 ml) and resulting mixture was heated to reflux for 3 hours. Reaction mixture was then cooled and filtered through Arbacel followed by washing with dimethylformamide (2x50 ml) and then with water (2x50 ml). Reaction mixture was quenched by the addition of dilute aqueous hydrochloric acid (3016 ml) followed by basification of aqueous layer by the addition of aqueous sodium hydroxide till pH reaches about 8. No solid material precipitated, only sticky material formed. The resulting reaction mixture was extracted with dichloromethane (3 x 150ml) and washed with water (2 x 50ml). Resulting organic layer was distilled off give 47.5 g (66 %) of residue having purity 86.7 % by HPLC. Resulting gummy material was treated with methanol (500 ml) and water (250ml). Even after treatment with aqueous methanol no product precipitated. Example 3: Preparation of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-1H-indole
[R]-1-[5-(2-Benzenesulfonyl-vinyl)-3-(1-methyl-pyrrolidin-2-ylmethyl)-indol-1-yl]-ethanone (7 g), methanol (70 ml), potassium carbonate (0.91 g) and demineralized water (7 ml) were stirred together at 40-45°C for 1.0 hour. After completion of reaction, solution was treated with active carbon (0.7g) at 20-25 °C for 30 minutes.
Carbon was filtered through hyflo bed and to the filtrate was added demineralized water (70 ml) slowly at 20-25°C and stirred for 3-4 hours. The resulting product was filtered and washed with mixture of methanol and demineralized water (1:1, 6ml) and dried to give 6.3 g of the title compound having purity 90.7% by HPLC. HPLC chromatogram as shown in Figure 1. Even after repeated purification with acetone and acetonitrile, purity of title compound achieved was only 95 % by HPLC. Example 4: Preparation of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-1H-indole
[R]-1 -[5-(2-Benzenesulfonyl-vinyl)-3-( 1 -methyl-pyrrolidin-2-ylmethyl)-indol-1 -yl]-ethanone (7 g), isopropanol (70 ml) and potassium carbonate (0.91 g) were stirred together at 60-65 °C for 14 hours. After completion of reaction, solution was treated with active carbon (0.7 g) at 20-25°C for 30 minutes. Carbon was filtered through hyflo bed and to the filtrate was added demineralized water (70 ml) slowly at 20-25°C and stirred for 3-4 hours. The resulting product was filtered and washed with mixture of methanol and demineralized water (1:1, 6ml) and suck dried to give 5.2 g of the title compound having purity 89 % by HPLC.
EXAMPLE:
Example 1: Preparation of (R)-l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone
Method A: A mixture of [R]-5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (300 g, 1.02 mol, having des bromo BIP: 0.5 %; hydroxy BIP: 0.12 %; keto BIP: 0.07% by HPLC), acetic anhydride (319.2g, 3.13 mol) and N,N-dimethyl formamide (15g, 0.205 mol) was heated at 95-100 °C for 2-3 hours. Thereafter, reaction mixture was cooled to 0-5 °C. Methyl tertiary butyl ether (750ml) and water (1500 ml) were added followed by layer separation. Aqueous layer was washed with methyl tertiary butyl ether (2 x 750 ml) and treated with activated carbon (60g) at 50 °C for 1 hour. The reaction mixture was filtered and basified with sodium bicarbonate (315 g) to pH 8-9 at 0-5 °C. The product was extracted by dichloromethane (3x900
ml). The combined organic extract was washed with water (600ml) and dried over sodium sulphate. Resulting organic layer was distilled off under vacuum at 45-50 °C to give 317g (92 %) of title compound having purity 95 % by HPLC; des bromo BIP acetate: 0.12 %; hydroxy BIP acetate and keto BIP acetate: not detected; DSC displays endothermic peak at 69 °C and melting point 62-64 °C. Method B: A mixture of [R]-5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (100 g, 0.34 mol, having des bromo BIP: 0.5 %; hydroxy BIP: 0.12 %; keto BIP: 0.07 % by HPLC), acetic anhydride (106.4 g, 1.042 mol) and N,N-dimethylformamide (5.0 g, 0.068 mol) was heated at 95-100 °C for 2-3 hours. Thereafter, reaction mixture was cooled to 0-5 °C. Methyl tertiary butyl ether (250ml) and demineralized water (500ml) were added followed by layer separation. Aqueous layer was washed with methyl tertiary butyl ether (2 x 250ml). The separated aqueous layer was treated with activated carbon (10 g) at 70 °C for 1 hour. The reaction mixture was filtered and basified with sodium bicarbonate (105 g) to pH 8-9 at 0-5 °C. The product was extracted by dichloromethane (3 x 300ml). The combined organic extract was washed with water (150 ml) and dried over sodium sulphate. Resulting organic layer was distilled off under vacuum at 45-50 °C. Cyclohexane (100 ml) was added to the resulting residue and distilled off under vacuum at 50-55 °C to give 97 g of the title compound having purity 95 %, des bromo BIP acetate: 0.10 %; hydroxy BIP acetate and keto BIP acetate: not detected by HPLC. Method C: A mixture of [R]-5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (5 g, 0.017 mol, having des bromo BIP: 0.5 %; hydroxy BIP: 0.12 %; keto BIP: 0.07 % by HPLC), acetic anhydride (5.22 g, 0.51 mol) and N,N-dimethylformamide (0.25 g, 0.0034 mol) was heated at 95-100 °C for 2-3 hours. Thereafter, reaction mixture was cooled to 0-5 °C. Methyl tertiary butyl ether (12.5 ml) and demineralized water (25ml) were added followed by layer separation. Aqueous layer was washed with methyl tertiary butyl ether (2 x 12.5 ml). The separated aqueous layer was treated with activated carbon (0.5g) at 70 °C. The

reaction mixture was filtered and basified with aqueous ammonia (25%, 5 ml) to pH 8-9 at 0-5°C. The product was extracted by dichloromethane (3 x 15ml). Combined organic extract was washed with water (7.5 ml) and dried over sodium sulphate. Resulting organic layer was distilled off under vacuum at 45-50 °C. Cyclohexane (10 ml) was added to the resulting residue and distilled off under vacuum at 50-55 °C to give 5.43g (95%) of the title compound having purity 95.3 %; des bromo BIP acetate: 0.15 %; hydroxy BIP acetate and keto BIP acetate: not detected by HPLC. Example 2: Preparation of [R]- l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone
Method A: A mixture of palladium acetate (11.03g, 0.002 mol) and tri-o-tolylphosphine (48.23g, 0.005 mol) in dimethylformamide (600ml) was stirred under nitrogen atmosphere for 1 hour. Phenyl vinyl sulphone (165g, 0.033 mol), N,N-diisopropyl ethylamine (138.8g, 0.036 mol), [R]- l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (300g, 0.895 mol) and dimethylformamide (600ml) were added to the reaction mixture and heated to 90-95°C for 3-4 hours. The reaction mixture was cooled to 20-25°C, followed by addition of toluene (1.5 L) and aqueous hydrochloric acid (3.375 L, 3.3%) at 30-35°C for 1.5 hours. The reaction mixture was stirred for 15 minutes, filtered through hyflo-bed and washed with dimethylformamide (60ml). The aqueous layer was separated, washed with toluene (1.5L), treated with active carbon (60g) at 40°C for 30 minutes, filtered and washed with acetone (600ml). Combined filtrate was cooled to 30-35°C and aqueous ammonia (420ml; 25%; till pH 9.0-9.5) was added to the reaction mixture. Reaction mixture was cooled to 25-30°C, stirred for 30 minutes, filtered, washed with water and dried to give 480 g of title compound having purity 94 % by HPLC. Method B: A mixture of palladium acetate (0.37g, 0.002 mol) and tri-o-tolylphosphine (1.63g, 0.005 mol) in dimethylformamide (20ml) was stirred under nitrogen atmosphere for 1 hour. Phenyl vinyl sulphone (5.5 g, 0.033 mol), N,N-diisopropyl ethylamine (4.63 g, 0.036 mol), [R]- l-[5-bromo-3-(l-methyl-pyrrolidin-
2-ylmethyl)-indol-l-yl]-ethanone (10g, 0.030 mol) and dimethylformamide (20ml) were added to the reaction mixture and heated to 90-95°C for 3-4 hours. The reaction mixture was cooled to 20-25 °C, filtered and poured into aqueous hydrochloric acid (112.5 ml, 3.3%), stirred for 20 minutes to obtain clear solution. This aqueous solution was washed with toluene (2 x 50ml) at 20-25°C and filtered. The aqueous layer was treated with activated carbon (2 g) at 40-45°C, filtered through hyflo bed under vacuum and the bed washed with acetone (30 ml). The filtrate was treated with aqueous ammonia (25%) till pH 9.0-9.5 and stirred for 10-15 hours. The product was filtered under vacuum and washed with water (2 x 15ml) and suck dried to afford 13 g of wet title compound having purity 91 % by HPLC. Resulting product (10 g) was stirred in methanol (40 ml) for 2 hours at 20-25°C, filtered, washed with methanol (10 ml) and dried to give 7.5 g of the title compound. The wet compound (0.2g) was dissolved in acetone (1 ml) followed by addition of methyl tertiary butyl ether (1ml). The product thus precipitated was filtered, washed with methyl tertiary butyl ether (1 ml) and suck dried to give 0.13 g of title compound having purity 95 % by HPLC. Method C: A mixture of dimethylformamide (50 ml), palladium acetate (0.92 g, 0.004 mol) and tri-o-tolylphosphine (4.08 g, 0.013 mol) was stirred under nitrogen atmosphere for 1 hour. Phenyl vinyl sulphone (13.8 g, 0.082 mol), N,N-diisopropyl ethylamine (11.56 g, 0.089 mol) and [R]- l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (25g, 0.075 mol) and dimethylformamide (50 ml) were added to the reaction mixture and heated to 90-95 °C for 3-4 hours. The reaction mixture was cooled to 20-25°C, filtered and poured into aqueous hydrochloric acid (281.25 ml, 3.3%) and stirred for 20 minutes to obtain clear solution. Toluene (125 ml) was added to the aqueous layer, stirred for 20 minutes and filtered. The aqueous layer was re-extracted with toluene (125 ml) at 20-25°C. The resulting aqueous layer was treated with activated carbon (5 g) at 40-45°C, filtered through hyflo bed under vacuum and the bed washed with acetone (75 ml). The filtrate was basified with aqueous ammonia (25%) till pH 9.0-9.5 and stirred for 10-15 hours. The product was
filtered under vacuum, washed with water (2 xl5ml) and dried to give 39 g of title compound having purity 92 % by HPLC.
The resulting product was stirred in methanol (100ml) for 2 hours at 20-25°C and filtered. The filtered solid was washed with methanol (25ml) and suck dried to give 24 g of title compound having purity 94 % by HPLC.
Method D: A mixture of palladium acetate (0.101 g) and tri-o-tolylphosphine (0.445 g, 0.002 mol) in dimethylformamide (20 ml) was stirred under nitrogen atmosphere for 1 hour. Phenyl vinyl sulphone (2.76 g, 0.016 mol), N,N-diisopropyl ethylamine (2.31 g, 0.018 mol) and [R]- l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (5g, 0.015 mol) and dimethylformamide (20 ml) were added to the reaction mixture and heated to 90-95 °C for 3-4 hours. The reaction mixture was cooled to 20-25°C, filtered and poured into aqueous hydrochloric acid (112.5 ml, 3.3%) and stirred for 20 minutes. Toluene (50 ml) was added to the aqueous layer, stirred for 20 minutes and filtered. The aqueous layer was re-extracted with toluene (50 ml) at 20-25°C. The resulting aqueous layer was treated with activated carbon (2 g) at 40-45°C, filtered through hyflo bed under vacuum and the bed washed with acetone (30 ml). The filtrate was basified with aqueous ammonia (25%) till pH 9.0-9.5 and stirred for 10-12 hours. The product was filtered under vacuum, washed with water (2 xl5ml) and dried to give the title compound having purity 88 % by HPLC. The resulting product was stirred in methanol (20 ml) at 20-25°C and filtered. The filtered solid was washed with methanol (5ml) and suck dried to give 4.5 g of title compound having purity 92 % by HPLC.
Method E: A mixture of palladium acetate (0.37 g, 0.002 mol) and tri-o-tolylphosphine (1.63 g, 0.005 mol) in dimethylformamide (20 ml) was stirred under nitrogen atmosphere for 1 hour. Phenyl vinyl sulphone (5.5g, 0.032 mol), N,N-diisopropyl ethylamine (4.63g, 0.036 mol) and [R]- l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (10 g, 0.030 mol) were added to the reaction mixture and heated to 90-95 °C for 3-4 hours. The reaction mixture was
cooled to 20-25°C, filtered and poured into aqueous hydrochloric acid (112.5 ml, 3.3%) and stirred for 20 minutes. Aqueous ammonia (25%, 70 ml) and toluene (250 ml) were added into the reaction mixture followed by stirring for 6-8 hours. The toluene layer was separated and treated with Norit carbon (1 g) at 70-80°C for 1 hour and filtered. The toluene layer was treated with aqueous hydrochloric acid (112.5 ml, 3.3 %) and stirred for 20 minutes. Aqueous layer was treated with aqueous ammonia (25%, 70ml). Methanol was added to the resulting residue was added, stirred for 1 hour, filtered and dried to give 7.5 g of title compound having purity 90 % by HPLC. Method F: A mixture of palladium acetate (14.36 g), tri-o-tolyl phosphine (63.32g) in dimethylformamide (780 ml) was stirred at 25-35 °C for 5 hours. Phenyl vinyl sulphone (215.08g), N,N-diisopropyl ethylamine (180.4g) and a solution of (R)-l-[5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (388g) in dimethylformamide (780 ml) were added to the reaction mass at 25-35 °C. The reaction mass was heated and stirred at 90-95 °C for 2.5 hours. After the completion of reaction, reaction mass was cooled to 30-35 °C for 1 hour followed by addition of toluene (1.95 L) and 3.3 % hydrochloric acid (4.4L) to the reaction mixture. Reaction mixture was stirred at 30-35 °C for 30 minutes, filtered through hyflo-bed and washed with dimethylformamide (75ml). Aqueous layer was separated, washed with toluene (1950 ml) and charcoalised. Mixture was filtered through hyflo bed and bed was washed with acetone (780ml). Aqueous ammonia (546ml) and seed of [R]-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin -2-ylmethyl)-indol-l-yl]-ethanone (1 g) were added to the resulting filtrate and stirred at 30-35 °C for 4 hours. Reaction mixture was filtered, washed with demineralised water (375 ml) and suck dried to give 500 g of title compound.
Example 3: Purification of [R]-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyI-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone
Mixture of [R]-1 -[5-(2-benzenesulfonyl-vinyl)-3-( 1 -methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (500 g) in methanol (1.5 L) was stirred at 15-20 °C for 30 minutes. Reaction mixture was filtered, washed with methanol (375 ml) and dried at 15-20°C for
30 minutes. Resulting product was washed with chilled toluene (375 ml) and dried at 20-
25 °C for 4 hours to give 385 g of title compound having purity 97 % by HPLC.
Example 4: Preparation of [R]-5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-
pyrrolidin-2-ylmethyl)-lH-indole
Method A: [R]-l-[5-(2-Benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-
indol-l-yl]-ethanone (7g), methanol (70ml) and sodium carbonate (0.9 lg) were stirred together at 40-45°C for 4 hours. After completion of reaction, the solution was treated with active carbon (0.7g) at 20-25°C. Carbon was filtered off and demineralized water (70 ml) was added to filtrate at 20-25 °C and stirred for 3-4 hours. Resulting product was filtered, washed with a mixture of methanol: water (1:1, 6ml) and suck dried to give 6 g of title compound having purity 98 % by HPLC. Method B: [R]-l-[5-(2-Benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (250g), methanol (2 L), sodium carbonate (25 g) were stirred together at 25-30°C for 2 hours. After completion of reaction, solution was treated with active carbon (25 g) at 25-30°C for 30 minutes. Carbon was filtered off on hyflo bed and washed with methanol (250ml). The combined filtrate was distilled at 45-50 °C/150 mmHg. Resulting product was stirred in acetonitrile: water, filtered and dried to give 285g of the title compound having purity 99.45 % by HPLC. HPLC chromatogram as shown in Figure 2.
Method C: [R]-l-[5-(2-Benzenesulfonyl-vinyl)-3-( 1 -methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (7g), ethanol (70ml) and sodium carbonate (0.91 g) were stirred together at 50-5 5°C for 7 hours. After completion of reaction the solution was treated with active carbon (0.7g) at 20-25°C for 30 minutes. Carbon was filtered off and demineralized water (70 ml) was added to filtrate at 20-25 °C and stirred for 3-4 hours. Resulting product was filtered, washed with mixture of methanol: demineralized water (1:1, 6ml) and suck dried to give 5.5 g of title compound having purity 98% by HPLC.
Method D: [R]-l-[5-(2-Benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (7g), isopropanol (70ml) and sodium carbonate (0.91 g) were stirred together at reflux for 20 hours. After completion of reaction the solution was treated with active carbon (0.7g) at 20-25°C for 30 minutes. Carbon was filtered on hyflo bed. Demineralized water (70 ml) was added at 20-25 °C to the reaction mixture and stirred for 3-4 hours. Resulting product was filtered, washed with mixture of methanol: demineralized water (1:1, 6ml) and suck dried to give 4.8 g of title compound having purity 96 % by HPLC.
Method E: A mixture of [R]-1 -[5-(2-benzenesulfonyl-vinyl)-3-( 1 -methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (7 g), methanol (70 ml) and lithium carbonate (0.91 g) were stirred together at 50-55 °C for 10 hours. After completion of reaction, active carbon (0.7 g) was added to the reaction mixture at 20-25°C for 30 minutes. Carbon was filtered on hyflo bed. Demineralized water (70 ml) was added at 20-25 °C to the reaction mixture and stirred for 3-4 hours. Resulting product was filtered, washed with mixture of methanol: demineralized water (1:1, 6ml) and suck dried to give 4.5 g of title compound having purity 99 % by HPLC.
Method F: A mixture of [R]-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (7 g), ethanol (70ml) and lithium carbonate (0.91 g) were stirred together at 50-55 °C for 10 hours. After completion of reaction, reaction mixture was charcoalized by adding active carbon (0.7 g) at 20-25 °C for 30 minutes. Carbon was filtered through hyflo bed. Demineralized water (70 ml) was added slowly at 20-25 °C to the reaction mixture and stirred for 3-4 hours. The resulting product was filtered, washed with mixture of methanol: demineralized water (1:1, 6 ml) and dried to give 4.3 g of the title compound having purity 99% by HPLC. Method G: A mixture of [R]-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (385 g), methanol (3.08 L) and sodium carbonate (38.64 g) was stirred at 25-30 °C for 2 hours. After completion of reaction, activated carbon (38.5g) was added to reaction mass at 25-30 °C and stirred for 1 hour. Mixture was
filtered through hyflo bed and washed with methanol (192.5 ml). Resulting filtrate was distilled at 45-50 °C for 4 hours. Acetone (1.16 L) was added to resulting residue, stirred at 25-30 °C for 10 minutes followed by addition of water (1.93 L). Reaction mixture was filtered, washed with water (385 ml) and dried at 25-30 °C for 2 hours to give title compound which was purified with acetone (1.16 L), water (1.54 L) to give 252 g of title compound which was further slurried in aqueous acetone (2.7 L, 57 % water) for 3 hours to give 230 g of title compound having purity 99.7 % by HPLC. Example 5: Preparation of eletriptan
Method A: A solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (150g) in acetone (1.2 L) at 10-15°C was added methanesulfonic acid (41.7g) was stirred for 5 minutes and 5% palladium on carbon (37.5g, m/c 52.4%) was added to the reaction mixture and stirred in hydrogen atmosphere (50 psi) at ambient temperature. Palladium on carbon was filtered and washed with aqueous acetone (5%, 2ml). The combined filtrate was distilled off. Water (750 ml) and sodium bicarbonate (66.22 g) was added to resulting residue followed by extraction with methyl tertiary butyl ether (2 x 600ml). The combined organic layer was washed with water (600 ml). Methyl tertiary butyl ether layer was treated with active carbon (15g) and silica gel (7.5 g) at 45-50°C for 30 minutes. The resulting reaction mixture was filtered through hyflo-bed and washed the bed with methyl tertiary butyl ether (150ml). Methyl tertiary butyl ether layer was distilled off to give 133 g of title compound having purity 98.56 % by HPLC. Method B: A solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (4.5g) in acetone (40ml) and methanesulfonic acid ( 1.25g) was stirred for 5 minutes and 10% palladium on carbon (2.2g, m/c 56%) was added to the reaction mixture and stirred in hydrogen atmosphere (50 psi) at ambient temperature. Palladium on carbon was filtered and washed with aqueous acetone (5%, 2ml). Water (94ml) was added to combined filtrate and washings. The reaction mixture was basified till pH 11 under stirring using 40% aqueous sodium hydroxide. The product
was extracted with methyl tertiary butyl ether (2 x 15ml), combined extracts were filtered and washed with demineralized water (5ml). The resulting organic layer was distilled off to give 4.6 g of title compound having purity 98 % by HPLC. Method C: A solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (4.5g) in acetone (40ml) and methanesulfonic acid (1.25g) was stirred for 5 minutes and 10% palladium on carbon (1.2g, m/c 56%) was added to the reaction mixture and stirred in hydrogen atmosphere (50 psi) at ambient temperature. Palladium on carbon was filtered and washed with acetone (10 ml). The reaction mixture was basified till pH 9.0-9.5 under stirring using 25% aqueous ammonia. The product was extracted with methyl tertiary butyl ether (2x15ml), combined extracts were filtered and washed with water (5ml). The resulting organic layer was distilled off to give 4.5g of title compound having purity 95 % by HPLC. Method D: A solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (4.5g) in acetone (40ml) and methanesulfonic acid 1.25g) was stirred for 5 minutes and 5% palladium on carbon (4.5g, m/c 56%) was added to the reaction mixture and stirred in hydrogen atmosphere (50 psi) at ambient temperature. Palladium on carbon was filtered and washed with acetone (10 ml). The reaction mixture was basified till pH 9.0 - 9.5 under stirring using 25% aqueous ammonia. The product was extracted with methyl tertiary butyl ether (2 x 15ml), combined extracts were filtered and washed with water (5ml). The resulting organic layer was distilled off to give 4.6 g of title compound having purity 97 % by HPLC. Method E: To a solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (200 g) in acetone (1.0 L) was added methanesulphonic acid (56.0g) at 10-15 °C followed by addition of 5% Pd/C (50.0g) and further stirred at ambient temperature. After completion of reaction, reaction mass was filtered through hyflo and washed with acetone (115 ml). Acetone was distilled off from filtrate under vacuum at 45-50 °C. Demineralised water (1.0L) and sodium bicarbonate (88.0 g) were added to resulting residue and mixture was stirred at 25-30 °C for 30 minutes. Thereafter
reaction mixture was extracted with toluene (800 Lx3). Combined organic extracts were washed with demineralised water (2 x 800 ml) and toluene was distilled off from organic layer to obtain 166 g of title compound having purity 99 .42 % by HPLC. A portion of resulting eletriptan was dissolved in toluene at 80-90°C and cooled to ambient temperature and stirred for three hours. The solid obtained was filtered and dried to obtain highly pure eletriptan having purity of 99.76 % by HPLC Example 6: Preparation of a- Form of eletriptan hydrobromide from eletriptan Method A: A solution of eletriptan (210 g) in dichloromethane (4.2 L) was stirred at 25-30 °C for 15 minutes and washed with demineralised water (2 x 1.05 L). Resulting organic layer was cooled at 0-5 °C for 30 minutes. A solution of monoethylene glycol (420 ml), water (210 ml) and aqueous hydrobromic acid (94.6 ml) was added into above dichloromethane layer and stirred at 0-5 °C for 30 minutes. Layers were separated and aqueous layer was extracted with dichloromethane (420 ml). Methanol (10ml) was added to combined organic extracts and charcoalised by adding Norit SX carbon (31.5 g). Mixture was filtered through hyflo bed and washed with dichloromethane (105 ml). Dichloromethane was distilled off from the filtrate and isopropanol (1.115 L) was added to resulting residue. Reaction mixture was heated to reflux for 1 hour and stirred at same temperature for 30 minutes. The reaction mixture was cooled to 25-30 °C and stirred for 1 hour. Resulting product was filtered, washed with isopropanol (225 ml) and dried at 25-30 °C to give 190 g of title compound having purity 99 % by HPLC. Method B: A mixture of monoethylene glycol (284ml), hydrobromic acid (75ml, 47% w/w) and water (142ml) was added to a solution of eletriptan free base (142g) in dichloromethane (2.84L) at 0-5°C and stirred for 30 minutes. Layers were separated. Aqueous layer was extracted with dichloromethane (370ml) and all dichloromethane extracts were combined and methanol (40ml) was added to it. To this, was added Norrit carbon-SX, refluxed for 1hour and filtered. Solvents of filtrate were distilled off to obtain oil. Isopropanol (710ml) was added to the residue and
heated to 80-85°C for 2.5hours and then cooled to 25-30°C. The solid, which precipitated out, was filtered and dried to afford 141 g of title compound. Method C: 49% w/w Hydrobromic acid (2.13 ml) was added to a stirred solution of the eletriptan free base (5.0 g) in dichloromethane (50 ml) at room temperature. After 15 minutes the reaction mixture was washed with water (2 x 10 ml), dried over anhydrous sodium sulphate. Reaction mixture was treated with active carbon, filtered and evaporated under reduced pressure. Isopropanol (20ml) was added to the resulting residue and distilled off. The resulting oil was dissolved in hot isopropanol (13ml) cooled and filtered to give 5.1 g of the title compound as a pale yellow solid. The filtered solid was washed with isopropanol and dried under vacuum to give 4.2 g of the title compound having purity 99.45 % by HPLC.
Method D: Monoethylene glycol (36 ml) and 49% w/w hydrobromic acid (3.8 ml) were added to a stirred solution of eletriptan free base (12 g) in dichloromethane (120ml) at 5-10 °C under nitrogen atmosphere, further stirred for 30 minutes. Dichloromethane layer was separated and solvent was distilled off to obtain oil. Isopropanol (120 ml) was added to the reaction mixture and heated to 70-75 °C for 30 minutes and cooled to 25-30 °C. Solid thus obtained was filtered and dried to give 8.2 g of the title compound having purity 99.57 % by HPLC. XRD matches with a-form as shown in Figure 4.
Method E: Monoethylene glycol (36 ml) and 49% w/w hydrobromic acid (3.8 ml) were added to a stirred solution of eletriptan free base (12 g) in dichloromethane (120ml) at 5-10 °C under nitrogen atmosphere, further stirred for 30 minutes. Dichloromethane layer was separated and solvent was distilled off to obtain oil. Ethyl acetate (120 ml) was added to the reaction mixture and heated to 70-75 °C for 30 minutes and cooled to 25-30 °C. Solid thus obtained was filtered and dried to give 8.2 g of the title compound having purity 99.47 % by HPLC.
Method F: Monoethylene glycol (36 ml), water (12 ml) and 49% w/w hydrobromic acid (3.8 ml) were added to a stirred solution of eletriptan free base (12 g) in
dichloromethane (120ml) at 5-10 °C under nitrogen atmosphere, further stirred for 30 minutes. Dichloromethane was separated and solvent was distilled off from organic layer to give oily residue. Isopropanol (120 ml) was added to the reaction mixture and heated to 70-75 °C for 30 minutes and cooled to 25-30 °C. Solid thus obtained was filtered and dried to give 8.2 g of the title compound having purity 99.5 % by HPLC. Method G: A mixture of monoethylene glycol (28.4ml), hydrobromic acid (7.5ml, 47% w/w) and water (14.2ml) was added to a solution of eletriptan (14.2g) in dichloromethane (284ml) at 0-5°C and stirred for 30 minutes. Layers were separated. Aqueous layer was extracted with dichloromethane (37ml) and all dichloro methane extracts were combined and methanol (4ml) added to it. To this was added Norrit carbon-SX , refluxed for lhr. and filtered. Solvents of the filtrate were distilled off to obtain oil. Isopropanol (71ml) and ethanol (3.5ml) were added and heated to 80-85°C for 2.5hrs and cooled to 25-30°C. The solid was filtered and dried to afford 13.8g of title compound.
Example 7: Preparation of a-form eletriptan hydrobromide A solution of [R]- 5-(2-benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-1H-indole (4.5g, 0.118 mol) in acetone (40 ml) and methanesulfonic acid (1.25 g, 0.13 mol) was stirred for 5 minutes and 10% palladium on carbon (2.2 g, 56%) was added to the reaction mixture. The reaction mixture was stirred in hydrogen atmosphere (50 psi) at ambient temperature. Palladium on carbon was filtered and washed with aqueous acetone (5%, 2 ml). The combined filtrate were distilled off and resulting product was extracted with dichloromethane (3 x 15ml), washed with water (2 x 10ml). Resulting organic layer was basified with aqueous ammonia (25%, 10ml), washed with water (2x10ml). 49% w/w Hydrobromic acid (2.13 ml) was added to the separated organic layer at room temperature. After 15 minutes, reaction mixture was washed with water (2x10ml). The reaction mixture was treated with active carbon, filtered and evaporated under reduced pressure. Isopropanol (20 ml) was added to the reaction mixture and distilled off. The resulting oil was dissolved in hot isopropanol
(13ml), cooled and filtered to give 5.1 g of title compound as a pale yellow solid.
The filtered solid was washed with isopropanol and dried under vacuum to give 4.2 g
of title compound having purity 99.56 % by HPLC.
Example 8: Purification of α-form eletriptan hydrobromide
Method A: A mixture of eletriptan hydrobromide (160 g), isopropanol (667 ml), n-
butanol (133 ml) was dehydrated using sodium sulphate (40 g) in soxhlet and mixture
was refluxed for 2.5 hours. Reaction mass was cooled to 25-30 °C and stirred for 2 hours.
Product thus formed was filtered, washed with isopronaol: n-butanol (80 ml, 5:1), dried
to give 150 g of tile compound having purity 99.6 % by HPLC.
Method B: A mixture of eletriptan hydrobromide (10 g), dichloromethane (50 ml)
and acetonitrile (10 ml) was stirred at ambient temperature for 2 hours, filtered and
dried to obtain 8.5 g of title compound having purity 99.75 % by HPLC.
Method C: Eletriptan hydrobromide (1 g) was dissolved in acetonitrile (2 ml) at 80°C
and allowed to cool at ambient temperature for 2 hours. The product was filtered and
dried to give 0.8 g of the title compound having purity 99.7 %by HPLC.
Method D: Eletriptan hydrobromide (125g) was dissolved in a mixture of ethanol
(1.25L) and isopropanol (125ml) by heating at 80-85°C, followed by addition of
activated carbon (10g, Norrit carbon SX). The reaction mixture was stirred for lhr. at
80-85°C and filtered through hyflo bed. The filtrate was distilled off (-90%) followed
by addition of isopropanol (625ml). The reaction mixture was again stirred for 2hrs. at
80-85°C and cooled to ambient temperature, stirred for another 2 hrs., filtered and
dried to afford 12lg of title compound having purity of 99.89% by HPLC.

WE CLAIM:
1. A process for preparation of eletriptan of formula I,
(Formula Removed)
and pharmaceutically acceptable salts thereof, comprising the steps of: a), protecting amine group of bromo indole intermediate of formula II,
(Formula Removed)
using a suitable acetylating agent in a solvent to form N-acetylated bromo indole intermediate of formula III,
(Formula Removed)
b). isolating N-acetylated bromo indole intermediate of formula III; c). reacting intermediate of formula III with phenyl vinyl sulfone in the presence of a suitable base and a catalyst to form acetylated dehydro intermediate of formula
rv,
(Formula Removed)
d). deprotecting acetylated dehydro intermediate of formula IV using a mild base to form dehydro eletriptan of formula V, and
(Formula Removed)
e). converting dehydro eletriptan of formula V in to eletriptan or pharmaceutically acceptable salts thereof.
2. The process according to claim 1, wherein in step a) suitable acetylating agent is selected from acetic anhydride, acetyl halide; suitable solvent is selected from aprotic solvent such as N,N- dimethylformamide, N,N-dimethyl acetamide, N-methyl pyrrolidone and the like or mixture thereof.
3. The process according to claim 1, wherein in step c) suitable base is selected from organic base which includes an amine of general formula NR1R2R3 (wherein R1, R2 and R3 can be same or different and can be selected independently from C1-10 alkyl group) such as diisopropyl ethyl amine; or inorganic base such as alkali metal carbonate, bicarbonates, hydroxides, alkoxides and the like; and catalyst is selected from palladium acetate, palladium chloride, or organometallic palladium as a complex with tri-o-tolylphosphine ligand or PR1R2R3 (wherein R1, R2 and R3 are same as defined above); palladium acetate as a complex with tri-o-tolylphosphine and the like
4. The process according to claim 1, wherein in step d) mild base is selected from sodium carbonate, lithium carbonate; ammonia, primary amine such as ethylamine, ethanolamine; secondary amine such as diethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene. H2O; 4-dimethylaminopyridine.H20 and the like.
5. A process for the preparation of eletriptan of formula I or pharmaceutically acceptable salts thereof, comprises the steps of:
a), deprotecting acetylated dehydro intermediate of formula IV,
(Formula Removed)
using a mild base to form dehydro eletriptan of formula V,
(Formula Removed)
b). converting dehydro eletriptan of formula V to eletriptan or pharmaceutically acceptable salts thereof.
6. The process according to claim 5, wherein in step b) mild base is selected from sodium carbonate, lithium carbonate; ammonia, primary amine such as ethylamine, ethanolamine; secondary amine such as diethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene. H2O; 4-dimethylaminopyridine.H20 and the like.
7. A process for preparation of a-form of eletriptan hydrobromide, comprises the steps of:
a), providing a solution of eletriptan free base in a solvent selected from glycols
or glycerols or a mixture of glycols or glycerols with other solvent; b). adding a suitable source of hydrogen bromide, c). stirring for a time sufficient for salt formation; d). removing the solvent from organic layer; e). crystallizing from a second solvent; f). isolating a-form of eletriptan hydrobromide.
8. The process according to claim 7, wherein in step a) other solvent is selected from water, halogenated solvent such as dichloromethane, chloroform and the like.
9. The process according to claim 7, wherein in step b) source of hydrobromide is selected from aqueous hydrobromic acid, gaseous hydrobromic acid, solvent
saturated with gaseous hydrobromic acid, ammonium bromide, hydrobromide salt of amines such as trialkyl amine, dialkyl amine or alkyl amine and the like. 10. The process according to claim 7, wherein in step e) second solvent is selected from alcohol such as isopropanol, ethanol, methanol, tertiary butanol, isobutanol; nitriles such as acetonitrile; ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, dimethoxy ethane; esters such as ethyl acetate; ketone such as acetone, methyl ethtyl ketone, methyl isobutyl ketone and the like or mixture thereof.