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WO2012004811A1 - Procédé pour la préparation de dérivé d'indole substitué en position 5 - Google Patents

Procédé pour la préparation de dérivé d'indole substitué en position 5 Download PDF

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Publication number
WO2012004811A1
WO2012004811A1 PCT/IN2011/000447 IN2011000447W WO2012004811A1 WO 2012004811 A1 WO2012004811 A1 WO 2012004811A1 IN 2011000447 W IN2011000447 W IN 2011000447W WO 2012004811 A1 WO2012004811 A1 WO 2012004811A1
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WO
WIPO (PCT)
Prior art keywords
formula
eletriptan
solvent
mixture
reaction
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PCT/IN2011/000447
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English (en)
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WO2012004811A8 (fr
Inventor
Shekhar Bhaskar Bhirud
Perminder Singh Johar
Ekta Sharma
Ramkaran Prajapaty
Chandan Kumar Gupta
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Ind-Swift Laboratories Limited
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Application filed by Ind-Swift Laboratories Limited filed Critical Ind-Swift Laboratories Limited
Publication of WO2012004811A1 publication Critical patent/WO2012004811A1/fr
Publication of WO2012004811A8 publication Critical patent/WO2012004811A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an improved and industrially advantageous process for the preparation of 5-substsituted i of formula I,
  • the present invention also relates to novel process for the preparation of a-form of eletriptan hydrobromide.
  • the present invention also relates to process for the preparation 5-bromo-3-[(R)-l-methyl-pyrrolidin-2- ylmethyl]-lH-
  • Formula II a key intermediate for synthesis of eletriptan or pharmaceutically acceptable salts thereof and process for purification of its purification.
  • Eletriptan of formula I is a selective 5-hydrotryptamine IB/ID receptor antagonist and is chemically known as (R)-3-(( 1 -methylpyrrolidone-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl) 1 H-indole.
  • 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.
  • Patent discloses process for preparation of BIP intermediate starting from N-benzyloxycarbonyl-D- proline.
  • BIP intermediate is then converted to eletriptan by acetylating (R)-5-bromo-3(N- methylpyrroldin-2-ylmethyl)-lH-indole using acetic anhydride in the presence of triethylamine and ⁇ , ⁇ -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.
  • Process involves time consuming recovery process for isolation of N- benzyloxycarbonyl intermediate as well as BIP intermediate of formula II and then purification of resulting oily residue with silica gel chromatography. Resulting oily residue is about 55-60% pure having about 26% of benzyl alcohol, which is bye product of this reaction along with other impurities (Ref US 2008/0319205; page 6, [0074]. Further, process involves use of chromatographic techniques, which is considered as time consuming and tedious process, therefore make the process not amenable to employ for industrial synthesis. Further, 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 a- form and ⁇ -form.
  • Patent discloses two processes for the preparation of a-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.
  • a solution of eletriptan in acetone or ether solvent at 0-10 °C is treated with an aqueous solution of hydrogen bromide to give ⁇ -form which is then crystallized from aqueous acetone and slurring give a-form of eletriptan hydrobromide.
  • This process proceeds via ⁇ -form and adds an extra step to the synthesis of a- form.
  • US patent 6,441,192 discloses a process for preparation of BIP intermediate of formula II by adding N- benzyloxy-prolinoyl chloride and ethyl magnesium bromide separately and simultaneously to a solution of 5-bromoindole in dichloromethane to give 2-(5-bromo-lH-indole-3-carbonyl)-pyrrolidine-l-carboxylic acid benzyl ester which is then reduced to BIP intermediate.
  • Process employs restriction to prepare separate solution of reactants in a solvent and then simultaneous addition of the two solutions to bromoindole intermediate in such a way that two stream of the solutions should not react together. The process requires extra care and specific apparatus which makes the process not amenable to employ freely at industrial synthesis.
  • 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, a- Form prepared by the above process also requires polymorph annealing step to increase resistance to subsequent hydration, which is extra step to the process.
  • 2-butanone is low boiling solvent so recovery losses are high which adds cost to the process.
  • US patent application 2008/0028719 exemplified several processes for preparation of a-form of eletriptan hydrobromide.
  • a-form is prepared by dissolving ⁇ -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 ⁇ -form of eletriptan hydrobromide in a solvent selected from isobutanol, methyl acetate, mixture of tetrahydrofuran and water, and cyclohexane. All processes proceed through ⁇ -form and adds extra step to the process that is unattractive for commercial synthesis.
  • US patent publication. 2008/0319205 discloses a process for preparation of BIP intermediate of formula II by reduction of 2-(5-bromo-lH-indole-3-carbonyl)-pyrrolidine-l-carboxylic acid benzyl ester using reducing agent selected from sodium dihydro-bis(2-methoxyethoxy)aluminate, lithium tris[(3-ethyl-3- pentyl)oxy]aluminohydride, lithium tri-tert-butoxyaluminum hydride and diisobutylaluminium hydride.
  • Crude BIP intermediate isolated after quenching of reaction mixture have purity of 66.49% and contains about more than 20% of benzyl alcohol which is bye product of this reaction.
  • US patent application 2009/0299077 discloses a process for the preparation of eletriptan involving the purification of dihydro eletriptan intermediate and BIP intermediate by salt formation followed by neutralization to give purified intermediate which is further used for the synthesis of pure eletriptan.
  • Purification of BIP intermediate involves treating BIP with potassium hydroxide , oxalic acid, succinic acid or furnaric acid and isolating said salts. These BIP salts are either converted directly to eletriptan hydrobromide or neutralized to give pure BIP intermediate which is converted to dihydroeletriptan
  • the disclosed process has more number of steps, purification using acid base treatment i.e. isolation of BIP salts and then neutralization to get pure BIP adds extra steps to process, 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 ⁇ , ⁇ -dimethylformamide which in situ undergoes reaction with phenylvinyl sulfone using palladium acetate, tri-o-tolylphosphine and diisopropyl amine as base to give N-acetylated home coupled intermediate which is then hydrolysed 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.
  • 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.
  • 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.
  • 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.
  • regulatory authorities worldwide require that drug manufacturers should isolate, identify and characterize the impurities in their products.
  • Prior art processes involve preparation of BIP intermediate of formula II using 2-(5-bromo-lH-indole-3-carbonyl)-pyrrolidine- 1-carboxylic acid benzyl ester as an intermediate and found to be associated with one or more disadvantages, such as purification by using column chromatography or through salt formation; strict condition for order of addition of reactant.
  • Main disadvantage is removal of impurities.
  • Benzyl alcohol is by product of this reaction, needs special acid base treatment for removal. If it remains in the reaction mixture, even in traces, leads to generation of more impurities and require extensive purifications.
  • 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.
  • present invention fulfills need in the art and provide an industrially advantageous, cost effective process for synthesis of eletriptan and its pharmaceutically acceptable salts thereof, wherein problem of removal of by product namely benzyl alcohol by special treatment has been avoided and produce the consistency in results during polymorph preparation.
  • the foremost objective of the invention is to provide an improved and industrially advantageous for the preparation of 5-substituted indole derivative, preferably eletriptan or 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)-l-[5- bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-indol-l-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.
  • Another objective of the invention is to provide a process for the preparation of a-polymorphic form of eletriptan hydrobromide.
  • Another objective of the present invention is to provide an industrially advantageous and cost effective process for the preparation of BIP intermediate of formula II, a key intermediate useful in the synthesis of eletriptan.
  • Another objective of the present invention is to provide a process for the preparation of BIP intermediate of formula II through novel keto carbamate intermediate.
  • Still another objective of the present invention is to provide a novel keto carbamate intermediate, useful in the preparation of BIP intermediate.
  • Yet another objective of the present invention is to provide an cost effective process for purification of BIP intermediate of formula II to reduce the presence of identified as well as unidentified impurities.
  • the present invention provides a process for preparation of eletriptan of formula I,
  • the process comprises the steps of:
  • present invention provides isolated N-acetyl bromo indole intermediate of formula III.
  • present invention provides a process for the preparation of eletriptan of formula I or pharmaceutically acceptable salts thereof, comprises the steps of:
  • present invention provides 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;
  • a process for the preparation of BIP intermediate of formula II comprises the steps of:
  • present invention provides a process for preparation of keto carbamate intermediate of formula ⁇ , comprising the steps of:
  • present invention provides a novel keto carbamate intermediate of formula IX.
  • present invention provides a process for the preparation of eletriptan or pharmaceutically acceptable salts thereof, comprising the steps of:
  • present invention provides a process for the purification of BIP intermediate of formula II, comprising the steps of:
  • Figure 3 HPLC chromatogram of pure dehydro eletriptan intermediate having impurities less than 0.15 % by HPLC
  • Figure 4 X-ray diffraction pattern of a-form of eletriptan hydrobromide.
  • BIP refers to 5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole
  • present invention provides a process for the preparation of eletriptan or pharmaceutically acceptable salts thereof starting from intermediate of formula II.
  • 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.
  • reaction can be carried out at reflux temperature of solvent for 1 to 12 hours, 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
  • Suitable solvent employed for the reaction includes aprotic solvent such as N,N- dimethylformamide, N.N-dimethyl acetamide, TV-methyl pyrrolidone, sulfolane, dimethyl sulfoxide and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • reaction is preferentially carried out in the absence of base. It is found by 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 the presence of base, the starting material remain unreacted in the reaction mixture (monitored by chromatographic techniques) as shown in the example 1.
  • N-acetyl bromo indole intermediate of formula III 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:
  • 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.
  • acetylation above impurities also get acetylated to form respective acetylated products.
  • N-acetyl intermediate is found to contain impurities less than 0.15 % by HPLC.
  • 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.
  • N-acetylated product is found to be free from hydroxy BIP acetate and/or keto BIP acetate impurities.
  • 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 NRaRbRc (wherein Ra, Rb and R c can be same or different and can be selected independently from Ci./ 0 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 PR a RbRc (wherein R a , Rb and Rc are same as defined above), and the like.
  • 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, ⁇ , ⁇ -dimethyl acetamide, N-methyl pyrrolidone and the like or mixture thereof.
  • 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.i 0 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.
  • 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.
  • 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.
  • 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- i 0 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; C 4-12 ether such as methyl tertiary butyl ether, isopropyl ether; C i -10 alcohol such as methanol, ethanol, iso- propanol; xylene, ethyl benzene, cyclohexane, n-hexane, n-heptane; C 3- io esters such as ethyl acetate; nitriles such as acetonitrile; aliphatic or aromatic hydrocarbon such as toluene, water and the like or mixture thereof.
  • a suitable solvent such as C 3- i 0 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone;
  • 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.
  • 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.
  • Solvent used for reaction includes alcohol such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dimethoxy ethane and the like or mixture thereof.
  • 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.
  • 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 purity of product and/or to minimize impurities present in the product.
  • Intermediate of formula V can be washed with a suitable solvent.
  • Suitable solvent includes water, C O alcohol such as methanol, ethanol, isopropanol; C 3.10 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile; C3-io ester like ethyl acetate; C4-i 2 ethers such as tetrahydrofuran or mixture thereof.
  • Formula X Alkyl hydroxy impurity wherein R 3 is hydrogen or alkyl depending upon nature of alcohol used for the reaction
  • the amount of alkyl hydroxy impurity of formula X 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.
  • impurity that may present in intermediate of formula V is hydroxy dehydro- eletriptan impurity of formula XI,
  • the precursor of this impurity is hydroxy BIP impurity that may present in the starting material or may generate during the reaction.
  • 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.
  • N-acetyl intermediate of formula III free from the hydroxy impurity or having less than 0.1 % yields intermediate of formula V free of hydroxy dehydro-eletriptan impurity or may be present less than 0.15 %.
  • 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:
  • Phenyl vinyl sulfone may react with pyrrolidine nitrogen to generate impurity of formula Xlla or with indole nitrogen to form impurity of formula Xllb.
  • 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.
  • 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.
  • 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 C 3.10 ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone; halogenated solvent such as dichloromethane; C Mo alcohol; C 3-10 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.
  • 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.
  • 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 and the like.
  • 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 1 1.
  • 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 C 5.10 ether such as methyl tertiary butyl ether, isopropyl ether, 2- methyl tetrahydrofuran, methyl cyclopentyl ether; C 5- io aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene, cyclohexane, n-heptane, n-hexane; C 3-1 o 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 the purity of the product.
  • suitable purification procedure such as, for example, crystallization, slurry wash, various chromatographic techniques, solvent anti-solvent system or combination of these procedures, may be employed to get the purified material.
  • Solvent for the 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 or mixtures thereof in suitable proportion.
  • Eletriptan thus prepared is then converted to its pharmaceutically acceptable salts.
  • 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 form mainly a- form and ⁇ -form.
  • Present invention provides a process for the preparation of a-form of eletriptan hydrobromide, which form another novel part of the invention.
  • 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 the salt formation.
  • reaction can be carried out at a temperature below 15°C, more preferably at a temperature of 5 to 15 °C till the completion of reaction.
  • 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.
  • solvent employed includes alcohol such as isopropanol, ethanol, methanol,; nitriles such as acetonitrile; ether such as isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran
  • 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 C i -8 alcohol such as isopropanol, ethanol, methanol, tertiary butanol, isobutanol; nitriles such as acetonitrile; C 4- io 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; aliphatic or aromatic hydrocarbon such as n-hexane, cyclohexane, n-heptane, toluene, ethylbenzene, xy
  • 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 XIII,
  • Mass analysis of the sample shows the presence of impurity showing M+l peak at 399. Above N-oxide impurity may be present in isomeric form.
  • organic impurity can be UK- 120 impurity having formula XIV,
  • Mass analysis of the sample shows the presence of impurity showing M+l 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.
  • 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.
  • other equivalent procedures such as acid-base treatment or acid-acid treatment could, also be used, to purify intermediates as well as final product.
  • Solvent for the purification can be chosen amongst water, Ci- alcohols such as methanol, ethanol, isopropanol, aliphatic C 3-8 ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, C3.10 aliphatic or aromatic hydrocarbons, C 3- io aliphatic esters such as ethyl acetate, isopropyl acetate, C -io 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, sulfo
  • eletriptan hydrobromide is crystallized from acetonitrile, dichloromethane: acetonitrile; dichloromethane: C 3-8 ketones; dichloromethane: C 3- io esters; dichloromethane: C 1-8 alcohols; dichloromethane: C 4-10 ethers; acetonitrile: C 3-8 ketones; or acetonitrile: C 3-8 ester.
  • Eletriptan hydrobromide used for purification can be any polymorphic form, it can be of a-form, ⁇ -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 % by HPLC, preferably more than 99.5 % by HPLC, more preferably 99.57 % by HPLC. Eletriptan hydrobromide found to have impurities less than 0.15 % or free from the impurities selected amongst UK- 120, N-oxide eletriptan, dehydro eletriptan, acetyl dehydro eletriptan and/ or l-[5-(2- Benzenesulfonyl-ethyl)-3 -( 1 -methyl-pyrrolidin-2-ylmethyl)-indol- 1 -yl]-ethanone or hydrobromide salts thereof.
  • BIP intermediate of formula II used in the present invention can be prepared by any prior art method or specifically by method as described herein.
  • present invention provides a novel, industrially advantageous and cost effective process for the preparation of BIP intermediate of formula II through novel phenyl or substituted phenyl keto carbamate intermediate of formula IX.
  • the present invention provides a process for the preparation of BIP intermediate by activation of intermediate of formula VI followed by condensation reaction with indole intermediate of formula VIII to form keto carbamate intermediate of formula IX which finally react with reducing agent.
  • process involves reaction of acid intermediate of formula VI with a suitable activating agent at a temperature of -10 to 100 °C for few minutes to several hours, preferably till completion of the reaction.
  • Activating agent employed for reaction includes thionyl halide such as thionyl chloride; oxalyl chloride, phosphorus trihalide or phosphorus pentahalide; acetyl halide, acetic anhydride, pivalolyl chloride, aryl sulfonyl halide such as p-toluene sulfonyl chloride; alkyl sulfonyl halide such as methane sulfonyl chloride and the like.
  • Solvent used for the reaction includes aprotic solvent such as NN-dimethylformamide, dimethylacetamide, dimethylsulfoxide; halogenated solvent such as dichloromethane, chloroform; aliphatic or aromatic solvent such as toluene; ether such as tetrahydrofuran and the like or mixture thereof.
  • Reaction can be advantageously carried out using a catalyst such as NN-dimethylformamide, 4- dimethylaminopyridine, and the like; and/or in the presence of base selected from organic or inorganic base such as triethylamine and the like.
  • reaction can be carried at 0 °C to reflux temperature for 1 to 48 hours.
  • activated intermediate of formula VII can be isolated from the reaction mixture using conventional methods such as removal of solvent from the reaction mixture by distillation, evaporation and the like or it can be used in situ for the further reaction to form intermediate of formula IX.
  • Activated intermediate of formula VII is then condensed with indole intermediate of formula VIII to form keto carbamate intermediate of formula IX, which forms novel part of the invention.
  • process involves reaction of activated intermediate of formula VII with indole intermediate of formula VIII in the presence of alkyl or aryl magnesium halide under Grignard reaction condition at a temperature of -40 to reflux temperature for few minutes to 20 hours.
  • reaction can be carried out at temperature of -20 to 35 °C till the completion of reaction.
  • Alkyl or aryl magnesium halide used for the reaction includes C 1-8 alkyl magnesium halide such as ethyl magnesium bromide; phenyl magnesium bromide, substituted phenyl magnesium halide and the like.
  • the reaction can be carried out in the presence of solvent for providing the reaction media and can be selected from halogenated solvents such as dichloromethane, chloroform; C 4- i 0 ether such as tetrahydrofuran; C3-io ester such as ethyl acetate; aromatic hydrocarbon such as toluene; aliphatic hydrocarbon such as cyclohexane; nitriles such as acetonitrile and the like or mixture thereof.
  • the reaction can be optionally carried out in the presence or absence of a suitable Lewis acid selected from zinc chloride, tin halide, cobalt halide, copper halide, aluminum halide and the like to enhance the kinetics of the reaction.
  • carbamate intermediate of form IX can be isolated from reaction mixture or can be used in situ for further reduction reaction.
  • intermediate of formula IX can be isolated from the reaction mixture by quenching reaction with a suitable quenching agent, wherever required.
  • Suitable quenching agent can be selected from aqueous ammonium chloride, carboxylic acids such as citric acid, hydrochloric acid, phosphoric acid, sulfuric acid and the like.
  • organic layer containing the desired intermediate can be separated from reaction mixture. Remaining reaction mixture can be optionally extracted by a suitable solvent.
  • Organic layer containing desired intermediate can be optionally washed with a suitable base and/or water and/or dried over a suitable drying agent and/or can optionally be charcoalised.
  • Suitable base can be organic base selected from primary, secondary or tertiary amine; or inorganic base such as alkali or alkaline metal hydroxide, carbonate, bicarbonate thereof selected from sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like.
  • Intermediate of formula IX can be recovered from the resulting organic layer by the removal of solvent using suitable techniques such as evaporation, distillation and the like.
  • reaction mixture is not critical, they can be added in any order. So reaction can be carried out by adding the reactant in any of the following way and another mode of adding the reactant are also possible.
  • indole intermediate of formula VIII can be first converted to its magnesium derivative by reaction with an alkyl or aryl magnesium halide in a solvent. Thereafter, magnesium derivative so formed can be reacted in situ with activated intermediate of formula VII under the reaction condition as specified above.
  • alkyl or aryl magnesium halide and activated intermediate of formula VII can be made to react with indole intermediate of formula VIII in such as way that both the reactant are added with a sufficient separation to prevent their reaction with each other and they are added simultaneously to the indole intermediate of formula VIII and yield the intermediate of formula IX.
  • indole intermediate of formula VIII activated intermediate of formula VII and alkyl or aryl magnesium halide can be combined together to form keto carbamate intermediate of formula IX.
  • Keto carbamate intermediate of formula ⁇ thus prepared can be purified by any suitable purification method selected from slurry wash, crystallization, acid base treatment and the like. Specifically, keto carbamate intermediate of formula IX in a suitable solvent can be stirred at a temperature of -10 to 50 °C for few minutes to few hours, preferably at a temperature of 0 to 35° C for 30 minutes to 2 hours.
  • Suitable solvent employed for the purification includes but not limited to C 4.10 ether such as isopropyl ether, diethyl ether, methyl tert-butyl ether; C 3- io ester such as ethyl acetate; C MO alcohol such as iso-propanol; halogenated solvent such as dichloromethane; aromatic hydrocarbon such as toluene; aliphatic hydrocarbon such as cyclohexane; ketone such as acetone; nitrile such as acetonitrile and the like.
  • Purified intermediate of formula IX can be isolated from the mixture by suitable techniques such as filtration, decantation, centrifugation and the like. Purification process can be optionally repeated to enhance the purity of the product or to minimize the impurities that may be present in the product.
  • eto carbamate intermediate of formula ⁇ can be reacted with a suitable reducing agent to form BIP intermediate of formula II.
  • process involves the reaction of intermediate of formula IX with a suitable reducing agent at a temperature of -20 to 120 °C for few minutes to several hours, preferably till the completion of reaction.
  • Reducing agent employed for the reaction includes sodium dihydro-bis(2-methoxyethoxy)aluminate (Red- Al), lithium tris[(3-emyl-3-pentyl)oxy]alurninohydride, lithium tri-tert-butoxyaluminium hydride, diisobutylaluminium hydride, lithium aluminium hydride with or without additives or its derivatives, lithium borohydride, lithium trialkylborohydride, sodium cyanoborohydride, sodium borohydride with or without additives or its derivatives, borane (BH 3 ); borane complex with tertrahydrofuran, dimethylsulfide, trialkyl amines, trisubstituted phosphines; diborane; transition metal catalyst such as palladium, platinum, Ra
  • Phase transfer catalyst can be selected from ammonium salts, phosphonium salts, poly ethylene glycol (PEG), crown ether, tetra-n-butylammonium bromide, triethylbenzylammonium chloride, tetrabutyl ammonium hydrogen sulfate, cetyl trimethylammonium bromide, tricetylmethyl ammonium bromide and the like or combination thereof.
  • Reaction can be carried out in the presence of a suitable solvent for providing the reaction media and can be selected from but not limited to C 4- i 0 ether such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether; aliphatic or aromatic hydrocarbon such as toluene, xylene, ethyl benzene and the like or mixture thereof.
  • Reaction can be carried out in presence of light or dark depending upon the reagent used for the reduction reaction. Usually, reaction can be carried out at a temperature of -20 to 120 °C for 30 minutes to 4 hours. After completion of reaction, reaction mixture can be quenched with a suitable quenching agent, wherever required.
  • Suitable quenching agent can be selected from suitable base.
  • suitable base includes alkali or alkaline metal hydroxide, carbonate, bicarbonate thereof such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and the like.
  • organic layer can be separated from the reaction mixture. Remaining aqueous layer can be optionally further extracted with a suitable water immiscible solvent to extract the desired compound which remains dissolved in aqueous layer.
  • Water immiscible solvent used for the extraction can be same as used for the reaction or different, preferably selected from ether such as methyl tertiary butyl ether, isopropyl ether, diethyl ether, 2-methyl tetrahydrofuran; aliphatic or aromatic hydrocarbon such as toluene; halogenated solvent such as dichloromethane and the like.
  • Organic layer can optionally be washed and/or dried on a suitable drying agent.
  • BIP intermediate of formula II can be isolated from the resulting organic layer by solvent removal using suitable techniques.
  • desired compound can be extracted from the resulting organic layer with a suitable acid.
  • Resulting aqueous layer can be optionally washed with water immiscible solvent in which impurities have more solubility.
  • Suitable acid can be organic acid selected from carboxylic acid, preferably tri-carboxylic acid such as citric acid, trimesic acid ; sulfonic acid; or inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like. Extraction of reaction mixture using tricarboxylic acid is found to more effective in terms of yield and purity.
  • BIP intermediate is then isolated from the aqueous layer by neutralization with a suitable base followed by extraction with a suitable solvent.
  • Suitable base can be organic base selected from primary, secondary or tertiary amine; or inorganic base such as alkali or alkaline metal hydroxide, carbonates, bicarbonate thereof selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and the like.
  • Intermediate of formula II can be isolated from the resulting organic layer by solvent removal using suitable techniques. Resulting product can be optionally washed with a suitable solvent.
  • Present invention employs use of phenyl or substituted phenyl carbamate intermediate specifically to circumvent the problem associated with removal of bye product (benzyl alcohol) generated by reaction of benzyl carbamate intermediate with reducing agent.
  • Benzyl alcohol if remains in reaction mixture, even in traces, may react with BIP intermediate to form corresponding ether impurity which in itself is very difficult to remove.
  • This ether impurity if present, prevents the solidification of further intermediate which is again a great problem in isolation and purification of these intermediate. Thus it is essential to remove benzyl alcohol before proceeding for next reaction to avoid generation of more impurities which may require extensive purification.
  • present invention provides a solution of above problem wherein phenol or substituted phenol, generated as by product during reaction of carbamate intermediate of formula DC with a reducing agent, are very easily removed even while quenching the reaction mixture and no specific treatment is required for their removal and there are no chances of further carrying forward of this by products.
  • Phenol or substituted phenol may be formed as by product during reaction of carbamate intermediate of formula IX with a reducing agent. Phenol or substituted phenol are removed easily during quenching of reaction mixture because of easy formation of their salt due to acidic nature of phenols with alkali or alkaline metals, which is not the case with benzyl alcohol. Further it is also observed that there are chances for formation of more impurities when reaction is carried out in light. So it is preferable to carry out reaction in dark to avoid generation of impurities. It is also advantageous to use reducing agent in excess to ensure complete reaction of carbamate intermediate of formula IX with a reducing agent, so that BIP intermediate of formula II, thus prepared, will be free from its corresponding keto BIP impurity.
  • BIP intermediate of formula I as prepared by prior art process or procured from commercial sources is found to contain impurities namely des bromo BIP, keto BIP and hydroxyl BIP along with other unknown impurities.
  • impurities namely des bromo BIP, keto BIP and hydroxyl BIP
  • 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 inventor have developed an efficient method for the purification of BIP intermediate of formula II using solvent of choice that proved efficient in minimizing the content of impurities and provide pure BIP intermediate having minimum amount of impurities, preferably free from such impurities which in turn yields eletriptan or pharmaceutically acceptable salt in high yield and high purity.
  • BIP intermediate of formula II thus prepared by the process of present invention or prepared by any other method can be optionally purified by employing a suitable purification method such as slurry wash, crystallization or acid base treatment and the like or combination of one or more to achieve the desired purity of the intermediate and to control the impurities
  • purification process involves stirring BIP intermediate in a suitable solvent at a temperature of - 20 to reflux temperature for few minutes to several hours.
  • suitable solvent selected from C 4.10 ethers such as isopropyl ether; alicyclic hydrocarbon such as cyclohexane or mixture thereof or mixture with second solvent selected from halogenated solvent such as dichloromethane; nitriles such as acetonitrile; C 3- io ketone such as methyl isobutyl ketone; C 6-12 aromatic hydrocarbon such as toluene; C 1-8 alcohols such as methanol, ethanol, isopropanol; C 3-1 o esters such as ethyl acetate and the like or mixture thereof.
  • Pure compound can be isolated from the mixture using suitable techniques such as filtration, decantation, centrifugation and the like. Purification process can be optionally repeated to achieve desired purity and to control the impurities in the product.
  • BIP intermediate prepared by the above process is found to have purity more than 98.5 %, preferably more than 98.7 %, more preferably more than 99%. Process is found to be highly advantageous as compared to prior art wherein even after even after lengthy crystallization and purification processes, purity of product obtained is only 97.7 % or require purification using salt formation to achieve high purity which makes process costly.
  • Starting material i.e. intermediate of formula VI used for the preparation of BIP intermediate can be procured from the commercial source or can be prepared by any of the prior art method or by the process described herein for the reference.
  • Intermediate of formula VI can be prepared by protection of amine group of D-proline by a suitable reagent that can protect the amine group of D-proline with a group of general formula,
  • process involves the reaction of D-proline with a suitable reagent in the presence of a suitable base at a temperature of -10 °C to reflux temperature for few minutes to several hours, preferably till the completion of reaction.
  • suitable reagent includes substituted or unsubstituted aryl haloformate such as phenyl chloroformate, substituted phenyl chloroformate (wherein one or more substitutent can be selected from alkyl, alkoxy, aryloxy, nitrile, nitro, halo etc.) and the like.
  • Suitable base can be selected from organic base selected from primary, secondary or tertiary amine; or inorganic base which includes alkali or alkaline metal hydroxide, carbonates, bicarbonate thereof such as sodium hydroxide and the like or combination thereof.
  • reaction mixture can be optionally washed with a suitable solvent selected amongst ether such as isopropyl ether, halogenated solvents such as dichloromethane, chloroform; aliphatic or aromatic hydrocarbon such as toluene, cyclohexane and the like.
  • Intermediate of formula VI can be isolated from the reaction mixture by adding a suitable acid to the reaction mixture followed by extraction of the mixture with a suitable solvent. Acid used can be organic or inorganic acid.
  • Organic acid can be selected from carboxylic acid, sulfonic acid and the like.
  • Inorganic acid can be hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like.
  • Suitable solvent used for the extraction includes but not limited to ether such as methyl tertiary butyl ether, isopropyl ether, toluene, ethyl acetate, 2-methyl tetrahydrofuran, and cyclohexane; halogenated solvent such as dichloromethane and the like.
  • Intermediate of formula VI can be recovered from organic layer by the solvent removal using distillation, evaporation and the like.
  • HPLC High performance liquid chromatography
  • GC gas chromatography
  • UPLC ultra pressure liquid chromatography
  • TLC thin layer chromatography
  • 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. Another advantage realized in the present invention is to provide an industrially advantageous and convenient process for the preparation of BIP intermediate of formula II, which is a key intermediate for the synthesis of eletriptan or pharmaceutically acceptable salts thereof, using novel keto carbamate intermediate of formula ⁇ . Present invention employs starting material i.e.
  • phenyl chloroformate which is quite cheaper as compared to benzyl chloroformate as used in the all prior art processes.
  • Another advantage of using phenyl or substituted phenyl chlorofomate is to avoid specific treatment required to remove by product such as benzyl alcohol.
  • Another advantage of present invention is to provide novel intermediate useful for synthesis of BIP intermediate of formula II. Use of phenyl or substituted phenyl carbamate intermediate also proved be quite beneficial in yielding BIP intermediate with high purity and high yield. Even at crude stage, i.e after quenching of reaction mixture with base, the product is about 93% pure and less purification is required and hence present invention provides a cost effective process for preparation of BIP intermediate of formula II with high yield and high purity.
  • the process of present invention is highly advantageous in the preparation of eletriptan hydrobromide having impurities in acceptable amounts or free from impurities.
  • 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.
  • Method B To a stirred solution of D-proline (200 g, 1.74 mol) and 16% sodium hydroxide (535 ml, 2.14 mol) at 0-5 °C, phenyl chloroformate (272 g, 1.74 mol) and 16 %, sodium hydroxide (535 ml, 2.14 mol) was added and mixture was stirred for 2 hours at 0-5 °C. Reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with toluene (2 x 600 ml) and aqueous layer was acidified by addition concentrated hydrochloric acid 250 ml). Reaction mixture was extracted with dichloromethane (3 x 600 ml). All the organic extracts were combined, washed with water (600 ml), dried, and distilled to give 384.2 g of the title compound having purity 99 % by HPLC.
  • reaction mixture was cooled to -5 to -10 °C and a solution of 2-chlorocarbonyl-pyrrolidine-l-carboxylic acid phenyl ester (107.84 g, 0.43 mol) in dichloromethane (100 ml) was added to the reaction mixture and stirred for 15 hours at 20 to 25 °C.
  • dichloromethane 100 ml
  • mixture was quenched with aqueous citric acid solution (300 ml, 10%) at 0 to 5 °C and then heated to 25-30 °C. Layers were separated and aqueous layer was extracted with dichloromethane (100 ml). The combined organic layer was washed demineralized water (100 ml).
  • Method B To a stirred solution of 5-bromoindole (166.7 g, 0.85 mol) in dichloromethane (800 ml) at 5-10 °C, a solution of ethyl magnesium bromide (312 ml, 3M in tetrahydrofuran, 0.94 mol) and anhydrous Zinc chloride (75.34 g, 0.55 mol) were added and stirred for 1 hour at 25-30 °C.
  • reaction mixture was cooled to -5 to -10 °C and a solution of 2-chlorocarbonyl-pyrrolidine-l-carboxylic acid phenyl ester (107.84 g, 0.43 mol) in dichloromethane (100 ml) was added to the reaction mixture and stirred for 15 hours at 20 to 25 °C.
  • dichloromethane 100 ml
  • mixture was quenched with aqueous citric acid solution (300 ml, 10%) at 0 to 5 °C and then heated to 25-30 °C. Layers were separated and aqueous layer was extracted with dichloromethane (100 ml). The combined organic layer was washed demineralized water (100 ml).
  • Method A To a stirred suspension of [R]-2-(5-bromo- 1 H-indole-3-carbonyl)-pyrrolidine- 1 -carboxylic acid phenyl ester (50 g, 0.12 mol) in toluene (350 ml), a solution of Red-Al (210 ml in toluene, 0.73 mol) was added at 10-15 °C under nitrogen atmosphere in dark. The reaction mixture was stirred at 25 °C for 15 minutes and then at 45 - 50 °C for 1 hour. The reaction mixture was cooled to 0-5 °C and quenched with 10 % sodium hydroxide (350 ml) in dark. The reaction mixture was warmed to 30-35 °C.
  • Method B To a stirred suspension of [R]-2-(5-bromo-lH-indole-3-carbonyl)-pyrrolidine-l-carboxylic acid phenyl ester (100 g, 0.24 mol) in toluene (900 ml), a solution of Red-Al (420 ml in toluene , 1.45 mol) was added at 15-20 °C under nitrogen atmosphere in dark. The reaction mixture was stirred at 25 °C for 15 minutes and then at 45 - 50 °C for 1 hour. The reaction mixture was cooled to 0-5 °C and quenched with 10 % sodium hydroxide (700 ml) in dark. The reaction mixture was warmed to 30-35 °C in dark.
  • Method B A suspension of [R]- 5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (5 g; having purity 97.2 % by HPLC) in cyclohexane (25 ml) and dichloromethane (5 ml) was stirred for 1 hour. Mixture was filtered, washed with cyclohexane (10 ml) and suck dried. The product thus obtained was dried at 50-55 °C in vacuum for 5 hours to give 4.2 g of title compound having purity 99.1% by HPLC.
  • Method C A suspension of [R]-5-bromc ⁇ 3-(l-memyl-pyrrolidin-2-ylmethyl)-lH-indole (5 g, having purity 96.7%) in cyclohexane (25 ml) and methyl isobutyl ketone (5 ml) was stirred for 1 hour. Mixture was filtered, washed with cyclohexane (10ml) and suck dried. The product thus obtained was dried at 50- 55 °C in vacuum oven at 150mmHg for 5 hours to give 4.2 g of title compound having purity 98.8% by HPLC.
  • 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 (319.2 g, 3.13 mol) and N,N-dimethylformamide (15 g, 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 (750 ml) and demineralized 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 (60 g) 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 (3 x 900 ml). The combined organic extract was washed with water (600 ml) and dried over sodium sulphate.
  • 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.
  • 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 (25 ml) 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). The 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.
  • Method D Mixture of [R]-5-bromo-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole (375 g) in dimethylformamide (19.8 ml) was stirred at 25-30 °C for 5 minutes. Acetic anhydride (399 g) was added to the reaction mixture. Reaction mixture was heated to 95-100 °C and stirred for 3 hours and cooled to 0-5 °C for 1 hour. Methyl tert-butyl ether (940 ml) and demineralized water (1.875 L) were added to the reaction mixture and stirred for 30 minute at 5-10 °C.
  • Method A A mixture of palladium acetate (1 1.03g, 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), ⁇ , ⁇ -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.
  • 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 480 g of the 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), ⁇ , ⁇ -diisopropyl ethylamine (4.63 g, 0.036 mol), [R]- l-[5-bromo-3-(l- methyl-pyrrolidin-2-ylmethyl)-indol-l-yl] -ethanone (lOg, 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.
  • aqueous hydrochloric acid 112.5 ml, 3.3%
  • 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.
  • 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.
  • 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.
  • 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), ⁇ , ⁇ -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 l5ml) and dried to give the title compound having purity 88 % 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), ⁇ , ⁇ -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.
  • 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 (63.32 g) in dimethylformamide (780 ml) was stirred at 25-35 °C for 5 hours. Phenyl vinyl sulphone (215.08g), ⁇ , ⁇ -diisopropyl ethylamine (180.4g) and a solution of (R)-l-[5-biOmo-3-(l-memyl-pyrrolidin-2-ylmethyl)-indol-l-yl]-ethanone (388 g) in dimethylformamide (780 ml) were added to the reaction mass at 25-35 °C.
  • 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 (4.4 L) to the reaction mixture. Reaction mixture was stirred at 30-35 °C for 30 minutes, filtered through hyflo-bed and washed with dimethylformamide (75 ml). 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.
  • Method E A mixture of [R]-l-[5-(2-benzenesulfonyl-vinyl)-3-(l-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.
  • 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.
  • Method G A mixture of [R]-l-[5-(2-benzenesulfonyl- ⁇ dnyl)-3-(l-memyl-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 ( ⁇ 92.5 ml). Resulting filtrate was distilled under vacuum at 45-50 °C for 4 hours.
  • Acetone (385 ml) was added to resulting residue, stirred at 45-50 °C for 5 minutes and distilled off.
  • Acetone (1.16 L) was added to resulting residue, stirred at 25-30 °C for 10 minutes followed by addition of demineralised water (1.93 L).
  • Reaction mixture was filtered, washed with demineralised water (385 ml) and dried at 25-30 °C for 2 hours to give title compound which was purified with acetone (1.16 L): demineralised water (1.54 L) to give 252 g of tide 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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), demineralised 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).
  • 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 lhour 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 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.
  • 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), demineralized 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 free base (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 dichloromethane 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.
  • Example 12 Preparation of a-form eletriptan hydrobromide directly from [R]- 5-(2- benzenesulfonyl-vinyl)-3-(l-methyl-pyrrolidin-2-ylmethyl)-lH-indole
  • 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 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 (lOg, Norrit carbon SX). The reaction mixture was stirred for lhr. at 80-85°C and filtered through hyflo bed. The filtrate was distilled off (up to 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 121g of title compound having purity of 99.89% by HPLC.
  • activated carbon lOg, Norrit carbon SX
  • Method E Mixture of eletriptan hydrobromide (190 g), ethanol (1.9 L) and isopropanol (190 ml) were stirred and refluxed for 30 minutes. Reaction mixture was charcoalised by adding Norit SX plus carbon (28.5g), stirred at 80-85 °C for 30 minutes. The reaction mass was filtered through hyflo bed and washed with ethanol (95ml). Solvents were partially distilled off from the reaction mixture at 65-70 °C. Isopropanol (950ml) was added to the resulting reaction mass and heated to reflux for 10 minutes. Reaction mass was cooled to 25-30 °C and stirred for 2 hours. Resulting product was filtered, washed with isopropanol (95 ml) and dried to give 160 g of title compound having purity 99 % by HPLC.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré et avantageux industriellement pour la préparation d'élétriptan de formule (I), ou des sels pharmaceutiquement acceptables de celui-ci, à partir d'intermédiaire de bromo indole de formule II, par l'isolement de bromo indole N-acétylé de formule III, pour éviter le transport d'impuretés à l'étape suivante. La présente invention concerne un procédé pour la préparation de 5-bromo-3-[(R)-l-méthyl-pyrrolidin-2-méthyl-lH-indole de formule II, un intermédiaire important pour la synthèse d'élétriptan ou de sels pharmaceutiquement acceptables de celui-ci, via un nouvel intermédiaire de type cétocarbamate. La présente invention concerne également un nouveau procédé pour la préparation de forme alpha de bromhydrate d'élétriptan.
PCT/IN2011/000447 2010-07-06 2011-07-04 Procédé pour la préparation de dérivé d'indole substitué en position 5 WO2012004811A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063752A1 (fr) 2012-10-26 2014-05-01 Synthon Bv Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan
CN104230895A (zh) * 2013-06-08 2014-12-24 上海医药工业研究院 一种依立曲坦中间体的制备方法
CN104292217A (zh) * 2013-04-08 2015-01-21 上海医药工业研究院 一种α晶型氢溴酸依立曲坦的制备方法及纯化方法
US9963513B2 (en) 2013-02-05 2018-05-08 Engmab Sàrl Method for the selection of antibodies against BCMA

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CN1082040A (zh) * 1992-04-14 1994-02-16 辉瑞研究及发展公司 吲哚类
CN1487932A (zh) * 2000-12-20 2004-04-07 新方法
CN1823060A (zh) * 2003-07-23 2006-08-23 辉瑞大药厂 制备α－多晶型氢溴酸依来曲普坦的改良方法

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Publication number Priority date Publication date Assignee Title
CN1082040A (zh) * 1992-04-14 1994-02-16 辉瑞研究及发展公司 吲哚类
CN1487932A (zh) * 2000-12-20 2004-04-07 新方法
CN1823060A (zh) * 2003-07-23 2006-08-23 辉瑞大药厂 制备α－多晶型氢溴酸依来曲普坦的改良方法

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014063752A1 (fr) 2012-10-26 2014-05-01 Synthon Bv Procédé de production de la forme cristalline alpha du bromhydrure d'élétriptan
US9963513B2 (en) 2013-02-05 2018-05-08 Engmab Sàrl Method for the selection of antibodies against BCMA
US10077315B2 (en) 2013-02-05 2018-09-18 Engmab Sàrl Bispecific antibodies against CD3 and BCMA
US10851171B2 (en) 2013-02-05 2020-12-01 Engmab Sarl Method for the selection of antibodies against BCMA
CN104292217A (zh) * 2013-04-08 2015-01-21 上海医药工业研究院 一种α晶型氢溴酸依立曲坦的制备方法及纯化方法
CN104230895A (zh) * 2013-06-08 2014-12-24 上海医药工业研究院 一种依立曲坦中间体的制备方法
CN104230895B (zh) * 2013-06-08 2017-02-08 上海医药工业研究院 一种依立曲坦中间体的制备方法

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