WO2012025772A1

WO2012025772A1 - Process for preparing pure 5-bromo-3-[(r)-1-methyl-pyrrolidin-2-ylmethyl]-1h-indole, intermediate for eletriptan

Info

Publication number: WO2012025772A1
Application number: PCT/IB2010/001889
Authority: WO
Inventors: Ramesh Babu Potluri; Hariharakrishnan Venkata Subramanaian; Hari Prasad Kodali; Srinivasa Rao Venturi
Original assignee: Ramesh Babu Potluri; Hariharakrishnan Venkata Subramanaian; Hari Prasad Kodali; Srinivasa Rao Venturi
Priority date: 2010-07-30
Filing date: 2010-07-30
Publication date: 2012-03-01

Abstract

Disclosed is a process for preparing pure 5-bromo-3-[(R)-1-methyl-pyrrolidin-2-ylmethyl]-1H-indole (BIP), an intermediate for eletriptan. The process comprises forming organic acid salt of BIP and then regenerating the said salt to give pure BIP.

Description

PROCESS FOR PREPARING PURE 5-BROMO-3-[(R)-l-METHYL-PYRROLIDM-2-YLMETHYL]-lH-INDOLE, INTERMEDIATE FOR ELETRIPTAN

Filed of the Invention:

The invention relates to a process for preparing pure (R)-5-BromO_'3-(N-methylpyrrolidin-2- ylmethyl)-lH-indole in excellent purity.

Background of the Invention and relevant prior art:

Eletriptan, the chemical entity 3-(((R>l-mcthylpyrrolidm-2-yl)methyl)-5-(2- (phenylsulfonyl)ethyl)-lH-indole of formula-II

Formula-IT

is widely used as a valuable antimigraine drug as hydrobromide salt. Eletriptan hydrobromide exhibits selective vasoconstrictor activity and are indicated for use in the treatment of migraine

The preparation of a compound of formula II can be achieved by process described in US5545644 by reacting the crucial intermediate (R)-5-bromo-3-(N-methylpyrroIidin-2-ylmethyl)- lH-indole of formula I and phenylvinylsulfone of formula-Ill

Formula-ϋΙ

The preparation of the compound of formula I, which is one of the key intermediate for the synthesis of formula-fl described in US patent number US554564 , is shown in the scheme-

Formula-IV Fonrnila-l

Scbeme-I

A similar process is described in WO 2008150500, where the reduction was performed with group consisting of: sodium dihydro-bis(2- methoxyethoxy)aluiJiimum hydride (vitrido) , lithium tris[(3-ethyl-3-pentyI)oxy]aluminohydride, lithium tri-tert-butoxyaluminum hydride and diiaobutylaluminum hydride which is shown in the scheme-Π. ]-

Formul8_'I

Schemc-Π

The purity of the product of formula-1, in above patents (US5545644, WO 2008150500) are less and it leads to more impurities in further synthetic protocol. Hence, there was a need to improve the purity of (R)-5-bromo-3-(N-methylpyrroIidin-2-ylmethyl lH-indo1e. The pure (R)-5-bromo- 3-(N-methylpyrrolidin-2-ylmethyl)-^] H-indoIe will give improved yield and purity of eletriptan hydrobormide. Summary of the Invention:

The present invention provides a method for purifying (R)-5-Bromo-3-(N-mctbylpynolidin-2- ylmethyl)-1H-indole of formula-T

Formula-I

by forming a addUiuu salt of (R)-5-b₍romo-3-(N-methylpyTn>lidin-2-ylmethyl)-IH-indoIe for formula-ΐ crude compound with an organic acid having reducing properties and selected from the group consisting of citric acid, ascorbic acid and oxalic acid. The preferred salt of crude formula- I is formed with oxalic acid and is prepared by treating crude product of formula-I with oxalic acid dihydrate in aqueous methanol at 20-65°C to give oxalate salt of formula-V

Formula-V

The purified base is regenerated by treating the oxalate salt of formuIa-Π with aqueous potassium carbonate at 25-35°C with an HPLC purity of > 99.6% and yield of > 90%

Detailed description of the invention:

The above and other objective features and advantages will be clear from the following

description. The present process describes methodology to get a (R)-5-bromc~3-( -methylpyrroHdin-2- ylmethyl)-lH-indole base of very excellent purity. The base of 85-90% purity (by HPLC) is converted into a oxalate salt. The mole ratio of the oxalic acid to the compound of formula I is preferred to be 1 : 3. It is more preferable to have a mole ratio of I : 1.5. It is most preferable to be maintain a mole ratio of 1 : 1.1-1.2. The salt formation can be carried out in solvents like pure alkanols, aqueous alkanols, alkoxy alkanols etc. Alkanol or aqueous a!kanol are more preferable. The salt formation takes place at a temperu-ure range of 10°C to 85°C. The preferable temperature range for the salt formation is 25°C to 65°C. A temperature range of 40-60°C is most preferable. The salt is isolated by cooling the reaction mixture to about 5°C to 10°C. The isolated salt is washed with the same solvent, which is used for the salt formation and the isolated salt is dried to get (R)-5-bi¾ino-3-(N-mcthylpyrrolidtn-2-yltxiethyl)-lH-indole oxalate. The salt is subjected to elemental analysis and found to be 1:1 salt of base: acid. The salt is dissolved in water and the base of formula I is precipitated by neutralizing with inorganic base like alkali/alkaline earth hydroxide, alkali/alkaline earth carbonates/bicarbonates, ammonia etc. It is more preferable to use alkali/alkaline earth hydroxide or alkali/alkaline earth carbonate/bicarbonates. It is most preferable to use alkali carbonates like sodium/potassium carbonates. The precipitated base is filtered and dried to get pure product (HPLC > 99.6%) of formula-I.

Advantages or the invention:

In this invention an efficient process has been developed, which has the following advantages,

1. avoiding repeated recrystallization in solvents

2. high yield and purity

The following examples further illustrate the present invention

The above description briefly outlines the preferred embodiments of the present invention, which enables those skilled in the art to undcratand the detailed description that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for preparation of similar derivatives. Those skilled in the art should realize such equivalent concept do not depart from the spirit and scope of the invention in its broadest sense. EXAMPLES

I - Preparation of ( V5-bromo-3-fN-methylpyrrolidin-2-y1methv1VlH-indole oxalate

Methanol (20L) was added to 5.0kg of (R)-5-brorao-3-( -rnethylpyrrolidin-2-ylmethyl)- I H-indole residue (90.6% by HPLC, prepared y example 27 of US55-15644 heated to 6Q-65°C. Oxalic acid (2.35kg) was added to methanolio solution and stirred for 30min at 60-65°C The reaction mixture was then cooled to 10-15°C, filtered, washed with methanol (5L) and dried to get 5.9kg of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-lH-indole oxalate salt with a purity of > 98.5% by HPLC.

II- Preparation of (R 5-bromo-3-^-methylpyrrolidin-2-ylmethyl lH--indole

5.5kg of 5-bromo-3-(N-methy1pyrrolidin-2-ylmethyl)-lH-indole oxalate salt obtained in previous example was added into demineralised water (27.5L) and pH was adjusted to 7.0 using potassium carbonate. . The obtained base was filtered and dried to get (R)-5-bromo-3-(N-methyl-pyTToIidin- 2-ylmethyl)-iH-indnle with a purity by HPLC >99.8%.

HI- Preparation of (R)-5-.3romo-3-rN-methylPyrrol)din-2-ylmcLhylVlH--indole fWO 20081 S0500. Example-I) and its conversion to oxalate salt

A solution of (R)-2-(5-Bromo-lH-indoIe-3-carbonyl)-pyrrolidine-l-carboxylic acid benzyl ester (60.0 g, 1.0 eq.) in dry tetrahydrofuran (600 ml) was added drop wise over the period of 60 min to the stirred 70 % solution of SDMA in toluene (210 ml, 2.1 eq.) diluted by dry tetrahydrofuran (270 ml) under atmosphere of dry nitrogen while maintaining the temperature between 30 and 40 °C. The mixture was stirred and heated to the temperature of 50°C for 60 min. Then the mixture was cooled to 5 °C and water (100 ml) was carefully added, followed by 10 % aqueous solution of sodium hydroxide (200 ml) and more water (400 ml). The resulting mixture was diluted with toluene (400 ml) and the phases were separated. The bottom aqueous phase was twice extracted with toluene (200 ml). The obtained organic phases were joined, dried over anhydrous sodium sulphate. 20gm of oxalio was added to the toluene layer and distilled off under reduced pressure. To the remaining residue, 135ml of methanol was added and temperature was raised to 50-60°C. After 30 minutes the reaction mixture was cooled to 5-10°C, filtered, washed with 25ml methanol and dried to get 48gm of (R 5-Bromo-3-(N-methylpyrro)idin-2-ylmethyl lH- indole oxalate with a purity by HPLC 98.2 %

Claims

We claim:

01. A process for preparing pure (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-lH- indole of formula I

Formula-I

by purifying the crude compound by forming salts with an organic acid

02. A process as claimed in claim 1, wherein the preferred organic acid is having reducing properties and selected from the group consisting of citrio acid, ascorbic acid and oxalic acid

03. A process as claimed in claim 1, wherein the preferred salt of crude fonnula-I is formed with oxalic acid dehydrate and is isolated as formula-V in aqueous methanol at 20-65°C .

04. A process as claimed in claim 3, isolated (R)-5-bromo-3-(N-methylpyrrolidin-2' ylmethyl)-! H-indole oxalate salt of formula-V has a purity υΓ> 98.0%

05. A process as claimed in claim 1, wherein the purified base is regenerated by treating the oxalate salt with aqueous potassium carbonate at 25-35°C

06. Λ process as claimed in claim 1, wherein 90% yield and > 99.6% HPLC purity.