WO2013054346A2 - Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants - Google Patents

Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants Download PDF

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Publication number
WO2013054346A2
WO2013054346A2 PCT/IN2012/000500 IN2012000500W WO2013054346A2 WO 2013054346 A2 WO2013054346 A2 WO 2013054346A2 IN 2012000500 W IN2012000500 W IN 2012000500W WO 2013054346 A2 WO2013054346 A2 WO 2013054346A2
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Prior art keywords
propargyl
free base
reaction mixture
amino indane
rasagiline
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PCT/IN2012/000500
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English (en)
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WO2013054346A3 (fr
Inventor
Vitthal Pune SANTOSH
Pandurang Pawar PRASHANT
Kumar Arvindbhai Patel DHARMESH
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Alkem Laboratories Limited
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Publication of WO2013054346A2 publication Critical patent/WO2013054346A2/fr
Publication of WO2013054346A3 publication Critical patent/WO2013054346A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention is directed to a process for the preparation of N-propargyl 1 -amino indane and pharmaceutically acceptable salts thereof.
  • R (+)-N-propargyl-l-aminoindan (hereinafter referred to as R (+) PAI or rasagiline), having formula
  • MAO-B monoamine oxidase
  • Rasagiline mesylate is approved for treating Parkinson's disease either as monotherapy or as an adjunct with other treatments. See, e.g. AGILECT®, Physician's Desk Reference (2007), 61st Edition, Thomson Healthcare.
  • Example 4 of US '415 teaches a process for the preparation of R-(+)-N-Propargyl-l- aminoindan by reacting R-(-)l-aminoindan with propargylchloride in the presence of potassium carbonate base in acetonitrile.However the '415 patent discloses isolation of the free R-(+)-N- propargyl-l-aminoindan base as an OIL'by chromatographic purification technique alone.
  • U.S. Patent No. 7,750,051, ⁇ herein referred to as US'051 ⁇ assigned to Teva Pharmaceutical Industries, Ltd. provides crystalline R(+)-N-propargyl-l-aminoindan [rasagiline], pharmaceutical compositions and methods of manufacture thereof.
  • the previously isolated rasagiline free base existed as an 'oil' due to presence of residual solvents and therefore the '051 patent attempted to provide a method to convert rasagiline free base as a 'Pure OIL' to a 'Pure SOLID Crystalline' form.
  • Examples 1 to 3 of US'051 teach a method to isolate rasagiline free base as a crystalline solid by basifying a cold aqueous solution of a salt of rasagiline by splitting and spontaneous crystallization from water while the other examples disclose a technique to isolate rasagiline free base as a crystalline solid by addition of water to an alcoholic solution of rasagiline free base.
  • US'051 teaches a technique for the isolation of rasagiline free base in crystalline solid form
  • the free base of rasagiline employed by US'051 was prepared by a process as per US '415 and isolated as an 'OIL' by column chromatographic techniques alone.
  • US'051 essentially teaches a technique to convert rasagiline free base in an OIL' form to 'CRYSTALLINE' form- however it fails to provide a solution to isolate rasagiline free base of acceptable purity directly from the crude reaction mixture or without column chromatographic techniques and the like.
  • U.S. patent application publication No.US20090318564 assigned to Teva Pharmaceuticals Ltd discloses crystalline R (+) -N-propargyl-l-aminoindane containing water at an amount of less than 0.5% by weight.
  • this application too fails to solve the problem of arriving at rasagiline free base in pure form directly from the reaction mixture without column chromatographic purification or solvent re-crystallisation techniques. Instead, it attempts to convert an 'OIL' form of rasagiline free base to a 'SOLID Crystalline' form.
  • patent application publication No.US20100029987 assigned to Dipharma Francis relates to a novel process for the preparation of rasagiline or a salt thereof by reacting 1-indanone with propargyl amine, in the presence of a mixture of sodiumborohydride and acetic acid, to obtain N- propargyl 1 -amino indane; and its conversion to a salt thereof.
  • It also provides a process for the isolation of rasagiline free base in solid crystalline form with its characteristic XRPD values by cooling a solution of the crude free rasagiline base as an oil or by adding an anti solvent or also by basifying an acid addition salt of rasagiline free base in a mixture of water and organic solvent and crystallizing the residue of rasagiline free base from an aprotic apolar solvent.
  • US20100029987 teaches various techniques and a variety of solvents to convert rasagiline free base as an OIL* to 'SOLID crystalline' form— however it fails to provide a solution to arrive at rasagiline free base of acceptable purity fit enough to be used for the next stage of conversion to its pharmaceutically acceptable salt directly from the reaction mixture without solvent re- crystallisation or complex column chromatographic purification techniques.
  • International patent application publication No.WO2010/013048 relates to novel crystalline form of rasagiline mesylate whiles another International patent application publication No.
  • the inventors of the present invention have succeeded in devising a novel eco-friendly process for preparing rasagiline free base and pharmaceutically acceptable salts thereof using reagents and solvents in a time and cost-effective manner at an industrially applicable scale.
  • the present inventors have succeeded in isolating rasagiline free base of purity as high as 99 % by a selective solvent extraction technique directly from the crude reaction mixture unlike the prior art processes wherein tedious column chromatographic purification strategies or solvent re- crystallisation processes for the isolation of pure rasagiline free base were inevitable steps for purification of rasagiline free base.
  • the inventors of the present invention have developed a process of isolation of rasagiline free base with the primary goal of achieving rasagiline free base of high purity and yield by a workup based on selective solvent extraction directly from the crude reaction mixture devoid of complex column chromatography or re-crystallization methods.
  • a main aspect of the present invention is to provide a process for the preparation of N-propargyl 1- amino indane and its pharmaceutically acceptable salts, by a simple process of purification of N-propargyl amino indane free base, which is free of the above-mentioned disadvantages, starting with commercially available materials and using simple reagents and low cost solvents, to afford high overall yield and purity of the product.
  • the reaction mixture comprising N-propargyl- 1 -amino indane may be from a reaction obtained by any suitable prior-art process, for example by a process according to U.S.Pat.no.5,532,415.
  • the term "1-aminoindan” as used herein throughout the description and claims implies 1- aminoindan and or any salt, solvate, stereoisomers or polymorphic form thereof, unless otherwise specified.
  • rasagiline as used herein throughout the description and claims implies rasagiline and/or any salt, solvate, stereoisomers or polymorphic form thereof, unless otherwise specified.
  • the current invention is particularly useful for the preparation of rasagiline free base.
  • the term 'exclusive' implies that the rasagiline free base was purified by selective solvent extraction technique alone and the conventional column chromatographic extraction or re- crystallisation methods were not used.
  • a process according to A above, wherein the purification of N-propargyl- 1 -amino indane free base comprises the steps of
  • step b) A process according to B above, wherein the preferred pH in step b) is about 2.0 to 3.0 and more preferably about 2.5 to 3.0.
  • step c) A process according to B above, wherein the preferred pH in step c) is about 4.0 to 1 1.0 and more preferably about 4.5 to 5.0.
  • reaction solvent optionally removing the reaction solvent from the reaction mixture, adding water and extracting the reaction mixture with an organic solvent
  • step c) optionally isolating N-propargyl aminoindane free base and/or converting N-propargyl aminoindane free base insitu to its pharmaceutically acceptable salt thereof.
  • step c) is about 2.0 to 3.0 and more preferably about 2.5 to 3.0.
  • step d A process according to E above, wherein the preferred pH in step d) is about 4.0 to 1 1.0 and more preferably about 4.5 to 5.0.
  • N-propargyl amino indane free base has a purity of about 99%.
  • a main aspect of the present invention is to provide a process for the preparation of N-propargyl 1- amino indane and its pharmaceutically acceptable salts by purification of N-propargyl amino indane free base, which is free of the above-mentioned disadvantages, starting with commercially available materials and using simple reagents and low cost solvents, to afford high overall yield and purity of the product.
  • the reaction mixture comprising N-propargyl- 1 -amino indane may be from a reaction obtained by any suitable prior-art process and evident to a person skilled-in the-art, for example by a process according to U.S.Pat.no.5, 532,415.
  • one aspect thereof, of the present invention provides a process for the preparation of N-propargyl-1 -amino indane and pharmaceutically acceptable salts thereof by a process of purification of N-propargyl amino indane free base directly from its crude reaction mixture comprising the steps of
  • another aspect thereof, of the present invention provides a process for the purification of N-propargyl-1 -amino indane directly from its crude reaction mixture comprising the steps of
  • N-propargyl-1 -amino indane free base or converting insitu to its pharmaceutically acceptable salt thereof:
  • another aspect thereof, of the present invention provides a process for preparing rasagiline and pharmaceutically acceptable salts thereof comprising a) providing a reaction mixture comprising N-propargyl- 1 -amino indane and/or a salt thereof, b) purifying N-propargyl-1 -amino indane free base exclusively by selective pH adjustment and selective extraction,
  • reaction solvent optionally removing the reaction solvent from the reaction mixture comprising N-propargyl 1- amino indane, adding water and extracting the reaction mixture with an organic solvent, c) adjusting pH of the reaction mixture to about 1.0 to 5.0, and optionally seperating the organic layer,
  • the reaction mixture comprising N-propargyl-1 -amino indane may be from a reaction obtained by any suitable prior-art process and evident to a person skilled-in the-art, for example by a process according to U.S.Pat.no.5, 532,415.
  • reaction solvent used may be any suitable solvent known in the prior art and evident to a person skilled in the art such as a nitrile, amide, hydrocarbon, ether, a ketone, an ester, alcohol and the like or mixtures thereof.
  • a nitrile, amide, hydrocarbon, ether, a ketone, an ester, alcohol and the like or mixtures thereof In a preferred embodiment of the present invention, acetonitrile was used.
  • the reaction may be carried out at any temperature between ambient temperature and the boiling point of the solvent.
  • ambient temperature in the present application is intended to indicate the temperature usually found in industrial laboratory and production facilities such as in the range of 15-40°C, preferably in the range of 20-30°C.
  • R (+) N propargyl amino indane was prepared by heating a mixture of R (-) aminoindane HC1 with propargylchloride in the presence of potassium carbonate in acetonitrile at 60-62C.
  • the crude reaction mixture containing the R (+) N propargyl amino indane was worked up by a process based on tactful pH adjustment of the aqueous and organic phases and selective extraction and wash techniques.
  • the extracting solvents used for the present invention may be selected from any conventional organic solvent used for extraction and apparent to a person skilled in the art such as halogenated solvents, esters, aliphatic or aromatic hydrocarbons, ethers and the like or mixtures thereof. Solvents of the like of Dichloromethane, Chloroform, Ethyl acetate, Toluene, Xylene, diethyl ether and the like or mixtures thereof apparent to a person skilled in art may be used.
  • reaction solvent-acetonitrile was distilled off under vacuum at 60-65deg C.
  • the reaction mixture was cooled to room temperature, water was added and the residue stirred for about 20 mins.
  • An aspect of the present invention provides a purification process of N-propargyl-1 -amino indane having a purity as high as 99% directly from the crude reaction mixture by extraction of the crude reaction mixture with suitable conventional organic solvents and by tactful adjustment of the pH of the aqueous reaction mixtures with an acid to about 1.0 to 5.0, preferably 2.0 to 3.0 and more preferably about 2.5 -3.0.
  • the acid used may be selected from any conventional inorganic or organic acids of the like of HC1 or methane sulfonic acids and the like and thus well known to a skilled person.
  • the aqueous layer may be washed with the extraction solvent to facilitate extraction of organic impurities of the reaction mixture into the organic extraction solvent which may be discarded.
  • the pH of aqueous reaction mixture may be adjusted to about 3.0 to 14.0, preferably about 4.0 to 11.0 and more preferably about 4.5 to 5.0 by addition of an aqueous solution of a base and subjected to extraction with an organic solvent.
  • the base may be any conventional base such as an organic base or an inorganic base.
  • a 50% aqueous solution of Potassium carbonate was used.
  • the combined organic extracts may be washed with an aqueous solution of a base to a pH of about 11.0 to 14.0, preferably 10.5-1 1.0, and the aqueous layer separated.
  • the unreacted 1 -amino indane present in the aqueous layer may be recovered back by extraction with an organic solvent.
  • rasagiline free base of exceptional purity as high as 99% was isolated by distillation of the combined organic extracts.
  • rasagiline free base of purity as high as 99% directly from the crude reaction mixture by a workup based on selective solvent extraction and tactful pH adjustment of the aqueous and organic phases.
  • the rasagiline free base may be converted to the desired pharmaceutically acceptable salts.
  • Salts of 1-aminoindan and rasagiline include acid addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, benzenesulfonic, toluene
  • a preferred salt of rasagiline is the methanesulfonic acid addition salt, also called rasagiline mesylate.
  • pure rasagiline free base was converted to technical rasagiline mesylate by adding a solution of methanesulfonic acid in isopropyl alcohol to a solution of the rasagiline free base in isopropyl alcohol.
  • a mixture of R(-)amino indane, propargylchloride and base potassium carbonate in acetonitrile were refluxed and the progress of the reaction monitored by TLC and HPLC.
  • the reaction solvent acetonitrile was distilled off under vacuum, the reaction mixture cooled, water added and extracted with DCM twice.
  • the aqueous layers were discarded, and to the combined DCM layers, water added, pH was adjusted to 2.0 to 2.5 by adding MSA.
  • the organic DCM layer was discarded, and the aqueous layer was adjusted to a pH of about 4.0 to 4.5 with 50% aqueous potassium carbonate solution and extracted thrice with DCM.
  • the combined DCM layers were distilled under vacuum to afford rasagiline free base as an OIL'.
  • a solution of MSA in IPA was added to the reaction mass and heated for around 30 minutes.
  • the reaction mass was cooled to RT and then to about 10°C and maintained for 1 hr.
  • the mass filtered under suction, finally washed with IPA and dried under vacuum to afford technical rasagiline mesylate of 99.9% purity.
  • the process of the present invention can be performed on an industrial scale.
  • Acetonitrile (700.00ml), R (-) Aminoindan HC1 (50.00g) and Potassium carbonate (80. lg) were charged to a reactor provided with the CaC ⁇ (fused) guard tube and the reaction mass was heated to 60-62 deg C under stirring for 1 hr.Propargyl chloride (17.0 g) was added to the mass dropwise and the reaction mass maintained for 28 hrs. A sample of the rcn mass was analysed after 28 hrs.Acetonitrile was distilled off at 60-65 deg C under 200 mbar vacuum.The RM was cooled to 25-30 deg C, Water (510ml) was added to the residue and stirred for 20 mins.
  • the aqueous reaction mass was then extracted with Dichloromethane (1x383ml; 1x125 ml) & the DCM. layer separated.
  • 500 ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2.5 by adding 55ml (1 :1 cone. HC1: DM water).
  • the DCM layer was separated while the aq. Layer was extracted with DCM (3 X 500ml) and DCM layers discarded.
  • the pH of aq. Layer was adjusted to 4.5-5.0 by addition of 40 ml of 50% aq. potassium carbonate solution.
  • the aq. Layer was extracted with DCM (3x500ml).
  • Acetonitrile (507.00ml), R (-) Aminoindan HC1 (50.00g) and Potassium carbonate (82.39g) were charged to a reactor provided with the CaCl 2 (fused) guard tube and the reaction mass was heated to 60-62 deg C under stirring for 1 hr. Propargyl chloride (18.13g) was added to the mass dropwise and the reaction mass maintained for 18 hrs. A sample of the reaction mass was analyzed after 18 hr; Acetonitrile was distilled off at 60-65 deg C under 200 mbar vacuum. The RM was cooled to 25-30 deg C, Water (510ml) was added to the residue and stirred for 20 mins.
  • the aqueous rcn mass was then extracted with Dichloromethane (1x383ml; 1x125 ml) & the DCM layer separated.
  • 500ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2,5 by adding 55ml Methane sulphonic acid.
  • the DCM layer was separated while the aq. Layer was extracted with DCM (3 X 500ml) and DCM layers discarded.
  • the pH of aq. Layer was adjusted to 4.5-5.0 by addition of 40 ml of 50% aq. potassium carbonate solution.
  • the aq. Layer was extracted with DCM (3x500ml).
  • Use combined DCM layer for isolation of Rasagiline base and use aq. Layer for the recovery of R-(-)-l-Aminoindane followed by taking pH l 1-12 and extraction with DCM and distillation.
  • Acetonitrile (507.00ml), R-(-)- Aminoindan HCl (50.00g), Propargyl chloride (18.13g) and Potassium carbonate (82.39g) were charged and the reaction mass maintained to 60-62 deg C for 18 hrs.
  • Acetonitrile was distilled off at 60-65 deg C under 200 mbar vacuum.
  • the RM was cooled to 25-30 deg C, Water (510ml) was added to the residue and stirred for 20 mins.
  • the aqueous reaction mass was then extracted with Dichloromethane (1x383ml; 1x75 ml) & the DCM layer separated. 250ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2.5 by adding 65ml dil. sulfuric acid. The DCM layer was separated while the aq. Layer was extracted with DCM (3 X 100ml) and DCM layers discarded.
  • the pH of aq. Layer was adjusted to 4.5-5.0 by addition of 50 ml of 50% aq. potassium carbonate solution.
  • the aq. Layer was extracted with DCM (2x100ml).
  • Acetonitrile (50.7ml), R (-) Aminoindan HCl (5.0g), Propargyl chloride (1.8g) and Potassium carbonate (8.9g) were charged and the reaction mass maintained to 60-62 deg C for 20 hrs. Acetonitrile was distilled off at 60-65 deg C. The RM was cooled to 25-30 deg C, Water (50ml) was added to the residue and stirred for 20 mins.
  • the aqueous reaction mass was then extracted with Dichloromethane (1 38ml; 1 8 ml) & the DCM layer separated. 25ml DM water was added to the combined Dichloromethane layer and the pH adjusted to 2.0-2.5 by adding 45ml Methanesulfonic acid. The DCM layer was separated while the aq. Layer was extracted with MDC (3 X 10ml) and DCM layers discarded.
  • the pH of aq. Layer was adjusted to 4.5-5.0 by addition of 5 ml of 50% aq. potassium carbonate solution.
  • the aq. Layer was extracted with DCM (2x10ml).
  • the combined DCM layer was distilled out and further stripped out by 5 ml isopropanol and 20 ml Isopropanol was added to dissolve the residue.
  • the temperature was then raised to 35-38 deg for 30 minutes.
  • the reaction mass was cooled to 10 +1-2 deg C and the mass maintained for I hr. filter the solid and wash the isopropanol and dried to afford Rasagiline Mesylate of purity

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de N-propargyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants, au moyen d'un procédé consistant: a) à obtenir un mélange réactionnel comprenant du N-propargyl-1-amino indane et/ou un sel correspondant, b) à purifier une base libre de N-propargyl-1-amino indane uniquement par ajustement de pH sélectif et extraction sélective, c) éventuellement à isoler la base libre de N-propargyl-1-amino indane ou à la convertir in situ en son sel pharmaceutiquement acceptable.
PCT/IN2012/000500 2011-07-15 2012-07-16 Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants WO2013054346A2 (fr)

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IN2036/MUM/2011 2011-07-15
IN2036MU2011 2011-07-15

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WO2013054346A3 WO2013054346A3 (fr) 2013-07-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070112217A1 (en) * 2005-11-17 2007-05-17 Anton Frenkel Methods for isolating propargylated aminoindans
WO2010059913A2 (fr) * 2008-11-20 2010-05-27 Dr. Reddy's Laboratories Ltd. Préparation de rasagiline et de ses sels

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070112217A1 (en) * 2005-11-17 2007-05-17 Anton Frenkel Methods for isolating propargylated aminoindans
WO2010059913A2 (fr) * 2008-11-20 2010-05-27 Dr. Reddy's Laboratories Ltd. Préparation de rasagiline et de ses sels

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