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WO2008104847A2 - Procédés de préparation du pramipexole et de ses sels - Google Patents

Procédés de préparation du pramipexole et de ses sels Download PDF

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Publication number
WO2008104847A2
WO2008104847A2 PCT/IB2008/000406 IB2008000406W WO2008104847A2 WO 2008104847 A2 WO2008104847 A2 WO 2008104847A2 IB 2008000406 W IB2008000406 W IB 2008000406W WO 2008104847 A2 WO2008104847 A2 WO 2008104847A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
pramipexole
acetate
compound
preparation
Prior art date
Application number
PCT/IB2008/000406
Other languages
English (en)
Other versions
WO2008104847A3 (fr
Inventor
Aziz Imam Quadri Syed
Mohammad Rafeeq
Mohammed Jaweed Mukarram Siddiqui
Original Assignee
Wockhardt Research Centre
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wockhardt Research Centre filed Critical Wockhardt Research Centre
Publication of WO2008104847A2 publication Critical patent/WO2008104847A2/fr
Publication of WO2008104847A3 publication Critical patent/WO2008104847A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the field of the invention relates to processes for the preparation of pramipexole or pharmaceutically acceptable salts thereof. More particularly, it relates to a process for the preparation of pramipexole dihydrochloride monohydrate.
  • the invention also relates to a novel compound, 2-bromo-4-aminocyclohexanone and processes for its preparation.
  • the 2-bromo-4-aminocyclohexanone is a useful intermediate in the preparation of pramipexole or salts thereof.
  • the invention further relates to a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole, an intermediate useful in the preparation of pramipexole or salts thereof.
  • Pramipexole dihydrochloride chemically known as (S)-2-amino-4,5,6,7-tetrahydro-6- (propylamino) benzothiazole dihydrochloride monohydrate, is represented by Formula I.
  • Pramipexole dihydrochloride is indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease.
  • Pramipexole is commercially available in the form of dihydrochloride salt as monohydrate.
  • U.S. Patent No. 4,886,812 discloses pramipexole or salts thereof and processes for their preparation. Several processes have been reported for the preparation of pramipexole and its intermediates for example, in U.S. Patent No. 6,727,367, U.S. Patent No. 6,770,761 ; U.S. Patent application No. 2006/0100256 and International (PCT) Publication No. WO 06/097014.
  • the inventors have found a novel compound, 2-bromo-4-aminocyclohexanone of Formula III as a useful intermediate for the preparation of pramipexole or salts thereof.
  • the inventors also have developed a single step cost-effective process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole, a useful intermediate in the preparation of pramipexole or salts thereof.
  • the process is simple and avoids multiple isolation steps.
  • a process for the preparation of 2- bromo-4-aminocyclohexanone of Formula III includes: a) brominating a compound of Formula II in glacial acetic acid; and
  • a solution of 4-aminocyclohexanone in glacial acetic acid may be stirred with bromine. After completion of the reaction, the reaction mass may be mixed with water and one or more solvents. The aqueous layer may be separated and organic layer may be concentrated under reduced pressure to get the 2-bromo-4-aminocyclohexanone of Formula III.
  • suitable solvents include ester solvents such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, and isopropyl acetate.
  • a process for the preparation of tetrahydrobenzothiazole of Formula IV includes: a) cyclizing a compound of Formula III with thiourea
  • Formula IV b) isolating the compound of Formula IV from reaction mass thereof.
  • a process for the preparation of pramipexole or salts thereof includes: a) cyclizing a compound of Formula III with thiourea
  • Formula V c) reacting the compound of Formula V with a propylating agent in alcohol; and d) isolating the pramipexole or a salt thereof from reaction mass thereof.
  • a process for the preparation of pramipexole or salts thereof includes: a) cyclizing a compound of Formula III with thiourea
  • a mixture of 2-bromo-4-aminocycIohexanone in glacial acetic acid may be stirred with thiourea at about 60-80 0 C.
  • the resulting mixture may be further heated for the completion of reaction.
  • the reaction mixture may be cooled and the compound of Formula IV may be isolated.
  • the compound of Formula IV may be converted to pramipexole or salts thereof by any of the following methods.
  • the racemic product of Formula IV may be resolved first by dissolving in a suitable aqueous organic solvent in the presence of a chiral auxiliary.
  • the compound of Formula IV may be resolved first by dissolving in a suitable aqueous organic solvent in the presence of a chiral auxiliary.
  • chiral auxiliary examples include (L)-tartaric acid, ditoluoyl-D- tartaric acid, dibenzoyl-D-tartaric acid, O,O-dibenzoyl tartaric acid, camphor acid, camphorsulphonic acid and ⁇ -methoxyphenylacetic acid.
  • the propylation may be done prior to resolving the racemic product of Formula IV to get pramipexole or salts thereof.
  • the propylating agent can be selected from a compound of Formula CH 3 -CH 2 -CH 2 -X, wherein X is a leaving group such as a tosylate, a mesylate or a halide.
  • the propylation reaction may be carried out in the presence of an aqueous organic solvent.
  • the reaction may be carried out a temperature from about 25°C to a reflux temperature of the solvent selected.
  • solvents which may be used include Q. 4 alcohols such as methanol, ethanol, propanol or mixtures thereof.
  • the desired compound may be obtained by removing the solvent under vacuum.
  • salt refers to a compound of Formula I or its monobasic or dibasic acid addition salt.
  • the acid addition salt can be selected from inorganic or organic acid addition salt.
  • the dibasic acid addition salt can be a mixed acid addition salt of two different acids.
  • the term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salts thereof.
  • a sixth aspect of the invention there is provided a single step process for the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole of Formula IV.
  • the process includes:
  • the intermediate compounds may not be isolated which may result in a higher yield and may reduce the processing time.
  • the process may result in the product with a higher purity.
  • the 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole may be converted to pramipexole or salts thereof by method known in the literature. In particular, it may be converted to pramipexole or salts thereof by methods described in U.S. Patent No. 4,886,812.
  • the preparation of 2,6-diamino-4,5,6,7-tetrahydrobenzathiazole of Formula IV may be carried out in a single step without isolating any intermediates thereof.
  • 4-trans- aminocyclohexanol may be reacted with an acetylating reagent like acetic anhydride or acetyl chloride in a solvent like dimethylformide, dimethylsulfoxide, tetrahydrofuran, N- methyltetrahydrofuran, dioxane, dimethylacetamide, hexamethyl phosphorictriamide, N- methylpyrrolidone, formamide or a mixture thereof.
  • the reaction mixture may be concentrated.
  • a ketone solvent such as acetone, methyl ethyl ketone, methyl iso-butyl ketone or a mixture thereof may be added to the residue so obtained and it may be cooled from about 5 0 C to about 20 0 C.
  • An oxidizing agent such as Jones reagent, sodium hypochlorite, manganese dioxide, pyridinium dichromate or potassium permanganate may be added to the reaction mixture at about 5 0 C to about 20 0 C. The resulting mixture may be further stirred for 2-6 hours. The reaction mixture may be quenched by adding isopropyl alcohol and it may be concentrated.
  • An ester solvent such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec-butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate or a mixture thereof may be added to the residue so obtained and it may be stirred for 10-30 minutes.
  • the organic layer may be separated and concentrated. Water may be added to the residue followed by the drop wise addition of bromine in 45-60 minutes at room temperature. The temperature may be raised to 45 0 C and further stirred for the completion of reaction.
  • Thiourea may be added to the reaction mixture and it may be heated from about 70 0 C to about 90 0 C for 3-6 hours.
  • Aqueous hydrobromic acid may be added after completion of reaction and the reaction mixture may be further refluxed for 5-10 hours.
  • the reaction mass may be cooled to about 5 0 C -20 0 C and basified with addition of a base like sodium hydroxide and resultant solid may be isolated from the reaction mass thereof.
  • a seventh aspect of the invention there is provided a process for the preparation of pramipexole dihydrochloride monohydrate.
  • the process includes the steps of:
  • a solution of anhydrous pramipexole dihydrochloride may be obtained in one or more solvents.
  • such a solution may be obtained directly from a reaction in which pramipexole dihydrochloride is formed.
  • solvents includes any solvent or solvent mixture in which pramipexole dihydrochloride can be solubilized, including, for example, water, methanol, ethanol, propanol, isopropyl alcohol, butanol and mixtures thereof.
  • the solution of pramipexole dihydrochloride can be obtained by dissolving, slurrying, stirring, or a combination thereof.
  • an antisolvent is characterized by the fact that pramipexole dihydrochloride monohydrate is insoluble, slightly soluble or practically insoluble but is miscible with a solvent or solvent mixture in which pramipexole dihydrochloride solution is obtained.
  • anti-solvents examples include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, sec- butyl acetate, tert-butyl acetate, isoamyl acetate, isobutyl acetate, isopropyl acetate and mixtures thereof.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • Isolation of the pramipexole dihydrochloride monohydrate from the reaction mass may include, for example, one or more isolating techniques such as filtration, distillation, evaporation, decantation and centrifugation.
  • the process may produce the pramipexole dihydrochloride monohydrate having purity 99.7% or more when measured by HPLC.
  • the pramipexole dihydrochloride monohydrate described herein can be formulated into ndosage forms that are suitable for administering to patients in need of the compound for treating a medical condition for which the compound is indicated, approved, or otherwise beneficial.
  • the pramipexole dihydrochloride monohydrate can be formulated with one or more pharmaceutically acceptable excipients into a dosage form and administered to treat signs and symptoms of idiopathic Parkinson's disease.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des procédés de préparation du pramipexole ou de ses sels pharmaceutiquement acceptables. Plus particulièrement, elle concerne un procédé de préparation du dichlorhydrate de pramipexole monohydraté. L'invention concerne également un nouveau composé, la 2-bromo-4-aminocyclohexanone et des procédés destinés à sa préparation. La 2-bromo-4-aminocyclohexanone est un intermédiaire utile dans la préparation du pramipexole ou de ses sels. L'invention concerne en outre un procédé mono-étape de préparation du 2,6-diamino-4,5,6,7-tétrahydrobenzathiazole, un intermédiaire utile dans la préparation du pramipexole ou de ses sels.
PCT/IB2008/000406 2007-02-26 2008-02-25 Procédés de préparation du pramipexole et de ses sels WO2008104847A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN374MU2007 2007-02-26
IN374/MUM/2007 2007-02-26
IN608MU2007 2007-03-30
IN608/MUM/2007 2007-03-30

Publications (2)

Publication Number Publication Date
WO2008104847A2 true WO2008104847A2 (fr) 2008-09-04
WO2008104847A3 WO2008104847A3 (fr) 2009-02-05

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2137171A4 (fr) * 2007-03-14 2010-05-19 Knopp Neurosciences Inc Synthèse de benzothiazole diamines substituées et purifiées du point de vue chiral
US8017598B2 (en) 2006-05-16 2011-09-13 Knopp Neurosciences, Inc. Compositions of R(+) and S(−) pramipexole and methods of using the same
US8518926B2 (en) 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole
US8524695B2 (en) 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same
CN104496936A (zh) * 2015-01-07 2015-04-08 海南康虹医药科技开发有限公司 一种盐酸普拉克索的制备方法
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9763918B2 (en) 2013-08-13 2017-09-19 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
CN109232471A (zh) * 2018-10-31 2019-01-18 安徽省庆云医药股份有限公司 一种盐酸普拉克索的制备方法
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2394951A (en) * 2002-11-04 2004-05-12 Cipla Ltd One pot synthesis of 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8518926B2 (en) 2006-04-10 2013-08-27 Knopp Neurosciences, Inc. Compositions and methods of using (R)-pramipexole
US8017598B2 (en) 2006-05-16 2011-09-13 Knopp Neurosciences, Inc. Compositions of R(+) and S(−) pramipexole and methods of using the same
US8445474B2 (en) 2006-05-16 2013-05-21 Knopp Neurosciences, Inc. Compositions of R(+) and S(−) pramipexole and methods of using the same
US8524695B2 (en) 2006-12-14 2013-09-03 Knopp Neurosciences, Inc. Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same
EP2137171A4 (fr) * 2007-03-14 2010-05-19 Knopp Neurosciences Inc Synthèse de benzothiazole diamines substituées et purifiées du point de vue chiral
US8519148B2 (en) 2007-03-14 2013-08-27 Knopp Neurosciences, Inc. Synthesis of chirally purified substituted benzothiazole diamines
US10179774B2 (en) 2007-03-14 2019-01-15 Knopp Biosciences Llc Synthesis of chirally purified substituted benzothiazole diamines
US9849116B2 (en) 2008-08-19 2017-12-26 Knopp Biosciences Llc Compositions and methods of using (R)-pramipexole
US9512096B2 (en) 2011-12-22 2016-12-06 Knopp Biosciences, LLP Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US10208003B2 (en) 2011-12-22 2019-02-19 Knopp Biosciences Llc Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds
US9956206B2 (en) 2013-02-28 2018-05-01 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10285981B2 (en) 2013-02-28 2019-05-14 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US9662313B2 (en) 2013-02-28 2017-05-30 Knopp Biosciences Llc Compositions and methods for treating amyotrophic lateral sclerosis in responders
US10383856B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10828284B2 (en) 2013-07-12 2020-11-10 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US12138249B2 (en) 2013-07-12 2024-11-12 Areteia Therapeutics, Inc. Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US11612589B2 (en) 2013-07-12 2023-03-28 Areteia Therapeutics, Inc. Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US11026928B2 (en) 2013-07-12 2021-06-08 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US10980783B2 (en) 2013-07-12 2021-04-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US9468630B2 (en) 2013-07-12 2016-10-18 Knopp Biosciences Llc Compositions and methods for treating conditions related to increased eosinophils
US10383857B2 (en) 2013-07-12 2019-08-20 Knopp Biosciences Llc Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils
US10456381B2 (en) 2013-08-13 2019-10-29 Knopp Biosciences Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US10028940B2 (en) 2013-08-13 2018-07-24 Knopp Biosciences Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US9642840B2 (en) 2013-08-13 2017-05-09 Knopp Biosciences, Llc Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders
US10195183B2 (en) 2013-08-13 2019-02-05 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
US9763918B2 (en) 2013-08-13 2017-09-19 Knopp Biosciences Llc Compositions and methods for treating chronic urticaria
CN104496936A (zh) * 2015-01-07 2015-04-08 海南康虹医药科技开发有限公司 一种盐酸普拉克索的制备方法
CN109232471B (zh) * 2018-10-31 2022-05-10 安徽省庆云医药股份有限公司 一种盐酸普拉克索的制备方法
CN109232471A (zh) * 2018-10-31 2019-01-18 安徽省庆云医药股份有限公司 一种盐酸普拉克索的制备方法

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