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WO2009153649A1 - Procédé de préparation de composés de pyrrolidine substitués en position 3 - Google Patents

Procédé de préparation de composés de pyrrolidine substitués en position 3 Download PDF

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Publication number
WO2009153649A1
WO2009153649A1 PCT/IB2009/005990 IB2009005990W WO2009153649A1 WO 2009153649 A1 WO2009153649 A1 WO 2009153649A1 IB 2009005990 W IB2009005990 W IB 2009005990W WO 2009153649 A1 WO2009153649 A1 WO 2009153649A1
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Prior art keywords
compound
formula
vii
reacting
organic solvent
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Ceased
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PCT/IB2009/005990
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English (en)
Inventor
Nuria Soldevilla Madrid
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Medichem SA
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Medichem SA
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Publication of WO2009153649A1 publication Critical patent/WO2009153649A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • Darifenacin is an active pharmaceutical substance indicated for the treatment of overactive bladder with symptoms of urge, urinary incontinence, urgency and frequency.
  • Darifenacin is the international common accepted name for (S)-2- ⁇ -[2-(2,3- dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl ⁇ -2,2-diphenylacetamide hydrobromide, having an empirical formula Of C 28 H 30 N 2 O 2 -HBr and the structure of formula (I) below:
  • this process has significant drawbacks in that it comprises the cumbersome and hazardous Mitsunobu reaction of enantiopure l-tosyl-3-(/?)-pyrrolidinol (compound of formula IV) in order to obtain the (5)-enantiomer of the 3 -substituted pyrrolidine compounds of formula (VII) or salts thereof. More particularly, compound (IV) is reacted with methyl tosylate, triphenylphosphine, and diethylazodicarboxylate (DEAD), a very toxic and dangerous reagent. Typically, the product is contaminated with triphenylphosphine oxide, which is very difficult to separate from the desired product.
  • the present invention provides an improved process for preparing 3 -substituted pyrrolidine compounds or salts thereof, as intermediate compounds useful for the synthesis of 1,3-disubstituted pyrrolidine compounds (e.g., (S)-2- ⁇ l-[2-(2,3-dihydrobenzofuran-5- yl)ethyl]-3-pyrrolidinyl ⁇ -2,2-diphenylacetamide hydrobromide, that is, darifenacin hydrobromide).
  • the present invention further provides a process for preparing darifenacin, and pharmaceutically acceptable salts thereof, using 3-substituted pyrrolidine compounds prepared according to a process of the invention.
  • Processes in accordance with the invention have one or more of the following advantages: avoid the hazardous Mitsunobu reaction, reduces the use of toxic and dangerous reagents, makes use of low-priced and easily available starting compounds, and hence are cost-effective and suitable for the preparation of darifenacin on a large scale.
  • the invention provides a process for preparing a compound of formula (S)-(VH):
  • a process for preparing a compound of formula (S)-(VU) comprises i) reacting (5)-malic acid of formula (S)-(VIII): with a compound of formula (XIV):
  • a process of the invention comprises ii) optionally, isolating a compound of formula (IX).
  • a process for preparing a compound of formula (S)-(VII) comprises iii) reacting compound of a formula (IX) with a carbonyl reducing agent, in a second organic solvent, to obtain a compound of formula (X):
  • a process of the invention comprises iv) optionally, isolating a compound of formula (X).
  • a process for preparing a compound of formula (S)-(VII) comprises v) converting the hydroxyl group of compound of formula (X) into a leaving group by reacting a compound of formula (X) with an oxygen activating agent, in a third organic solvent, and a base, to obtain a compound of formula (XI):
  • a process of the invention comprises vi) optionally, isolating a compound of formula (XI).
  • a process for preparing a compound of formula (S)-(VH) comprises vii) reacting a compound of formula (XI) with a compound of formula (XV):
  • a process of the invention comprises viii) optionally, isolating a compound of formula (XII).
  • a process for preparing a compound of formula (S)-(VII) comprises ix) removing the nitrogen protecting group Q of compound of formula (XII), to obtain a compound of formula (S)-(VII).
  • a process of the invention comprises x) optionally, if R 1 is
  • a process of the invention comprises xi) optionally, isolating a compound of formula (S)-(VII).
  • illustrative nitrogen protecting groups suitable in a process of the invention are arylalkyl and sulfonyl, e.g., arylsulfonyl groups.
  • the nitrogen protecting group, Q is selected from the group consisting of benzyl, j5-toulenesulfonyl (tosyl), and/?-nitrobenzenesulfonyl (nosyl).
  • the reaction of (S)-malic acid of formula (S)-(VIII) with a compound of formula (XIV) further comprises a non-oxidizing acid in catalytic amounts.
  • the non-oxidizing acid is an aryl sulfonic acid, such as, for example, /?-toluenesulfonic acid.
  • illustrative solvents suitable as a first organic solvent in step i) of processes of the invention include one or more aromatic hydrocarbons.
  • the first organic solvent comprises a xylene.
  • illustrative reducing agents suitable as a carbonyl reducing agent in processes of the invention include any suitable reducing agent capable of reducing the carbonyl groups of a compound of formula (IX) in step iii) to obtain a compound of formula (X) such as, for example, a hydride.
  • a suitable reducing agent capable of reducing the carbonyl groups of a compound of formula (IX) in step iii) to obtain a compound of formula (X) such as, for example, a hydride.
  • the hydride is provided by a metal hydride agent such as, for example, lithium aluminium hydride.
  • illustrative solvents suitable as a second organic solvent in step iii) of processes of the invention include polar, aprotic ether solvents.
  • the second organic solvent comprises tetrahydrofuran.
  • illustrative oxygen activating agents suitable for step v) in processes of the invention include any suitable oxygen activating agent capable of converting the hydroxyl group of a compound of formula (X) into a leaving group.
  • the oxygen activating agent is a sulfonyl compound, more preferably the oxygen activating agent is a/?-toluenesulfonyl chloride.
  • illustrative solvents suitable as a third organic solvent in step v) of processes of the invention include one or more aromatic heterocyclic solvents.
  • the third organic solvent comprises pyridine.
  • illustrative bases suitable in step v) of processes of the invention include any base capable of catalyzing the reaction of a compound of formula (X) with an oxygen activating agent.
  • the solvent and base of step v) of processes of the invention are the same and comprise pyridine.
  • illustrative bases suitable in step vii) of processes of the invention are any bases capable of catalyzing the reaction of a compound of formula (XI) with a compound of formula (XV) to obtain a compound of formula (XII).
  • the base of step vii) is selected from the group consisting of an alkali metal hydride, an alkali metal hydroxide, and an alkaline-earth metal hydroxide, more preferably the base of step vii) is sodium hydride.
  • illustrative solvents suitable as a fourth organic solvent in step vii) of processes of the invention include one or more aromatic hydrocarbon solvents.
  • the fourth solvent comprises toluene.
  • processes of the invention comprise removing a nitrogen protecting group Q of a compound of formula (XII) to obtain a compound of formula (.S)-(VII).
  • the nitrogen protecting group Q is benzyl
  • Q is removed by hydrogenating a compound of formula (XII) with a hydrogen donor compound in the presence of palladium on carbon catalyst and in an alcohol solvent.
  • illustrative hydrogen donor compounds suitable for processes of the invention include formate salts.
  • the hydrogen donor compound is ammonium formate.
  • Q is removed by reacting a compound of formula (XII) with a concentrated acid and a reducing agent.
  • the nitrogen protecting group Q is nosyl
  • Q is removed by reacting a compound of formula (XII) with samarium iodide or tributyltin hydride, a concentrated acid, and a reducing agent.
  • R 1 of a compound of formula (S)-(VII) is converted from
  • illustrative hydrolyzing agents of step x) of processes of the invention include any suitable hydrolyzing agent capable of converting a -CN of a compound of formula (S)-(VII) to a -CONH 2 .
  • the hydrolyzing agent is aqueous acid such as aqueous sulphuric acid.
  • processes of the invention further comprise preparing a salt of compound of formula (S)-(VII).
  • the salt of compound of formula (S)-(VII) is the L-tartrate salt of compound of formula (S)-(VII).
  • L-tartrate salt of compound of formula (S)-(VII) is prepared by reacting a compound of formula (S)-(VII) with L-tartaric acid in an alcohol solvent.
  • the present invention provides an improved process for the preparation of 3 -substituted pyrrolidine compounds of formula (VII) (e.g., a compound of formula (S)-(VIIa) and a compound of formula (S)-(VIIb) or salts thereof according to Scheme 3.
  • VI 3 -substituted pyrrolidine compounds of formula (VII)
  • racemic malic acid the racemic 3 -substituted pyrrolidine (VII) or salts thereof will be obtained.
  • the present invention provides a process for preparing darifenacin, or pharmaceutically acceptable salts thereof, using a compound of formula (VII), or a salt thereof, which has been prepared in accordance with a process of the invention.
  • the L-(+)-tartrate salt of (S)-(VIIb) obtained according to the process of the invention is used for preparing darifenacin or a pharmaceutically acceptable salt thereof.
  • the process for preparing darifenacin can be any suitable process for preparing darifenacin or a pharmaceutically acceptable salt thereof from a compound of formula (VII).
  • the invention provides an improved process for preparing darifenacin or a pharmaceutically acceptable salt thereof, comprising a) reacting the compound of formula (iS)-(VII), or a salt thereof, with a compound of formula (XIII): wherein Z is a leaving group, in the presence of an organic solvent and with a base, to obtain a compound of formula (XVI):
  • Suitable leaving groups, Z, of processes of the invention include, for example, halogens and sulfonate esters.
  • Illustrative halogen leaving groups are fluoride, chloride, bromide, and iodide.
  • Illustrative sulfonate esters leaving groups are methanesulfonate or mesylate, j7-toluenesulfonate or tosylate, /7-nitrobenzenesulfonate or nosylate, and p-bromobenzenesulfonate or brosylate.
  • the leaving group is bromide.
  • R 1 of a compound of formula (XVI) is -CONH 2 (i.e., a compound of formula (XVI) is darifenacin base).
  • R 1 of a compound of formula (XVI) is -CN.
  • a compound of formula (XVI) is reacted with a hydrolyzing agent to convert the -CN to -CONH 2 , thereby obtaining darifenacin base.
  • the hydrolyzing agent is aqueous sulphuric acid.
  • darifenacin base is converted to a pharmaceutically acceptable salt.
  • darifenacin base is reacted with hydrogen bromide to obtain darifenacin hydrobromide of formula (I).
  • the compound of formula (S)-(VU), or a salt thereof is the L-(+)-tartrate salt of (S)-(VII) wherein R 1 is -CONH 2 (i.e., a compound of formula
  • the present invention provides a pharmaceutical composition comprising darifenacin obtained according to the process of the invention.
  • Example 1 Preparation of (3S)-./V-benzyl-3-hydroxysuccinimide (i.e., a compound of formula (IX)).
  • Example 2 Preparation of (35)-N-benzyl-3-hydroxypyrrolidine (i.e., compound of formula (X)).
  • This example demonstrates a process for preparing a compound of formula (X) in accordance with an embodiment of the invention.
  • Example 3 Preparation of (35)-N-benzyl-3-hydroxysuccinimide (i.e., compound of formula (IX)).
  • Example 4 Preparation of (35)-N-benzyl-3-hydroxypyrrolidine (i.e., compound of formula (X)).
  • Example 5 Preparation of (3iS)-7V-benzyl-3-tosylpyrrolidine (i.e., compound of formula (XI)).
  • Example 6 Preparation of 2,2-diphenyl-2-[(35)-N-benzyl-pyrrolidin-3- yl]acetonitrile (i.e., compound of formula (XII)).
  • This example demonstrates a process for preparing a compound of formula (XII) in accordance with an embodiment of the invention.
  • Example 7 Preparation of 2,2-diphenyl-2-[(3S)-pyrrolidin-3-yl]acetonitrile (i.e., compound of formula ( ⁇ !?)-(VIIa)).
  • Example 8 Preparation of 2,2-diphenyl-2-[(55)-pyrrolidin-3-yl]acetamide (i.e., compound of formula (S)-(VIIb)).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de composés pyrrolidine substitués en position 3 de formule (VII) ou des sels de ceux-ci, dans laquelle R1 est tel que défini dans la description, qui sont des composés intermédiaires utiles pour la synthèse de la darifénacine qui est recommandée pour le traitement de la vessie hyperactive avec symptômes d’incontinence urinaire par impériosité et analogue, et des sels pharmaceutiquement acceptables de ceux-ci. L’invention concerne également un procédé de préparation de darifénacine et des sels pharmaceutiquement acceptables de celle-ci.
PCT/IB2009/005990 2008-06-19 2009-06-19 Procédé de préparation de composés de pyrrolidine substitués en position 3 Ceased WO2009153649A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7400008P 2008-06-19 2008-06-19
US61/074,000 2008-06-19

Publications (1)

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WO2009153649A1 true WO2009153649A1 (fr) 2009-12-23

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PCT/IB2009/005990 Ceased WO2009153649A1 (fr) 2008-06-19 2009-06-19 Procédé de préparation de composés de pyrrolidine substitués en position 3

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0692471A1 (fr) * 1994-07-15 1996-01-17 Degussa Aktiengesellschaft Procédé pour la préparation de dérivés de 3-hydroxypyrrolidine optiquement actifs à haute pureté enantiomerique
WO2004041806A2 (fr) * 2002-10-30 2004-05-21 Theravance, Inc. 4-amino-1-(pyridylmethyl) piperidine substituee et composes associes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0692471A1 (fr) * 1994-07-15 1996-01-17 Degussa Aktiengesellschaft Procédé pour la préparation de dérivés de 3-hydroxypyrrolidine optiquement actifs à haute pureté enantiomerique
WO2004041806A2 (fr) * 2002-10-30 2004-05-21 Theravance, Inc. 4-amino-1-(pyridylmethyl) piperidine substituee et composes associes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOCALKA P ET AL: "Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 62, no. 24, 12 June 2006 (2006-06-12), pages 5763 - 5774, XP025002048, ISSN: 0040-4020, [retrieved on 20060612] *

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