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WO2009063170A1 - Préparation de rotigotine à base cristalline - Google Patents

Préparation de rotigotine à base cristalline Download PDF

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Publication number
WO2009063170A1
WO2009063170A1 PCT/GB2008/003729 GB2008003729W WO2009063170A1 WO 2009063170 A1 WO2009063170 A1 WO 2009063170A1 GB 2008003729 W GB2008003729 W GB 2008003729W WO 2009063170 A1 WO2009063170 A1 WO 2009063170A1
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WO
WIPO (PCT)
Prior art keywords
rotigotine
base
acetone
group
rotigotine base
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2008/003729
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English (en)
Inventor
Amir Avdagic
Ivica Grebenar
Marina Markovic
Dubravka Pavlicic
Zvonimir Siljkovic
Mihaela Tuksar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pliva Hrvatska doo
Original Assignee
Pliva Hrvatska doo
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 Pliva Hrvatska doo filed Critical Pliva Hrvatska doo
Publication of WO2009063170A1 publication Critical patent/WO2009063170A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to new processes for preparing rotigotine as a free base in solid crystalline form.
  • Aminotetralins constitute an important class of biologically active compounds.
  • aminotetralin drug rotigotine ((S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)- 5,6,7,8-tetrahydronaphthalen-l-ol) is a non-ergot (or non-ergotamine) dopamine D2 agonist and is used for the treatment of Parkinson's disease and restless legs syndrome.
  • Rotigotine has been reported in at least two forms.
  • U.S. Patent No. 6,884,434 describes the HCl salt and the free base ("rotigotine base").
  • This patent also describes a pharmaceutical formulation of rotigotine in the form of a transdermal therapeutic system (transdermal patch) comprising an adhesive matrix layer containing rotigotine in an amount effective for the treatment of the symptoms of Parkinson's disease.
  • the present invention provides new processes of preparing solid crystalline rotigotine base (rotigotine base) having superior chemical and enantiomeric purity.
  • the processes include neutralizing rotigotine heminaphthalene-1,5- disulfonate to give rotigotine base and crystallizing rotigotine base from a solvent, selected from the group consisting of an alcohol, ketone, alkane, chlorinated alkane, ether, and combinations of any two or more thereof.
  • the rotigotine naphthalene-1 ,5-disulfonate can be neutralized by contacting it with at least one suitable base such as an alkali metal hydroxide and/or a carbonate.
  • suitable bases include NaOH, KOH, sodium carbonate, and potassium carbonate.
  • suitable alcohols for use in the methods herein include methanol, ethanol, and isopropanol.
  • Suitable ketones for use in the methods herein include acetone, methyl ethyl ketone, cyclohexanone and 3-pentanone.
  • Chlorinated alkanes suitable for use in the methods described herein include dichloromethane and chloroform.
  • Suitable ethers for use in inventive methods include diethyl ether and diisopropyl ether.
  • a combination solvents may be used such as a ketone and an alkane. Exemplary combinations include acetone with heptane and acetone with cyclohexane.
  • FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline rotigotine base.
  • FIG. 2 is an infrared (IR) spectrum of a polymorph of crystalline rotigotine base.
  • FIG. 3. is a differential scanning calorimetry (DSC) thermogram of a polymorph of crystalline rotigotine base.
  • FIG. 4. is a thermogravimetric (TG) thermogram of crystalline rotigotine base.
  • Processes for the preparation of N,N-disubstituted aminotetralins, specifically, for the preparation of enantiomerically enriched or enantiomerically pure rotigotine base are provided herein.
  • the processes include the step of:
  • each R is independently selected from hydrogen or a methyl group.
  • the reaction may be performed without added base because Formula (I) serves as both the reactant and the base at the same time.
  • the compound of Formula (II) can be 2-(2-thienyl)ethanol benzenesulfonate or 2-(2-thienyl)ethanol toluenesulfonate.
  • the reaction is typically carried out in an organic solvent, heated to a temperature of from about 60 0 C to about 120 0 C, and preferably from about 80 0 C to about 110 0 C. Suitable solvents that may be heated to such temperatures include but are not limited to isopropyl acetate, isobutyl acetate, isoamyl acetate, toluene and xylene.
  • the amount of the compound of Formula (II) is present at about 1 to about a 2.5-fold molar excess, preferably from about a 1.2 to about a 2.0-fold molar excess with respect to the amount the compound of Formula (I).
  • the present processes may further comprise the following step: b) filtering the reaction mixture to isolate the precipitate comprising the salt having Formula (III).
  • the filtrate will therefore comprise the product, the compound of Formula (IV).
  • the present processes may further comprise the following step: c) contacting the salt having Formula (III) with a suitable base to convert it to the compound of Formula (II).
  • suitable bases include, e.g., alkali metal hydroxides, carbonates, and the like.
  • 10% aqueous NaOH may be used to neutralize the salt and allow the compound of Formula (II) to be extracted into an organic solvent such as dichloromethane or the like.
  • the present processes may further comprise the following step: d) treating the filtrate containing the compound of Formula (IV) with 1,5-naphthalenedisulfonic acid or its hydrates, to give the enantiomerically enriched or enantiomerically pure salt having Formula (V),
  • the salt having Formula (V) is a useful intermediate in the synthesis allowing ready purification of the N,N-disubstituted aminotetralin by crystallization, and avoiding the use of chromatography. Treatment of the filtrate is optionally conducted with the addition of an organic solvent, such as acetone, methanol, isopropanol, or the like. Optionally, the salt having Formula (V) is recrystallized.
  • the processes for preparing N,N-disubstituted aminotetralins as the free base may further include the following step: e) contacting the salt of Formula (V) with a suitable base to provide the enantiomerically enriched or enantiomerically pure compound of Formula (IV).
  • suitable bases for salt neutralization are well known in the art and include for example, alkali metal hydroxides and carbonates. When R is H, rotigotine base is produced.
  • enantiomerically enriched it is meant that the enantiomeric excess (ee) is greater than 80%. In some embodiments greater than 90% or greater than 95%.
  • enantiomerically pure it is meant that the enantiomeric excess (ee) is greater than 98%, ideally greater than 99% and ideally enantiomerically pure means greater than 99.5%.
  • Rotigotine base produced by the processes disclosed herein may be crystallized from a variety of solvent or solvent combinations including alcohols, ketones, alkanes, chlorinated alkanes, ethers, and combinations of any two or more thereof.
  • Suitable solvents include methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, cyclohexanone, 3- pentanone, dichloromethane, chloroform, diethyl ether and diisopropyl ether.
  • Suitable combinations of solvents that may be used to crystallize rotigotine base include ketones and alkanes, such as acetone with heptane or acetone with cyclohexane.
  • Crystalline rotigotine base was characterized by XRPD, IR, DSC and TG analysis.
  • XRPD was carried out as described in Example 4 and provided the diffractogram shown in FIG. 1. Characteristic diffraction peaks were observed at °2 ⁇ : 10.8, 14.7, 15.3, 15.6, 16.7, 20.3 and 11.3, 12.7, 13.2 17.1, 18.2, and 19.7.
  • FIG. 2 shows a typical IR spectrum of rotigotine base. In the IR spectrum characteristic bands are observed as shown in Table 1.
  • a typical DSC thermogram of rotigotine base is shown in FIG. 3.
  • the observed melting point is 76 0 C ⁇ 2 0 C.
  • FIG. 4 A typical TG thermogram of rotigotine base is shown in FIG. 4.
  • Crystalline rotigotine base was prepared by crystallization of (S)-6-(propyl(2- thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-l-ol from single solvents, including dichloromethane, diisopropyl ether and ethanol. Crystalline rotigotine base was also prepared by crystallization from solvent/antisolvent mixtures, including acetone/cyclohexane and acetone/heptane.
  • Example 3A 20 mg of rotigotine prepared according to Example 2 was dissolved in 1 ml of dichloromethane. Prepared solution was filtered and left at room temperature in N 2 atmosphere to evaporate and crystallize. Crystals of rotigotine base were obtained.
  • Example 3B 20 mg of rotigotine according to Example 2 was dissolved in 1 ml of diisopropyl ether. The resulting solution was filtered and left at room temperature under nitrogen atmosphere to evaporate and crystallize. Crystals of rotigotine base were obtained.
  • Example 3C 20 mg of rotigotine according to Example 2 was dissolved in 1 ml of ethanol. The resulting solution was filtered and left at room temperature under nitrogen atmosphere to evaporate and crystallize. Crystals of rotigotine base were obtained.
  • Example 3D lOO mg of rotigotine according to Example 2 was dissolved in
  • Example 3E 150 mg of rotigotine according to Example 2 was dissolved in
  • Example 4 X-ray Powder Diffraction [0034] X-ray powder diffraction analysis of rotigotine base was performed according to the experimental parameters detailed in Table 2 on Philips X'Pert PRO diffractometer using CuK ⁇ l radiation.
  • the DSC thermogram of rotigotine base is shown in FIG. 3, and was measured on a Q 1000 MDSC TA instrument under a dynamic flow of nitrogen (50 ml/min) and a heating rate of 10 C/min. A standard closed aluminum pan was used.
  • thermogram Thermogravimetric analysis was performed on a TGA 2950 TA Instrument, under dynamic flow of nitrogen (60 ml/min) and a heating rate of 10 °C/min. The resulting thermogram is shown in FIG. 4.
  • a range includes each individual member.
  • a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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 des procédés de préparation de rotigotine à partir de son sel d'héminaphtalène-1,5-disulfonate sous la forme d'une base libre sous une forme cristalline solide.
PCT/GB2008/003729 2007-11-16 2008-11-05 Préparation de rotigotine à base cristalline Ceased WO2009063170A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98858007P 2007-11-16 2007-11-16
US60/988,580 2007-11-16

Publications (1)

Publication Number Publication Date
WO2009063170A1 true WO2009063170A1 (fr) 2009-05-22

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PCT/GB2008/003729 Ceased WO2009063170A1 (fr) 2007-11-16 2008-11-05 Préparation de rotigotine à base cristalline

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2170323A2 (fr) 2007-05-30 2010-04-07 Chemagis Ltd. Base de rotigotine cristalline et son procédé de préparation
EP2215072B1 (fr) 2007-11-28 2015-09-02 UCB Pharma GmbH Forme polymorphique de rotigotine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4564628A (en) * 1983-01-03 1986-01-14 Nelson Research & Development Co. Substituted 2-aminotetralins
WO2002015903A2 (fr) * 2000-08-24 2002-02-28 Schwarz Pharma Ag Nouvelle composition pharmaceutique permettant l'administration de n-0923

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4564628A (en) * 1983-01-03 1986-01-14 Nelson Research & Development Co. Substituted 2-aminotetralins
WO2002015903A2 (fr) * 2000-08-24 2002-02-28 Schwarz Pharma Ag Nouvelle composition pharmaceutique permettant l'administration de n-0923

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HORN A S ET AL: "Synthesis and radioreceptor binding activity of N-0437, a new, extremely potent and selective D2 dopamine receptor agonist", PHARMACEUTISCH WEEKBLAD SCIENTIFIC EDITION, BOHN, SCHELTEMA AND HOLKEMA, AMSTERDAM, NL, vol. 7, no. 5, 1 October 1985 (1985-10-01), pages 208 - 211, XP008091164, ISSN: 0167-6555 *
TIMMERMAN W ET AL: "Microdialysis and striatal dopamine release: stereoselective actions of the enantiomers of N-0437", EUROPEAN JOURNAL OF PHARMACOLOGY, ELSEVIER BV, NL, vol. 162, no. 1, 1 January 1989 (1989-01-01), pages 143 - 150, XP002325505, ISSN: 0014-2999 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2170323A2 (fr) 2007-05-30 2010-04-07 Chemagis Ltd. Base de rotigotine cristalline et son procédé de préparation
EP2215072B1 (fr) 2007-11-28 2015-09-02 UCB Pharma GmbH Forme polymorphique de rotigotine

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