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WO2006068617A1 - Nouveau procede de fabrication pour la preparation 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione a substitution halogene - Google Patents

Nouveau procede de fabrication pour la preparation 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione a substitution halogene Download PDF

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Publication number
WO2006068617A1
WO2006068617A1 PCT/SE2005/002019 SE2005002019W WO2006068617A1 WO 2006068617 A1 WO2006068617 A1 WO 2006068617A1 SE 2005002019 W SE2005002019 W SE 2005002019W WO 2006068617 A1 WO2006068617 A1 WO 2006068617A1
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WO
WIPO (PCT)
Prior art keywords
process according
group
acid
manufacturing
chloro
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/SE2005/002019
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English (en)
Inventor
Sahar Abbas
Stuart Norman Lile Bennett
Simon Nicholas Black
Catherine J. Brear
Louis Diorazio
Michael D. Golden
Ruth Kr Moyes
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AstraZeneca AB
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AstraZeneca AB
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Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2006068617A1 publication Critical patent/WO2006068617A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new process for the preparation of halogen substituted A- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5 , 10-tetrahydropyridaz ⁇ io[4,5-b] quinoline- 1,10- dione using a diacid intermediate.
  • the invention relates to new intermediates prepared therein suitable for manufacturing of halogen substituted 4-hydroxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10-dione and to the use of the intermediates for the manufacturing of a pharmaceutically active compound.
  • Halogen substituted 4-hydroxy-2-(2-chloro-4-methylphenyl)- 1,2,5,10- tetrahydropyridazino[4,5-b]quinoline-l,10-diones exhibit the property of binding to the NMDA receptor glycine site has a utility for the amelioration of pain and particularly for the amelioration of neuropathic pain. This is especially true for compound 7-chloro-4- hydroxy-2-(2-chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5- ⁇ ]quinoline- 1,10- dione.
  • halo is chloro, fluoro or bromo.
  • WO 95/11244 describes the synthesis of pyridazino quinoline compounds.
  • WO 01/47927 describes a method of preparation for compound 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5- ⁇ ]quinoline-l,10-dione.
  • This method employs an inefficient four stage synthesis from methyl-2-amino-4- chlorobenzoate to reach the key intermediate Acid Amide with an overall yield to this intermediate of only 17%.
  • WO 01/47927 also describes the conversion of the Acid Amide to the compound of 5 formula A in an inefficient two step process (via the isolated intermediate Acyl Hydrazide), and uses an expensive coupling reagent, CMC and an environmentally undesirable solvent DCM. Further the relative volumes used are large, yields are low (54% across the two stages) and the reaction time for the coupling in this prior art process are over 20 hours.
  • the present invention provides for a new process to 7-chloro-4-hydiOxy-2-(2-chloro-4- methylphenyl)-l,2,5,10-tetrahydropyridazino[4,5- ⁇ ]quinoline-l,10-dione . Further, it provides for new intermediates and a process to prepare-said intermediates, especially with regard to large-scale manufacturing.
  • Step 1 One embodiment of the invention relates to a process for the manufacturing of Diacid comprising steps Ia, Ib and Ic as described below;
  • DMAD Dimethyl acetylenedicarboxylate
  • MACB 2-amino-4- chlorobenzoate
  • DMAD is slowly added to an agitated solution of MACB in methanol.
  • the mixture is stirred to generate the intermediate Michael Adduct (1C).
  • the reaction mixture is cooled and aqueous KOH is cautiously added. After a solvent swap into water, the di-potassium salt of the Diacid is generated.
  • the batch is cooled and the reaction mixture is slowly added to an aqueous hydrochloric acid to liberate the Diacid as a solid.
  • the product is isolated by filtration, washed with water and dried under vacuum.
  • step Ib is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium t-butoxide and sodium methoxide.
  • step Ia is selected from the group consisting of methanol, ethanol, propanol, butanol, THF or acetonitrile.
  • step Ic is selected from the group consisting of hydrochloric acid, sulphuric acid or its salts, methanesulphonic acid, acetic acid, phosphoric acid or other suitable acids.
  • the reaction time on laboratory scale is approximately 10 hours (disregarding drying time of the solid product).
  • the yield of the Diacid process may be between 85 and 95 %.
  • One embodiment of the invention relates to a process for the manufacturing of Acid Amide (2C) comprising steps 2a and 2b as described below;
  • the Diacid is slurried with triethylamine in NMP. Acetic anhydride is added, followed by pyrrolidine. Water and aqueous hydrochloric acid are then added to precipitate the product, which is filtered and washed with aqueous NMP and then acetonitrile.
  • the base in step 2a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine.
  • the solvent is selected from the group comprising acetonitrile, N-methyl-2-pyrrolidinone (NMP) or toluene, DMF, sulpholane or DMSO.
  • the mixture is heated to a temperature up to about 80 0 C, preferably around 5O 0 C during the cyclisation and amide formation. In one embodiment the temperature is between 4O 0 C and 6O 0 C.
  • the reaction time on laboratory scale is approximately 6 hours (disregarding drying time of the solid product).
  • the yield of the Acid Amide process may be between 85 and 95 %.
  • step 2 is among others that in combination with step 1, that this provides a much more efficient processing route to the intermediate Acid Amide. Only two steps are required, the overall yield for the two steps is higher (>80%), processing times are much shorter and the two processes are more concenirated (allowing for greater batch sizes and less solvent waste).
  • One embodiment of the invention relates to a process for the manufacturing of compounds of formula A comprising steps 3 a and 3b as described below;
  • a mixture of Acid Amide (3A) and Boc Hydrazine (3B), toluene and N 1 N- diisopropylethylamine is concentrated to remove water.
  • Pivaloyl chloride is added, followed by acetonitrile and water.
  • the mixture is separated, and the organic phase is added to a solution of methanesulphonic acid in acetonitrile before solvent swapping into acetonitrile.
  • Water is added to crystallize the compound of formula A, which is washed with aqueous acetonitrile then IMS and dried under vacuum.
  • the organic solvent in step 3 a is selected from the group consisting of N-methylpyrrolidinone, heptane, cyclohexane, sulpholane, methyl isobutylketone, ethyl acetate, butyl acetate and isopropyl acetate, THF or mixtures thereof.
  • the base used in step 3 a is selected from the group consisting of triethylamine, pyridine, N-methylmorpholine, tripropylamine diisopropylethylamine, pyridine, tributylamine and N-methyl-piperidine
  • the temperature of the solution during the pivaloyl chloride addition in step 3a is approximately 70 0 C.
  • the coupling product mixture is added to a solution of acid (instead of the other way round), which provides for a cleaner reaction profile (step 3b).
  • the precipitation of the product in step 3b is from aqueous acetonitrile at 5O 0 C.
  • the cyclisation solvent is selected from a group comprising of acetonitrile, toluene, THF, heptane, and cyclohexane.
  • Advantages of step 3 is the use of a much cheaper coupling agent (pivaloyl chloride), non- isolation of the Acyl Hydrazide intermediate and an improvement in yield (to >65% in a single step). Processing time (from Acid Amide to compound of formula A) is reduced and the process is more concentrated. The need for an environmentally undesirable solvent (DCM) is eliminated and less solvent waste is generated overall.
  • DCM environmentally undesirable solvent
  • halo is fluoro, chloro or bromo.
  • Another embodiment of the invention related to diacid wherein halo is chloride.
  • a further embodiment of the invention relates to intermediate 3Db
  • One embodiment of the invention relates to the use of the compounds IA to ID, Diacid, 2B to 2C and 3A to 3D as defined above, as intermediates for the manufacturing of compounds of formula A, especially for the manufacturing of 7-chloro-4-hydroxy-2-(2- chloro-4-methylphenyl)- 1 ,2,5, 10-tetrahydropyridazino[4,5-b]quinoline-l , 10-dione.
  • Another embodiment of the invention related to the use of the process as defined above for the large scale manufacturing of compounds of formula A.
  • One embodiment of the invention relates to the use of the compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, as intermediates for the manufacturing of a pharmaceutically active compound.
  • Another embodiment of the invention relates to the use of the intermediate compounds IA to ID, 2A to 2C and 3 A to 3Db as defined above, prepared according to the process described above under step 1, 2 and 3, for the manufacturing of a medicament for the treatment of pain.
  • Acid Amide (50.0Og 5 0.1559 mol), BOC Hydrazine (4Og, 0.1559 mol), N, N- diisopropylethylamine (81.5 ml, 0.4677 mol) and toluene (500ml) were mixed together and distilled at 250mbar to remove 100ml of solvent. The temperature of the dry solution was then adjusted to 70 0 C and pivaloyl chloride (43.2ml, 0.3508 mol) was slowly added under nitrogen. The reaction mixture was held at 70 0 C for two hours before adding acetonitrile (150ml) and water (250ml).
  • the resulting two-phase mixture was separated at 5O 0 C and the upper organic layer then added slowly to a solution of methanesulphonic acid (50.6ml, 0.7795mols) in acetonitrile (250ml) maintaining 40 0 C.
  • the reaction mixture was then distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (550ml).
  • the reaction mixture was again distilled at 250mbar to remove 550ml of solvent before adding acetonitrile (350ml).
  • the temperature of the reaction mixture was adjusted to 50 0 C the,n water (200ml) was slowly added to precipitate the product.
  • the product slurry was filtered at 50 0 C, washed with aqueous acetonitrile (1:1, 2 x 100ml), then IMS (2 x 100ml) and dried at 50 0 C ( ⁇ 250mbar) to afford the product as a solid (44.5g, 93.4%w/w, 0.1071 mol, 68.6%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de 4-hydroxy-2-(2-chloro-4-méthylphényl)-1,2,5,10-tétrahydropyridazino[4,5-b]quinoline-1,10-dione à substitution halogène utilisant un intermédiaire diacide. L'invention concerne également de nouveaux intermédiaires préparés et convenant à la fabrication de 4-hydroxy-2-(2-chloro-4-méthylphényl)-1,2,5,10-tétrahydropyridazino[4,5-b]quinoline-1,10-dione à substitution halogène ainsi que l'utilisation de ces intermédiaires pour fabriquer un composé pharmaceutiquement actif.
PCT/SE2005/002019 2004-12-23 2005-12-22 Nouveau procede de fabrication pour la preparation 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione a substitution halogene Ceased WO2006068617A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0403172A SE0403172D0 (sv) 2004-12-23 2004-12-23 Manufacturing process
SE0403172-0 2004-12-23

Publications (1)

Publication Number Publication Date
WO2006068617A1 true WO2006068617A1 (fr) 2006-06-29

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PCT/SE2005/002019 Ceased WO2006068617A1 (fr) 2004-12-23 2005-12-22 Nouveau procede de fabrication pour la preparation 4-hydroxy-2-(2-chloro-4-methylphenyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione a substitution halogene

Country Status (2)

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SE (1) SE0403172D0 (fr)
WO (1) WO2006068617A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047524A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Methode et composition pour traiter la douleur
WO2001047927A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Compose et procede de traitement de la douleur
WO2001047923A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et procedes de traitement de la douleur
WO2001047523A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Methode et composition de traitement de la douleur
WO2001047926A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et methodes de traitement de la douleur
WO2001047924A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Procedes et compositions pour le traitement de la douleur

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047524A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Methode et composition pour traiter la douleur
WO2001047927A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Compose et procede de traitement de la douleur
WO2001047923A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et procedes de traitement de la douleur
WO2001047523A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Methode et composition de traitement de la douleur
WO2001047926A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Composes et methodes de traitement de la douleur
WO2001047924A1 (fr) * 1999-12-23 2001-07-05 Astrazeneca Ab Procedes et compositions pour le traitement de la douleur

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BARE T.M.: "Pyridazino[4,5-b]quinolinediones: Novel Glycine/N-Methyl-D-asparate Antagonists for the Treatment of Stroke", J. HETEROCYCLIC CHEM., vol. 35, 1998, pages 1171 - 1186, XP002905994, DOI: doi:10.1002/jhet.5570350513 *
BIERE H. ET AL.: "Verfahren zur Darstellung von 4-Oxo-1,4-dihydropyridincarbonsäurederivaten", LIEBIGS ANN. CHEM., vol. 11, 1976, pages 1972 - 1981 *
BRENK R. ET AL.: "From Hit to Lead: De Novo Design Based on Virtual Screening Hits of Inhibitors of tRNA-Guanine Transglycosylase, a Putative Target of Shigellosis Therapy", HELVETICA CHIMICA ACTA, vol. 86, 2003, pages 1435 - 1452 *
LIU KANG-CHIEN ET AL.: "Potential Antiallergic Agents II. Synthesis and Biological Evaluation of 4(1H)-Quinolone-2,3-dicarboxylic Acid Derivatives1", JOURNAL OF THE TAIWAN PHARMACEUTICAL ASSOCIATION, vol. 35, no. 1, 1983, pages 46 - 56 *
TAYLOR E.C.: "Cyclizations of Anthranilate-Acetylenedicarboxylate Adducts. A Facile Route to 2,8-Dicarboalkoxy-4(IH)-quinolinones1", J. ORG. CHEM., vol. 32, 1967, pages 3339 - 3343 *

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