WO2015150887A1 - Process for the preparation of anagliptin or its salts - Google Patents

Process for the preparation of anagliptin or its salts Download PDF

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Publication number
WO2015150887A1
WO2015150887A1 PCT/IB2014/066940 IB2014066940W WO2015150887A1 WO 2015150887 A1 WO2015150887 A1 WO 2015150887A1 IB 2014066940 W IB2014066940 W IB 2014066940W WO 2015150887 A1 WO2015150887 A1 WO 2015150887A1
Authority
WO
WIPO (PCT)
Prior art keywords
anagliptin
formula
solvent
pyrimidine
methylpyrazolo
Prior art date
Application number
PCT/IB2014/066940
Other languages
English (en)
French (fr)
Inventor
Naveen Reddy
Damodara NAIDU
Pramodkumar SHARMA
Bhatraju Srinivasa RAO
Keshav Deo
Original Assignee
Wockhardt Limited
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 Limited filed Critical Wockhardt Limited
Publication of WO2015150887A1 publication Critical patent/WO2015150887A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention direct to a process for the preparation of Anagliptin or its pharmaceutically acceptable salts and intermediates.
  • present invention provides an industrially advantageous process for the preparation of Anagliptin.
  • the drug compound having the adopted name "Anagliptin” has chemical name,N-[2-( ⁇ 2- [(2S)-2-Cyanopyrrolidin-l-yl]-2-oxoethyl ⁇ amino)-2-methylpropyl]-2-methylpyrazolo
  • the pharmaceutical product Suini® tablets contain Anagliptin as active ingredient.
  • Anagliptin is a DPP-4 (dipeptidyl peptidase-4) inhibitor useful for the treatment of diabetes.
  • US Patent No. 7,345, 180 describes Anagliptin and process for the preparation thereof.
  • the process of US' 180 involves reaction of 2-methylpyrazolo [1, 5-a] pyrimidin-6-yl with (S)-l-(2'-Chloroacetyl) pyrrolidine-2-carbonitrile in presence of potassium carbonate and sodium iodide in acetone for a period of 8 hours at room temperature.
  • the present invention provides a economically viable industrial eco-friendly process for the preparation of Anagliptin or its pharmaceutically acceptable salts thereof
  • the process includes steps of:
  • catalyst includes metal halides like potassium iodide, sodium bromide, sodium iodide and the like.
  • suitable organic solvent includes a mixture of one or more halogenated solvent and ethers, where the preferred solvent is a halogenated solvent.
  • organic solvent includes halogenated solvent.
  • the intermediates and starting materials of the present invention may be used as free bases.
  • the process includes steps of:
  • the reaction between 2-methylpyrazolo[l,5-a] pyrimidine-6-carboxylic acid and ⁇ , ⁇ '- carbonyldiimidazole may be carried out in an inert atmosphere at a temperature in the range of 20°C to 40°C.
  • the solvent may be selected from a suitable organic solvent.
  • the suitable organic solvent may be a mixture of one or more halogenated solvent and ethers.
  • the halogenated solvent may be selected from dichloromethane, dichloroethane, chloroform, chlorobenzene and the like.
  • the ether solvent may be selected from dimethyl ether, diethyl ether, dioxane and the like.
  • the obtained 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid-N,N'-carbonyl diimidazole mixture may be added to 2-methyl- 1 ,2-propane diamine at a temperature range of -10°C to 10°C. After completion of reaction, water may be added and N-(2- amino-2-methylpropyl)2-methylpyrazolo[ 1 ,5-a]pyrimidine-6-carboxamide may be isolated from the reaction mixture.
  • l-(2-chloroacetyl)-2S-pyrrolidine carbonitrile may be added to N-(2-amino-2-methylpropyl)2-methylpyrazolo[l,5-a]pyrimidine-6-carboxamide at the temperature in the range of 20°C to 30°C in an organic solvent.
  • the organic solvent may be halogenated solvent.
  • the halogenated solvent is selected from dichlorome thane, dichloroethane, chloroform, chlorobenzene and the like.
  • Anagliptin After completion of reaction, water may be added and crude Anagliptin may be isolated from the organic solvent.
  • the isolation process involves the removal of solvent under reduced pressure, plain distillation at atmospheric pressure or addition of anti-solvent in the solution or syrupy mass of Anagliptin.
  • the Anti-solvent is the solvents in which the Anagliptin is insoluble or has low solubility and it is sufficient enough to precipitate the Anagliptin.
  • the condensation reaction may be conducted in the presence of an organic base, which includes but is not limited to triethylamine, 4-dimethylaminopyridine, diisopropylamine and the like and in the presence of a catalyst, which includes, but is not limited to sodium iodide, potassium iodide and sodium bromide.
  • an organic base which includes but is not limited to triethylamine, 4-dimethylaminopyridine, diisopropylamine and the like
  • a catalyst which includes, but is not limited to sodium iodide, potassium iodide and sodium bromide.
  • the crude Anagliptin may be purified using solvents like esters for example isopropyl acetate.
  • the crude Anagliptin may be purified by dissolving in isopropyl acetate.
  • the purification process involves the dissolution of Anagliptin in isopropyl acetate at the elevated temperature more than 35°C. Further the partial removal of solvent from the solution of Anagliptin. The partial removal includes the solvent quantity which is finally present in the mass is 2-5 times of the weight of Anagliptin.
  • the process further includes the cooling of solution or syrupy mass of Anagliptin at the temperature below the 0°C - 20°C for the complete precipitation of the product.
  • the purified Anagliptin has purity 99.5% or more when measured by HPLC.
  • the present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.
  • Example 1 Process for preparation of N-(2-amino-2-methylpropyl)-2-methyl- pyrazolo [1, 5-a] pyrimidine-6-carboxamide
  • N, N'-carbonyldiimidazole (9.6g) was added to a solution of 2-methylpyrazolo [1, 5-a] pyrimidin-6-carboxylic acid (lO.Og) in dichloromethane under nitrogen at 25°C-30°C and stirred the reaction mixture for 1 hour.
  • the reaction mixture was added slowly to a solution of 2-methyl- 1 ,2-propanediamine (5.5g) in dichloromethane at 0°C-10°C. The reaction mixture was maintained till completion of reaction. Water was added to the reaction mixture and dichloromethane layer was separated. The combined dichloromethane layers were concentrated to get N-(2-amino-2-methylpropyl)-2-methyl- pyrazolo [l,5-a]pyrimidine-6-carboxamide (8.8g).
  • Anagliptin (2g) was dissolved in isopropyl acetate (20ml) at reflux temperature. The clear solution obtained was filtered. Filtrate was put under reduced pressure for the partial removal of isopropyl acetate (15ml). The reaction mixture was cooled to temperature of 5°C -8°C, stirred for an hour and filtered. Solid was washed with isopropyl acetate and dried to get pure Anagliptin.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/IB2014/066940 2014-03-29 2014-12-16 Process for the preparation of anagliptin or its salts WO2015150887A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1191/MUM/2014 2014-03-29
IN1191MU2014 IN2014MU01191A (enrdf_load_html_response) 2014-03-29 2014-12-16

Publications (1)

Publication Number Publication Date
WO2015150887A1 true WO2015150887A1 (en) 2015-10-08

Family

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Family Applications (1)

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PCT/IB2014/066940 WO2015150887A1 (en) 2014-03-29 2014-12-16 Process for the preparation of anagliptin or its salts

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IN (1) IN2014MU01191A (enrdf_load_html_response)
WO (1) WO2015150887A1 (enrdf_load_html_response)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006060122A2 (en) 2004-11-30 2006-06-08 Artesian Therapeutics, Inc. Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase
US7345180B2 (en) 2003-01-31 2008-03-18 Sanwa Kagaku Kenkyusho Co., Ltd. Compound inhibiting dipeptidyl peptidase IV
WO2009047240A1 (en) 2007-10-09 2009-04-16 Smithkline Beecham Corporation Indole derivatives useful as ppar activators
JP2010064982A (ja) 2008-09-10 2010-03-25 Dainippon Sumitomo Pharma Co Ltd アルキルアミノ誘導体
WO2011006074A1 (en) 2009-07-09 2011-01-13 Array Biopharma Inc. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
WO2011026241A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Substituted heterocyclic derivatives for the treatment of pain and epilepsy
WO2011075699A2 (en) 2009-12-18 2011-06-23 Sunovion Pharmaceuticals Inc. Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof
WO2014034626A1 (ja) * 2012-08-28 2014-03-06 株式会社 三和化学研究所 N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミドの結晶

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345180B2 (en) 2003-01-31 2008-03-18 Sanwa Kagaku Kenkyusho Co., Ltd. Compound inhibiting dipeptidyl peptidase IV
WO2006060122A2 (en) 2004-11-30 2006-06-08 Artesian Therapeutics, Inc. Cardiotonic compounds with inhibitory activity against beta-adrenergic receptors and phosphodiesterase
WO2009047240A1 (en) 2007-10-09 2009-04-16 Smithkline Beecham Corporation Indole derivatives useful as ppar activators
JP2010064982A (ja) 2008-09-10 2010-03-25 Dainippon Sumitomo Pharma Co Ltd アルキルアミノ誘導体
WO2011006074A1 (en) 2009-07-09 2011-01-13 Array Biopharma Inc. SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS
WO2011026241A1 (en) 2009-09-04 2011-03-10 Zalicus Pharmaceuticals Ltd. Substituted heterocyclic derivatives for the treatment of pain and epilepsy
WO2011075699A2 (en) 2009-12-18 2011-06-23 Sunovion Pharmaceuticals Inc. Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof
WO2014034626A1 (ja) * 2012-08-28 2014-03-06 株式会社 三和化学研究所 N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミドの結晶

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
FREIRE FELIX, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 23, 2009, pages 7970 - 7972
ISFORT ET AL., CHRISTIAN SCHULZE ET AL., IN CHEMISTRY - A EUROPEAN JOURNAL, vol. 13, no. 8, 2007, pages 2344 - 2357
KATO NORIYASU ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, no. 23, 2011, pages 7221 - 7227
KATO NORIYASU ET AL., BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 19, no. 23, 2011, pages 7221 - 7227
NORIYASU KATO ET AL: "Discovery and pharmacological characterization of-[2-({2-[(2)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor", BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 19, no. 23, 23 September 2011 (2011-09-23), pages 7221 - 7227, XP028104550, ISSN: 0968-0896, [retrieved on 20111002], DOI: 10.1016/J.BMC.2011.09.043 *

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