WO2016012927A1 - A process for preparation of anagliptin hydrochloride - Google Patents

A process for preparation of anagliptin hydrochloride Download PDF

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WO2016012927A1
WO2016012927A1 PCT/IB2015/055481 IB2015055481W WO2016012927A1 WO 2016012927 A1 WO2016012927 A1 WO 2016012927A1 IB 2015055481 W IB2015055481 W IB 2015055481W WO 2016012927 A1 WO2016012927 A1 WO 2016012927A1
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amino
anagliptin
methylpropan
pyrrolidine
acetyl
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PCT/IB2015/055481
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French (fr)
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Shahid Akhtar Ansari
Ashok Keshavlal YADAV
Tushar Yashwant PATIL
Dharmendrakumar Shripati PATHAK
Reenaben Ratansing Baria
Shashikant Prabhakar PATIL
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile.
  • Anagliptin is used for the treatment of diabetes.
  • GLP-1 Glucagon-like peptide- 1
  • T2DM type 2 diabetes mellitus
  • DPP-IV dipeptidyl peptidase IV
  • US Patent 7,345, 180 B2 relates to one such DPP-IV inhibitor, Anagliptin Hydrochloride (Formula I).
  • US Patent ' 180 also discloses process and intermediates for preparation of Anagliptin Hydrochloride.
  • the object of the present invention is to provide a novel salt of methane sulfonic acid (Ila) of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile (Formula II).
  • Another object of the present invention is to provide a process for preparation of novel salt (Ila) of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile (Formula II).
  • Further object of the present invention is use of novel salt of methane sulfonic acid (Ila) of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
  • novel salt (Ila) of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2- carbonitrile (Formula II).
  • novel salt of methane sulfonic acid (Ila) of (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2- carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
  • the present invention involves synthesis of methane sulfonic acid salt (Ila) of (2S)-1- ⁇ [(1- Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile (formula II) and its use for the preparation of anagliptin free base or its hydrochloride salt.
  • Anagliptin free base generated by this process has improved quality and overall yield as compared with prior art process. Also, content of total impurity is decreased.
  • Anagliptin free base generated by the process of said invention has less than 1% of total impurities and purity of 98.92% by HPLC.
  • (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile methane sulfonate is prepared by reacting t-butyl (S)- ⁇ 2-[(2-cyanopyrrolidin-l-yl)-2-oxoethylamino]- 2-methyl- 1 -propyl ⁇ carbamate hydrochloride (compound 3) with methane sulfonic acid.
  • the present invention also provides novel polymorph L of (2S)-l- ⁇ [(l-Amino-2- methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile methane sulfonate salt.
  • This condensation can be carried out using various condensation reagent (for example, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide or its hydrochloride, ⁇ , ⁇ '-carbonyldiimidazole or the like) as in the literature either alone or in combination with an additive (N-hydroxysuccinimide, hydroxybenzotriazole or the like) in the presence or absence of a base (for example, triethylamine, 4-dimethylaminopyridine or the like) in a suitable solvent (for example, tetrahydrofuran, dichloromethane, ⁇ , ⁇ -dimethylformamide or the like).
  • a base for example, triethylamine, 4-dimethylaminopyridine or the like
  • a suitable solvent for example, tetrahydrofuran, dichloromethane, ⁇ , ⁇ -dimethylformamide or the like.
  • the above reaction can be carried out in polar and non-polar solvents.
  • solvents include, but are not limited to, Pentane, Cyclopentane, Hexane, Cyclohexane,
  • DCM Diethyl ether Dichloromethane
  • THF Tetrahydrofuran
  • Ethyl acetate Acetone
  • Dimethylformamide DMF
  • MeCN Acetonitrile
  • DMSO Dimethyl sulfoxide
  • Propylene carbonate Formic acid, n-Butanol, Isopropanol (IPA), n-Propanol, Ethanol,
  • Anagliptin free base can be converted to its hydrochloride salt by the processes as disclosed in the literature.
  • XRPD X-ray powder diffraction spectrum
  • DSC Differential scanning calorimetry
  • the starting material for (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2-carbonitrile methane sulfonate salt is t-butyl (S)- ⁇ 2-[(2-cyanopyrrolidine-l-yl)- 2-oxoethylamino]-2-methyl-l -propyl ⁇ carbamate hydrochloride which could be prepared by prior art process.
  • Example 2 (2S)-l- ⁇ [(l-Amino-2-methylpropan-2-yl) amino] acetyl ⁇ pyrrolidine-2- carbonitrile methane sulfonate salt
  • Titled compound was prepared by adding t-butyl (S)- ⁇ 2-[(2-cyanopyrrolidine-l-yl)-2- oxoethylamino]-2-methyl-l -propyl ⁇ carb-amate (lOg, 0.0277) to Toluene (60ml, 6 volumes) at 25-30°C, followed by drop-wise addition of methane sulfonic acid (4.0g, 0.0416 moles) at 25-30°C. The reaction mass was heated to50-55°C for 2 hours.
  • reaction mass was cooled to 0-5 °C and stirred for 1 hour at same temperature.
  • the obtained solid was filtered and washed with chilled toluene (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt.
  • the Wet-cake was dried under vacuum till a constant weight.
  • Anagliptin free base could be converted to Anagliptin hydrochloride by processes as disclosed in the literature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (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)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-1-{[(1-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula IIa). Anagliptin is used for the treatment of diabetes.

Description

A PROCESS FOR PREPARATION OF ANAGLIPTIN HYDROCHLORIDE
Field of the Invention:
The present invention relates to process for preparing dipeptidyl peptidase IV inhibitor Anagliptin free base or its hydrochloride salt by using novel methane sulfonic acid salt of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile.
Anagliptin is used for the treatment of diabetes.
Background of the Invention:
Glucagon-like peptide- 1 (GLP-1), a thirty-amino acid peptide hormone, is secreted by intestinal L-cells in response to food ingestion and stimulates insulin secretion from b-cells in a glucose-dependent manner. GLP-1 is also known to have multiple actions such as suppression of glucagon secretion, inhibition of gastric emptying and induction of satiety. Based on these findings, GLP-1 has been considered to be an attractive target for the therapy of type 2 diabetes mellitus (T2DM). However, GLP-1 is rapidly degraded into inactive GLP- 1 by a serine protease, dipeptidyl peptidase IV (DPP-IV), which fueled the development of biologically stable GLP-1 analogs. Therefore, inhibitors of DPP-IV capable of increasing the circulating concentration of active GLP- 1 have now emerged as promising treatments for T2DM. In addition, it was demonstrated in a clinical study of diabetic patients receiving active GLP- 1 infusion that a 24-h infusion of active GLP- 1 resulted in a more marked improvement in glycemic control than a 16-h infusion, and based on accumulating clinical studies, greater than 2-fold enhancement of circulating levels of active GLP-1 is known to result from inhibition of 80% or more of the plasma DPP-IV activity. Consequently, optimal glycemic control requires continuous high-level exposure to DPP-IV inhibitors.
US Patent 7,345, 180 B2 relates to one such DPP-IV inhibitor, Anagliptin Hydrochloride (Formula I). US Patent ' 180 also discloses process and intermediates for preparation of Anagliptin Hydrochloride.
Figure imgf000003_0001
Object of the invention The object of the present invention is to provide a novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
Another object of the present invention is to provide a process for preparation of novel salt (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
Further object of the present invention is use of novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
Summary of Invention: In an embodiment of the present invention is disclosed a novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula II).
In another embodiment of the present invention is disclosed a process for preparation of novel salt (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2- carbonitrile (Formula II). In a further embodiment of the present invention is disclosed use of novel salt of methane sulfonic acid (Ila) of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2- carbonitrile (Formula II) in preparation of Anagliptin free base or its hydrochloride salt.
Brief Description Of The Accompanying Drawings Fig.l XRD of polymorph L of ((2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
Fig.2 DSC of polymorph L of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
Detail Description of the Invention: According to present invention, there is provided a novel salt (Ila) of (2S)-l-{ [(l-Amino-2- methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II).
Figure imgf000004_0001
II Ila US Patent 7,345,180 B2 patent discloses dihydrochloride salt of (2S)-l-{ [(l-Amino-2- methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II) and its conversion to Anagliptin free base.
The present invention involves synthesis of methane sulfonic acid salt (Ila) of (2S)-1-{ [(1- Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula II) and its use for the preparation of anagliptin free base or its hydrochloride salt. Anagliptin free base generated by this process has improved quality and overall yield as compared with prior art process. Also, content of total impurity is decreased.
Anagliptin free base generated by the process of said invention has less than 1% of total impurities and purity of 98.92% by HPLC. (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate is prepared by reacting t-butyl (S)-{2-[(2-cyanopyrrolidin-l-yl)-2-oxoethylamino]- 2-methyl- 1 -propyl } carbamate hydrochloride (compound 3) with methane sulfonic acid.
Figure imgf000005_0001
3 The present invention also provides novel polymorph L of (2S)-l-{ [(l-Amino-2- methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt.
(2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate is reacted with 2-methylpyrazolo[l,5-a]pyrimidine-6-carboxylic acid to get Anagliptin free base. This condensation can be carried out using various condensation reagent (for example, dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide or its hydrochloride, Ν,Ν'-carbonyldiimidazole or the like) as in the literature either alone or in combination with an additive (N-hydroxysuccinimide, hydroxybenzotriazole or the like) in the presence or absence of a base (for example, triethylamine, 4-dimethylaminopyridine or the like) in a suitable solvent (for example, tetrahydrofuran, dichloromethane, Ν,Ν-dimethylformamide or the like).
The above reaction can be carried out in polar and non-polar solvents. These solvents include, but are not limited to, Pentane, Cyclopentane, Hexane, Cyclohexane,
Benzene,Toluene, l,4-Dioxane, Chloroform, Diethyl ether Dichloromethane (DCM), Tetrahydrofuran (THF), Ethyl acetate, Acetone, Dimethylformamide (DMF), Acetonitrile (MeCN), Dimethyl sulfoxide (DMSO), Propylene carbonate, Formic acid, n-Butanol, Isopropanol (IPA), n-Propanol, Ethanol, Methanol, Acetic acid, Nitromethane and Water.
Anagliptin free base can be converted to its hydrochloride salt by the processes as disclosed in the literature.
(2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt was characterized by XRD, DSC and HPLC.
The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X'Pert PRO diffractogram with Cu Ka radiation (λ = 1.54060 A), running at 45 kV and 40 mA.
Differential scanning calorimetry (DSC) was done using Diamond DSC Perkin Elmer instrument. The scans were recorded between 50 and 300 °C at a constant heating rate of 10°C/min.
The starting material for (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt is t-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)- 2-oxoethylamino]-2-methyl-l -propyl} carbamate hydrochloride which could be prepared by prior art process.
Example 1
(2S)-l-{[(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt
Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)-2- oxoethylamino]-2-methyl-l -propyl} carbamate (25. Og) to acetonitrile (150 ml) followed by drop-wise addition of methane sulfonic acid (10 g). The reaction mass was heated to 50- 55 °C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5°C and stirred for 1 hour at same temperature. Obtained solid was filtered and washed with chilled acetonitrile (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt , Wet-cake was dried under vacuum till a constant weight was obtained (22.6g, yield 91.58% purity 99.93%).
Example 2 (2S)-l-{[(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2- carbonitrile methane sulfonate salt Titled compound was prepared by adding t-butyl (S)-{2-[(2-cyanopyrrolidine-l-yl)-2- oxoethylamino]-2-methyl-l -propyl} carb-amate (lOg, 0.0277) to Toluene (60ml, 6 volumes) at 25-30°C, followed by drop-wise addition of methane sulfonic acid (4.0g, 0.0416 moles) at 25-30°C. The reaction mass was heated to50-55°C for 2 hours. Completion of reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to 0-5 °C and stirred for 1 hour at same temperature. The obtained solid was filtered and washed with chilled toluene (15ml). The obtained solid is less hydroscopic, crystalline as compared with hydrochloric salt. The Wet-cake was dried under vacuum till a constant weight.
Example 3 Anagliptin free base
2-methylpyrazolo [1, 5-a] pyrimidine-6-carboxylic acid was coupled with (2S)-1-{ [(1- Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt in presence of EDC.HC1, HOBT, TEA. The reaction was carried out in DCM (yield 69.3%, purity 99.73%).
Anagliptin free base could be converted to Anagliptin hydrochloride by processes as disclosed in the literature.

Claims

1. Methane sulfonic acid salt of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula Ila).
Figure imgf000008_0001
Formula Ila
2. Process for preparation of methane sulfonic acid salt of (2S)-l-{ [(l-Amino-2- methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (Formula Ila) comprising reacting a compound of compound 3 with methane sulfonic acid.
Figure imgf000008_0002
compound 3
3. Process for preparation of Anagliptin comprising reacting (2S)-l-{ [(l-Amino-2- methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt with 2- methylpyrazolo[ 1 ,5-a]pyrimidine-6-carboxylic acid.
Figure imgf000008_0003
4. Use of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile methane sulfonate salt for preparing Anagliptin or its hydrochloride salt.
5. Anagliptin free base having a purity of greater than 98.92%, in particular greater than 99.3%.
6. Anagliptin free base having content of total impurity less than 1.5%.
7. Form L of Methane sulfonate salt of (2S)-l-{ [(l-Amino-2-methylpropan-2-yl) amino] acetyl} pyrrolidine-2-carbonitrile (formula Ila).
Formula Ila
8. Form L as claimed in claim 6 having XRD as per Fig.l.
9. Form L as claimed in claim 6 having DSC as per Fig.2.
PCT/IB2015/055481 2014-07-23 2015-07-20 A process for preparation of anagliptin hydrochloride WO2016012927A1 (en)

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Citations (1)

* 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

Patent Citations (1)

* 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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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