Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
  • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • 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
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to a method for production of linagliptin via a novel crystalline form of lingliptin intermediate. More particularly the present invention relates to novel crystalline form of linagliptin intermediate and methods for production of novel crystalline form of linagliptin intermediate represented by the following structural formula V.
• TRADJENTA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1.1).
• Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. It is chemically designated as lH-purine-2,6-dione, 8-[(3R)-3-amino-l- piperidinyl] -7-(2- butyn- 1 -yl)-3 ,7-dihydro-3 -methyl- 1 -[(4-methyl-2-quinazolinyl)methyl].
• Linagliptin was disclosed in U.S. Pat. No. 7,407,955. Linagliptin, chemically lH-Purine- 2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-butyn-l-yl)-3,7-dihydro-3-methyl-l-[(4- methyl-2quinazolinyl)methyl] . Crystalline forms A, B, C, D, E and anhydrous form A/B of Linagliptin are disclosed in US 9,266,888.
• One aspect of the present invention is novel crystalline form B 1 Linagliptin intermediate of Formula V.
• novel crystalline form B l Linagliptin intermediate of Formula V is further characterized by PXRD having few prominent 2-theta values 3.14 ⁇ 0.2, 6.31 ⁇ 0.2, 8.33 ⁇ 0.2, 10.92 ⁇ 0.2, 13.74 ⁇ 0.2, 14.45 ⁇ 0.2, 19.67 ⁇ 0.2 and the PXRD pattern in accordance with the Figure- 1.
• novel crystalline form B l Linagliptin intermediate of Formula V is further characterized by DSC having endotherms at around 53.87 °C & 163 °C and the DSC pattern in accordance with the Figure-2.
• novel crystalline form B l Linagliptin intermediate of Formula V is further characterized by FT-IR and the FT-IR pattern is in accordance with the Figure-3.
• novel crystalline form B2 Linagliptin intermediate of Formula V is further characterized by PXRD having few prominent 2-theta values at 3.43+ 0.2, 8.10+ 0.2, 9.96+ 0.2 & 17.02 + 0.2 degrees 2 ⁇ and the PXRD pattern in accordance with the Figure-4.
• is novel crystalline form B2 Linagliptin intermediate of Formula V is further characterized by DSC having endotherm at around 168.69 °C and the DSC pattern in accordance with the Figure-5.
• FT-IR, DSC and PXRD techniques were used for characterising the co-crystal.
• the infrared spectroscopy presents a great quantity of information about the chemical bonds and interaction. It is a fast analysis method, non-destructive.
• the Powder X-ray diffraction is one of the most used techniques to determine different crystalline structures. This technique can distinguish the presence of a new crystallographic motif, which can be a polymorph or a co-crystal. It is a non-destructive method and presents diffractions patterns unique for each structure.
• the differential scanning calorimetry is a characterization method based on the heat of reaction involved in different thermal events.
• the DSC is mostly used to obtain melting points of the API and thus, determine its purity.
• DSC was performed on a Discovery DSC (TA instruments). About 3-5 mg of sample placed in crimped aluminium sample pan to be positioned on auto sampler. The temperature range was from 30-350 °C @ 10 °C/min. Samples were purged by a stream of nitrogen flowing at 50 mL/min.
• the powder X-ray powder diffractogram (XRPD) was obtained by using the instrument XRD BRUKER D8 ADVANCE, equipped with LYNXEYE detector with 40mA current intensity and 40kV voltage.
• An API can exist in a variety of solid state forms, which include: polymorphs; solvates; hydrates; salts; co-crystals and amorphous forms. Each form exhibits unique physiochemical properties that can profoundly influence the bioavailability, stability, manufacturability and other performance characteristics of the Formulated API.
• Crystalline forms when compared to the amorphous form often show desired unique physical and/or biological characteristics which usually contributes in the manufacture or Formulation of the active compound, to the purity levels and uniformity required for regulatory approval. Hence, it is desirable to provide the pharmaceutically active ingredient in a substantially pure, crystalline and stable form of API.
• Figure 1 Illustrates the PXRD pattern of novel crystalline Linagliptin intermediate of Formula V as obtained from Step 2 of Example-2a.
• Figure 2 Illustrates the DSC thermogram of novel crystalline Linagliptin intermediate of Formula V as obtained from Step 2 of Example-2a.
• Figure 3 Illustrates the FT-IR of novel crystalline Linagliptin intermediate of Formula V as obtained from Step 2 of Example-2a.
• Figure 4 Illustrates the PXRD pattern of novel crystalline Linagliptin intermediate of Formula V as obtained from Step 2 of Example-2b.
• Figure 5 Illustrates the DSC thermogram of novel crystalline Linagliptin intermediate of Formula V as obtained from Step 2 of Example-2b.
• Figure 6 Illustrates the DSC thermogram of anhydrous form A/B of Linagliptin as obtained from Step 3 of Example-3.
• DSC was performed on a Mettler Toledo DSC 822e module. 4-6 mg of sample was placed in crimped but vented aluminium sample pans. The temperature range was from 30-250 °C @ 10 °C/min. Samples were purged by a stream of nitrogen flowing at 80 mL/min.
• IR was performed on a Fisher Scientific (NICOLET-iS50-FTIR). About 5 mg of sample was spread over the region of diamond ATR sampling station and collected the sample spectrum between 4000 cm-1 to 400 cm-1 to obtain a spectrum of suitable intensity (above 60 % transmission at 2000 cm-1).
• Example 2a Preparation of tert-butyl (R)-(l-(7-(but-2-yn-l-yl)-3-methyl-l-((4- methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin -3-yl) carbamate (Formula V):
• the novel crystalline Linagliptin intermediate of Formula V which is prepared as per Example-2 is characterized by XPRD as represented in Figure- 1.
• the novel crystalline Linagliptin intermediate of Formula V which is prepared as per Example-2 is characterized by DSC as represented in Figure-2.
• Example 2b Preparation of tert-butyl (R)-(l-(7-(but-2-yn-l-yl)-3-methyl-l-((4- methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl) piperidin -3-yl) carbamate (Formula V):
• the product as obtained was filtered off, washed with MTBE (200 mL) and suck dried.
• the product was dried at 45+5 °C under vacuum for lOh to obtain Linagliptin as a pale yellow solid.
• the product was kept at -5+5°C for 36 h, raised the temperature to 25+5°C and hold it for 4-5 h to obtain anhydrous crystalline form A/B of Linagliptin.
• the anhydrous crystalline form A/B of Linagliptin which is prepared as per Example-3 is characterized by DSC as represented in Figure-6.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Endocrinology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Emergency Medicine (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2018
  • 2018-09-27 MX MX2020004050A patent/MX2020004050A/es unknown
  • 2018-09-27 KR KR1020207012196A patent/KR20200092946A/ko not_active Ceased
  • 2018-09-27 CN CN201880076836.6A patent/CN111511743A/zh active Pending
  • 2018-09-27 CA CA3076980A patent/CA3076980A1/en active Pending
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• 2020
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