WO2021250995A1 - Morphologie cristalline de 1- [(4-méthyl-quinazoline-2-yl)méthyl]-3-méthyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-péperidine-1-yl)-xanthine - Google Patents

Morphologie cristalline de 1- [(4-méthyl-quinazoline-2-yl)méthyl]-3-méthyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-péperidine-1-yl)-xanthine Download PDF

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WO2021250995A1
WO2021250995A1 PCT/JP2021/015338 JP2021015338W WO2021250995A1 WO 2021250995 A1 WO2021250995 A1 WO 2021250995A1 JP 2021015338 W JP2021015338 W JP 2021015338W WO 2021250995 A1 WO2021250995 A1 WO 2021250995A1
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methyl
crystal
powder
linagliptin
ray diffraction
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PCT/JP2021/015338
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Japanese (ja)
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祐未子 田中
柚美華 清水
朝典 翁長
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有機合成薬品工業株式会社
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Priority to JP2022530623A priority Critical patent/JPWO2021251467A1/ja
Priority to PCT/JP2021/022157 priority patent/WO2021251467A1/fr
Priority to CN202180042237.4A priority patent/CN115916781A/zh
Publication of WO2021250995A1 publication Critical patent/WO2021250995A1/fr

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    • 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
    • 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

Definitions

  • the present invention relates to 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine- 1-Il) -Regarding the crystal morphology of xanthine.
  • linagliptin 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (hereinafter sometimes referred to as linagliptin) is known to inhibit dipeptidyl peptidase.
  • Dipeptidyl peptidase is an enzyme involved in the degradation of incretins, and by inhibiting dipeptidyl peptidase, the concentration of glucagon-like peptide-1 (GLP-1) in the blood increases, the serum insulin concentration increases, and It is believed that a decrease in blood sugar level occurs. Therefore, the linagliptin is used as a therapeutic agent for diabetes (Patent Document 1).
  • An object of the present invention is 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3-), which exhibits excellent stability. It is to provide the crystalline form of (R) -amino-piperidine-1-yl) -xanthine.
  • the present inventor has excellent stability of 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3-( As a result of diligent research on the crystal morphology of R) -amino-piperidine-1-yl) -xanthine, surprisingly, a new crystal morphology having a specific peak in powder X-ray diffraction (diffraction angle 2 ⁇ ) was found. .. The present invention is based on these findings.
  • the present invention [1] In powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14 1-[(4-methyl-quinazoline-2-yl) methyl] -3 showing at least three peaks selected from the group consisting of .5 ° ⁇ 0.2 ° and 20.8 ° ⁇ 0.2 ° Crystal form of -methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidin-1-yl) -xanthine, [2] The crystal morphology is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14 in powder X-ray diffraction (diffraction angle 2 ⁇ ).
  • the crystal morphology is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15.4 ° ⁇ 0.2 °, 17 in powder X-ray diffraction (diffraction angle 2 ⁇ ).
  • Crystal form (1) 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xanthine crystal morphology (1) is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. .At least 3 peaks selected from the group consisting of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °, preferably at least 4 peaks. Shown, most preferably five peaks.
  • the linagliptin has the following formula (1). It is a compound represented by, and exhibits an inhibitory action on dipeptidyl peptidase. Dipeptidyl peptidase is an enzyme that degrades incretins and can increase the concentration of glucagon-like peptide-1 (GLP-1) in the blood by inhibiting dipeptidyl peptidase. This action induces an increase in serum insulin concentration and a decrease in blood glucose level. It is marketed as Trazenta (trade name) in Japan.
  • GLP-1 glucagon-like peptide-1
  • the crystal morphology (1) of linagliptin is 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. Shows at least three peaks selected from the group consisting of ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °. The five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any three peaks can also identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 7.6 ° ⁇ 0.2 °.
  • the crystal morphology (1) of the linagliptin is preferably 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9. Shows at least four peaks selected from the group consisting of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °.
  • the five peaks are characteristic of the linagliptin crystal morphology (1) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (1) of the present invention. It is possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, and 9.3 ° ⁇ 0.2 °. Is.
  • the crystal form (1) of the linagliptin is more preferably 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows peaks of 3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °.
  • the five peaks are the peaks characteristic of the linagliptin crystal morphology (1) of the present invention, and the crystal morphology (1) of the linagliptin of the present invention can be specified by the combination of the five peaks.
  • the crystal morphology (1) of linagliptin has a peak of 7.3 ° ⁇ 0.2 ° and / / in addition to the above 3 to 5 peaks in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. Alternatively, it may have a peak of 17.7 ° ⁇ 0.2 °. That is, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2. It may have at least 4-6 peaks selected from the group consisting of ° and 7.3 ° ⁇ 0.2 °.
  • 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 It may have at least 4-6 peaks selected from the group consisting of ° and 17.7 ° ⁇ 0.2 °. Furthermore, 6.9 ° ⁇ 0.2 °, 7.6 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 It may have at least 5-7 peaks selected from the group consisting of °, 7.3 ° ⁇ 0.2 °, and 17.7 ° ⁇ 0.2 °.
  • the crystal form (1) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
  • the error of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum in the crystal form (1) of linagliptin of the present invention is about ⁇ 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field.
  • the crystal form (1) of linagliptin of the present invention includes those having the same peak pattern of powder X-ray diffraction (diffraction angle 2 ⁇ ) but different relative intensities of peaks.
  • the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum is 100.
  • the crystal form (1) of linagliptin of the present invention has an endothermic peak at 173.3 ° C ⁇ 5 ° C by differential thermal analysis.
  • the crystal form (1) of linagliptin of the present invention is presumed to be a hydrate.
  • the crystal form (1) of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating diabetes.
  • the crystal form (1) of linagliptin of the present invention has excellent stability, and the pharmaceutical composition also exhibits excellent stability. Therefore, the crystalline form (1) of linagliptin of the present invention can be used for producing a pharmaceutical composition for treating diabetes.
  • Crystal form (2) 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl) -8- (3- (R) -amino-piperidine-1) of the present invention -Il) -Xantin crystal morphology (2) is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. At least four peaks selected from the group consisting of .4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °. , Preferably showing at least 5 peaks, more preferably 6 peaks.
  • the crystal form (2) of linagliptin is 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15.4 ° in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows at least four peaks selected from the group consisting of ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °.
  • the six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the four peaks can identify the linagliptin crystal morphology (2) of the present invention. Possible, but most preferably a combination of peaks of 6.9 ° ⁇ 0.2 °, 15.4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, and 20.8 ° ⁇ 0.2 °. Is.
  • the crystal form (2) of the linagliptin is preferably 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15. At least 5 peaks selected from the group consisting of 4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2 °. show.
  • the six peaks are characteristic of the linagliptin crystal morphology (2) of the present invention. Therefore, the combination of any of the five peaks can identify the linagliptin crystal morphology (2) of the present invention.
  • the crystal morphology (2) of the linagliptin is more preferably 6.9 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 15 in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It shows peaks of .4 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 20.8 ° ⁇ 0.2 °, and 23.8 ° ⁇ 0.2.
  • the six peaks are the peaks characteristic of the linagliptin crystal morphology (2) of the present invention, and the crystal morphology of the linagliptin of the present invention can be specified by the combination of the six peaks.
  • the crystal morphology (2) of linagliptin is 7.1 ° ⁇ 0.2 °, 13.7 ° in addition to the above 4 to 6 peaks in powder X-ray diffraction (diffraction angle 2 ⁇ ) by Cu—K ⁇ irradiation. It may have one or more peaks selected from the group consisting of ⁇ 0.2 °, 14.5 ° ⁇ 0.2 °, and 16.2 ° ⁇ 0.2 °. That is, 6.9 ° ⁇ 0.2 °, 7.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, 14.5 ° ⁇ 0.2.
  • the crystal form (2) of the linagliptin most preferably has the powder crystal diffraction pattern shown in FIG.
  • the error of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum in the crystal form (2) of linagliptin of the present invention is about ⁇ 0.2 °. This error is caused by the equipment used for the measurement, the preparation of the sample, the method of data analysis, and the like, and is a common general technical knowledge in the present technical field.
  • the crystal form (2) of linagliptin of the present invention includes those having the same peak pattern of powder X-ray diffraction (diffraction angle 2 ⁇ ) but different relative intensities of peaks.
  • the relative intensity is a relative value of each peak area when the peak area of the peak of the diffraction angle 2 ⁇ in the powder X-ray diffraction spectrum is 100. It is presumed that the crystal form (2) of linagliptin of the present invention is not a hydrate.
  • the first method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-yl). -8- (3- (R) -Amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution. (B1) In the methanol solution, 35. A step of adding a seed crystal at ⁇ 45 ° C. to confirm crystal precipitation, (c) a step of cooling the obtained suspension to 15 ° C. or lower to obtain a crystal, (d) a step of filtering the crystal, and ( e) The step of drying the obtained crystals under reduced pressure at 20 to 100 ° C. is included.
  • the second method for producing the crystal form of linagliptin of the present invention is (a) 1-[(4-methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butin-1-).
  • Il) -8- (3- (R) -amino-piperidin-1-yl) -xanthin is heated in methanol and dissolved at 40 to 65 ° C to obtain a methanol solution, (b2) 35 to 45 ° C.
  • a step of adding tert.-butylmethyl ether and confirming crystal precipitation (c) a step of cooling the obtained suspension to 15 ° C. or lower to obtain crystals, (d) a step of filtering the crystals, and a step of filtering the crystals.
  • the step of drying the obtained crystals under reduced pressure at 20 to 100 ° C. is included.
  • the first production method and the second production method of the crystal form (1) of linagliptin of the present invention are the same in steps (a), (c), (d) and (e), and the first production method.
  • the step (b1) of the second manufacturing method is different from the step (b2) of the second manufacturing method.
  • the common processes are collectively described below, and the different processes are described individually.
  • linagliptin is heated in methanol and dissolved at 40 to 65 ° C. to obtain a methanol solution.
  • the melting temperature is preferably 40 to 60 ° C, more preferably 40 to 50 ° C.
  • the amount of methanol with respect to linagliptin is not particularly limited as long as the crystalline form of the present invention can be obtained, but it is 0.5 to 30 times the amount (weight / weight) with respect to linagliptin, preferably 1 to 1 to. The amount is 10 times, more preferably 1.5 to 5 times. Methanol with a purity of 97% or more may be used.
  • the dissolution of linagliptin in methanol is preferably carried out with stirring.
  • the stirring method a known method may be used, and for example, a stirrer, a stirring blade, a magnetic stirrer, or the like can be appropriately selected and used.
  • the methanol solution is preferably cooled to about 40 ° C.
  • the cooling method is not limited, but for example, a methanol solution may be left in a water bath or at room temperature.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, preferably 200 to 300 rpm.
  • the stirring time is also not particularly limited, but is, for example, 10 minutes to 10 hours, preferably 20 minutes to 3 hours, and more preferably 40 minutes to 2 hours. If it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
  • tert.-butylmethyl ether is added at 35 to 45 ° C., and crystal precipitation is confirmed.
  • the amount of tert.-butylmethyl ether is not particularly limited, but is, for example, 0.5 to 5 times, preferably 1 to 4 times, and more preferably 1.5 times the amount of the methanol solution. The amount is up to 3 times, more preferably 1.7 to 2.5 times.
  • the method for adding tert.-butylmethyl ether is also not limited, but it is preferable to add the tert.-butylmethyl ether by dropping it into a methanol solution. The crystal precipitation can be confirmed visually.
  • the methanol solution is stirred at 40 ° C. to promote crystal growth.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, preferably 200 to 300 rpm.
  • the stirring time is also not particularly limited, but is, for example, 5 minutes to 10 hours, preferably 10 minutes to 2 hours, more preferably 20 minutes to 2 hours, still more preferably 30 minutes to 1 hour. Is. If it is too short, crystal precipitation may not be sufficient, and if it is too long, linagliptin decomposition may occur.
  • the obtained suspension is cooled to 15 ° C. or lower to obtain crystals.
  • the cooling temperature is not limited as long as it is 15 ° C. or lower, but is preferably 0 to 10 ° C., more preferably 0 to 5 ° C.
  • the suspension is stirred after cooling to promote crystal growth.
  • the stirring method is not particularly limited, but a stirrer, a stirring blade, or a magnetic stirrer may be used, and stirring is performed at 150 to 350 rpm, preferably 200 to 300 rpm.
  • the stirring time is also not particularly limited, but is, for example, 10 minutes to 10 hours, preferably 20 minutes to 3 hours, and more preferably 40 minutes to 2 hours.
  • the crystals are filtered.
  • Filtration is not particularly limited, but can be performed by, for example, vacuum filtration (suction filtration), pressure filtration, centrifugal filtration, or the like using filter paper or the like.
  • the filtered crystals may be washed. Since the solvent used for washing the crystals is preferably the one used for producing the crystals, methanol or a methanol / tert.-butylmethyl ether solution or the like is used.
  • the obtained crystals are dried under reduced pressure at 20 to 100 ° C., preferably 20 to 70 ° C., more preferably 30 to 60 ° C.
  • the pressure for vacuum drying is, for example, 0.1 atm (atm) or less, preferably 0.05 atm or less.
  • the crystalline form of the present invention can be used as an active ingredient of a pharmaceutical composition. Specifically, it can be used as an active ingredient of a pharmaceutical composition for treating type 2 diabetes. That is, the crystalline form of the present invention can be used for producing a pharmaceutical composition for treating diabetes. In addition, the crystalline form of the present invention can be used in a method for treating diabetes, which comprises a step of administering an effective amount thereof to a patient. Furthermore, the crystalline form of the present invention is a crystalline form for use in a method of treating diabetes.
  • the pharmaceutical composition can contain, but is not limited to, the active ingredient in an amount of 0.01 to 99% by weight, preferably 0.1 to 80% by weight.
  • the dose when the pharmaceutical composition is used can be appropriately determined according to the age, sex, body weight, degree of symptoms, administration method, etc. of the patient, and can be administered orally or parenterally. Is.
  • the dosage form of the pharmaceutical composition is not particularly limited, and for example, powders, fine granules, granules, tablets, capsules, suspensions, emulsions, syrups, extracts, rounds and the like.
  • Oral preparations or parenteral preparations such as injections, external solutions, ointments, suppositories, topically administered creams, or eye drops can be mentioned.
  • the pharmaceutical composition includes, for example, gelatin, sodium alginate, starch, corn starch, sucrose, lactose, glucose, mannitt, carboxymethyl cellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean residue, sucrose, fatty acid ester, talc, stearic acid.
  • Excipients such as magnesium, polyethylene glycol, magnesium silicate, anhydrous silicate, or synthetic aluminum silicate, binders, disintegrants, surfactants, talc, fluidity promoters, diluents, preservatives, coloring It can be produced according to a conventional method using an agent, a fragrance, a flavoring agent, a stabilizer, a moisturizing agent, a preservative, an antioxidant or the like.
  • parenteral administration methods include injection (subcutaneous, intravenous, etc.), rectal administration, and the like. Of these, injections are most preferably used.
  • a water-soluble solvent such as physiological saline or Ringer's solution, a water-insoluble solvent such as vegetable oil or fatty acid ester, an isotonic agent such as glucose or sodium chloride, etc.
  • a solubilizing agent, a stabilizer, a preservative, a suspending agent, an emulsifier and the like can be arbitrarily used.
  • administration form is not limited to pharmaceutical products, and various forms such as functional foods, health foods (including beverages), or animals can be given in the form of food and drink as feed.
  • Example 1 the crystal form (1) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -40 g (85 mmol) of xanthine (linagliptin) and 100 g of methanol were mixed and heated to 40 to 50 ° C. to dissolve. Then, it was filtered hot and washed with 20 g of methanol. The filtrate was cooled to 40 ° C. and seed crystals were added. After confirming the crystal precipitation, the mixture was stirred at 40 ° C.
  • Example 2 the crystal form (1) of linagliptin was prepared by a process different from that of Example 1.
  • 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 33 g (70 mmol) and methanol 82.5 g were mixed and heated to 40-50 ° C to dissolve. Then, it was filtered hot and washed with 16.5 g of methanol. The filtrate was cooled to 40 ° C. and 198 g of tert.-butylmethyl ether was added dropwise.
  • the mixture was stirred at 40 ° C. for 30 minutes.
  • the suspension was cooled to 0-5 ° C and stirred for 1 hour.
  • the crystals were filtered and washed with a mixture of 22 g of methanol and 44 g of tert.-butylmethyl ether. By drying the wet crystals under reduced pressure at 30 to 60 ° C., 31 g (66 mmol) of white linagliptin crystals were obtained.
  • Example 1 Powder X-ray diffraction measurement
  • Example 2 The crystals obtained in Example 1 or Example 2 were stored in a general laboratory at room temperature and humidity of 50% or more for a whole day and night, and then powder X-ray diffraction was measured under the following conditions.
  • Table 1 and FIG. 1 show the powder X-ray diffraction measurement of the crystal obtained in Example 1, and Table 2 shows the powder X-ray diffraction measurement of the crystal obtained in Example 2.
  • Example 3 the crystal form (2) of linagliptin was prepared.
  • 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the crystal precipitation, the mixture was stirred at 40 ° C. for 1 hour. The suspension was cooled to 0-5 ° C. and stirred for 1 hour.
  • Example 4 the crystal form (2) of linagliptin was prepared. 1-[(4-Methyl-quinazoline-2-yl) methyl] -3-methyl-7- (2-butyne-1-yl) -8- (3- (R) -amino-piperidine-1-yl) -Xanthine (linagliptin) 10 g (21 mmol) and methanol 30 g were mixed and heated to 40-50 ° C to dissolve. Then, it cooled to 40 degreeC and the seed crystal was added. After confirming the crystal precipitation, the mixture was stirred at 40 ° C. for 1 hour and 30 minutes. The suspension was cooled to 0-5 ° C. and stirred for 1 hour.
  • the crystal forms (1) and (2) of the present invention showed excellent storage stability.
  • the crystalline form of linagliptin of the present invention can be used as an active ingredient of a pharmaceutical composition for treating type 2 diabetes.

Abstract

L'objectif de la présente invention est de fournir une morphologie cristalline de 1- [(4-méthyl-quinazoline-2-yl) méthyl]-3-méthyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-péperidine-1-yl)-xanthine, qui présente une stabilité supérieure.　Le problème ci-dessus peut être résolu par : la morphologie cristalline du 1- [(4-méthyl-quinazoline-2-yl)méthyl]-3-méthyl-7-(2-butyn-1-yl))-8-(3-(R)-amino-peperidine-1-yl)-xanthine, qui présente au moins trois pics choisis dans le groupe constitué de 6,9° ± 0,2°, 7,6° ± 0,2°, 9,3° ± 0,2°, 14,5° ± 0,2°, et 20,8° ± 0,2° dans la diffraction des rayons X sur poudres (angle de diffraction 2θ)) par un rayonnement Cu-Ka ; ou la morphologie cristalline du 1-[(4-méthyl-quinazoline-2-yl)méthyl]-3-méthyl-7-(2-butyn-1-yl)-8-(3- (R)-amino-peperidine-1-yl)-xanthine, qui présente au moins quatre pics choisis dans le groupe constitué de 6,9° ± 0,2°, 10,4° ± 0,2°, 15,4° ± 0,2°, 17,9° ± 0,2°, 20,8° ± 0,2°, et 23,8° ± 0,2° dans la diffraction des rayons X sur poudres (angle de diffraction 2θ) par un rayonnement Cu-Ka.
PCT/JP2021/015338 2020-06-10 2021-04-13 Morphologie cristalline de 1- [(4-méthyl-quinazoline-2-yl)méthyl]-3-méthyl-7-(2-butyn-1-yl)-8-(3-(r)-amino-péperidine-1-yl)-xanthine WO2021250995A1 (fr)

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