WO2015090259A1 - Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib - Google Patents

Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib Download PDF

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Publication number
WO2015090259A1
WO2015090259A1 PCT/CZ2014/000160 CZ2014000160W WO2015090259A1 WO 2015090259 A1 WO2015090259 A1 WO 2015090259A1 CZ 2014000160 W CZ2014000160 W CZ 2014000160W WO 2015090259 A1 WO2015090259 A1 WO 2015090259A1
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WIPO (PCT)
Prior art keywords
dasatinib
solvate
temperature
sample
mecn
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Application number
PCT/CZ2014/000160
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English (en)
Inventor
Jan RYMES
Michal Zapadlo
Ondrej Dammer
Original Assignee
Zentiva, K.S.
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Publication date
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015090259A1 publication Critical patent/WO2015090259A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a new method of preparing the polymorphic anhydrous form N-6 of dasatinib ; chemically: (N-(2-cbioro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)- 1 - piperazinyl]-2-me1hyl-4-pyrirriidinyl]amino]-5-thiazole carboxamide, CAS: 302962-49-8)), described by the formula (1), and its key solvates, enabling formation of the chemically highly pure Form N-6.
  • CML chronic myeloid leukaemia
  • Hl-7 A large number of polymorphic forms of dasatinib are described in the literature, designated as: Hl-7, BU-2, E2-1, N-6, T1H1-7, and T1E2-1.
  • Patent document WO2005/077975 A2 describes the preparation of dasatinib monohydrate (Hl-7) and butanol solvate (BU-2).
  • Another patent document (US2006/0004067A1) linked up with the previous one describes two ethanol solvates (E2-1, T1E2-1) and further two anhydrous forms (N-6, T1H1-7).
  • a large number of preparations of various polymorphic forms are also described in TEVA patent application WO 2009/053854 A2.
  • the present invention relates to a new method of preparing the anhydrous Form N-6, in particular new use of selected solvate forms (MeOH, MeCN) and their mixtures, which allow conversion to the anhydrous Form N-6 under elevated temperature and vacuum. This phenomenon has also been observed under laboratory conditions, only with a lower conversion rate. From the viewpoint of industrial utilization, this is a very simple, robust, and relatively fast process of preparing the anhydrous Form N-6; its production has also been reproducibly tested in kilogram amounts.
  • selected solvate forms MeOH, MeCN
  • the preparation of the compound of formula (1) includes the following direct steps 1 to 3 (Scheme 1).
  • Next step is reaction of the (SNAT) intermediate (3) 2-(6-chloro-2-methylpyrimidine-4-ylamino)-N-(2-chloro-6- methylphenyl)thiazole-5-carboxamide with l-(2-hydroxyethyl)-piperazine (2) in an environment of NMP.
  • the reaction runs in the temperature range of 65 to 100°C.
  • Acetonitrile is used as the anti-solvent for isolation of crude dasatinib (1).
  • the crude product is dried in vacuo at a temperature of 55 - 65°C.
  • An NMP solvate is obtained with predominant amounts of two residual solvents NMP with an admixture of MeCN.
  • the final step of the synthesis is crystallization from the mixture of solvents MeOH and MeCN at a temperature of 55 - 62°C.
  • the obtained isolated wet crystalline product again shows the solvate structure corresponding to a MeCN solvate (Fig. 2) or a MeOH solvate (Fig. 3).
  • the type to be isolated depends on the selected procedure of preparation and on the ratio of both solvents (examples 3 + 4).
  • the crystallized wet product is further dried in vacuo at a temperature in the range of 55 - 65°C. After drying for 2 - 3 hours, the expected polymorphic Form N-6 is obtained. The duration of drying depends on residual moisture in the sample, type of the drying oven, attained vacuum, and heating rate to the final temperature of drying.
  • the described process is an efficient method of preparing dasatinib that is also convenient for larger scales.
  • the procedure according to Scheme 1 makes it possible to obtain, in a reproducible way, dasatinib (1) characterized by chemical purity higher than 99.8 % and containing individual impurities under 0.1 % (according to UPLC).
  • Figure 1 X-ray powder pattern of polymorphic anhydrous Form N-6 of dasatinib
  • Figure 2 X-ray powder pattern of the MeCN solvate form of dasatinib
  • Figure 3 X-ray powder pattern corresponding to the MeOH solvate of dasatinib
  • Figure 4 Evolution of X-ray powder patterns in the course of conversion of the MeCN solvate form to the Form N-6 during drying in vacuo and at a temperature of 55 °C (shelf drier).
  • Example 1 serve for a more detailed illustration of the method of producing dasatinib of the polymorphic anhydrous Form N-6 according to the present invention on the industrial scale.
  • the temperature of the reaction mixture is kept between 15 and 30°C. After the dosing is completed, the reaction mixture is stirred at 20 ⁇ 2°C for 60 min. The reaction mixture is cooled to 10 - 15°C, 12.5 1 of demineralized water is added dropwise, and the mixture is stirred for 15 min. Then, its temperature is brought to 5°C and diluted 1.5 M HCl (2,550 ml of 35 % HCl + 16.5 1 of demi water) is added dropwise within about 35 - 45 min. The amount of the HCl solution is chosen in order to reach final pH of 4.0 - 6.5 (optimally 5.0 - 5.5).
  • the stirring goes on at 5 - 8°C for 15 - 20 min (checking of pH, adjusted, as required). 22.5 1 of acetone is added, the mixture is heated to 40°C, and stirred at this temperature for 30 minutes. Then it is cooled down slowly to 10 - 15°C and stirred for 1.5 h. The separated product is centrifuged, washed with a warm (40 °C) 1 :1 mixture of acetone / demi water (1 x 5.0 1) and then with cold acetone (1 x 5.0 1). The product is dried in a vacuum drier at 55 - 65°C for 12 hours.
  • dasatinib intermediate (3) CAS: 302964-08-5 (4.500 kg) is suspended in 18.0 I of NMP.
  • the suspension is heated to a temperature of 67 - 68°C.
  • a solution of HEPIP (7.313 kg of HEPIP + 3.8 1 of NMP) is prepared and added dropwise to the reaction mixture within 5 - 10 min. During the addition the temperature is kept at 65 ⁇ 3°C. After the addition is completed, the mixture is stirred at 65°C for 60 min. Then, temperature is brought to 100°C and stirring goes on for 20 min. All the time, the reaction is carried out under N 2 and access of light is prevented! After the reaction is completed, the reaction mixture is cooled down to 40 - 45°C and filtered.
  • the filter is washed with 1.0 1 NMP.
  • the filtered reaction mixture is added dropwise to MeCN (113 1), heated at 25 - 30°C, within 15 - 20 min. Stirring continues at 25 - 30°C for 30 min.
  • the mixture is heated to 45 - 50°C and stirred for 0.5 h.
  • Then, is slowly cooled down to 10 - 15°C within 75 - 90 min and stirred for 1.0 - 1.5 h.
  • the separated product is centrifuged, and washed with cold (2 - 8°C) MeCN (2 x 6.0 1). It is dried in a vacuum drier at 60°C for 12 hours. Yield: 82%, sum of impurities according to UPLC: 0.2%; content of residual solvents: 30,000 ppm NMP, 17,000 ppm CH3OH; X-ray powder pattern corresponds to the NMP solvate.
  • the crude dasatinib (1.00 kg) is suspended in 10.5 1 of MeCN and 17.5 1 of MeOH. The suspension is heated up to 58 - 62°C and stirred for 0.5 h. Then, it is cooled down to 40 - 45°C and stirred for 1 hour. Cooling is continued to -5 to 0°C and stirred for 1.0 - 1.5 h. The separated product is centrifuged, and washed with cold MeCN (2 x 3.0 1). All the time, the crystallization is carried out under the inert atmosphere of N 2 and access of light is prevented! Drying is carried out as in Example 5. The X-ray pattern of the wet sample corresponds to the MeCN solvate.
  • the MeCN solvate is characterized by the reflexions listed in Table 1:
  • the crude dasatinib (1.00 kg) is suspended in 5.0 1 of MeCN and 25 1 of MeOH.
  • the suspension is heated up to 58 - 62°C and stirred for 0.5 h.
  • it is cooled down to 30 - 35°C and stirred for 1 hour. Cooling is continued to -5 to 0 °C and stirred for 1.0 - 1.5 h.
  • the separated product is centnfuged, and washed with cold MeCN (2 x 3.0 1). All the time, the crystallization is carried out under the inert atmosphere of N 2 and access of light is prevented! Drying is carried out as in Example 6.
  • the X-ray pattern of the wet sample corresponds to the MeOH solvate and is characterized by the reflexions listed in Table 2: Table 2: MeOH solvate
  • the wet crystalline dasatinib (solvate form - MeCN, Example 3) is dried in a vacuum tray drier with suction of N 2 at 55 - 65 °C for 16 h. Yield: 91% (from crude API); sum of impurities according to UPLC: 0.11%, content of residual solvents less than 500 ppm, content of water according to KF 0.5%; X-ray pattern of the dry sample corresponds to the pure anhydrous Form N-6.
  • the wet crystallized dasatinib (solvate form - MeOH, Example 4) is dried in a stirred vacuum drier with suction of N 2 at 55— 65 °C for 1 h.
  • the measurement was performed on a flat powdered sample placed on an Si plate or X-ray holders with a cavity of the diameter 16 mm and height 2.4 mm (so-called back-loading technique) were used.
  • Programmable divergent diaphragms with irradiated area of the sample of 10 mm, Soller diaphragms 0.02 rad, and an anti-scattering diaphragm 1 ⁇ 4 were used for setting the primary optics.
  • a detector X'Celerator with maximum opening of the detection slot, Soller diaphragms 0.02 rad, and an anti-scattering diaphragm 5.0 mm were used for setting the secondary optics.
  • Capillary column CP Sil 5 CB (30 m x 0.32 mm x 3.0 ⁇ ) or equivalent
  • Carrier gas helium for chromatography R; 1.6 ml/min
  • Reference solution 2.5 ml of the basic solution is diluted with ⁇ , ⁇ -dimethylacetamide to 50.0 ml.
  • Reference sample 1.0 ml of the reference solution is pipetted to the 20 ml HS vial and the vial is closed with a cap.
  • Blank experiment 1.0 ml of N,N-dimethylacetamide is pipetted to the 20 ml HS vial and the vial is closed with a cap.
  • Tested sample 20.0 mg of the tested substance is weighed into the 20 ml HS vial, 1.0 ml of N,N-dimethylacetamide is added, and the vial is closed with a cap.
  • This residual solvent was determined by the method of gas chromatography in an instrument Agilent 6890 with direct injection and FI detection.
  • Carrier gas helium for chromatography R; 40 cm/s
  • Re ference solution 125 ⁇ of the basic solution is diluted with pyridine to 25 ml.
  • Blank sample 1.0 ml of pyridine is pipetted to a 2 ml GC vial and the vial is closed with a cap.
  • Reference sample 1.0 ml of the reference solution is pipetted to a 2 ml GC vial and the vial is closed with a cap.
  • Tested sample 50.0 mg of the tested substance are dissolved in 1 ml of pyridine in a 2 ml GC vial and the vial is closed with a cap.
  • A" f peak area of N-methyl-2-pyrrolidone in the chromatogram of the reference sample; m r ...weight of N-methyl-2-pyrrolidone in the basic solution in mg;
  • Mobile phase A 1 ml of HC10 4 R is dissolved in 1000 ml of water R.
  • Test solution 15 mg of the sample are dissolved in 25 ml of the sample solvent, the mixture is placed into an ultrasound bath for 5 minutes, and, after dissolving and cooling down to room temperature, the solution is made up to 50.0 ml with the sample solvent. The sample must be well protected against light!

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de la forme N-6 cristalline de dasatinib, caractérisée par les réflexions suivantes dans le diagramme de poudre par rayons X, mesuré avec le rayonnement de faisceau CuKα: 6,8; 12,3; 13,2; 13,8; 16,7; 21,0; 24,3 et 24,8 ± 0,2° 2-thêta. Le procédé consiste à sécher un solvate de dasatinib sélectionné dans le groupe comprenant du solvate d'éthanol, du solvate de méthanol, et du solvate d'acétonitrile de dasatinib, ou leurs mélanges.
PCT/CZ2014/000160 2013-12-19 2014-12-18 Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib WO2015090259A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2013-1046 2013-12-19
CZ2013-1046A CZ306732B6 (cs) 2013-12-19 2013-12-19 Způsob přípravy bezvodé polymorfní formy N-6 Dasatinibu

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117196A (zh) * 2016-06-09 2016-11-16 青岛辰达生物科技有限公司 一种制备抗癌药物达沙替尼的方法
WO2017087818A1 (fr) * 2015-11-19 2017-05-26 The Regents Of The University Of Michigan Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques
WO2018100585A1 (fr) * 2016-12-01 2018-06-07 Natco Pharma Limited Procédé amélioré de préparation de polymorphe de dasatinib
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
WO2005077945A2 (fr) * 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
WO2005077975A2 (fr) 2004-02-10 2005-08-25 Cyclacel Limited Polypeptide
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2009053854A2 (fr) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2014086326A1 (fr) * 2012-12-06 2014-06-12 Zentiva, K.S. Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102643275B (zh) * 2011-02-21 2016-04-20 江苏先声药物研究有限公司 一种达莎替尼n-6晶型新的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
WO2005077945A2 (fr) * 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2005077975A2 (fr) 2004-02-10 2005-08-25 Cyclacel Limited Polypeptide
WO2009053854A2 (fr) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2014086326A1 (fr) * 2012-12-06 2014-06-12 Zentiva, K.S. Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087818A1 (fr) * 2015-11-19 2017-05-26 The Regents Of The University Of Michigan Double inhibiteur de kinase p38/src et leur utilisation comme agents thérapeutiques
CN106117196A (zh) * 2016-06-09 2016-11-16 青岛辰达生物科技有限公司 一种制备抗癌药物达沙替尼的方法
WO2018100585A1 (fr) * 2016-12-01 2018-06-07 Natco Pharma Limited Procédé amélioré de préparation de polymorphe de dasatinib
US10800771B2 (en) 2016-12-01 2020-10-13 Natco Pharma Limited Process for the preparation of dasatinib polymorph
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11007195B2 (en) 2018-06-15 2021-05-18 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11052088B2 (en) 2018-06-15 2021-07-06 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof

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CZ20131046A3 (cs) 2015-07-01

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