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WO2015090259A1 - Method of preparing anhydrous polymorphic form n-6 of dasatinib - Google Patents

Method of preparing anhydrous polymorphic form n-6 of 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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WO
WIPO (PCT)
Prior art keywords
dasatinib
solvate
temperature
sample
mecn
Prior art date
Application number
PCT/CZ2014/000160
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English (en)
French (fr)
Inventor
Jan RYMES
Michal Zapadlo
Ondrej Dammer
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2015090259A1 publication Critical patent/WO2015090259A1/en

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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)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/CZ2014/000160 2013-12-19 2014-12-18 Method of preparing anhydrous polymorphic form n-6 of dasatinib WO2015090259A1 (en)

Applications Claiming Priority (2)

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

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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 (en) * 2015-11-19 2017-05-26 The Regents Of The University Of Michigan Dual src/p38 kinase inhibitor compounds and their use as therapeutic agents
WO2018100585A1 (en) * 2016-12-01 2018-06-07 Natco Pharma Limited An improved process for the preparation of dasatinib polymorph
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 (en) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Cyclic protein tyrosine kinase inhibitors
WO2005077975A2 (en) 2004-02-10 2005-08-25 Cyclacel Limited Polypeptides comprising the pleckstrin homology domain of ect2 and their binding specificities to phosphatidylinositols
WO2005077945A2 (en) * 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2009053854A2 (en) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphs of dasatinib and process for preparation thereof
WO2014086326A1 (en) * 2012-12-06 2014-06-12 Zentiva, K.S. A method for the preparation and purification of new and known polymorphs and solvates of 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 (en) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Cyclic protein tyrosine kinase inhibitors
WO2005077945A2 (en) * 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
US20060004067A1 (en) 2004-02-06 2006-01-05 Bang-Chi Chen Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2005077975A2 (en) 2004-02-10 2005-08-25 Cyclacel Limited Polypeptides comprising the pleckstrin homology domain of ect2 and their binding specificities to phosphatidylinositols
WO2009053854A2 (en) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphs of dasatinib and process for preparation thereof
WO2014086326A1 (en) * 2012-12-06 2014-06-12 Zentiva, K.S. A method for the preparation and purification of new and known polymorphs and solvates of dasatinib

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087818A1 (en) * 2015-11-19 2017-05-26 The Regents Of The University Of Michigan Dual src/p38 kinase inhibitor compounds and their use as therapeutic agents
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 (en) * 2016-12-01 2018-06-07 Natco Pharma Limited An improved process for the preparation of dasatinib polymorph
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
US12064430B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US12064428B2 (en) 2018-06-15 2024-08-20 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof

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CZ306732B6 (cs) 2017-05-31

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