CZ306732B6 - A method of preparation of the anhydrous polymorphic form of N-6 Dasatinib - Google Patents

Abstract

The method of preparation of the crystalline form of N-6 Dasatinib, characterized by the following reflexes in the X-ray powder-time recording, measured using CuK.alpha. radiation: 6.8; 12.3; 13.2; 13.8; 16.7; 21.0; 24.3 and 24.8. + -. 0.2° 2-theta, which consists of drying the dasatinib solvate from the group of ethanol solvate, the methanol solvate and the acetonitrile solvate of dasatinib, or their mixtures, which is carried out in vacuum at a temperature in the range of 55 to 65°C for at least 2 hours .

Description

A process for preparing the anhydrous polymorphic form of N-6 Dasatinib

Technical field

The present invention relates to a novel process for the preparation of polymorphic anhydrous form N-6 of Dasatinib, chemically: N- (2-chloro-6-methylphenyl) -2 - [[6- [4- (2-hydroxyethyl) -1-piperazinyl] -2- methyl-4-pyrimidinyl] amino] -5-thiazolo carboxamide, (CAS: 302962-49-8), described by Formula 1 and its key solvates, allowing the formation of the chemically highly pure form of N-6.

BACKGROUND OF THE INVENTION

Treatment of chronic myeloid leukemia (CML) has changed significantly over the last decade. The discovery of imatinib (Gleevec), a BCR-ABL tyrosine kinase inhibitor, was a major turning point in CML therapy. However, despite the efficacy of imatinib, there remains a group of CML patients who are resistant or intolerant to imatinib treatment. In these patients, dasatinib (BMS-354825), a BCR-ABL inhibitor, Src, and other kinases may be indicated. It was developed by Bristol-Meyers Squibb (W00062778A1, 2000) and sold under the trademark Sprycel20.

A large number of polymorphic forms of Dasatinib are described in the literature as designated: H1-7, 25 BU-2, E2-1, N-6, T1H1-7 and T1E2-1. WO2005 / 077975 A2 describes the preparation of Dasatinib monohydrate (H1-7) and butanol solvate (BU-2). In another patent (US2006 / 0004067AI) following the foregoing, two ethanol solvates (E2-1, T1E2-1) and two anhydrous forms (N-6, TIH1-7) are described. A large number of preparations of various polymorphic forms are also described in TEVA patent WO 2009/053854 A2.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of the anhydrous form of N-6, in particular to the new uses of selected solvate forms (MeOH, MeCN) and mixtures thereof which allow the conversion to the anhydrous form of N-6 at elevated temperature and vacuum. This phenomenon was also observed under laboratory conditions with only a lower conversion rate. In terms of industrial use, this is a very simple, robust and relatively fast process for preparing the anhydrous form of N-6, whose production has been reproducibly tested even in kilograms.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the compound of formula 1 consists of the following direct steps 1 to 3 (Scheme 1).

Scheme I: Synthesis of Dasatinib

Step 1

Molecular Weight: 163.00 (5)

(4)

Molecular Weight: 267.73

Cl

NaO-r-Bu / THF

+ t-BuOH

Step 2

Molecular Weight: 394.28

NMP; MeCN

Molecular Weight: 130.19

Molecular Weight: 488.01

In the first step, 2-amino-N - (- (2-chloro-6-methylphenyl) -thiazolo-5-carboxamide (4) is reacted with 4,6-dichloro-2-methylpyrimidine (5). The reaction is carried out in THF medium. at 10 to 30 ° C. As the base used is sodium tert-butoxide (NaOtBu). the reaction is completed within l hr. Izolo15 tubs yield ranged from 80-83%. the next step of the reaction (S _N Ar) intermediate ( 3) 2- (6-chloro-2-methylpyrimidin-4-ylamino) -N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide with 1- (2-hydroxyethyl) -piperazine (HEPIP) (2) N-methyl-2-pyrrolidone (NMP) The reaction is carried out at a temperature range of 65 to 100 [deg.] C. Acetonitrile is used as an antisolvent for the isolation of crude dasatinib (1). 65 DEG C. An NMP solvate with a predominance of two residual NMP solvents with MeCN admixture is obtained.

The last step of the synthesis is crystallization from a mixture of MeOH and MeCN solvents at 55-62 ° C. The recovered isolated wet crystalline product again exhibits a solvate structure corresponding to the MeCN (Fig. 2) or MeOH (Fig. 3) solvate. The type to be isolated depends on the preparation procedure chosen and the ratio of the two solvents (Example 3 + 4). The crystallized wet product 25 is further dried under vacuum at a temperature in the range of 55 to 65 ° C. After 2-3 hours of drying, the expected polymorphic form N-6 is obtained. The drying time depends on the residual moisture content of the sample, the type of dryer, the vacuum reached and the heating rate to the final drying temperature. Usually already after 1 hour of drying at 55 ° C in a hazel drier, most of the starting MeCN / MeOH solvate is transformed to form N-6 (Fig. 4). The isolated yield ranged from 73 to 77% (crude and crystallized product 30 dasatinib). The total synthesis yield was then in the range of 58 to 63%.

Furthermore, it has been verified that the polymorphic form of N-6 can be obtained by drying other solvates such as EtOH, Acetone, IPA and mixtures thereof under reduced vacuum and elevated temperature. Also, the monohydrate containing especially MeCN, MeOH as residual solvents can be converted under reduced pressure and elevated temperature to form N-6.

The described process represents an efficient method of preparing dasatinib suitable for larger scale. The procedure of Scheme 1 allows to reproducibly obtain Dasatinib (1) having a chemical purity greater than 99.8%, with individual impurity contents below 0.1% (according to UPLC).

Clarification of drawings

Figure 1 X-ray powder pattern of polymorphic anhydrous form of N-6 dasatinib

Figure 2 X-ray powder record of MeCN solvate form of Dasatinib

Figure 3 X-ray powder record corresponding to MeOH solvate of Dasatinib

Figure 4 Development of X-ray powder recordings during conversion of MeCN solvate form to N-6 under vacuum drying at 55 ° C (hazel drier).

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate in greater detail the process for producing Dasatinib polymorphic anhydrous form N-6 of the present invention on an industrial scale.

Example 1

Preparation of intermediate (3) (2- (6-chloro-2-methylpyrimidin-4-ylamino) -N- (2- chloro-6-methylphenyl) thiazolo-5-carboxamide)

2-amino-N - (- (2-chloro-6-methylphenyl) -thiazolo-5-carboxamide (4) (3,750 kg) and 2,4-dichloro-2-methylpyrimidine (5) (2,889 kg) are suspended in the chemical reactor. in 50.01 THF, stirred until dissolved at 25-30 ° C, cooled to 10 ° C, and a pre-prepared solution of NaOt-Bu was added dropwise under N ₂ : 4.444 kg NaOt-Bu in 25.0 L THF. NaOt-Bu is added dropwise over 15 to 25 min under N ₂ (vigorous stirring) Finally, the separator is rinsed with 1.5 L THF while the temperature of the reaction mixture (RS) is maintained between 15 and 30 ° C. The reaction mixture is cooled to 10-15 ° C, added dropwise with 12.5 liters of demi water and stirred for 15 minutes, allowed to warm to 5 ° C and added dropwise over ca 35-45 minutes. diluted with 1.5 M HCl (2550 mL 35% HCl + 16.5 L demi water) The amount of HCl solution is selected to achieve a final pH of 4.0 to 6.5 (optimally 5.0 to 5.5). with 15 to 20 min at 5 to 8 ° C (pH control, acc Add 22.5 L of acetone and heat to 40 ° C. Stir at this temperature for 30 min. It is then slowly cooled to 10 to 15 ° C and stirred for 1.5 h. The precipitated product is centrifuged, washed with warm (40 ° C) 1: 1 1: 1 acetone / demi water and then chilled acetone 1x5.0. 1. Dry in a vacuum oven at 55 to 65 ° C / 12h.

Yield: 4610 g (83.5%), UPLC impurity sum: 1.4%, drying loss: 0.3%

Example 2

Preparation of crude dasatinib (NMP solvate)

Dasatinib intermediate (3), CAS: 302964-08-5 (4,500 kg) is suspended in 18.0 L of NMP in a chemical reactor. The suspension is heated to 67-68 ° C. Prepare a HEPIP solution (7.313 kg HEPIP + 3.8 l NMP) and add dropwise to RS over 5-10 min. The temperature is maintained at 65 ± 3 ° C during the dropwise addition. After addition, stir at 65 ° C for 60 min. The temperature was then raised to 100 ° C and stirred for 20 min. The reaction is carried out under N ₂ all the time and light is prevented! After completion of the reaction, the reaction mixture was cooled to 40-45 ° C and filtered. The filter was washed with 1.0 L of NMP.

(7. 306732 B6

(l) MeCN (113 L) tempered to 25-30 ° C is added dropwise / filtered RS over 15-20 min. Stir 30 ° C for 30 min. Heat to 45 to 50 ° C and stir for 0.5 h. Then slowly cool to 10 to 15 ° C over 75 to 90 min and stir for 1.0 to 1.5 h. The precipitated product is centrifuged, washed with chilled ( 2 to 8 ° C) MeCN 2x6.0 I. Dry in a vacuum oven for 60 to 12 h.

Yield: 82%, IJPLC impurity sum: 0.2%, residual solvent content: 30,000 ppm NMP, 17,000 ppm CH 2 OH, X-ray powder record corresponds to NMP solvate.

Example 3

Preparation of crystallized dasatinib - moist (MeCN solvate)

Crude dasatinib (1.00 kg) was suspended in 10.5 L of MeCN and 17.5 L of MeOH. The suspension is heated to 58-62 ° C. Stir 0.5 h. Then cool to 40 to 45 ° C and stir for 1 h. Cool to -5 to 0 ° C and stir for 1.0 to 1.5 h. The precipitated product is centrifuged, washed Chilled MeCN 2x3.0 I. Crystallization is carried out all the time under an internal atmosphere of N ₂ and the light is prevented! It is dried according to Example 5. The X-ray record of the wet sample corresponds to the MeCN solvate. The MeCN solvate is characterized by the reflections listed in Table I:

Tab. 1 MeCN solvate

pos [° 2Th.J interplanar distance [Á] rel. int. [%] 5.66 15,602 100.0 5.86 15,080 81.5 11.77 7,514 10.5 12.25 7,222 36.9 14.86 5,958 27.2 16.05 5,518 16.6 17.11 5,179 8.7 18.53 4,785 5.7 19.11 4,642 4.8 21.63 4,106 7.4 22.13 4,013 12.0 22.97 3,869 7.3 24.67 3,606 13.0 25.34 3,511 15.5

Example 4

Preparation of crystallized dasatinib - moist (MeOH solvate)

Crude dasatinib (1.00 kg) was suspended in 5.0 L of MeCN and 25 L of MeOH. The suspension is heated to 58-62 ° C. Stir for 0.5 h. Then cool to 30 to 35 ° C and stir for 1 h. Cool to -5 to 0 ° C and stir for 1.0 to 1.5 h. The precipitated product is centrifuged, washed with chilled MeCN. 2x3.0 I. Crystallization is carried out all the time under an internal atmosphere of N ₂ and light is prevented! It is dried according to Example 6. The X-ray record of the wet sample corresponds to the MeOH solvate and is characterized by the reflections listed in Table 2:

Tab. 2 MeOH solvate

pos [° 2Th.J inter-plane distance [A] rel. int. [%] 7.36 11,994 74.4 12.20 7,252 21.5 13.43 6,585 19.7 14.58 6,069 36.7 16.39 5,404 100.0 16.99 5,215 15.1 19.02 4,662 17.8 19.44 4,562 13.0 20.86 4,256 5.3 21.95 4,047 11.6 24.54 3,624 45.0 25.44 3,498 28.6 30.94 2,888 9.9

Example 5

Preparation of crystallized dasatinib - dry (anhydrous form N-6)

The wet crystallized dasatinib (solvate form - MeCN, Example 3) is dried in a vacuum hazel drier at 55 to 65 ° C for 16 h with suction of N ₂ .

Yield: 91% (from crude API), sum of impurities according to UPLC: 0.11% residual solvent content below 500 ppm, water content according to K.F 0.5%, X-ray record of dry sample corresponds to pure anhydrous N6 form.

Example 6

Preparation of crystallized dasatinib - dry (anhydrous form N-6)

The wet crystallized dasatinib (solvate form - MeOH, Example 4) is dried in a vacuum stirred oven at 55-65 ° C for 3.0 h with suction of N ₂ .

Yield: 85% (from crude API), UPLC impurity sum: 0.13%, residual solvent content below 1500 ppm, KF water content 0.7%. The X-ray record of the dry sample corresponds to the pure anhydrous form of N6.

CZ 306732 Bft

Overview of analytical methods

The samples given in the previous examples were characterized by X-ray powder diffraction. Residual solvent amounts were determined by GC. The chemical purity of the samples was determined by UPEC.

X-ray powder diffraction measurement parameters: Diffractograms were measured on an X'PERT PRO MPD PANalytical diffractometer, using CuKa radiation (λ = 1.542 Λ), excitation voltage: 45 kV, anode current: 40 mA, measuring range: 2 - 40 ° 20, step size: 0.01 ° 20. The measurement was performed on a flat powder sample, which was placed on a Si plate or using X-ray holders with a cavity of 16 mm diameter and a height of 2.4 mm (back-loading technique). Programmable divergence irradiators with irradiated sample area of 10 mm, Soller iris diaphragm 0.02 rad and anti-diffuser iris 14 were used for primary optics adjustment. 15 X'Celerator detector with maximum opening of the detection slot was used for secondary optics, 0.02 rad and 5.0 mm anti-scattering screen.

Method Λ: The following solvents are monitored: methanol, ethanol, acetonitrile

The determination of these residual solvents was performed by the headspace gas chromatography method on a PerkinElmer Autosystem XL with FI detection using the TurboMatrix headspace autosampler 40

Chromatographic conditions:

Capillary column: Temperature program: Carrier gas: Injector: Detector:

CP Sil 5 CB (30 m x 0.32 mm x 3.0 µm) or equivalent 40 ° C - 3 min, gradient 20 ° C / min to 160 ° C - 2 min helium for chromatography R; 1.6 ml / min split flow 4.0 ml / min, 165 ° C

FID, 300 ° C, Range: 1, Attn: -3

HS autosampler conditions: Furnace temperature: Mp 110 ° C Needle temperature: 115 ° C Transferline temperature: 120 [deg.] C Thermostat time: 30.0 min Pressure time: 1.0 min Injection time: 0.05 min Rinse time: 0.2 min Pressure: 21 psi GC cycle: 20 min Preparation of solutions: Base solution: Methanol 100 mg Ethanol 100 mg Acetonitrile 100 mg Acetone 100 mg Dichloromethane 100 mg

CZ 306732 Β6

Dissolve these amounts in Ν, Ν-dimethylacetamide and make up to 25,0 ml with this solvent. Reference solution: Dilute 2.5 ml of the stock solution to 50.0 ml with Ν, Ν-dimethylacetamide. Reference sample: 1.0 ml of the reference solution is pipetted into a 20 ml HS vial and capped. Blank: 1.0 ml of Ν, Ν-dimethylacetamide is pipetted into a 20 ml HS vial and capped.

Test sample: Weigh 20.0 mg of the test substance into a 20 ml HS vial, add 1.0 ml of Ν, im-dimethylacetamide and cap.

Chromatographic system capability test:

- repeatability: relative standard deviation of the peak areas of a given residual solvent of not more than 15.0% calculated from five consecutive injections of the reference sample;

- resolution: at least 1.5 between the peaks of the individual residual solvents in the fifth injection of the reference sample.

Evaluation:

The residual solvent content expressed in% is evaluated by the external standard method according to the formula:

A ^test · m ^ref x = - _f --— x 0.2 where

A ' ^e ' ¹ _in ... the peak area of the individual residual solvent in the chromatogram obtained with the test sample;

A'f ... peak area of the individual residual solvent in the chromatogram of the reference sample;

m ^re, _x ... weight of individual residual solvent in the stock solution in mg;

mff ... test portion in mg.

Method B: Monitor 1-Methyl-2-pyrrolidone (NMP1)

Determination of this residual solvent was carried out by gas chromatography on an Agilent 6890 instrument with direct injection and F1 detection.

Chromatographic conditions:

Capillary column: Temperature program: Carrier gas: Injector: Injection: R.tx-5 Amine (30 m x 0.53 mm x 3.0 µm) or equivalent 115 ° C - 0 min, gradient 15 ° C / min to 235 ° C - 0 min helium for chromatography R; 40 cm / sec split ratio 1: 2, 220 ° C 1 μΙ Detector: FID 290 ° C

. 7.

Preparation of the solution:

Stock solution: Dissolve 53.0 mg of reference substance N-methyl-2-pyrrolidone and 150.0 mg of reference substance 5 I - (2-hydroxyethyl) piperazine in pyridine in a 10 ml volumetric flask and make up to the mark with pyridine.

Reference solution: Dilute 125 μΙ of the stock solution to 25 ml with pyridine.

κι Blank: 1.0 ml of pyridine is pipetted into a 2 ml GC vial and capped.

Reference sample: 1.0 ml of the reference solution is pipetted into a 2 ml GC vial and capped.

Test sample: Dissolve 50.0 mg of the test substance in 1 ml of pyridine in a 2 ml GC vial and cap.

Approximate retention times:

N-methyl-2-pyrrolidone 4.5 min.

2o 1- (2-hydroxyethyl) piperazine 5.6 min.

Chromatographic system capability test:

- repeatability: relative standard deviation of the peak areas of N-methyl-2-pyrrolidone - not more than 15.0%, calculated from five consecutive injections of the reference sample;

- resolution: at least 10 between the peaks due to N-methyl-2-pyrrolidone and 1- (2-hydroxyethyl) piperazine in the fifth injection of the reference sample.

Evaluation:

The N-methyl-2-pyrrolidone content, expressed in ppm, is evaluated by the external standard method according to the formula:

^{i.e. the} peak area of N-methyl-2-pyrrolidone in the chromatogram obtained with the test sample; A ^rc, x ... area of the peak due to N-methyl-2-pyrrolidone in the chromatogram obtained with the reference sample; mf ... weight of N-methyl-2-pyrrolidone in stock in mg;

test sample weight in mg.

Method C: Monitor impurities in the product

Chromatographic conditions:

Apparatus:

Column:

Stationary phase:

Size:

Temperature:

UPLC / UHPLC with UV / VIS or PDA detector

ACQUITY CSH Phenyl-Hexyl (1.7 µm) = 0.100 m, 0 3.0 mm ° C

Mobile phase A: Dissolve 1 ml of ICIO ₄ R in 1000 ml of water R.

Mobile phase B: Acetonilril R1

Elution gradient:

Time [min] Mobile phase [% v / v] Mobile phase B [% I / O] 0 90 10 10 50 50 11 50 50 12 90 10 Flow: 0.5 ml / min Detection: UV 220 nm Injection: 1,0 μΐ Autosampler temperature: Low: 14 ° C Analysis time: 10 min Next injection delay: 1 min Approximate retention time: Dasatinib 5.6 min Relative retention time: (due to Dasatinib ') Impurity DAS 4 RRT 0.72 Impurity DAS 6 RRT 0,93 Impurity DAS 1 RRT 0.97 Impurity DAS 3 RRT 1.07 Impurity DAS 5 RRT 1,82 Sample Solvent: Acetonitrile R1 / water R 50/50 (I / O)

Test solution: Dissolve 15 mg of the sample in 25 ml of the sample solvent, place in ultrasound for 5 minutes and, after dissolution and cooling to room temperature, make up to 50,0 ml with the sample solvent. The sample must be well protected from light!

Evaluation: The content of individual impurities is evaluated by the internal normalization method:

Limits:

- Impurity DAS 1

- Impurity DAS 3

- Impurity DAS 4

- Impurity DAS 5

- Impurity DAS 6

- Any other impurity

Water (2.5.32): Micro-determination: max. 2.0%, determined from 0.100 g.

NMT 0,15%

NMT 0,15%

NMT 0,15%

NMT 0,15%

NMT 0,15%

NMT 0,10%

Claims (1)

A process for the preparation of crystalline form N-6 of Dasatinib, characterized by the following reflections in an X-ray powder record measured using CuKα radiation: 6.8; 12.3; 13.2; 13.8; 16.7; io 21.0; 24.3 and 24.8 ± 0.2 ° 2-theta, characterized in that they are prepared by drying a solvate of dasatinib from the group ethanol solvate. the methanol solvate and the acetonitrile solvate of dasatinib, or mixtures thereof, wherein the drying is performed under vacuum at a temperature in the range of 55 to 65 ° C for at least 2 hours.