Nilotinib intermediate and preparation method thereof

Abstract

The present invention relates to a nilotinib drug intermediate formula (1) compound, and a method for preparing the compound. The formula (1) compound provided by the present invention has high purity, good stability, and is easy to store. It is more suitable for use as a synthetic raw material in industrial production than 3-guanidino-4-methylbenzoic acid methyl ester nitrate in the prior art; the crystal preparation process is simple to operate and has a short reaction time; the post-treatment filtration is rapid, the product yield and purity are high, and it is suitable for industrial production. In addition, the reaction yield of preparing nilotinib using the provided formula (1) compound crystal as a reaction raw material is high, the three wastes generated are less, it is environmentally friendly, and it is more suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a nilotinib drug intermediate compound of formula (1), and a method for preparing the compound. Background Art

[0002] Nilotinib capsules are more effective than imatinib in the treatment of newly diagnosed Philadelphia chromosome-positive CML chronic phase patients.

[0003] The prior art uses 3-guanidino-4-methylbenzoic acid methyl nitrate as a raw material to prepare nilotinib, but concentrated nitric acid or ammonium nitrate is used as a salt-forming reagent in the preparation process of the nitrate, and a large amount of waste gas is generated when concentrated nitric acid is used, and the operation process is dangerous. The prepared nitrate is easy to absorb moisture, the product properties are unstable, and it is not easy to store, which is not suitable for industrial production. In addition, the use of 3-guanidino-4-methylbenzoic acid methyl nitrate as a raw material to prepare nilotinib has a long reaction time, a low yield, and cumbersome post-processing, which is not suitable for industrial production. Summary of the invention

[0004] The purpose of the present invention is to provide a nilotinib intermediate compound of formula (1):

[0005]

[0006] The inventors have found that the compound of formula (1) is an important intermediate for the preparation of nilotinib. The crystalline form of the compound of formula (1) has good stability. The compound of formula (1) is used as a reaction raw material to prepare nilotinib with high yield, less three wastes, environmental friendliness, and convenient post-treatment. Therefore, the compound has industrial use value. How to prepare the above compound with high yield and high purity is particularly important.

[0007] The purpose of the present invention can be achieved by the following measures:

[0008] Provided is a compound represented by the following formula (1):

[0009]

[0010] Its X-ray powder diffraction has characteristic peaks at diffraction angles 2θ of 10.0±0.2, 10.1±0.2, 17.4±0.2, 17.9±0.2, 19.6±0.2, 19.9±0.2, and 27.0±0.2; the X-ray powder diffraction of the crystal has characteristic peaks at diffraction angles 2θ of 10.0±0.2, 10.1±0.2, 13.3±0.2, 14.2±0.2, 16.1±0.2, 16.7±0.2, 17.4±0.2, 17.9±0.2, 19.2±0.2, 19.6±0.2, 19.9±0.2, 20.3±0.2, 22.0±0.2 , 22.7±0.2, 22.8±0.2, 23.6±0.2, 23.8±0.2, 24.0±0.2, 24.2±0.2, 25.0±0.2, 25.5±0.2, 26.6±0.2, 27.0±0.2, 27.5±0.2, 28.3±0.2, 28.9±0.2, 30.0±0.2, 30.7±0.2, 31.5±0.2, 32.9±0.2, 34.2±0.2, 35.2±0.2, 36.1±0.2, 37.2±0.2, 37.8±0.2, 38.8±0.2 degrees have characteristic peaks, which are basically as Figure 1 Powder X-ray diffraction pattern shown.

[0011] The preparation method of the compound comprises the steps of reacting formula (1a), cyanamide and concentrated hydrochloric acid:

[0012]

[0013] a) dissolving the formula (1a) and cyanamide in an organic solvent A, adding concentrated hydrochloric acid, and heating to react;

[0014] b) After the reaction is completed, the temperature is controlled at 0°C to 50°C, and an organic solvent B is added for crystallization, filtration and drying.

[0015] Furthermore, in step a), the organic solvent A is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, and isoamyl alcohol, preferably isopropanol, n-butanol, or n-pentanol; in step b), the organic solvent B is selected from one or more of methyl tert-butyl ether, cyclohexane, n-hexane, petroleum ether, isopropyl ether, and tetrahydrofuran, preferably n-hexane or methyl tert-butyl ether; the molar ratio of formula (1a), cyanamide, and concentrated hydrochloric acid is 1.0:1.1-3.0:0.8-2.0, preferably 1.0:1.5-2.5:1.0-1.5; the volume weight ratio of organic solvent A to formula (1a) is 2-5:1, in mL / g; the volume weight ratio of organic solvent B to formula (1a) is 2-15:1, preferably 8-10:1, in mL / g.

[0016] Furthermore, the reaction temperature in step a) is 40°C to 100°C; the reaction temperature in step b) is 0°C to 30°C, preferably 0 to 10°C.

[0017] Furthermore, the purity of the product obtained by the preparation method is above 85%, preferably above 95%, and more preferably above 99%.

[0018] In addition, the present invention provides a method for preparing nilotinib, using the compound of formula (1) as an intermediate, comprising the following steps: 1) reacting the compound of formula (2) with the compound of formula (1) in the presence of a base to obtain a compound of formula (3); 2) reacting the compound of formula (3) with a chlorinating agent, and then reacting with the compound of formula (4) to obtain nilotinib;

[0019]

[0020] The chlorinating agent is selected from thionyl chloride, oxalyl chloride or phosphorus oxychloride.

[0021] Furthermore, the specific steps of the preparation method are as follows:

[0022] a) reacting the compound of formula (2) with the compound of formula (1) in the presence of a base, adding an acid to adjust the pH to 3-4, and crystallizing at 0-20°C to obtain a compound of formula (3);

[0023] b) dissolving the compound of formula (3) in an organic solvent C, reacting with a chlorinating agent, adding a compound of formula (4), controlling the temperature not to exceed 70° C., and adjusting the pH to 9 to 11 with an alkali to obtain nilotinib;

[0024] The base is selected from sodium hydroxide, potassium hydroxide or sodium carbonate; the acid is selected from hydrochloric acid or glacial acetic acid; and the organic solvent C is selected from N-methylpyrrolidone, N,N-dimethylformamide or dimethyl sulfoxide.

[0025] Furthermore, in the method for preparing nilotinib, the formula (1) is substantially as follows Figure 1 Powder X-ray diffraction pattern shown.

[0026] The crystal form of the compound of formula (1) provided by the present invention has high purity, good stability, and is easy to store. It is more suitable for use as a synthetic raw material in industrial production than 3-guanidino-4-methylbenzoic acid methyl ester nitrate in the prior art; the crystal preparation process is simple to operate and has a short reaction time of about 5h to 8h; the post-treatment filtration is rapid, the product yield is above 90%, and the purity is above 95%, which is suitable for industrial production. In addition, the reaction yield of preparing nilotinib using the provided crystal form of the compound of formula (1) as a reaction raw material is high, the three wastes generated are less, it is environmentally friendly, and it is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1: X-ray powder diffraction pattern of 3-guanidino-4-methylbenzoic acid methyl ester hydrochloride monohydrate crystals;

[0028] Figure 2 : Infrared spectrum of 3-guanidino-4-methylbenzoic acid methyl ester hydrochloride monohydrate crystals; Implementation

[0029] Experimental Example 1-10 Preparation of Crystalline Form of Compound of Formula (1)

[0030] Add 20 ml of isopropanol into a 100 ml reaction bottle, start stirring, add 10 g of formula (1a), add the corresponding amount of cyanamide as shown in the table below, drop the corresponding amount of concentrated hydrochloric acid into the system, heat to 60-80°C for reaction for 2 h, cool the system to below 20°C, add 52.8 g of petroleum ether for crystallization, control the temperature at 0°C-10°C for crystallization for 1 h, centrifuge, rinse once with a small amount of petroleum ether, collect the filter cake and dry under reduced pressure at 45°C±5°C for 3 h to obtain the crystalline form of the compound of formula (1). The yield and purity are shown in the following table.

[0031]

[0032]

[0033] Experimental Example 11-15 Preparation of Crystalline Form of Compound of Formula (1)

[0034] Add 15 ml of n-butanol to a 100 ml reaction bottle, start stirring, add 5 g of formula (1a), add a corresponding amount of monocyanamide as shown in the table below, drop a corresponding amount of concentrated hydrochloric acid into the system, heat the system for reaction for 3 h as shown in the table, cool the system to below 30°C, add 60 ml of methyl tert-butyl ether for crystallization, drop the internal temperature to 0°C-10°C and crystallize for 1 h, centrifuge, rinse once with a small amount of methyl tert-butyl ether, collect the filter cake and dry it under reduced pressure at 50°C±5°C for 1 h to obtain the crystalline form of the compound of formula (1), with yield and purity as shown in the table.

[0035]

[0036] Experimental Example 16-20 Preparation of Crystalline Forms of Compounds of Formula (1)

[0037] According to the table, add the corresponding amount of n-pentanol to a 200ml three-necked flask, add 20g of formula (1a), add the corresponding amount of and cyanamide according to the table under stirring, drop the corresponding amount of concentrated hydrochloric acid into the system, raise the temperature to 65-75℃ and react for 5h, cool the system to below 30℃, add 90ml of n-hexane for crystallization, drop the internal temperature to 0℃-10℃ and crystallize for 30min, centrifuge, rinse once with a small amount of n-hexane, collect the filter cake and dry it under reduced pressure at 50℃±5℃ for 6h to obtain the crystal form of the compound of formula (1), the yield and purity are as shown in the table.

[0038]

[0039] Experimental Example 21-26 Preparation of Crystalline Forms of Compounds of Formula (1)

[0040] Add 40 mL of n-pentanol to a 200 mL three-necked flask, add 20 g of the compound of formula (1a), add a corresponding amount of cyanamide as shown in the table below, drop a corresponding amount of concentrated hydrochloric acid into the system, heat to 65-75°C and react for 3 h, cool the system to below 30°C, add methyl tert-butyl ether for crystallization as shown in the table below, cool the system to crystallize for 1 h, centrifuge, rinse once with a small amount of methyl tert-butyl ether, collect the filter cake and dry under reduced pressure at 50°C±5°C for 1 h to obtain the crystalline form of the compound of formula (1). The yield and purity are shown in the table below.

[0041]

[0042] Example 1 Preparation of the Crystalline Form of the Compound of Formula (1)

[0043] 13 ml of n-pentanol was added to a 200 ml three-necked flask, and 6.5 g (39.35 mmol) of formula (1a) and 2.7 g (64.22 mmol) of monocyanamide were added under stirring. 4.3 g (43.73 mmol) of concentrated hydrochloric acid was added dropwise to the system. The temperature was raised to 70-75°C for reaction for 5 h. The system was cooled to below 30°C, and 65 ml of n-hexane was added for crystallization. After the internal temperature was lowered to 0°C-10°C, crystallization was carried out for 30 min. The mixture was centrifuged, rinsed once with a small amount of n-hexane, and the filter cake was collected and dried under reduced pressure at 50°C±5°C for 6 h to obtain a crystalline compound of formula (1). The yield was 95.7%, the purity was 99.8%, and its XRD spectrum was basically as shown below: Figure 1 As shown, the infrared spectrum is Figure 2 shown.

[0044] Example 2 Preparation of Crystalline Form of Compound of Formula (1)

[0045] 60L of n-butanol was added to a 500L reactor, stirring was started, 30.0kg of formula (1a) (181.61mol) and 11.44kg (272.42mol) of cyanamide were added, and then 20.4kg (199.77mol) of concentrated hydrochloric acid was added dropwise to the system. After the addition, the reaction temperature was raised to 60-70°C, and the reaction was kept warm for 4h. The system was cooled to below 30°C, 240L of methyl tert-butyl ether was added for crystallization, and the internal temperature was reduced to 0°C-10°C before crystallization for 4h. The mixture was centrifuged, rinsed once with a small amount of methyl tert-butyl ether, and the filter cake was collected and dried under reduced pressure at 45°C±5°C for 6h to obtain a crystalline compound of formula (1) with a yield of 94.5% and a purity of 99.7%. Its XRD spectrum is basically as shown below. Figure 1 As shown, the infrared spectrum is Figure 2 shown.

[0046] The stability test of the above crystal form was carried out at a temperature of 40°C and a humidity of 75%. The results are as follows:

[0047]

[0048] Example 3 Synthesis of Nilotinib

[0049]

[0050] 1) Add 50 kg of anhydrous ethanol to a 500 L glass-lined reaction tank, stir, then add 10 kg of the compound of formula (1), 5.3 kg of the compound of formula (2) and 3.8 kg of sodium hydroxide, heat to 40°C to 50°C, keep warm for 12 hours, add the prepared sodium hydroxide solution to the above reaction solution, continue to keep warm for 2 hours, cool to 0-20°C, adjust the pH value of the system to pH = 3-5 with an appropriate amount of hydrochloric acid solution, and after adjustment, keep warm at 0°C to 20°C and stir for 2 hours. Filter by suction and collect the filter cake. Dry with air at 60°C to obtain the compound of formula (3), with a yield of 95.3%.

[0051] 2) Add 86 kg of methyl pyrrolidone to a 500 L glass-lined reaction tank, start stirring, add 10 kg of the compound of formula (3), slowly add 5.8 kg of thionyl chloride, heat to 90 ° C, and keep warm for 1 hour. Add 10 kg of the compound of formula (4), add, keep warm at 90 ° C, keep warm for 2 hours, add 100 kg of purified water to the above reaction solution, and adjust the pH value of the system to pH = 9-11 with an appropriate amount of sodium hydroxide solution. After adjustment, cool to 20 ° C ± 5 ° C, keep warm and stir for 3 hours, filter, collect the filter cake, control the temperature at 60 ° C, and air dry to obtain nilotinib with a yield of 87.1% and a purity of 99.9%.

[0052] The stability test of nilotinib prepared by the above method was carried out, and the results were as follows (the illumination experimental conditions were 200w.hr / cm2)+(4500lx±500lx); impurity 1 was 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid; impurity 2 was 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzoic acid methyl ester; impurity 3 was 4-methyl-N-[3-(4-ethyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]benzamide):

[0053]

[0054] The nilotinib prepared by the above method was subjected to an accelerated test (40°C ± 2°C, 75% ± 5% RH), and the results were as follows:

[0055]

[0056]

[0057] The results showed that there was no significant change in the maximum single impurity and total impurity compared with day 0 under light, high temperature (60℃), high humidity (RH75%), high humidity (RH92.5%) and accelerated conditions.

[0058] Comparative Example 1: Synthesis of Nilotinib

[0059]

[0060] 1) Synthesis of 3-guanidino-4-methylbenzoic acid ethyl ester nitrate (intermediate 1):

[0061] Add cyanamide (5.2g, 124mmol) and ethyl 3-amino-4-methylbenzoate (10g, 55.8mmol) to ethanol (60ml), and add concentrated hydrochloric acid (7.2ml, 84.7mmol) dropwise within 10min under stirring. Heat under reflux and react for 12h under stirring. Concentrate to dryness under reduced pressure, add water (60ml) to the residue, cool to 10℃, and add an aqueous solution (26.8ml) of ammonium nitrate (9.0g, 112mmol) dropwise under stirring, and the mixture is finished within about 30min. Add ice water (56ml), continue stirring for 30min, filter, wash the filter cake with ice water (50ml), and dry under reduced pressure at room temperature to obtain a white crystalline solid (11.6g, yield 73.2%, purity 98.3%)

[0062] 2) Synthesis of ethyl 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoate (Intermediate 2):

[0063] Intermediate 1 (3.6 g, 12.7 mmol), formula (2) (2.5 g, 14.2 mmol) and solid sodium hydroxide (0.6 g, 15 mmol) were added to ethanol (48 ml), stirred, heated and refluxed for 68 h. Concentrated to dryness under reduced pressure, ethyl acetate (62 ml) and water (45 ml) were added to the residue, stirred and allowed to stand for stratification. The organic layer was separated and extracted with ethyl acetate (31 ml × 2). The organic layers were combined, washed with water (31 ml) and saturated brine (31 ml) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. n-hexane (10 ml) was added to the residue, stirred for crystallization, filtered, and the filter cake was dried under reduced pressure to obtain a white crystalline solid (3.2 g, yield 73.7%, purity 98.9%).

[0064] 3) Synthesis of Nilotinib:

[0065] Intermediate 2 (2.0 g, 4.9 mmol), 1-hydroxybenzotriazole (HOBT, 1.0 g, 7.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 1.11 g, 5.6 mmol) and triethylamine (TEA, 1.94 ml, 14.8 mmol) were added to acetonitrile (120 ml) under nitrogen protection, stirred until completely dissolved, and reacted at room temperature for 20 min. Formula (4) (1.25 g, 5.4 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure to remove acetonitrile, water (48 ml) was added to the residue, and after complete dissolution, it was extracted with ethyl acetate (48 ml×2), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, n-hexane (12 ml) was added to the residue, stirred for crystallization, filtered, and the filter cake was dried under reduced pressure to obtain an off-white solid nilotinib (2.2 g, yield 71.6%, purity 98.7%).

Claims

1. A method for preparing nilotinib, characterized in that The compound of formula (1) is used as an intermediate, comprising the following steps: 1) in the presence of a base, the compound of formula (2) reacts with the compound of formula (1) to obtain a compound of formula (3); 2) reacting the compound of formula (3) with a chlorinating agent, and then reacting with the compound of formula (4) to obtain nilotinib; wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride or phosphorus oxychloride; The preparation method of the compound of formula (1) comprises the steps of reacting a compound of formula (1a), cyanamide and concentrated hydrochloric acid: a) dissolving the compound of formula (1a) and cyanamide in an organic solvent A, adding concentrated hydrochloric acid, and heating to react; b) after the reaction is completed, the temperature is controlled at 0°C to 50°C, an organic solvent B is added for crystallization, filtration and drying; The organic solvent A is selected from isopropanol, n-butanol or n-pentanol; The organic solvent B is selected from n-hexane or methyl tert-butyl ether; In step a), the volume weight ratio of the organic solvent A to the compound of formula (1a) is 2 to 5:1, in units of mL / g; In step b), the volume weight ratio of the organic solvent B to the compound of formula (1a) is 8 to 10:1, in units of mL / g.

2. The preparation method according to claim 1, wherein the specific operations of step 1) and step 2) are as follows: 1) in the presence of a base, reacting the compound of formula (2) with the compound of formula (1), adding an acid to adjust the pH to 3-4, and crystallizing at 0-20°C to obtain the compound of formula (3); 2) the compound of formula (3) is dissolved in an organic solvent C, reacted with a chlorinating agent, and the compound of formula (4) is added, the temperature is controlled not to exceed 70° C., and the pH is adjusted to 9 to 11 with an alkali to obtain nilotinib; The base is selected from sodium hydroxide, potassium hydroxide or sodium carbonate; The acid is selected from hydrochloric acid or glacial acetic acid; The organic solvent C is selected from N-methylpyrrolidone, N,N-dimethylformamide or dimethyl sulfoxide.

3. The preparation method according to claim 1 or 2, wherein in the preparation method of the compound of formula (1), the molar ratio of the compound of formula (1a), cyanamide and concentrated hydrochloric acid in step a) is 1.0:1.5-2.5:1.0-1.

5.

4. The preparation method according to claim 3, wherein the reaction temperature in step a) is 40°C to 100°C; and the temperature in step b is controlled at 0 to 10°C.

5. The preparation method according to claim 4, wherein the purity of the compound of formula (1) obtained by the preparation method of the compound of formula (1) is above 95%.

6. The preparation method according to claim 1, wherein the X-ray powder diffraction of the compound of formula (1) has characteristic peaks at diffraction angles 2θ of 10.0±0.2, 10.1±0.2, 17.4±0.2, 17.9±0.2, 19.6±0.2, 19.9±0.2, and 27.0±0.

2.

7. The preparation method according to claim 6, wherein the compound of formula (1) has a powder X-ray diffraction pattern substantially as shown in Figure 1.

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