Process for the preparation of a neratinib intermediate

Abstract

The application provides a preparation method of a new intermediate (a compound of formula III) of neratinib. The preparation method provided by the application is simple in operation, high in yield, avoids generation of potential genotoxic impurities ethyl methanesulfonate, controllable in product quality, and more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing a neratinib intermediate. Background Technology

[0002] Neratinib, also known as neratinib, is a receptor tyrosine kinase inhibitor with the chemical name (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinoline-6-yl)-4-(dimethylamino)but-2-enamide, and has the following structure:

[0003]

[0004] Neratinib maleate is an orally administered, irreversible pan-human epidermal growth factor receptor (EGFR) inhibitor that inhibits HER1, HER2, and HER4 receptors and their associated tyrosine kinases. Originally developed by Wyeth Pharmaceuticals, it was acquired by Pfizer and licensed to PUMA Biosciences for research, development, marketing, production, and sales. Neratinib maleate was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for extended adjuvant therapy in patients with early-stage HER2-positive breast cancer who have received standard adjuvant therapy with trastuzumab, under the brand name Nerlynx®.

[0005] Wyeth, the original manufacturer, disclosed a method for preparing neratinib in its process patent WO2006 / 127207. In the process of condensing N-(4-chloro-3-cyano-7-ethoxyquinoline-6-yl)acetamide (compound I) with [3-chloro-4-(pyridin-2-methoxy)phenyl]methylamine (compound II) in ethanol solvent to obtain the key intermediate N-(4-((3-chloro-4-(pyridin-2-methoxy)phenyl)amino)-3-cyano-7-ethoxyquinoline-6-yl)acetamide (compound III), the catalyst methanesulfonic acid reacts with ethanol to generate ethyl methanesulfonate, a potentially genotoxic impurity.

[0006] Therefore, developing a new method for preparing a compound of formula III is of great significance for the quality control and industrial production of neratinib.

[0007] Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a new method for preparing neratinib intermediate (compound of formula III). This method is simple to operate, has a high yield, and has controllable quality, making it more suitable for industrial production.

[0009] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0010] A method for preparing a compound of formula III, characterized by comprising the following steps:

[0011]

[0012] Step (1): React compound I with compound II in the presence of a catalyst;

[0013] Step (2): Cool the reaction solution obtained in step (1) to allow it to crystallize, and separate the solid and liquid to obtain compound III.

[0014] In one embodiment of the present invention, the catalyst in step (1) is selected from one or more of pyridine, pyridine hydrochloride, glacial acetic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0015] In one specific embodiment of the present invention, the catalyst in step (1) is pyridine.

[0016] In one embodiment of the present invention, the reaction solvent in step (1) is an alcohol solvent; preferably, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol; more preferably, the alcohol solvent is ethanol.

[0017] In one specific embodiment of the present invention, the reaction solvent in step (1) is anhydrous ethanol.

[0018] In one specific embodiment of the present invention, the reaction solvent in step (1) is 95% ethanol.

[0019] In one embodiment of the present invention, the molar ratio of compound I to compound II in step (1) is 1: (0.8~1.2), preferably 1: (1~1.1), and more preferably 1: 1.05.

[0020] In one embodiment of the present invention, the percentage of catalyst mass to reactant mass in step (1) is 0.1% to 10%, preferably 0.3% to 3%, more preferably 0.5% to 2%; the reactant mass refers to the sum of the masses of compound I and compound II.

[0021] In one specific embodiment of the present invention, the percentage of catalyst mass to reactant mass in step (1) is 1%; the reactant mass refers to the sum of the masses of compound I and compound II.

[0022] In one exemplary embodiment of the present invention, the mass of the catalyst in step (1) is 92.5 mg, and the sum of the masses of the compounds of formula I and formula II is 9.25 g.

[0023] In one embodiment of the present invention, the mass-to-volume ratio of the sum of the masses of compound I and compound II to the reaction solvent in step (1) is 1: (5~40) g / ml, preferably 1: (10~30) g / ml, and more preferably 1:20 g / ml.

[0024] In one exemplary embodiment of the present invention, the sum of the masses of compound I and compound II in step (1) is 9.25 g, and the volume of the reaction solvent is 185 ml.

[0025] In one embodiment of the present invention, the reaction temperature in step (1) is 50~90℃ and the reaction time is 2~10h; preferably, the reaction temperature is 73~83℃ and the reaction time is 4~8h.

[0026] In one embodiment of the present invention, the cooling and crystallization temperature in step (2) is 5~50℃ and the crystallization time is 0.5~5h; preferably, the cooling and crystallization temperature is 20~30℃ and the crystallization time is 0.5~2h.

[0027] Furthermore, the present invention also provides a method for preparing neratinib and its pharmaceutically acceptable salts from compounds of formula III, wherein the preparation method may refer to the synthetic route disclosed in WO2006 / 127207.

[0028] The term "pharmaceutical acceptable" means that, with respect to those compounds, materials, compositions, and / or dosage forms, they are suitable for use in contact with human and animal tissues, within the limits of reliable medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0029] In one embodiment of the present invention, the pharmaceutically acceptable salt of neratinib is a maleate salt having the structure shown in Formula IV:

[0030] .

[0031] The terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0032] "Percentage by volume" or "% (w / v)" or "% w / v" is a way of expressing mass-volume concentration, indicating the number of grams of solute contained in 100 ml of solution. For example, 20% (w / v) means that 100 ml of solution contains 20 g of solute.

[0033] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0034] The beneficial effects of this invention are:

[0035] This invention provides a novel method for preparing a neratinib intermediate (compound of formula III). The preparation method provided by this invention is simple to operate, has a high yield, avoids the generation of potentially genotoxic impurity ethyl methanesulfonate, and ensures controllable product quality, making it more suitable for industrial production. Detailed Implementation

[0036] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Equivalent substitutions or corresponding improvements made to the present invention are still within the scope of protection of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0037] Example 1

[0038] Anhydrous ethanol (295.99 kg) was added to a 500 L reactor and stirred. Then, compound I (10.140 kg), compound II (8.624 kg), and pyridine (0.189 kg) were added. The reaction mixture was heated to 80 ± 3 °C and reacted for 4 h.

[0039] After the predetermined reaction time, the temperature of the reaction solution was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5h to induce crystallization. The solid and liquid were separated by centrifugation to obtain the wet product of compound III.

[0040] The wet product of Formula III compound can be directly used for the next feeding step.

[0041] Example 2

[0042] Anhydrous ethanol (295.99 kg) was added to a 500 L reactor and stirred. Then, compound I (10.140 kg), compound II (8.624 kg), and pyridine (0.189 kg) were added. The reaction mixture was heated to 80 ± 3 °C and reacted for 4.5 h.

[0043] After the predetermined reaction time, the temperature of the reaction solution was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5h to induce crystallization. The solid and liquid were separated by centrifugation to obtain the wet product of compound III.

[0044] Example 3

[0045] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0046] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 93.4% and a purity of 99.66%.

[0047] Example 4

[0048] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (46.3 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0049] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 91.8% and a purity of 96.81%.

[0050] Example 5

[0051] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (185 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0052] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, and the filter cake was dried to obtain compound III with a yield of 94.3% and a purity of 99.69%.

[0053] Example 6

[0054] Add 181 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.05 g, 17.26 mmol, 1 eq), and pyridine (90.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0055] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 90.6% and a purity of 97.28%.

[0056] Example 7

[0057] Add 189 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.45 g, 18.96 mmol, 1.1 eq), and pyridine (94.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0058] After the predetermined reaction time, the temperature of the reaction solution was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 97.7% and a purity of 90.31%.

[0059] Example 8

[0060] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 8 h.

[0061] After the predetermined reaction time, the temperature of the reaction solution was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, and the filter cake was washed and dried to obtain compound III with a yield of 94.3% and a purity of 99.78%.

[0062] Example 9

[0063] Add 185 ml of methanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0064] After the predetermined reaction time, the temperature of the reaction solution was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 72.3% and a purity of 99.42%.

[0065] Example 10

[0066] Add 185 ml of 95% ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0067] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 78.1% and a purity of 93.46%.

[0068] Example 11

[0069] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0070] After the predetermined reaction time, the temperature of the reaction solution was lowered to 40±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III, with a yield of 92.3% and a purity of 99.72%.

[0071] Example 12

[0072] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0073] After the predetermined reaction time, the temperature of the reaction solution was lowered to 10±5℃, and the mixture was stirred under controlled temperature for 0.5 h to induce crystallization. The mixture was then filtered, the filter cake was washed and dried to obtain compound III with a yield of 94.4% and a purity of 99.77%.

[0074] Example 13

[0075] Add 185 ml of anhydrous ethanol to the reaction flask and stir. Then add compound I (5 g, 17.26 mmol, 1 eq), compound II (4.25 g, 18.11 mmol, 1.05 eq), and pyridine (92.5 mg). Heat the reaction mixture to 78 ± 5 °C and react for 4 h.

[0076] After the predetermined reaction time, the reaction solution temperature was lowered to 25±5℃, and the mixture was stirred under controlled temperature for 2 hours to induce crystallization. The mixture was then filtered, and the filter cake was washed and dried to obtain compound III with a yield of 95.2% and a purity of 99.79%.

[0077] Comparative Example 1

[0078] Other reaction conditions were the same as in Example 3, except that the reaction time was adjusted to 2 hours. Some of the product contained unreacted compound I.

[0079] Comparative Example 2

[0080] Other reaction conditions were the same as in Example 3, except that the solvent was replaced with ethyl acetate, and no reaction occurred.

[0081] Comparative Example 3

[0082] Other reaction conditions were the same as in Example 3, except that the solvent was replaced with isopropanol, and some of the product contained unreacted compound I.

[0083] Comparative Example 4

[0084] Other reaction conditions were the same as in Example 3, except that the solvent was replaced with acetonitrile, and no reaction occurred.

[0085] Comparative Example 5

[0086] Other reaction conditions were the same as in Example 3, except that the solvent was replaced with tetrahydrofuran, and no reaction occurred.

[0087] Comparative Example 6

[0088] Other reaction conditions are the same as in Example 3, except that the reaction temperature is adjusted to 55±5℃, and there is basically no reaction.

[0089] Comparative Example 7

[0090] Other reaction conditions are the same as in Example 3, except that the reaction temperature is adjusted to 65±5℃, and there is basically no reaction.

[0091] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula III, characterized in that, The steps include the following: Step (1): React compound I with compound II in the presence of a catalyst; Step (2): Cool the reaction solution obtained in step (1) to allow it to crystallize, and separate the solid and liquid to obtain compound III.

2. The method according to claim 1, characterized in that, The catalyst in step (1) is selected from one or more of pyridine, pyridine hydrochloride, glacial acetic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably pyridine.

3. The method according to claim 1, characterized in that, The reaction solvent in step (1) is an alcohol solvent; preferably, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol; more preferably, the alcohol solvent is ethanol.

4. The method according to claim 1, characterized in that, In step (1), the molar ratio of compound I to compound II is 1: (0.8~1.2), preferably 1: (1~1.1), and more preferably 1: 1.

05.

5. The method according to claim 1, characterized in that, In step (1), the percentage of catalyst mass to reactant mass is 0.1% to 10%, preferably 0.3% to 3%, and more preferably 0.5% to 2%; The mass of the reactants refers to the sum of the masses of compounds of formula I and formula II.

6. The method according to claim 1, characterized in that, In step (1), the mass-to-volume ratio of the sum of the masses of compound I and compound II to the reaction solvent is 1: (5~40) g / ml, preferably 1: (10~30) g / ml, and more preferably 1:20 g / ml.

7. The method according to claim 1, characterized in that, The reaction temperature in step (1) is 50~90℃ and the reaction time is 2~10h; preferably, the reaction temperature is 73~83℃ and the reaction time is 4~8h.

8. The method according to claim 1, characterized in that, In step (2), the cooling and crystallization temperature is 5~50℃ and the crystallization time is 0.5~5h; preferably, the cooling and crystallization temperature is 20~30℃ and the crystallization time is 0.5~2h.

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