A method for preparing olaratumab maleate

Abstract

The application discloses a preparation method of a trans-7H-pyrrolo[2,3-d]pyrimidine compound, and the full name of the trans-7H-pyrrolo[2,3-d]pyrimidine compound is trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, which is prepared from trans-4-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic acid and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine as starting materials through reduction, chlorination, substitution, oxidation, methylation, condensation and salt formation reactions. The preparation method has the advantages of few reaction steps, simple operation, low production cost, high production efficiency, high yield, high product purity and suitability for scale-up production.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug technology, specifically relating to a method for preparing olatinib maleate. Background Technology

[0002] The full name of the 7H-pyrrolo[2,3-d]pyrimidine compound is trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate (generic name: olalatinib maleate). It was approved by the US FDA in 2013 for the control of itching and atopic dermatitis caused by canine atopic dermatitis. It is a novel Janus kinase inhibitor (JAKi) with dual indications for controlling itching associated with atopic dermatitis and treating atopic dermatitis (AD) in dogs 12 months and older. The chemical structure of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate is as follows:

[0003]

[0004] Currently reported synthetic routes for trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate mainly include:

[0005] Patent WO2010 / 020905 reports a process using trans-4-tert-butoxycarbonylamide cyclohexanecarboxylic acid as a starting material, which is reduced with red aluminum to obtain trans-4-(methylamino)-cyclohexyl]methanol, then condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine under triethylamine catalysis, followed by protection of the hydroxyl and amino groups with p-toluenesulfonyl chloride, substitution with potassium thioacetate, oxidation with hydrogen peroxide / formic acid, chlorination with thionyl chloride, methylation with methylaminetetrahydrofuran, and deprotection with lithium hydroxide to obtain olatinib, which is finally formed as a salt with maleic acid to obtain olatinib maleate.

[0006]

[0007] The synthetic route involves numerous steps. The preparation of [trans-4-(methyl{7-[(4-tolyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclohexyl]methanesulfonic acid requires the use of the explosive chemical hydrogen peroxide, posing a safety risk. Each intermediate undergoes post-processing to separate it. In particular, the preparation of [trans-4-(methyl{7-[(4-tolyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)cyclohexyl]methanesulfonyl chloride requires crystallization from ethyl acetate and hexane, followed by storage in nitrogen, making the process difficult.

[0008] Patent US2017 / 0233397 reports a method for obtaining olatinib maleate from a starting material consisting of benzyl bromide, substituted with sodium sulfite, substituted with methylamine, reduced benzene ring by palladium-catalyzed hydrogenation on carbon, condensed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, chlorinated, methylated, and salted.

[0009]

[0010] Although this route has fewer steps, the hydrogenation of (4-(methylamino)phenyl)methanesulfonic acid onto the benzene ring via Pd / C catalysis produces a mixture of cis and trans products. After recrystallization, approximately 30% of the cis product cannot be isomerized, resulting in low raw material utilization and a large amount of solid waste generated.

[0011] Therefore, it is necessary to develop other, better synthetic methods to produce trans-7H-pyrrolo[2,3-d]pyrimidine compounds. Summary of the Invention

[0012] To address the aforementioned technical problems, the present invention aims to provide a method for preparing olatinib maleate, which has fewer reaction steps, is simple to operate, has low production cost, high production efficiency, high yield, and high product purity, making it suitable for large-scale production.

[0013] To achieve the above-mentioned technical objectives and effects, the present invention is implemented through the following technical solution:

[0014] A method for preparing olatinib maleate includes the following steps:

[0015] (1) Reduction and chlorination: Add trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to the solvent, add reducing agent solution dropwise, heat and reflux to maintain the temperature for reaction; add 5% to 10% sodium hydroxide solution to quench, separate the aqueous layer, concentrate the organic layer to dryness; add dichloromethane, cool and add thionyl chloride dropwise, after the addition is complete, react at room temperature, add saturated sodium bicarbonate solution to wash, separate the layers, dry the lower organic layer with a desiccant, filter, concentrate the filtrate to dryness, and obtain the compound shown in Formula I;

[0016] (2) Substitution and oxidation: Add the compound of formula I obtained in step (1) to the solvent, then add thiourea, reflux the reaction, concentrate and dry to obtain the product of formula II; stir and mix NCS with acetonitrile or acetone, add the acid solution of the product of formula II at low temperature, react at room temperature, add water, concentrate and dry to obtain the white solid of formula III.

[0017] (3) Methylamine and condensation: Add the product of formula III obtained in step (2) to the solvent, cool down, add methylamine solution dropwise, keep the reaction at the temperature after the addition is complete, add water to precipitate the solid, filter, dry to obtain the product of formula IV; add organic solvent, acid-binding agent, potassium iodide and 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to the product of formula IV, reflux condensation reaction, cool to precipitate crystals, filter, wash with water, filter and dry to obtain the product of formula V: trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidine-4-ylamino)cyclohexylmethanesulfonamide;

[0018] (4) Salt formation: Add the product shown in formula V to isopropanol / ethanol, stir, add maleic acid and water, after reaction, cool and crystallize, and dry under vacuum to obtain trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, i.e. olatinib maleate;

[0019] The synthesis route is as follows:

[0020] .

[0021] Furthermore, in step (1), the reducing agent solution is a 70% red aluminum toluene solution or a 1.5M diisobutylaluminum hydride toluene solution.

[0022] Furthermore, in step (1), the molar ratio of the reducing agent to trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid is (5.5-6.0):1; the mass of the sodium hydroxide solution used for quenching the reaction is 6-13 times the mass of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid; wherein, the temperature of the heat preservation reaction is 80-110℃, and the reaction time is 5-6 hours.

[0023] Furthermore, in step (1), the molar ratio of thionyl chloride to trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid is (1.2~1.3):1.

[0024] Furthermore, in step (2), the molar ratio of the compound represented by formula I to thiourea is 1:1.

[0025] Furthermore, in step (2), the molar ratio of NCS to the product shown in Formula II is (3.8~4.0):1.

[0026] Furthermore, in step (3), the molar ratio of the product shown in Formula III to monomethylamine is 1:(5.0~5.5); the temperature for the reaction of the product shown in Formula III with monomethylamine in step (3) is 25℃.

[0027] Furthermore, in step (3), the molar ratio of the product shown in Formula IV, the acid-binding agent, potassium iodide and 4-chloro-7H-pyrrolo[2,3D]pyrimidine is (1-1.5):(1.3-1.8):(0.05-0.15):1; the temperature of the reflux condensation reaction is 80-100℃ and the reaction time is 8h.

[0028] Furthermore, the acid-binding agent in step (3) is potassium carbonate or sodium carbonate.

[0029] Furthermore, in step (4), the molar ratio of the product shown in formula V to maleic acid is 1:1.

[0030] Furthermore, the reaction temperature in step (4) is 25°C and the reaction time is 2 to 4 hours.

[0031] The beneficial effects of this invention are:

[0032] This invention presents a novel preparation method that utilizes inexpensive and readily available raw materials, involves fewer reaction steps, is simple to operate, has low production costs, high production efficiency, high yield, and high product purity, making it suitable for mass production and meeting market demand. The novel route designed in this invention involves reacting the product from the reduction reaction of trans-4-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic acid with thionyl chloride to obtain a chloride, which is then reacted with thiourea and NCS to yield the corresponding sulfonyl chloride. This avoids the use of odorous potassium thioacetate and hazardous hydrogen peroxide, as well as the cumbersome catalytic hydrogenation step, thus not only improving yield but also reducing production costs and minimizing environmental impact. Attached Figure Description

[0033] Figure 1 The NMR spectrum of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate prepared in Example 1 of this invention is shown. Detailed Implementation

[0034] The technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] This invention provides a method for preparing olatinib maleate, comprising the following steps:

[0036] (1) Reduction and chlorination: Add trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to the solvent, add reducing agent solution dropwise, heat and reflux to maintain the temperature for reaction; add 5% to 10% sodium hydroxide solution to quench, separate the aqueous layer, concentrate the organic layer to dryness; add dichloromethane, cool and add thionyl chloride dropwise, after the addition is complete, react at room temperature, add saturated sodium bicarbonate solution to wash, separate the layers, dry the lower organic layer with a desiccant, filter, concentrate the filtrate to dryness, and obtain the compound shown in Formula I;

[0037] In step (1), the reducing agent solution is a 70% red aluminum toluene solution or a 1.5M diisobutylaluminum hydride toluene solution. The molar ratio of the reducing agent (red aluminum or diisobutylaluminum hydride) to trans-4-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic acid is (5.5–6.0):1; the mass of the sodium hydroxide solution used for the quenching reaction is 6–13 times the mass of trans-4-[(tert-butoxycarbonyl)amino]cyclohexane carboxylic acid; the temperature of the reduction and heat preservation reaction is 80–110°C, and the reaction time is 5–6 hours.

[0038] In step (1), the molar ratio of thionyl chloride to trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid is (1.2-1.3):1.

[0039] The solvent used in step (1) is preferably toluene or tetrahydrofuran.

[0040] (2) Substitution and oxidation: Add the compound of formula I obtained in step (1) to the solvent, then add thiourea, reflux the reaction, concentrate and dry to obtain the product of formula II; stir and mix NCS with acetonitrile or acetone, add the acid solution of the product of formula II at low temperature, react at room temperature, add water, concentrate and dry to obtain the white solid of formula III.

[0041] In step (2), the molar ratio of [trans-4-(chloromethyl)cyclohexane](methyl)amine to thiourea is 1:1.

[0042] In step (2), the molar ratio of NCS to the product shown in Formula II is (3.8-4.0):1.

[0043] The solvent used in step (2) is preferably one of ethanol, isopropanol, and methanol.

[0044] (3) Methylamine and condensation: Add the product of formula III obtained in step (2) to the solvent, cool down, add methylamine solution dropwise, keep the reaction at the temperature after the addition is complete, add water to precipitate the solid, filter, dry to obtain the product of formula IV; add organic solvent, acid-binding agent, potassium iodide and 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to the product of formula IV, reflux condensation reaction, cool to precipitate crystals, filter, wash with water, filter and dry to obtain the product of formula V: trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidine-4-ylamino)cyclohexylmethanesulfonamide;

[0045] In step (3), the molar ratio of the product shown in Formula III to monomethylamine is 1:(5.0~5.5); the reaction temperature of the product shown in Formula III and monomethylamine in step (3) is 25℃.

[0046] In step (3), the molar ratio of the product shown in Formula IV, the acid-binding agent, potassium iodide, and 4-chloro-7H-pyrrolo[2,3-D]pyrimidine is (1-1.5):(1.3-1.8):(0.05-0.15):1; the temperature of the reflux condensation reaction is 80-100℃, and the reaction time is 8h.

[0047] The acid-binding agent in step (3) is potassium carbonate or sodium carbonate.

[0048] (4) Salt formation: Add the product shown in Formula V to isopropanol / ethanol, stir, add maleic acid and water, and after reaction, cool and crystallize, and dry under vacuum to obtain trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, i.e., olatinib maleate.

[0049] In step (4), the molar ratio of the product shown in formula V to maleic acid is 1:1;

[0050] The reaction temperature in step (4) is 25℃ and the reaction time is 2 to 4 hours.

[0051] The synthetic route of this preparation method is as follows:

[0052] .

[0053] Example 1

[0054] A method for preparing olatinib maleate includes the following steps:

[0055] Step 1: Preparation of the compound shown in Formula I

[0056]

[0057] Add 1000 ml of toluene and 90 g (0.37 mol) of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to a 3 L four-necked reaction flask. Stir, purge twice with nitrogen, cool to 0-5 °C, and add 630 g (2.18 mol) of 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution dropwise, maintaining the temperature at approximately 5 °C. After the addition is complete, raise the temperature to 110 °C and maintain the reaction temperature for 5-6 hours. Cool down, add 1120 g of 5% sodium hydroxide solution dropwise, and stir for 30 minutes after the addition is complete. The mixture separates into layers, and the organic phase is dried and concentrated to dryness. Add 500 ml of dichloromethane, stir, and cool to 0 °C. Add 53 g (0.445 mol) of thionyl chloride dropwise, and stir at room temperature for 30 minutes after the addition is complete. Then reflux for 1 hour, cool to room temperature, wash with 100 ml of saturated sodium bicarbonate solution, separate into layers, dry the organic phase, and concentrate to dryness to obtain 51 g of the compound shown in Formula I, with a yield of 86.5%.

[0058] Step 2: Preparation of the product shown in Formula II

[0059]

[0060] Add 400 ml of ethanol, 50 g (0.31 mol) of the compound shown in Formula I, and 23.6 g (0.31 mol) of thiourea to a four-necked reaction flask. Heat under reflux for 2 hours, cool to 25°C, concentrate under reduced pressure to remove more than half of the ethanol, cool to 0°C, and a large amount of solid precipitates. Filter, and wash the filter cake with cold ethanol. Continue to concentrate the mother liquor to remove most of the solid, and another solid precipitates. Cool, filter, combine, and vacuum dry to obtain 56 g of the product shown in Formula II. No purification is required; proceed directly to the next step.

[0061] Step 3: Preparation of the compound shown in Formula III

[0062]

[0063] Add 350 ml of acetonitrile and 106 g (0.794 mol) of NCS to a reaction flask, cool to 5-10 °C in an ice bath, add 50 ml of 2M hydrochloric acid dropwise, maintaining the temperature at around 10 °C, and stir for 10 minutes after the addition is complete. Add 40 g (0.2 mol) of the compound shown in Formula II in portions, maintaining the temperature at 10-25 °C. When about half of the compound has been added, the system becomes clear and transparent. After all the compound has been added, continue to keep the reaction at this temperature for 1 hour until all the starting materials have reacted. Add 250 ml of water dropwise, stir for 30 minutes, and a solid precipitates. Add the reaction solution to a rotary evaporator, concentrate under reduced pressure to precipitate the solid, filter, wash the filter cake with 100 ml of water, dissolve the solid in 300 ml of dichloromethane, dry with anhydrous sodium sulfate, concentrate to dryness, and dry under vacuum to obtain 41.2 g of the compound shown in Formula III.

[0064] Step 4: Preparation of the product shown in Formula IV

[0065]

[0066] 30 g (0.133 mol) of the compound shown in Formula III and 300 ml of anhydrous tetrahydrofuran were added to reaction flask A. 100 ml of tetrahydrofuran was added to reaction flask B. The mixture was cooled to -30 °C in a dry ice bath. 21 g (0.677 mol) of monomethylamine gas was introduced. The mixture was cooled to about 0 °C. The solution in reaction flask B was added dropwise to flask A. The temperature was controlled below 15 °C. After the addition was complete, the freezer was turned off, and the mixture was allowed to rise naturally to 25 °C. The mixture was stirred for 10 hours. The mixture was filtered, and the filter cake was washed with 100 ml of water. The filter cake was then filtered again and dried under vacuum to obtain 23.4 g of the product shown in Formula IV.

[0067] Step 5: Preparation of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide, the product shown in Formula V

[0068]

[0069] 22 g (0.1 mol) of the compound shown in Formula IV was added to a reaction flask, followed by 100 ml of 1,4-dioxane. 18 g (0.13 mol) of potassium carbonate, 1.9 g (0.011 mol) of potassium iodide, and 15.3 g (0.1 mol) of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine were added under stirring. The mixture was heated to 100 °C and reacted for 8 hours. After cooling to approximately 40 °C, the mixture was filtered, the filter cake was washed with methanol, and the filtrates were combined. The mixture was concentrated under reduced pressure to remove about half of the residue. 100 ml of ethyl acetate was added, and the mixture was stirred at 50 °C. After cooling to 10 °C, the mixture was filtered and dried under vacuum to obtain 27.2 g of trans-N-methyl-4-(methyl7Hpyrrolo[2,3d]pyrimidine-4-ylamino)cyclohexylmethanesulfonamide.

[0070] Step 6: Salt formation

[0071]

[0072] 35 g (0.104 mol) of the compound shown in Formula V, 200 ml of ethanol, and 12.1 g (0.104 mol) of maleic acid were added to a reaction flask. The mixture was stirred and heated to reflux for 2 hours. After cooling to 0°C, crystals were precipitated for 2 hours. The mixture was filtered, and the filter cake was washed with cold ethanol and dried under vacuum to obtain 40 g of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, with a purity of 98.7% and a water content of 0.1%. Figure 1 The NMR spectrum of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate obtained in Example 1 is shown below.

[0073] :

[0074] 1.26-1.31(2H), 1.72-1.86(5H), 2.05-2.08(2H), 2.53-2.60(3H), 2.97-2.98(2H), 3.19-3.34(3H), 4.68(1H), 6.56(1H), 6.90(1H) 7.13(1H), 8.11(1H), 11.63(1H).

[0075] Example 2

[0076] A method for preparing olatinib maleate includes the following steps:

[0077] Step 1: Preparation of the compound shown in Formula I

[0078]

[0079] Add 3000 ml of toluene and 250 g (1.03 mol) of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to a 10 L four-necked reaction flask. Stir, purge twice with nitrogen, cool to 0-5 °C, and add 1750 g (6.06 mol) of 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution dropwise. Maintain the temperature at around 5 °C. After the addition is complete, raise the temperature to 110 °C and maintain the reaction temperature for 5-6 hours. Cool down and add 3100 g of 5% sodium hydroxide solution dropwise. Stir for 30 minutes after the addition is complete. The mixture separates into layers. Dry the organic phase and concentrate it to dryness. Add 1300 ml of dichloromethane, stir, cool to 0 °C, add 150 g (1.26 mol) of thionyl chloride dropwise, stir at room temperature for 30 minutes after the addition is complete, then reflux for 1 hour, cool to room temperature, wash with 300 ml of saturated sodium bicarbonate solution, separate into layers, dry the organic phase, concentrate to obtain the compound shown in Formula I: 138 g, yield 84.1%.

[0080] Step 2: Preparation of the product shown in Formula II

[0081]

[0082] Add 600 ml of isopropanol, 75 g (0.466 mol) of the compound shown in Formula I, and 35.5 g (0.467 mol) of thiourea to a four-necked reaction flask. Heat under reflux for 2 hours, cool to 25°C, concentrate under reduced pressure to remove more than half of the isopropanol, cool to 0°C, and a large amount of solid precipitates. Filter, and wash the filter cake with cold isopropanol. Continue to concentrate the mother liquor to remove most of the solid, and another solid precipitates. Cool, filter, combine, and vacuum dry to obtain 90.3 g of the product shown in Formula II. No purification is required; proceed directly to the next step.

[0083] Step 3: Preparation of the compound shown in Formula III

[0084]

[0085] Add 1050 ml of acetonitrile and 318 g (2.38 mol) of NCS to a reaction flask, cool to 5-10 °C in an ice bath, add 150 ml of 2M hydrochloric acid dropwise, maintaining the temperature at around 10 °C, and stir for 10 minutes after the addition is complete. Add 120 g (0.597 mol) of the compound shown in Formula II in portions, maintaining the temperature at 10-25 °C. When about half of the compound has been added, the system becomes clear and transparent. After all the compound has been added, continue to maintain the temperature for 1 hour to ensure that all the starting materials have reacted. Add 750 ml of water dropwise, stir for 30 minutes, and a solid precipitates. Add the reaction solution to a rotary evaporator, concentrate under reduced pressure to precipitate the solid, filter, wash the filter cake with 300 ml of water, dissolve the solid in 1000 ml of dichloromethane, dry with anhydrous sodium sulfate, concentrate to dryness, and dry under vacuum to obtain 130.7 g of the compound shown in Formula III.

[0086] Step 4: Preparation of the product shown in Formula IV

[0087]

[0088] 135 g (0.6 mol) of the compound shown in Formula III and 1350 ml of anhydrous tetrahydrofuran were added to reaction flask A. 400 ml of tetrahydrofuran was added to reaction flask B. The mixture was cooled to -30°C in a dry ice bath, and 95 g (3.05 mol) of monomethylamine gas was introduced. Reaction flask A was cooled to approximately 0°C. The solution from reaction flask B was added dropwise to flask A, maintaining the temperature below 15°C. After the addition was complete, the freeze was shut off, and the mixture was allowed to naturally warm to 25°C. The mixture was stirred for 10 hours. The mixture was filtered, and the filter cake was washed with 400 ml of water, filtered again, and vacuum dried to obtain 106.1 g of the product shown in Formula IV.

[0089] Step 5: Preparation of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide, the product shown in Formula V

[0090]

[0091] Add 30 g (0.136 mol) of the compound shown in Formula IV to a reaction flask, add 110 ml of acetonitrile, and add 24.4 g (0.177 mol) of potassium carbonate, 2.2 g (0.0136 mol) of potassium iodide and 20.9 g (0.1 mol) of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine while stirring. Heat to 80 °C and react for 8 hours. Cool to about 40 °C, filter, wash the filter cake with methanol, combine the filtrates, concentrate under reduced pressure to remove about half, add 120 ml of ethyl acetate, stir at 50 °C, cool to 10 °C, filter, and dry under vacuum to obtain 39.3 g of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidine-4-ylamino)cyclohexylmethanesulfonamide.

[0092] Step 6: Salt formation

[0093]

[0094] 100 g (0.297 mol) of the compound shown in Formula V, 600 ml of ethanol, and 34.5 g (0.297 mol) of maleic acid were added to a reaction flask. The mixture was stirred and heated to reflux for 2 hours. After cooling to 0°C, crystals were precipitated for 2 hours. The mixture was filtered, and the filter cake was washed with cold ethanol and dried under vacuum to obtain 115 g of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, with a purity of 99.3% and a water content of 0.16%.

[0095] Example 3

[0096] A method for preparing olatinib maleate includes the following steps:

[0097] Step 1: Preparation of the compound shown in Formula I

[0098]

[0099] Add 1500 ml of anhydrous tetrahydrofuran and 135 g (0.556 mol) of trans-4-[(tert-butyloxycarbonyl)amino]cyclohexanecarboxylic acid to a 5 L four-necked reaction flask. Stir, purge twice with nitrogen, cool to 0-5 °C, and add 2200 ml (3.3 mol) of 1.5 M diisobutylaluminum hydride toluene solution dropwise, maintaining the temperature at approximately 5 °C. After the addition is complete, raise the temperature to 80 °C and maintain the reaction temperature for 5-6 hours. Cool down, add 1700 g of 5% sodium hydroxide solution dropwise, and stir for 30 minutes after the addition is complete. The mixture separates into layers, and the organic phase is dried and concentrated to dryness. Add 800 ml of dichloromethane, stir, and cool to 0 °C. Add 80 g (0.669 mol) of thionyl chloride dropwise, and stir at room temperature for 30 minutes after the addition is complete. Then reflux for 1 hour, cool to room temperature, wash with 140 ml of saturated sodium bicarbonate solution, separate into layers, dry the organic phase, and concentrate to dryness to obtain 68.3 g of the compound shown in Formula I, with a yield of 79.5%.

[0100] Step 2: Preparation of the product shown in Formula II

[0101]

[0102] Add 400 ml of methanol, 50 g (0.31 mol) of the compound shown in Formula I, and 23.6 g (0.31 mol) of thiourea to a four-necked reaction flask. Heat under reflux for 2 hours, cool to 25°C, concentrate under reduced pressure to remove most of the methanol, cool to 0°C, and a large amount of solid precipitates. Filter, and wash the filter cake with cold methanol. Continue to concentrate the mother liquor to remove most of the solid, and another solid precipitates. Cool, filter, combine, and vacuum dry to obtain 52 g of the product shown in Formula II. No purification is required; proceed directly to the next step.

[0103] Step 3: Preparation of the compound shown in Formula III

[0104]

[0105] Add 550 ml of acetone and 159 g (1.19 mol) of NCS to a reaction flask, cool to 5-10 °C in an ice bath, add 75 ml of 1M sulfuric acid dropwise, maintaining the temperature at approximately 10 °C. After the addition is complete, stir for 10 minutes. Add 60 g (0.298 mol) of the compound shown in Formula II in portions, maintaining the temperature at 10-25 °C. When about half of the compound has been added, the system becomes clear and transparent. After all the compound has been added, continue to maintain the temperature for 1 hour to ensure that all the starting materials have reacted. Add 375 ml of water dropwise, stir for 30 minutes, and a solid precipitates. Add the reaction solution to a rotary evaporator, concentrate under reduced pressure to precipitate the solid, filter, wash the filter cake with 150 ml of water, dissolve the solid in 450 ml of dichloromethane, dry with anhydrous sodium sulfate, concentrate to dryness, and dry under vacuum to obtain 63.3 g of the compound shown in Formula III.

[0106] Step 4: Preparation of the product shown in Formula IV

[0107]

[0108] 63 g (0.28 mol) of the compound shown in Formula III and 650 ml of dichloromethane were added to reaction flask A. 200 ml of dichloromethane was added to reaction flask B. The mixture was cooled to -30°C in a dry ice bath. 44.2 g (1.42 mol) of monomethylamine gas was introduced. Reaction flask A was cooled to approximately 0°C. The solution from reaction flask B was added dropwise to flask A, maintaining the temperature below 15°C. After the addition was complete, the freeze was shut off, and the mixture was allowed to naturally warm to 25°C. The mixture was stirred for 10 hours. The mixture was filtered, and the filter cake was washed with 200 ml of water, filtered again, and then vacuum dried to obtain 50.1 g of the product shown in Formula IV.

[0109] Step 5: Preparation of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide, the product shown in Formula V

[0110]

[0111] Add 81.4 g (0.37 mol) of the compound shown in Formula IV to a reaction flask, add 400 ml of 1,4-dioxane, and add 51.4 g (0.485 mol) of sodium carbonate, 6 g (0.036 mol) of potassium iodide and 56.8 g (0.37 mol) of 4-chloro-7H-pyrrolo[2,3D]pyrimidine while stirring. Heat to 100 °C and react for 8 hours. Cool to about 40 °C, filter, wash the filter cake with methanol, combine the filtrates, concentrate under reduced pressure to remove about half, add 300 ml of ethyl acetate, stir at 50 °C, cool to 10 °C, filter, and dry under vacuum to obtain 99.5 g of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3d]pyrimidine-4-ylamino)cyclohexylmethanesulfonamide.

[0112] Step 6: Salt formation

[0113]

[0114] 60 g (0.178 mol) of the compound shown in Formula V, 400 ml of isopropanol, and 20.7 g (0.178 mol) of maleic acid were added to a reaction flask. The mixture was stirred and heated to reflux for 2 hours. After cooling to 0°C, crystals were precipitated for 2 hours. The mixture was filtered, and the filter cake was washed with cold isopropanol and dried under vacuum to obtain 70.5 g of trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, with a purity of 99.13% and a moisture content of 0.11%.

[0115] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any modifications or equivalent transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for preparing olatinib maleate, characterized in that, Includes the following steps: (1) Reduction and chlorination: Add trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid to the solvent, add reducing agent solution dropwise, heat and reflux to maintain the temperature for reaction; add 5% to 10% sodium hydroxide solution to quench, separate the aqueous layer, and concentrate the organic layer to dryness; Add dichloromethane, cool and add thionyl chloride dropwise. After the addition is complete, react at room temperature, wash with saturated sodium bicarbonate solution, separate into layers, dry the lower organic layer with a desiccant, filter, concentrate the filtrate to dryness, and obtain the compound shown in Formula I. (2) Substitution and oxidation: Add the compound of formula I obtained in step (1) to the solvent, then add thiourea, reflux the reaction, concentrate and dry to obtain the product of formula II; stir and mix NCS with acetonitrile or acetone, add the product of formula II at low temperature, add water, concentrate and dry to obtain the white solid of formula III. (3) Methylamine and condensation: Add the product of formula III obtained in step (2) to the solvent, cool down, add methylamine solution dropwise, keep the reaction at the temperature after the addition is complete, add water to precipitate the solid, filter, dry to obtain the product of formula IV; add organic solvent, acid-binding agent, potassium iodide and 4-chloro-7H-pyrrolo[2,3-D]pyrimidine to the product of formula IV, reflux condensation reaction, cool to precipitate crystals, filter, wash with water, filter and dry to obtain the product of formula V: trans-N-methyl-4-(methyl-7H-pyrrolo[2,3d]pyrimidine 4-ylamino)cyclohexylmethanesulfonamide; (4) Salt formation: Add the product shown in formula V to isopropanol / ethanol, stir, add maleic acid and water, after reaction, cool and crystallize, and dry under vacuum to obtain trans-N-methyl-4-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexylmethanesulfonamide maleate, i.e. olatinib maleate; The synthesis route is as follows: 。 2. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (1), the reducing agent solution is a 70% red aluminum toluene solution or a 1.5M diisobutylaluminum hydride toluene solution.

3. A method for preparing olatinib maleate according to claim 1 or 2, characterized in that, The molar ratio of the reducing agent to trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid is (5.5-6.0):1; the mass of the sodium hydroxide solution used for the quenching reaction is 6-13 times the mass of trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid; wherein, the temperature of the heat preservation reaction is 80-110℃, and the reaction time is 5-6 hours.

4. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (1), the molar ratio of thionyl chloride to trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid is (1.2-1.3):

1.

5. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (2), the molar ratio of the compound represented by formula I to thiourea is 1:

1.

6. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (2), the molar ratio of NCS to the product shown in Formula II is (3.8-4.0):

1.

7. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (3), the molar ratio of the product shown in Formula III to monomethylamine is 1:(5.0~5.5); the reaction temperature of the product shown in Formula III and monomethylamine in step (3) is 25℃.

8. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (3), the molar ratio of the product shown in Formula IV, the acid-binding agent, potassium iodide and 4-chloro-7H-pyrrolo[2,3-D]pyrimidine is (1-1.5):(1.3-1.8):(0.05-0.15):1; the temperature of the reflux condensation reaction is 80-100℃ and the reaction time is 8h.

9. The method for preparing olatinib maleate according to claim 1, characterized in that, The acid-binding agent in step (3) is potassium carbonate or sodium carbonate.

10. The method for preparing olatinib maleate according to claim 1, characterized in that, In step (4), the molar ratio of the product shown in formula V to maleic acid is 1:1; the reaction temperature in step (4) is 25℃ and the reaction time is 2 to 4 hours.

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