Preparation method of apixaban

Abstract

The invention provides a preparation method of apixaban, and belongs to the technical field of raw material medicine synthesis. The intermediate product 5 is prepared by adopting continuous flow equipment, so that the defect of low heat and mass transfer efficiency of an intermittent reaction kettle is overcome, the reaction danger coefficient is reduced, the reaction time is shortened, the product quality is improved, and the product yield is increased; a ferric trichloride / activated carbon-hydrazine hydrate system is adopted for nitro reduction, so that the selectivity is good, and the product purity and yield are improved; the ethanol solution of ammonia is adopted to replace ammonia water, CH3ONa / HCOONH2, mixed anhydride-ammonia water and the like in the prior art, the defects that in the prior art, the content of acid impurities is high, and the amount of post-treated ammonia-containing wastewater is large are overcome, and the environmental protection pressure is reduced while the product quality is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug synthesis, and particularly relates to a method for preparing apixaban. Background Art

[0002] Apixaban is a potent, reversible, and highly selective factor Xa inhibitor, which is mainly used in the clinical treatment of various thromboembolic diseases, including reducing the risk of stroke in non-valvular atrial fibrillation, preventing thrombus formation after hip or knee replacement surgery, treating deep vein thrombosis or pulmonary embolism, and preventing recurrent deep vein thrombosis and pulmonary embolism. It has become one of the most widely used oral anticoagulants in clinical practice.

[0003] There are many reports on the synthetic process routes of apixaban. For example, the use of tert-butyl lithium, a super base that is flammable, easy to absorb moisture and deteriorate, and expensive, is not conducive to industrial production; or the use of reducing agents (palladium carbon, sodium borohydride / copper sulfate) for reduction, but Pd / C is expensive, and a large amount of selectively reduced double bond product impurities are generated during the reduction process, and sodium borohydride / copper sulfate will produce a large amount of over-reduction impurities; or the use of iron powder or zinc powder will produce a large amount of solid waste, seriously polluting the environment; or the use of sodium sulfide reduction method, sodium sulfide has a strong odor, a large amount of process wastewater, and is not environmentally friendly , and due to the strong alkalinity of the system, the purity of the prepared compound is not high, and it is often mixed with impurities that are difficult to remove; or aminolysis occurs in the sodium methoxide and formamide system, and a large amount of nitrogen-containing wastewater is generated during the post-treatment process, which is not conducive to environmental protection. Moreover, about 2.5% of apixaban acid is generated in the apixaban obtained by this method. Since its structure is similar to that of apixaban, it is difficult to purify and remove it; or 25% ammonia water is used as an aminating agent for the aminolysis of apixaban ethyl ester. A large amount of ammonia water is used in the reaction process, and a large amount of nitrogen-containing wastewater is generated during the post-treatment process.

[0004] Therefore, there is an urgent need for a method for preparing apixaban that does not require the use of a strong base of tert-butyl lithium or sodium hydride and a palladium-carbon catalyst, has low cost, and has high product purity and yield. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing apixaban. The preparation method provided by the present invention has low cost, no "nitrogen-containing wastewater", and high product purity and yield.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing apixaban, comprising the following steps:

[0008] (1) subjecting p-methoxyaniline to a diazotization reaction with an aqueous solution of hydrochloric acid and an aqueous solution of sodium nitrite through a continuous flow device to obtain an intermediate product 3;

[0009] (2) subjecting the intermediate product 3 obtained in step (1), an aqueous sodium acetate solution and an alcohol solution of ethyl 2-chloroacetoacetate to a Japp-Klingmann hydrazone reaction through a continuous flow device to obtain an intermediate product 5;

[0010] (3) mixing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, a first solvent and hydrazine hydrate to perform a nitro reduction reaction to obtain an intermediate product 7;

[0011] (4) mixing the intermediate product 7 obtained in step (3), a second solvent, triethylamine and 5-chlorovaleryl chloride, and performing an amidation reaction to obtain an intermediate product 9;

[0012] (5) mixing the intermediate product 9 obtained in step (4) with potassium tert-butoxide to carry out a cyclization reaction to obtain an intermediate product 10;

[0013] (6) mixing the intermediate product 10 obtained in step (5), the intermediate product 5 obtained in step (2), potassium iodide, triethylamine and a third solvent, performing a 1,3-dipolar cycloaddition reaction, and then adding concentrated hydrochloric acid to perform a morpholine elimination reaction to obtain an intermediate product 11;

[0014] (7) mixing the intermediate product 11 obtained in step (6), anhydrous ethanol and ammonia gas, and performing an aminolysis reaction to obtain apixaban;

[0015] There is no chronological order between step (1) and step (3).

[0016] Preferably, in step (3), the molar ratio of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon and hydrazine hydrate is 1:(0.4-0.6):(2.5-2.6):(1.9-2.1).

[0017] Preferably, in step (3), the volume ratio of the amount of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone to the first solvent is 1 mol: (3000-3100) mL.

[0018] Preferably, in step (4), the molar ratio of the intermediate product 7, triethylamine and 5-chlorovaleryl chloride is (0.8-0.9): (1-1.1): (1-1.1).

[0019] Preferably, in the step (4), the volume ratio of the amount of the intermediate product 7 to the second solvent is (0.8-0.9) mol: (1300-1310) mL.

[0020] Preferably, the temperature of the amidation reaction in step (4) is 0 to 10° C., and the time of the amidation reaction is 1 to 3 hours.

[0021] Preferably, the molar ratio of the intermediate product 7 in step (4) to the potassium tert-butoxide in step (5) is (0.8-0.9):(1-1.1).

[0022] Preferably, in step (6), the molar ratio of the intermediate product 10, the intermediate product 5, potassium iodide and triethylamine is (0.8-0.9): (0.9-1.0): (0.08-0.09): (1-1.1).

[0023] Preferably, in step (6), the volume ratio of the amount of the intermediate product 10 to concentrated hydrochloric acid is (0.8-0.9) mol: (140-150) mL.

[0024] Preferably, in step (7), the mass ratio of the intermediate product 11 to ammonia is (2.7-3.0):1.

[0025] The invention provides a method for preparing apixaban, comprising the following steps: (1) subjecting a hydrochloric acid aqueous solution of p-methoxyaniline and a sodium nitrite aqueous solution to a diazotization reaction through a continuous flow device to obtain an intermediate product 3; (2) subjecting the intermediate product 3 obtained in the step (1), a sodium acetate aqueous solution and an alcohol solution of ethyl 2-chloroacetoacetate to a Japp-Klingmann hydrazone reaction through a continuous flow device to obtain an intermediate product 5; (3) mixing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, a first solvent and hydrazine hydrate to a nitro reduction reaction to obtain an intermediate product 7; and (4) subjecting the intermediate product obtained in the step (3) to a nitro reduction reaction. The intermediate product 7, the second solvent, triethylamine and 5-chlorovaleryl chloride are mixed to carry out an amidation reaction to obtain an intermediate product 9; (5) the intermediate product 9 obtained in the step (4) is mixed with potassium tert-butoxide to carry out a cyclization reaction to obtain an intermediate product 10; (6) the intermediate product 10 obtained in the step (5), the intermediate product 5 obtained in the step (2), potassium iodide, triethylamine and the third solvent are mixed to carry out a 1,3-dipolar cycloaddition reaction, and then concentrated hydrochloric acid is added to carry out a morpholine elimination reaction to obtain an intermediate product 11; (7) the intermediate product 11 obtained in the step (6), anhydrous ethanol and ammonia are mixed to carry out an aminolysis reaction to obtain apixaban; there is no chronological order between the steps (1) and (3). The present invention adopts continuous flow equipment to prepare intermediate product 5, overcomes the defect of low heat and mass transfer efficiency of intermittent reactor, reduces the reaction risk coefficient, shortens the reaction time, improves product quality, and improves product yield; adopts ferric chloride / activated carbon-hydrazine hydrate system to carry out nitro reduction, has good selectivity, and improves product purity and yield; adopts ammonia ethanol solution to replace ammonia water, CH3ONa / HCOONH2, mixed anhydride-ammonia water, etc. in the prior art, overcomes the defects such as high acid impurity content and large amount of post-treatment "ammonia-containing wastewater" in the prior art, and reduces environmental pressure while improving product quality. The results of the embodiment show that when the preparation method of the present invention is adopted, the HPLC purity of apixaban is 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Schematic diagram of the process and equipment for preparing the intermediate product 5 in step (1) of Example 1 of the present invention;

[0027] Figure 2 The present invention is a schematic flow diagram of the method for preparing apixaban in Example 1;

[0028] Figure 3 The HPLC spectrum of Apixaban prepared in Example 1;

[0029] Figure 4 The solvent blank diagram when the apixaban prepared in Example 1 was subjected to HPLC detection;

[0030] Figure 5 The HPLC spectrum of Apixaban prepared in Comparative Example 1;

[0031] Figure 6 The solvent blank diagram when the apixaban prepared in Comparative Example 1 was tested by HPLC;

[0032] Figure 7 HPLC spectrum of compound 7 prepared in Comparative Example 2;

[0033] Figure 8 This is a solvent blank diagram when the compound 7 prepared in Comparative Example 2 was tested by HPLC;

[0034] Fig. 9 HPLC spectrum of intermediate product 7 prepared in step (2) of Example 1;

[0035] Fig.10 This is the solvent blank chart when the intermediate product 7 prepared in step (2) of Example 1 was tested by HPLC. DETAILED DESCRIPTION

[0036] The present invention provides a method for preparing apixaban, comprising the following steps:

[0037] (1) subjecting p-methoxyaniline to a diazotization reaction with an aqueous solution of hydrochloric acid and an aqueous solution of sodium nitrite through a continuous flow device to obtain an intermediate product 3;

[0038] (2) subjecting the intermediate product 3 obtained in step (1), an aqueous sodium acetate solution and an alcohol solution of ethyl 2-chloroacetoacetate to a Japp-Klingmann hydrazone reaction through a continuous flow device to obtain an intermediate product 5;

[0039] (3) mixing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, a first solvent and hydrazine hydrate to perform a nitro reduction reaction to obtain an intermediate product 7;

[0040] (4) mixing the intermediate product 7 obtained in step (3), a second solvent, triethylamine and 5-chlorovaleryl chloride, and performing an amidation reaction to obtain an intermediate product 9;

[0041] (5) mixing the intermediate product 9 obtained in step (4) with potassium tert-butoxide to carry out a cyclization reaction to obtain an intermediate product 10;

[0042] (6) mixing the intermediate product 10 obtained in step (5), the intermediate product 5 obtained in step (2), potassium iodide, triethylamine and a third solvent, performing a 1,3-dipolar cycloaddition reaction, and then adding concentrated hydrochloric acid to perform a morpholine elimination reaction to obtain an intermediate product 11;

[0043] (7) mixing the intermediate product 11 obtained in step (6), anhydrous ethanol and ammonia gas, and performing an aminolysis reaction to obtain apixaban;

[0044] There is no chronological order between step (1) and step (3).

[0045] Unless otherwise specified, the present invention has no particular limitation on the sources of the raw materials, and any commercially available product or product prepared by a conventional preparation method well known to those skilled in the art may be used.

[0046] The present invention conducts diazotization reaction of hydrochloric acid aqueous solution of p-methoxyaniline and sodium nitrite aqueous solution through continuous flow equipment to obtain intermediate product 3.

[0047] In the present invention, the concentration of the hydrochloric acid aqueous solution of p-methoxyaniline is preferably 0.9-1.1 mol / L, more preferably 1 mol / L; the concentration of hydrochloric acid in the hydrochloric acid aqueous solution of p-methoxyaniline is preferably 3.5-4.5N, more preferably 4N.

[0048] In the present invention, the concentration of the sodium nitrite aqueous solution is preferably 0.9 to 1.1 mol / L, more preferably 1 mol / L.

[0049] In the present invention, the volume ratio of the hydrochloric acid aqueous solution of p-methoxyaniline to the sodium nitrite aqueous solution is preferably 1:(0.9-1.1), more preferably 1:1.

[0050] The present invention has no particular limitation on the continuous flow device, and any device well known to those skilled in the art may be used.

[0051] In the present invention, the hydrochloric acid aqueous solution of p-methoxyaniline and the sodium nitrite aqueous solution are preferably mixed through a mixer through a first flow path and a second flow path respectively and then enter a continuous reactor.

[0052] In the present invention, the flow rates of the first flow path and the second flow path are independently preferably 1 to 6 mL / min, more preferably 1 to 5 mL / min.

[0053] In the present invention, the temperature of the diazotization reaction is preferably 0-5° C. In an embodiment of the present invention, the temperature of the diazotization reaction may be specifically 0° C., 1° C., 2° C., 3° ​​C., 4° C. or 5° C.

[0054] In the present invention, the time of the diazotization reaction is preferably 15 to 25 seconds, more preferably 20 seconds. In the present invention, the diazotization reaction time is the residence time of the raw materials in the continuous reactor. The present invention limits the concentration, ratio, temperature and time of the diazotization reaction of each raw material within the above range, so that the diazotization reaction can be fully carried out.

[0055] In the present invention, the chemical structural formula of the intermediate product 3 is

[0056] After the diazotization reaction is completed, the product of the diazotization reaction is not subjected to post-treatment in the present invention, and is directly used in the subsequent Japp-Klingmann hydrazone reaction.

[0057] After obtaining the intermediate product 3, the present invention conducts a Japp-Klingmann hydrazone reaction of the intermediate product 3, an aqueous sodium acetate solution and an alcohol solution of ethyl 2-chloroacetoacetate through a continuous flow device to obtain an intermediate product 5.

[0058] In the present invention, the concentration of the sodium acetate aqueous solution is preferably 1.5 to 2.5 mol / L, more preferably 2 mol / L.

[0059] In the present invention, the volume ratio of the sodium nitrite aqueous solution to the sodium acetate aqueous solution is preferably 1:(0.9-1.1), more preferably 1:1.

[0060] In the present invention, the alcohol solution of ethyl 2-chloroacetoacetate is preferably a methanol solution of ethyl 2-chloroacetoacetate; the concentration of the alcohol solution of ethyl 2-chloroacetoacetate is preferably 0.9 to 1.1 mol / L, more preferably 1 mol / L.

[0061] In the present invention, the volume ratio of the sodium acetate aqueous solution to the alcohol solution of ethyl 2-chloroacetoacetate is preferably 1:(0.9-1.1), more preferably 1:1.

[0062] The present invention has no particular limitation on the type and model of the continuous flow device, and any continuous flow device well known to those skilled in the art may be used.

[0063] In the present invention, the intermediate product 3 is preferably mixed with the sodium acetate aqueous solution through the third flow path through the fourth flow path, and then mixed with the alcohol solution of ethyl 2-chloroacetoacetate through the fifth flow path to enter the continuous reactor.

[0064] In the present invention, the flow rates of the third flow channel, the fourth flow channel and the fifth flow channel are independently preferably 1 to 6 mL / min, more preferably 1 to 5 mL / min.

[0065] In the present invention, the temperature of the Japp-Klingmann hydrazone fusion reaction is preferably 0-5° C. In an embodiment of the present invention, the temperature of the Japp-Klingmann hydrazone fusion reaction may be specifically 0° C., 1° C., 2° C., 3° ​​C., 4° C. or 5° C.

[0066] In the present invention, the time of the Japp-Klingmann hydrazone fusion reaction is preferably 1 to 3 minutes, more preferably 2 minutes. In the present invention, the Japp-Klingmann hydrazone fusion reaction time is the residence time of the raw materials in the continuous reactor. The present invention limits the concentration, ratio, temperature and time of the Japp-Klingmann hydrazone fusion reaction of each raw material within the above range, so that the Japp-Klingmann hydrazone fusion reaction can be fully carried out.

[0067] After the Japp-Klingmann hydrazone fusion reaction is completed, the present invention preferably extracts the product of the Japp-Klingmann hydrazone fusion reaction, separates the organic phase, washes and concentrates under reduced pressure to obtain an intermediate product 5.

[0068] In the present invention, the extraction agent is preferably ethyl acetate. In the present invention, the volume ratio of the sodium nitrite aqueous solution to ethyl acetate is preferably 1: (3-5), more preferably 1: 4. The present invention limits the amount of ethyl acetate to the above range, which can make the extraction more complete.

[0069] The present invention has no particular limitation on the operation of separating the organic phase, and the organic phase can be obtained by using a separation scheme well known to those skilled in the art.

[0070] In the present invention, the washing liquid is preferably a saturated sodium chloride solution. The present invention has no special limitation on other operations of the washing, and the unreacted raw materials can be fully washed and removed.

[0071] In the present invention, the temperature of the reduced pressure concentration is preferably ≤40° C. The present invention has no special limitation on the pressure and time of the reduced pressure concentration, and the technical solutions well known to those skilled in the art can be adopted.

[0072] In the present invention, the structural formula of the intermediate product 5 is

[0073] Diazonium salts are a class of substances with active chemical properties. High temperature, friction, impact, drying and other conditions can cause explosion of diazonium salt solutions. The present invention adopts continuous flow equipment to prepare intermediate product 5, which can improve the reaction mixing effect, shorten the reaction time, improve the reaction efficiency and safety factor, overcome the defect of low heat and mass transfer efficiency of intermittent reactors, and improve product quality and reaction yield while reducing the reaction risk factor.

[0074] The present invention mixes 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, a first solvent and hydrazine hydrate, and performs a nitro reduction reaction to obtain an intermediate product 7.

[0075] In the present invention, the molar ratio of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon and hydrazine hydrate is preferably 1:(0.4-0.6):(2.5-2.6):(1.9-2.1), more preferably 1:0.5:2.525:2.

[0076] In the present invention, the first solvent preferably includes dichloromethane or an alcohol solvent, and more preferably dichloromethane. The present invention uses dichloromethane as a solvent, which is consistent with the solvent of the subsequent amidation and cyclization reactions and is easy to recycle and reuse.

[0077] In the present invention, the volume ratio of the amount of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone to the first solvent is preferably 1 mol:(3000-3100) mL, more preferably 1 mol:3033 mL.

[0078] In the present invention, the mixture of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, the first solvent and hydrazine hydrate is preferably: 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon and the first solvent are mixed, the temperature is raised to reflux, and then hydrazine hydrate is added dropwise.

[0079] The present invention has no special limitation on the dripping rate of the hydrazine hydrate, and the dripping technical scheme well known to those skilled in the art can be adopted.

[0080] In the present invention, the nitro reduction reaction is preferably carried out at reflux temperature; the time of the nitro reduction reaction is preferably 2 to 4 hours, more preferably 3 hours. The present invention limits the amount of each raw material, the mixing method, the reaction temperature and the time to the above range, so that the nitro reduction reaction can be fully carried out.

[0081] After the nitro reduction reaction is completed, the present invention preferably filters the product of the nitro reduction reaction while hot, then concentrates it under reduced pressure, adds an alcohol solvent, heats to reflux, stirs for 20 to 40 minutes, and finally cools to 0 to 10° C. and filters to obtain an intermediate product 7.

[0082] The present invention has no special limitation on the operations of hot filtration, reduced pressure concentration and filtration, and the technical solutions well known to those skilled in the art can be adopted.

[0083] In the present invention, the alcohol solvent preferably includes methanol, ethanol or isopropanol, more preferably methanol.

[0084] In the present invention, the volume ratio of the amount of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone to the alcohol solvent is preferably 1 mol:(1100-1300)mL, more preferably 1 mol:1200mL. The present invention limits the amount of the alcohol solvent to the above range, which can fully purify the product and obtain an intermediate product 7 with higher purity.

[0085] In the present invention, the structural formula of the intermediate product 7 is

[0086] The present invention adopts the inexpensive and readily available FeCl3 / activated carbon-hydrazine hydrate system to carry out nitro reduction, has good selectivity, a yield of more than 95%, and an HPLC purity of more than 99%, thereby overcoming the defects of the prior art such as expensive catalysts, much "three wastes", and poor selectivity, thereby reducing production costs, alleviating environmental pressures, improving reduction specificity, and having good applicability to reduced substrates.

[0087] After obtaining the intermediate product 7, the present invention mixes the intermediate product 7, a second solvent, triethylamine and 5-chlorovaleryl chloride to carry out an amidation reaction to obtain the intermediate product 9.

[0088] In the present invention, the molar ratio of the intermediate product 7, triethylamine and 5-chlorovaleryl chloride is preferably (0.8-0.9):(1-1.1):(1-1.1), and more preferably 0.896:1.052:1.004.

[0089] In the present invention, the second solvent is preferably dichloromethane.

[0090] In the present invention, the volume ratio of the amount of the intermediate product 7 to the second solvent is preferably (0.8-0.9) mol: (1300-1310) mL, and more preferably 0.896 mol: 1306.5 mL.

[0091] In the present invention, the intermediate product 7, the second solvent, triethylamine and 5-chlorovaleryl chloride are preferably mixed by: mixing the intermediate product 7, the second solvent and triethylamine, cooling to 0-10° C., and then dropping 5-chlorovaleryl chloride.

[0092] The present invention has no particular limitation on the dropping rate of the 5-chlorovaleryl chloride, and a dropping technical scheme well known to those skilled in the art can be used.

[0093] In the present invention, the temperature of the amidation reaction is preferably 0-10° C. In an embodiment of the present invention, the temperature of the amidation reaction may be specifically 0° C., 1° C., 2° C., 3° ​​C., 4° C., 5° C., 6° C., 7° C., 8° C., 9° C. or 10° C.

[0094] In the present invention, the time of the amidation reaction is preferably 1 to 3 hours, more preferably 1.5 to 2.5 hours, and further preferably 2 hours. In the present invention, the time of the amidation reaction is preferably calculated from the completion of the dropwise addition of 5-chlorovaleryl chloride. The present invention limits the amount of each raw material, the reaction temperature and the time within the above range, so that the amidation reaction can be fully carried out.

[0095] In the present invention, the structural formula of the intermediate product 9 is

[0096] After the amidation reaction is completed, the product of the amidation reaction is not subjected to post-treatment and is directly used in the subsequent cyclization reaction.

[0097] After obtaining the intermediate product 9, the present invention mixes the intermediate product 9 with potassium tert-butoxide to carry out a cyclization reaction to obtain the intermediate product 10.

[0098] In the present invention, the molar ratio of the intermediate product 7 to potassium tert-butoxide is preferably (0.8-0.9):(1-1.1), and more preferably 0.896:1.052.

[0099] In the present invention, the cyclization reaction is preferably carried out at reflux temperature; the cyclization reaction time is preferably 4 to 6 hours, more preferably 5 hours. The present invention limits the amount of each raw material, reaction temperature and time within the above range, so that the cyclization reaction can be fully carried out.

[0100] After the cyclization reaction is completed, the present invention preferably adds distilled water to the product of the cyclization reaction, stirs for 5 to 15 minutes, stands for stratification, separates the organic phase, and then concentrates it, then adds n-heptane, heats to reflux, stirs for 0.5 to 1.5 hours, cools to 20 to 30° C., and filters to obtain the intermediate product 10.

[0101] In the present invention, the volume ratio of the amount of the intermediate product 7 to distilled water is preferably 0.896 mol: (350-450) mL, and more preferably 0.896 mol: 400 mL.

[0102] The present invention has no particular limitation on the stirring rate, static stratification, separation of the organic phase, concentration, and filtration operations, and the technical solutions well known to those skilled in the art may be adopted.

[0103] In the present invention, the volume ratio of the amount of the intermediate product 7 to n-heptane is preferably 0.896 mol: (450-550) mL, and more preferably 0.896 mol: 500 mL.

[0104] In the present invention, the structural formula of the intermediate product 10 is

[0105] After obtaining the intermediate product 10, the present invention mixes the intermediate product 10, the intermediate product 5, potassium iodide, triethylamine and a third solvent to carry out a 1,3-dipolar cycloaddition reaction, and then adds concentrated hydrochloric acid to carry out a morpholine elimination reaction to obtain the intermediate product 11.

[0106] In the present invention, the molar ratio of the intermediate product 10, the intermediate product 5, potassium iodide and triethylamine is preferably (0.8-0.9): (0.9-1.0): (0.08-0.09): (1-1.1), and more preferably 0.872: 0.959: 0.0872: 1.046.

[0107] In the present invention, the third solvent preferably includes ethyl acetate, dichloromethane or tetrahydrofuran, and more preferably ethyl acetate.

[0108] In the present invention, the volume ratio of the amount of the intermediate product 10 to the third solvent is preferably 0.872 mol: (1500-1600) mL, and more preferably 0.872 mol: 1550 mL.

[0109] The present invention has no special limitation on the mixing operation of the intermediate product 10, the intermediate product 5, potassium iodide, triethylamine and the third solvent, and the technical scheme of material mixing well known to those skilled in the art can be adopted.

[0110] In the present invention, the 1,3-dipolar cycloaddition reaction is preferably carried out under reflux; the time of the 1,3-dipolar cycloaddition reaction is preferably 3 to 5 hours, more preferably 4 hours. The present invention limits the amount of each raw material and the reaction time within the above range, so that the 1,3-dipolar cycloaddition reaction can be fully carried out.

[0111] After the 1,3-dipolar cycloaddition reaction is completed, the present invention does not perform post-treatment on the product of the 1,3-dipolar cycloaddition reaction, but directly mixes it with concentrated hydrochloric acid to perform subsequent morpholine elimination reaction.

[0112] In the present invention, the product of the 1,3-dipolar cycloaddition reaction is preferably cooled to 0-10° C., and then concentrated hydrochloric acid is added.

[0113] In the present invention, the volume ratio of the amount of the intermediate product 10 to concentrated hydrochloric acid is preferably (0.8-0.9) mol: (140-150) mL, and more preferably 0.872 mol: 145 mL.

[0114] In the present invention, the temperature of the morpholine elimination reaction is preferably 0-10° C. In an embodiment of the present invention, the temperature of the morpholine elimination reaction may be specifically 0° C., 1° C., 2° C., 3° ​​C., 4° C., 5° C., 6° C., 7° C., 8° C., 9° C. or 10° C.

[0115] In the present invention, the time of the morpholine elimination reaction is preferably 1 to 3 hours, more preferably 2 hours. The present invention limits the amount of each raw material, the reaction temperature and time within the above ranges, so that the reaction can proceed fully.

[0116] After the morpholine elimination reaction is completed, the present invention preferably adds distilled water to the product of the morpholine elimination reaction, stirs at room temperature for 10 to 30 minutes, stands for stratification, separates the organic phase, concentrates until solid precipitates, then heats to reflux, stirs for 20 to 40 minutes, cools to 0 to 10°C, filters, and washes the filter cake with ethyl acetate at 0 to 5°C to obtain the intermediate product 11.

[0117] In the present invention, the volume ratio of concentrated hydrochloric acid to distilled water is preferably 145:(650-750), more preferably 145:700.

[0118] The present invention has no particular limitation on the operations of standing to separate layers, separating the organic phase, concentrating until solids are precipitated, filtering, and washing, and the technical solutions well known to those skilled in the art may be adopted.

[0119] In the present invention, the structural formula of the intermediate product 11 is

[0120] After obtaining the intermediate product 11, the present invention mixes the intermediate product 11, anhydrous ethanol and ammonia gas to perform an aminolysis reaction to obtain apixaban.

[0121] In the present invention, the mass ratio of the intermediate product 11 to ammonia is preferably (2.7-3.0):1, and more preferably 2.8096:1.

[0122] In the present invention, the volume ratio of the amount of the intermediate product 11 to anhydrous ethanol is preferably 0.719 mol: (3500-3600) mL, and more preferably 0.719 mol: 3512 mL.

[0123] In the present invention, the mixing of the intermediate product 11, anhydrous ethanol and ammonia is preferably carried out by mixing the intermediate product 11 and anhydrous ethanol, cooling the mixture to -10 to 0°C, and then introducing ammonia.

[0124] In the present invention, the temperature of the ammonolysis reaction is preferably -10 to 0° C. In an embodiment of the present invention, the temperature of the ammonolysis reaction may be specifically -10° C., -9° C., -8° C., -7° C., -6° C., -5° C., -4° C., -3° C., -2° C., -1° C. or 0° C.

[0125] In the present invention, the time of the aminolysis reaction is preferably 4 to 6 hours, more preferably 5 hours. The present invention limits the amount of each raw material, the reaction temperature and the time to the above ranges, so that the reaction can proceed fully.

[0126] After the aminolysis reaction is completed, the present invention preferably concentrates the product of the aminolysis reaction under reduced pressure, then adds anhydrous ethanol, heats to reflux, adds activated carbon for decolorization for 20 to 40 minutes, filters while hot, cools the filtrate to 0 to 10° C., filters, and washes the filter cake with 0 to 5° C. ethanol to obtain apixaban.

[0127] The present invention has no special limitation on the operations of concentration under reduced pressure, filtering while hot, filtering and washing, and the technical solutions well known to those skilled in the art can be adopted.

[0128] In the present invention, the volume ratio of the amount of the intermediate product 11 to anhydrous ethanol is preferably 0.719 mol: 1700-1800 mL, and more preferably 0.719 mol: 1756 mL.

[0129] In the present invention, the mass ratio of the intermediate product 11 to the activated carbon is preferably (19-20):1.

[0130] The present invention limits the post-treatment operation to the above range, which can further improve the purity and yield of the product.

[0131] The present invention adopts an ethanol solution of ammonia to replace ammonia water, CH3ONa / HCOONH2, mixed anhydride-ammonia water and the like in the prior art, thereby overcoming the defects of high apixaban acid impurity content and large amount of post-processing "nitrogen-containing wastewater" in apixaban, and reducing environmental pressure while improving product quality. In addition, the method adopts a method of introducing ammonia gas into anhydrous ethanol to carry out the aminolysis reaction of the ester, thereby increasing the reaction rate and improving the purity of apixaban. After the reaction is completed, the solvent can be recycled and reused, and the process is more environmentally friendly.

[0132] The present invention adopts continuous flow equipment to prepare intermediate product 5, overcomes the defect of low heat and mass transfer efficiency of intermittent reactor, reduces the reaction risk factor, shortens the reaction time, improves product quality, and increases product yield; adopts ferric chloride / activated carbon-hydrazine hydrate system for nitro reduction, has good selectivity, and improves product purity and yield; adopts ethanol solution of ammonia to replace ammonia water, CH3ONa / HCOONH2, mixed anhydride-ammonia water, etc. in the prior art, overcomes the defects of high acid impurity content and large amount of post-processing "ammonia-containing wastewater" in the prior art, and reduces environmental pressure while improving product quality; controls various reaction parameters to improve the purity and yield of apixaban.

[0133] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0134] Example 1

[0135] The preparation method of apixaban is as follows: (1) 1L of 4N hydrochloric acid aqueous solution of p-methoxyaniline (compound 2) with a concentration of 1 mol / L is used as one of the flow paths, and 1L of sodium nitrite aqueous solution with a concentration of 1 mol / L is used as the other flow path, the flow rates of the two flow paths are both 5 mL / min, after being mixed in a mixer (the volume ratio of the hydrochloric acid aqueous solution of p-methoxyaniline to the sodium nitrite aqueous solution is 1:1), entering a continuous reactor, the reaction temperature is 0°C, the residence time is 20s for diazotization reaction, and an intermediate product 3 is obtained. After the diazotization reaction, the intermediate product 3 is mixed with 1L of sodium acetate aqueous solution with a concentration of 2 mol / L in another flow path, and then mixed with 1L of 2-chloroacetoacetic acid ethyl ester (compound 4) with a concentration of 1 mol / L. The mixture was mixed with methanol solution (the volume ratio of sodium nitrite aqueous solution to sodium acetate aqueous solution was 1:1, and the volume ratio of sodium acetate aqueous solution to methanol solution of ethyl 2-chloroacetoacetate was 1:1), and entered into a continuous reactor. The flow rates of the three flow paths were all 5 mL / min, the reaction temperature was 0°C, and the residence time was 2 min. Japp-Klingmann hydrazone reaction was carried out. After all the reaction liquid flowed out, 4 L of ethyl acetate (the volume ratio of sodium nitrite aqueous solution to ethyl acetate was 1:4) was added to the reaction liquid, and extraction was performed. The organic phase was separated, and the organic phase was washed with 1 L of saturated sodium chloride aqueous solution, and concentrated to dryness under reduced pressure at 40°C to obtain a yellow solid compound, intermediate product 5 (240.3 g, yield 93.6%), with HPLC purity of 99.1%;

[0136] (2) 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone (Compound 6, 303.3 g, 1 mol), ferric chloride (81.1 g, 0.5 mol), activated carbon (30.3 g, 2.525 mol) and dichloromethane (3033 mL, the volume ratio of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone to dichloromethane is 1 mol:3033 mL) were added to a reaction flask, the temperature was raised to reflux, and hydrazine hydrate (125 g, 2 mol, 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone) was added dropwise. After the addition, the nitro reduction reaction was continued for 3 h, filtered while hot, concentrated to dryness under reduced pressure, and methanol (1200 mL, the volume ratio of the amount of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone to methanol was 1 mol:1200 mL) was added, heated to reflux, stirred for 0.5 h, cooled to 0°C, and filtered to obtain a light yellow solid compound, intermediate product 7 (261.3 g, 0.956 mol, yield 95.6%), with HPLC purity of 99.8%;

[0137] (3) The intermediate product 7 (261.3 g, 0.896 mol), dichloromethane (1306.5 mL, the volume ratio of the intermediate product 7 to dichloromethane is 0.896 mol:1306.5 mL), and triethylamine (106.4 g, 1.052 mol) were added to the reaction flask, the temperature was lowered to 0°C, and 5-chlorovaleryl chloride (compound 8, 155.6 g, 1.004 mol, the volume ratio of the intermediate product 7, triethylamine and 5-chlorovaleryl chloride is 0.896:1.052:1.004) was added dropwise. After the addition was completed, the temperature was kept at 0°C for 2 h to carry out the amidation reaction to obtain the intermediate product 9. Potassium tert-butoxide (118.0 g, 1.05 2mol, the molar ratio of intermediate product 7 to potassium tert-butoxide is 0.896:1.052), heated to reflux for cyclization reaction for 5h, added distilled water (400mL, the volume ratio of the molar ratio of intermediate product 7 to distilled water is 0.896mol:400mL), stirred for 10min, allowed to stand for stratification, the organic phase was separated, concentrated to dryness, added n-heptane (500mL, the volume ratio of the molar ratio of intermediate product 7 to n-heptane is 0.896mol:500mL), heated to reflux, stirred for 1h, cooled to 20°C, filtered, and a yellow solid compound, intermediate product 10 (310.0g, 0.872mol, yield 91.2%), HPLC purity 98.5%;

[0138] (4) The intermediate product 10 (310.0 g, 0.872 mol), the intermediate product 5 (245.3 g, 0.959 mol), potassium iodide (14.5 g, 0.0872 mol), triethylamine (105.9 g, 1.046 mol) and ethyl acetate (1550 mL, the volume ratio of the intermediate product 10 to ethyl acetate is 0.872 mol:1550 mL) were added to the reaction flask (the volume ratio of the intermediate product 10, the intermediate product 5, potassium iodide and triethylamine is 0.872:0.959:0.0872:1.046), and heated to reflux for 1,3-dipolar cycloaddition reaction. 4h, cooled to 0℃, added concentrated hydrochloric acid (145mL, the volume ratio of the amount of substance of intermediate product 10 and concentrated hydrochloric acid is 0.872mol:145mL), maintained at 0℃ for morpholine elimination reaction for 2h, added distilled water (700mL, the volume ratio of concentrated hydrochloric acid and distilled water is 145:700), stirred at room temperature for 20min, allowed to stand for stratification, separated the organic phase, concentrated until solid precipitated, heated to reflux, stirred for 30min, cooled to 0℃, filtered, and the filter cake was washed with 0℃ ethyl acetate to obtain a light yellow solid compound, intermediate product 11 (351.2g, 0.719mol, yield 82.4%), HPLC purity 99.1%;

[0139] (5) The intermediate product 11 (351.2 g, 0.719 mol) and anhydrous ethanol (3512 mL, the volume ratio of the intermediate product 11 to anhydrous ethanol is 0.719 mol:3512 mL) were added to the reaction flask, the temperature was lowered to -10°C, ammonia (125 g, the mass ratio of the intermediate product 11 to ammonia is 2.8096:1) was introduced, the temperature was kept to carry out the aminolysis reaction for 5 h, the solution was concentrated to dryness under reduced pressure, and anhydrous ethanol (1756 mL, the intermediate product 11 to ammonia) was added to the residue after concentration. The amount of substance of product 11 and the volume ratio of anhydrous ethanol are 0.719 mol: 1756 mL), the temperature is raised to reflux, activated carbon (17.6 g, the mass ratio of intermediate product 11 and activated carbon is 19.95: 1) is added, reflux decolorization is carried out for 0.5 h, filtered while hot, the filtrate is slowly cooled to 0 ° C, filtered, and the filter cake is washed with 0 ° C ethanol to obtain white crystalline solid apixaban (compound 1, 301.6 g, 0.656 mol, yield 91.3%), HPLC purity 99.9%.

[0140] The schematic diagram and equipment diagram of the process for preparing the intermediate product 5 in step (1) of Example 1 are as follows: Figure 1 shown.

[0141] The schematic flow diagram of the preparation method of apixaban in Example 1 is as follows Figure 2 shown.

[0142] Comparative Example 1:

[0143] The difference from Example 1 is only step (5): intermediate product 11 (10 g, 0.022 mol) and DMF (50 mL) are added to a reaction flask, cooled to 0°C, sodium methoxide (1.66 g, 0.031 mol) and formamide (6 mL, 0.15 mol) are added, the temperature is raised to 40°C, and the reaction is carried out for 4 h. The reaction solution is cooled to room temperature and poured into deionized water (200 mL) to precipitate a brown solid, which is filtered off with suction, stirred at room temperature for 1 h, filtered off with suction, dried at 50°C for 6 h, and recrystallized from anhydrous ethanol (100 mL) to obtain a white crystalline solid apixaban (7.73 g, 0.0168 mol, 76.5%) with an HPLC purity of 96.37%.

[0144] Comparative Example 2:

[0145] Sodium sulfide nonahydrate (57.0 g, 0.237 mol) and deionized water (60 mL) were added to a reaction flask, the temperature was raised to 55°C, and the mixture was stirred for 0.5 h. Sulfur (7.6 g, 0.237 mol) was added, and the stirring was continued for 1 h. Anhydrous ethanol (60 mL) and compound 6 (9 g, 0.0184 mol) were added in sequence. The temperature was kept at 55°C for 3 h. Dichloromethane (70 mL) was added and extracted. The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate (10 g), filtered, and concentrated to dryness under reduced pressure at 40°C to obtain yellow compound 7 (6.9 g, 0.296 mol, 85.3%, HPLC purity 91.47%).

[0146] Figure 3 The HPLC spectrum of the apixaban prepared in Example 1, Figure 4 The solvent blank diagram when the apixaban prepared in Example 1 was subjected to HPLC detection; Figure 5 The HPLC spectrum of the apixaban prepared in Comparative Example 1, Figure 6 This is a solvent blank diagram for HPLC detection of apixaban prepared in Comparative Example 1. The HPLC detection method is: using octadecylsilane bonded silica gel (Xbridge Shield RP18 column, 4.6mm×150mm, 3.5μm) as a filler; using 30mmol / L ammonium acetate solution-acetonitrile (volume ratio of 90:10) as mobile phase A, 30mmol / L ammonium acetate solution-acetonitrile (volume ratio of 5:95) as mobile phase B, and performing linear gradient elution according to Table 1; the flow rate is 1.5mL per minute; the column temperature is 40℃; the detection wavelength is 240nm; the injection volume is 10μL.

[0147] Table 1 Linear gradient elution table

[0148] Time (minutes) Mobile phase A% Mobile phase B% 0 86 14 2 86 14 19 60 40 27 10 90 32 10 90 32.01 86 14 36 86 14

[0149] Figure 7 The HPLC spectrum of compound 7 prepared in Comparative Example 2 is: Figure 8 This is a solvent blank diagram when the compound 7 prepared in Comparative Example 2 was tested by HPLC; Fig. 9 This is the HPLC spectrum of the intermediate product 7 prepared in step (2) of Example 1, Fig.10 This is the solvent blank diagram of the intermediate product 7 prepared in step (2) of Example 1 when subjected to HPLC detection. The HPLC detection method is: Chromatographic column: Merck STAR RP-18 endcapped, 250*4.6mm 5μm; column temperature: 25℃; detection wavelength: 240nm; flow rate: 1.5mL / min; injection volume: 20μL; mobile phase A: 0.1% phosphoric acid aqueous solution, pH 6.0 buffer adjusted with triethylamine; mobile phase B: acetonitrile, diluent: acetonitrile: water = 30:70, gradient elution according to Table 2.

[0150] Table 2 Gradient elution table

[0151] Time (min) Mobile phase A Mobile phase B 0 80 20 20 65 35 40 25 75 45 25 75 45.1 80 20 66 80 20

[0152] Control solution: Accurately weigh 50 mg of compound 7 prepared in comparative example 2 into a 50 mL volumetric flask, dissolve and dilute to scale with a diluent, and mix well; accurately transfer 1.0 mL into a 100 mL volumetric flask and dilute to scale with a diluent. Sample solution: Accurately weigh 50 mg of intermediate product 7 prepared in step (2) of Example 1 into a 50 mL volumetric flask, dissolve and dilute to scale with a diluent, and mix well; accurately transfer 1.0 mL into a 100 mL volumetric flask and dilute to scale with a diluent.

[0153] Figure 3 The detection data of HPLC spectrum are shown in Table 3.

[0154] Table 3 Figure 3 HPLC chromatogram test data

[0155]

[0156] Figure 5 The detection data of HPLC spectrum are shown in Table 4.

[0157] Table 4 Figure 5 HPLC chromatogram test data

[0158]

[0159]

[0160] Figure 7 The detection data of HPLC spectrum are shown in Table 5.

[0161] Table 5 Figure 7 HPLC chromatogram test data

[0162]

[0163] Fig. 9 The detection data of HPLC spectrum are shown in Table 6.

[0164] Table 6 Fig. 9 HPLC chromatogram test data

[0165]

[0166] from Figures 3 to 10 It can be seen that the purity of compound 7 and apixaban prepared by the preparation method of the present invention is higher.

[0167] It can be seen from the comparison between the examples and the comparative examples that the preparation method provided by the present invention provides the yield and purity of apixaban.

[0168] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing apixaban, comprising the following steps: (1) subjecting p-methoxyaniline to a diazotization reaction with an aqueous solution of hydrochloric acid and an aqueous solution of sodium nitrite through a continuous flow device to obtain an intermediate product 3; (2) subjecting the intermediate product 3 obtained in step (1), an aqueous sodium acetate solution and an alcohol solution of ethyl 2-chloroacetoacetate to a Japp-Klingmann hydrazone reaction through a continuous flow device to obtain an intermediate product 5; (3) mixing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon, a first solvent and hydrazine hydrate to perform a nitro reduction reaction to obtain an intermediate product 7; (4) mixing the intermediate product 7 obtained in step (3), a second solvent, triethylamine and 5-chlorovaleryl chloride, and performing an amidation reaction to obtain an intermediate product 9; (5) mixing the intermediate product 9 obtained in step (4) with potassium tert-butoxide to carry out a cyclization reaction to obtain an intermediate product 10; (6) mixing the intermediate product 10 obtained in step (5), the intermediate product 5 obtained in step (2), potassium iodide, triethylamine and a third solvent, performing a 1,3-dipolar cycloaddition reaction, and then adding concentrated hydrochloric acid to perform a morpholine elimination reaction to obtain an intermediate product 11; (7) mixing the intermediate product 11 obtained in step (6), anhydrous ethanol and ammonia gas, and performing an aminolysis reaction to obtain apixaban; There is no chronological order between step (1) and step (3).

2. The method for preparing apixaban according to claim 1, characterized in that, In the step (3), the molar ratio of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, ferric chloride, activated carbon and hydrazine hydrate is 1:(0.4-0.6):(2.5-2.6):(1.9-2.1).

3. The method for preparing apixaban according to claim 1, characterized in that, In the step (3), the volume ratio of the amount of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone to the first solvent is 1 mol: (3000-3100) mL.

4. The method for preparing apixaban according to claim 1, characterized in that, In the step (4), the molar ratio of the intermediate product 7, triethylamine and 5-chlorovaleryl chloride is (0.8-0.9): (1-1.1): (1-1.1).

5. The method for preparing apixaban according to claim 1, characterized in that, In the step (4), the volume ratio of the amount of the intermediate product 7 to the second solvent is (0.8-0.9) mol: (1300-1310) mL.

6. The method for preparing apixaban according to claim 1, characterized in that: The temperature of the amidation reaction in step (4) is 0 to 10° C., and the time of the amidation reaction is 1 to 3 hours.

7. The method for preparing Apixaban according to claim 1, characterized in that: The molar ratio of the intermediate product 7 in step (4) to the potassium tert-butoxide in step (5) is (0.8-0.9):(1-1.1).

8. The method for preparing apixaban according to claim 1, characterized in that: In the step (6), the molar ratio of the intermediate product 10, the intermediate product 5, potassium iodide and triethylamine is (0.8-0.9): (0.9-1.0): (0.08-0.09): (1-1.1).

9. The method for preparing apixaban according to claim 1, characterized in that: In the step (6), the volume ratio of the amount of the intermediate product 10 to concentrated hydrochloric acid is (0.8-0.9) mol: (140-150) mL.

10. The method for preparing Apixaban according to claim 1, characterized in that: The mass ratio of the intermediate product 11 to ammonia in the step (7) is (2.7-3.0):1.

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