Apixaban intermediate 5, 6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2 (1H)-piperidone and synthesis method thereof

Abstract

The invention discloses an apixaban intermediate 5, 6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2 (1H)-piperidone and a synthesis method thereof, and relates to the technical field of synthesis of medical intermediates.The preparation method comprises the following steps that paranitroaniline is dissolved in chlorobenzene, organic alkali and pentachlorovaleryl chloride are added, a reaction is performed for 2-4 hours, and a mixture is obtained; after paranitroaniline is reacted, sodium hydroxide is added for continuous reaction, and then water is added for treatment to obtain 1-(4-nitrophenyl)-2-piperidone; adding phosphorus pentachloride until the reaction of the 1-(4-nitrophenyl)-2-piperidone is finished, and then adding water for treatment to obtain 3, 3-dichloro-1-(4-nitrophenyl)-2-piperidone; and after the reaction is finished, removing the solvent to obtain the 5, 6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2 (1H)-piperidone. The industrial operation is simplified, and the cost is saved.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, and in particular to an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone and a synthesis method thereof. Background Art

[0002] Apixaban, chemically known as l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]piperidine-3-carboxamide, is a novel direct Factor Xa inhibitor developed jointly by Bristol-Myers Squibb and Pfizer. It was approved by the European Union in March 2011 and by the U.S. FDA on December 28, 2012. It is marketed under the trade name Eliquis and is used to prevent venous thromboembolism (VTE) and atrial fibrillation in adult patients undergoing hip or knee replacement surgery. The molecular formula is: C 25 H 25 N5O4, structural formula:

[0003]

[0004] Apixaban is a new oral anticoagulant that, by inhibiting an important coagulation factor, Factor Xa, prevents thrombin generation and thrombosis. Its launch provides a safe and effective new option for anticoagulation after orthopedic surgery, bringing hope to patients undergoing elective hip / knee replacement surgery in China. Clinical studies have demonstrated that, compared with a single subcutaneous injection of 40 mg enoxaparin, apixaban (2.5 mg) taken orally twice daily is more effective in preventing venous thromboembolic events after hip or knee replacement surgery without increasing the risk of bleeding.

[0005] The literature (Pinto D. JP et al. J. Med. Chem. 2007, 50(22): 5339-5356) discusses the discovery process of apixaban in detail and provides a pharmaceutical chemical synthesis route:

[0006]

[0007] The above synthetic route begins with p-iodoaniline and 5-bromovaleryl chloride as raw materials, and a one-pot amidation-cyclization reaction is used to prepare compound 2. Compound 2 then undergoes a condensation-elimination reaction in chloroform with phosphorus pentachloride to dichlorinate the α-active hydrogen and in the presence of excess morpholine to produce intermediate 3. Next, p-methoxyaniline is diazotized and reacted with ethyl 2-chloroacetoacetate in a sequential Japp-Klingmann hydrazone synthesis to produce pyrazole compound IV. Compound IV and intermediate 3 undergo a [3+2] cyclization-elimination strategy to produce compound 4. Compound 4 is condensed with valerolactam under conditions similar to the Ullmann reaction to produce compound II. Compound II is then ammonolyzed in an ammonia solution in ethylene glycol to produce the target product 1. Clearly, the use of expensive iodide and the low yield of 21% in the condensation reaction of compound 4 with valerolactam make this route of low practical value.

[0008] In Chinese patent CN101967145A published by East China University of Science and Technology in 2011, p-nitroaniline is used as the starting material. The target compound, apixaban intermediate, is obtained through amidation and cyclization, dichlorination, elimination, cyclization elimination, catalytic hydrogenation reduction, and amidation and cyclization. The synthetic route is as follows:

[0009]

[0010] The above-mentioned route has a high synthesis yield, with an overall yield of 35%, and the raw materials are readily available. However, the use of sodium hydride in the reaction leads to high production costs and high operational risks. Furthermore, the reaction also requires the use of various solvents, such as tetrahydrofuran and chloroform, which are highly irritating and somewhat toxic. Multiple concentrations are required, resulting in cumbersome post-processing and making industrial production difficult. Further optimization is needed.

[0011] Among them, 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone is one of the important intermediates of apixaban. The quality of its synthesis method has a great impact on the quality of the product. Its molecular formula is: C 15 H 17 N3O4, the intermediate structure is as follows:

[0012]

[0013] The following synthetic methods for 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone have been reported so far:

[0014] Patent publication number CN101967145A discloses the amidation of p-nitroaniline, using sodium hydride for ring-closure reaction to generate 1-(4-nitrophenyl)-2-piperidone. Under the action of phosphorus pentachloride, two chlorine atoms are substituted at the α position of the carbonyl group. Morpholine is then used as the reaction substrate and solvent to synthesize 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. The specific reaction formula is as follows:

[0015]

[0016] In this method, sodium hydride is used as a condensing agent in the amidation and cyclization step, resulting in high production costs and high operational risks. In the first step, tetrahydrofuran has a pungent odor and is easily peroxidized, resulting in a low solvent recovery rate, which is highly harmful to production personnel in industrial production and has low production practicality. In the second step, chloroform is used as a solvent, which is highly toxic, has a low boiling point, and easily generates volatile organic gases. In addition, morpholine is used as a solvent in the final step of the method. Morpholine and the hydrogen chloride generated by the reaction undergo an acid-base neutralization reaction, which is highly exothermic. At the same time, morpholine, as a reaction substrate, directly reacts with the raw material, which also releases heat. The reaction temperature is 120°C to 130°C, close to the boiling point of morpholine, so the reaction is very likely to boil over, posing a production safety hazard.

[0017] Patent publication number CN113912598A discloses the use of potassium hydroxide aqueous solution as a condensing agent in the amidation cyclization step, the use of a phase transfer catalyst such as tetrabutylammonium bromide for cyclization, and the use of xylene as the reaction solvent for the first and third steps. The specific reaction formula is as follows:

[0018]

[0019] This method requires the use of a phase transfer catalyst such as tetrabutylammonium bromide, which is difficult to recover in water, and the wastewater pollutes the environment, violating the concept of green chemistry. Recovery through concentration and other methods results in significant energy loss and increased production costs. The fourth step uses morpholine as a solvent, which is prone to explosive boiling and poses a production safety hazard. The conversion of p-nitroaniline to 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone involves three different solvents: xylene, water, and morpholine. Post-processing is cumbersome, the scale-up cost is high, and it is not conducive to industrial operation. Summary of the Invention

[0020] In view of the problems of complicated post-processing and high production cost in the synthesis method of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone in the prior art, the present invention aims to provide an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone and a synthesis method thereof. The invention adopts a single solvent, and the first two steps only require simple water washing before the solution can be directly used for subsequent reactions. Meanwhile, the triethylamine in the first step can be recovered by atmospheric distillation, which greatly simplifies industrial operations. The recovered triethylamine and chlorobenzene can be put into the reaction again to complete the closed loop, thus saving costs. In addition, the reaction conditions are mild, and the third step, in which morpholine is used as a solvent and prone to explosive boiling, is avoided.

[0021] The present invention is achieved through the following technical solutions:

[0022] In a first aspect, the present application provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, comprising the following steps:

[0023] (1) dissolving p-nitroaniline in chlorobenzene, adding an organic base and pentachlorovaleryl chloride, and adding sodium hydroxide to continue the reaction until the p-nitroaniline reacts completely, and then adding water to obtain 1-(4-nitrophenyl)-2-piperidone;

[0024] (2) adding phosphorus pentachloride to a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone to react until the reaction of 1-(4-nitrophenyl)-2-piperidone is complete, and then adding water for treatment to obtain 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone;

[0025] (3) Morpholine is added to a chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, and the mixture is refluxed until the reaction of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone is complete. After removing the solvent, the compound 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone is obtained.

[0026] In a specific embodiment, the conditions for the post-treatment of adding water in step (1) are: adding water at 10°C to 35°C, stirring for 1h to 2h, then separating the layers and taking the upper chlorobenzene organic phase.

[0027] In a specific embodiment, the organic base used in step (1) includes any one of triethylamine, potassium tert-butoxide, sodium tert-butoxide, and sodium acetate.

[0028] In a specific embodiment, in step (1), the molar ratio of p-nitroaniline, pentachlorovaleryl chloride, organic base and sodium hydroxide is 1: (1-1.6): (0.5-1.5): (3-5); the amount ratio of chlorobenzene, water and p-nitroaniline is (5ml-20ml): (5ml-10ml): 1g.

[0029] In a specific embodiment, in step (1), pentachlorovaleryl chloride is added dropwise at 20°C to 30°C for 1 hour to 3 hours, and then the temperature is raised to 20°C to 40°C for chlorination reaction, and the reaction time is 4 hours to 24 hours.

[0030] In a specific embodiment, in step (1), sodium hydroxide is added in batches. Specifically, sodium hydroxide can be added in three batches at 20°C to 40°C, with an interval of one hour between each batch, for a total of two hours. The temperature is then raised to 40°C to 60°C, and the ring-closure reaction time is 5 hours to 24 hours.

[0031] In a specific embodiment, in step (2), the ratio of chlorobenzene, water and 1-(4-nitrophenyl)-2-piperidone is (5ml~20ml):(5ml~20ml):1g, preferably (10ml~20ml):(5ml~10ml):1g; the molar ratio of 1-(4-nitrophenyl)-2-piperidone to phosphorus pentachloride is 1:(2~5), preferably 1:3.

[0032] In a specific embodiment, in step (2), phosphorus pentachloride is added in batches. Specifically, phosphorus pentachloride is added in three equal batches at a temperature of 20°C to 50°C, with an interval of one hour between each batch, for a total addition time of two hours. The temperature is then raised to 50°C to 60°C, and the reaction time is 2 hours to 24 hours.

[0033] In a specific embodiment, in step (2), the conditions for post-treatment after adding water are: adding water at 10°C to 35°C, stirring for 1h to 2h, then separating the layers and taking the upper chlorobenzene organic phase.

[0034] In a specific embodiment, in step (3), triethylamine is recovered by atmospheric distillation at 90°C to 130°C, and a fraction at 88°C to 100°C is received. The distillation time is 2 hours to 12 hours, and the atmospheric distillation temperature is preferably 90°C to 100°C, and the received fraction temperature is 88°C to 92°C.

[0035] In a specific embodiment, in step (3), the ratio of chlorobenzene to 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone is (3 ml to 20 ml): 1 g, preferably (6 ml to 10 ml): 1 g; the molar ratio of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone to morpholine is 1:(2.5 to 10), preferably 1:3.8.

[0036] In a specific embodiment, the reaction temperature in step (3) is 120° C. to 130° C., and the reaction time is 4 h to 8 h.

[0037] In a second aspect, the present application provides an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is synthesized using the above-mentioned synthesis method.

[0038] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0039] (1) The present invention provides a method for synthesizing the intermediate apixaban 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone by a three-step reaction using a single solvent. In the synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, chlorobenzene is used instead of solvents such as morpholine, xylene, and chloroform. This allows the entire reaction process to use a single reaction solvent, and the next reaction can be carried out directly after simple post-treatment, greatly simplifying the process operation. At the same time, the reaction temperature is very mild, avoiding the problem of morpholine being used as a solvent in the third step and the reaction being extremely prone to boiling. The obtained product has good quality and yield, and is easy to industrialize.

[0040] (2) The present invention provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. In the process of synthesizing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, the same solvent is used before and after, thereby avoiding the influence of the residual solvent in the previous step on the next step. At the same time, the operation is simple, no catalyst is required to be added during the reaction, the reaction process is stable, the process is simple, and a yield of 95% can be achieved.

[0041] (3) The present invention provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. The synthetic route is simple, the raw materials are readily available and the cost is low, the reaction conditions are mild, the operation is simple, chlorobenzene has a high boiling point and is difficult to produce volatile organic compounds (VOCs), and the solvent recovery rate is greater than 95%. It is an efficient, green and environmentally friendly synthetic process. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the examples. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be considered as limiting the scope. A person of ordinary skill in the art can also derive other relevant drawings based on these drawings without inventive effort. In the drawings:

[0043] Figure 1 This is the H-NMR spectrum of 1-(4-nitrophenyl)-2-piperidone synthesized in Example 1 of the present invention;

[0044] Figure 2 This is the H-NMR spectrum of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone synthesized in Example 1 of the present invention;

[0045] Figure 3 This is the H-NMR spectrum of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0046] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with examples. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not intended to limit the present invention.

[0047] In the following description, numerous specific details are set forth to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that these specific details are not necessarily employed to practice the present invention. In other embodiments, well-known materials or methods are not specifically described to avoid obscuring the present invention.

[0048] Throughout this specification, references to "one embodiment," "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Therefore, appearances of the phrases "one embodiment," "an embodiment," "an example," or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, structures, or characteristics may be combined in one or more embodiments or examples in any suitable combinations and / or subcombinations. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. Furthermore, one skilled in the art will be able to combine and combine different embodiments or examples, and features of different embodiments or examples, described in this specification, without mutual inconsistency.

[0049] The "ranges" disclosed herein are defined in terms of lower and upper limits, where a given range is defined by selecting a lower limit and an upper limit, and the selected lower and upper limits define the boundaries of the particular range. Ranges defined in this manner can be inclusive or exclusive of the end values and can be combined arbitrarily, i.e., any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60 to 120 and 80 to 110 are listed for a particular parameter, it is understood that ranges of 60 to 110 and 80 to 120 are also contemplated. Furthermore, if minimum range values of 1 and 2 are listed, and if maximum range values of 3, 4, and 5 are listed, the following ranges are all contemplated: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, and 2 to 5. In this application, unless otherwise indicated, the numerical range "a to b" is a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, a numerical range of "0-5" indicates that all real numbers between "0-5" are listed herein, and "0-5" is simply an abbreviation for these numerical combinations. Furthermore, when a parameter is expressed as an integer ≥ 2, this is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0050] Unless otherwise specified, all steps of the present application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), indicating that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0053] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0054] S1-1, 179.55g of p-nitroaniline (p-nitroaniline) was dissolved in 1256.71ml (1389.92g) of chlorobenzene, 157.71g of triethylamine was added, and 201.52g of pentachlorovaleryl chloride was added dropwise at 24 ℃. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform speed. Then the temperature was raised to 20-40℃ and the reaction was carried out for 6h.

[0055] S1-2. At a temperature of 30°C, 208.00 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 897.65 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 718.12 ml of chlorobenzene. The combined organic phases were washed twice with 538.59 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 90°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0056] S1-3, 2g of chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was taken for HPLC content analysis to obtain 269.71g of 1-(4-nitrophenyl)-2-piperidone. Figure 1 As shown, HPLC: 97.9%, yield 94.25%.

[0057] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0058] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 882.59 g of phosphorus pentachloride was added in three equal batches at 20°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 54°C and the reaction time was 3 hours.

[0059] S2-2. After the reaction is completed, 1321.38 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 440.46 ml of chlorobenzene. The combined organic phases are washed twice with 110.11 ml of water and dried over anhydrous sodium sulfate.

[0060] S2-3, 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone was taken for HPLC content analysis to obtain 333.22 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone. Figure 2 As shown, HPLC: 98.7%, yield 93.37%.

[0061] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0062] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 331.05 g of morpholine, then heat to 126° C. and react for 4.5 h.

[0063] S3-2, after the reaction, the solvent was removed by distillation under reduced pressure, and the vacuum degree was selected to be 3KPa and the distillation temperature was 70°C to remove chlorobenzene, and 335.54g of the apixaban intermediate 3-morpholine-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one was obtained as a yellow solid. Figure 3 As shown, HPLC: 94.75%, yield 91.28%. 1321.42 g of chlorobenzene was recovered, and the solvent recovery rate was 95%.

[0064] The above synthetic route is as follows:

[0065]

[0066] Wherein, the recycling of chlorobenzene and triethylamine is as follows:

[0067]

[0068] Example 2

[0069] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0070] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0071] S1-1, 197.50g of p-nitroaniline (p-nitroaniline) was dissolved in 1382.38ml (1528.91g) of chlorobenzene, 65.70g of triethylamine was added, and 201.49g of pentachlorovaleryl chloride was added dropwise at 23°C. The addition time was controlled within 2h, and the addition was carried out dropwise at a uniform rate. Then the temperature was raised to 20-40°C and the reaction was carried out for 6h.

[0072] S1-2. At a temperature of 20°C, 155.97 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 327.41 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 789.93 ml of chlorobenzene. The combined organic phases were washed twice with 592.45 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 91°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0073] S1-3. 2 g of chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was subjected to HPLC content analysis to obtain 303.05 g of 1-(4-nitrophenyl)-2-piperidone; HPLC: 97.9%, yield 96.22%.

[0074] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0075] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 970.85 g of phosphorus pentachloride was added in three equal batches at 25°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 h.

[0076] S2-2. After the reaction is completed, 1453.52 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 484.51 ml of chlorobenzene. The combined organic phases are washed twice with 121.12 ml of water and dried over anhydrous sodium sulfate.

[0077] S2-3. Take 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone and perform HPLC content analysis to obtain 369.68 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone: HPLC: 99.1%, yield 94.17%.

[0078] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0079] S3-1. Add 364.15 g of morpholine to the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, then heat to 120-130° C. and react for 4.5 h.

[0080] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. The vacuum was selected at 5 kPa and the distillation temperature was 70°C to remove chlorobenzene to obtain 370.21 g of a yellow solid of 3-morpholine-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one, an intermediate of apixaban: HPLC: 94.66%, yield 91.56%. 1469.43 g of chlorobenzene was recovered, with a recovery rate of 96%.

[0081] Example 3

[0082] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0083] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0084] S1-1, 217.25g of p-nitroaniline (p-nitroaniline) was dissolved in 1520.62ml (1681.80g) of chlorobenzene, 238.56g of triethylamine was added, and 390.26g of pentachlorovaleryl chloride was added dropwise at 30°C. The addition time was controlled within 2h, and the addition was carried out dropwise at a uniform rate. Then the temperature was raised to 20-40°C and the reaction was carried out for 6h.

[0085] S1-2. At a temperature of 40°C, 314.63 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 360.15 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 868.90 ml of chlorobenzene. The combined organic phases were washed twice with 651.69 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 92°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0086] S1-3. 2 g of chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was subjected to HPLC content analysis to obtain 334.26 g of 1-(4-nitrophenyl)-2-piperidone; HPLC: 98.4%, yield 96.48%.

[0087] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0088] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, add 1067.93 g of phosphorus pentachloride in three equal batches at 50°C, with an interval of one hour between each batch, for a total of two hours. Then, raise the temperature to 50-60°C and react for 3 hours.

[0089] S2-2. After the reaction is completed, 1598.87 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 532.96 ml of chlorobenzene. The combined organic phases are washed twice with 133.23 ml of water and dried over anhydrous sodium sulfate.

[0090] S2-3. Take 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone and perform HPLC content analysis to obtain 409.48 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone: HPLC: 98.98%, yield 94.82%.

[0091] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0092] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 400.56 g of morpholine, then heat to 130° C. and react for 4.5 h.

[0093] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. The vacuum was selected at 5 kPa and the distillation temperature was 65 ° C. to remove chlorobenzene and obtain 405.53 g of the apixaban intermediate 3-morpholine-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one as a yellow solid: HPLC: 95.11%, yield 91.15%. 1648.50 g of chlorobenzene was recovered, with a recovery rate of 98%.

[0094] Example 4

[0095] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0096] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0097] S1-1, 232.45g of p-nitroaniline (p-nitroaniline) was dissolved in 1627.06ml (1799.52g) of chlorobenzene, 204.17g of triethylamine was added, and 260.91g of pentachlorovaleryl chloride was added dropwise at 25°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 30°C and the reaction was allowed to proceed for 6h.

[0098] S1-2. At a temperature of 40°C, 269.29 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at 35°C for 6 h. After the reaction was completed, 385.36 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 929.72 ml of chlorobenzene. The combined organic phases were washed twice with 697.30 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 90°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0099] S1-3. 2 g of a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was subjected to HPLC content analysis to obtain 352.18 g of 1-(4-nitrophenyl)-2-piperidone; HPLC: 98.82%, yield 95.00%.

[0100] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0101] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 1142.68 g of phosphorus pentachloride was added in three equal batches at 20°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 55°C and the reaction time was 3 hours.

[0102] S2-2. After the reaction is completed, 1717.79 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 570.26 ml of chlorobenzene. The combined organic phases are washed twice with 142.55 ml of water and dried over anhydrous sodium sulfate.

[0103] S2-3. Take 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone and perform HPLC content analysis to obtain 429.73 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone: HPLC: 97.58%, yield 93.01%.

[0104] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0105] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 428.60 g of morpholine, then heat to 120° C. and react for 4.5 h.

[0106] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. The vacuum was selected at 4 kPa and the distillation temperature was 69 ° C. Chlorobenzene was removed to obtain 428.45 g of the apixaban intermediate 3-morpholino-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one as a yellow solid: HPLC: 95.53%, yield 89.97%. 1733.47 g of chlorobenzene was recovered, with a recovery rate of 96%.

[0107] Example 5

[0108] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0109] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0110] S1-1, 253.37g of p-nitroaniline (p-nitroaniline) was dissolved in 1773.49ml (1961.47g) of chlorobenzene, 222.54g of triethylamine was added, and 284.39g of pentachlorovaleryl chloride was added dropwise at 20°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 40°C and the reaction was allowed to react for 6h.

[0111] S1-2. At 20°C, 293.52 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was continued at 35°C for 6 h. After the reaction was completed, 420.04 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 1013.39 ml of chlorobenzene. The combined organic phases were washed twice with 760.05 ml of water, dried over anhydrous sodium sulfate, and triethylamine was distilled off at 90°C under normal pressure to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0112] S1-3. 2 g of a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was subjected to HPLC content analysis to obtain 376.91 g of 1-(4-nitrophenyl)-2-piperidone; HPLC: 99.44%, yield 93.28%.

[0113] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0114] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 1245.52 g of phosphorus pentachloride was added in three equal batches at 50°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 h.

[0115] S2-2. After the reaction is completed, 1872.39 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 621.58 ml of chlorobenzene. The combined organic phases are washed twice with 155.38 ml of water and dried over anhydrous sodium sulfate.

[0116] S2-3. Take 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone and perform HPLC content analysis to obtain 482.15 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone: HPLC: 98.61%, yield 95.73%.

[0117] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0118] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 454.31 g of morpholine, then heat to 120° C. and react for 4.5 h.

[0119] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. The vacuum was selected at 5 kPa and the distillation temperature was 70°C to remove chlorobenzene to obtain 479.30 g of a yellow solid of 3-morpholine-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one, an intermediate of apixaban: HPLC: 96.35%, a yield of 92.37%. 1910.66 g of chlorobenzene was recovered, with a recovery rate of 97%.

[0120] Example 6

[0121] This embodiment provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, which is carried out according to the following steps:

[0122] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0123] S1-1, 304.04g of p-nitroaniline (p-nitroaniline) was dissolved in 2128.18ml (2353.76g) of chlorobenzene, 267.04g of triethylamine was added, and 341.26g of pentachlorovaleryl chloride was added dropwise at 30°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 40°C and the reaction was allowed to react for 6h.

[0124] S1-2. At a temperature of 40°C, 352.22 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 504.04 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 1216.06 ml of chlorobenzene. The combined organic phases were washed twice with 912.06 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 93°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0125] S1-3. 2 g of chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was subjected to HPLC content analysis to obtain 471.01 g of 1-(4-nitrophenyl)-2-piperidone; HPLC: 98.74%, yield 97.14%.

[0126] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0127] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 1494.62 g of phosphorus pentachloride was added in three equal batches at 50°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 h.

[0128] S2-2. After the reaction is completed, 2246.86 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 745.89 ml of chlorobenzene. The combined organic phases are washed twice with 186.45 ml of water and dried over anhydrous sodium sulfate.

[0129] S2-3. Take 2 g of chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone and perform HPLC content analysis to obtain 585.16 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone: HPLC: 98.77%, yield 96.82%.

[0130] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0131] S3-1. Add 545.17 g of morpholine to the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, then heat to 120-130° C. and react for 4.5 h.

[0132] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. The vacuum was selected at 5 kPa and the distillation temperature was 68 ° C. Chlorobenzene was removed to obtain 571.18 g of the apixaban intermediate 3-morpholine-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one as a yellow solid: HPLC: 95.95%, yield 91.73%. 2291.62 g of chlorobenzene was recovered, with a recovery rate of 97%.

[0133] Example 7

[0134] This example provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. Unlike Example 1, the organic base used in this example is potassium tert-butoxide, and the other processes are the same as those in Example 1.

[0135] Follow these steps:

[0136] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0137] S1-1, 179.55g of p-nitroaniline (p-nitroaniline) was dissolved in 1256.71ml (1389.92g) of chlorobenzene, 157.71g of potassium tert-butoxide was added, and 201.52g of pentachlorovaleryl chloride was added dropwise at 30°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 40°C and the reaction was allowed to proceed for 6h.

[0138] S1-2. At a temperature of 40°C, 208.00 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 897.65 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 718.12 ml of chlorobenzene. The combined organic phases were washed twice with 538.59 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 90°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0139] S1-3. 2 g of a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 269.71 g of 1-(4-nitrophenyl)-2-piperidone. HPLC: 97.9%, yield 94.25%.

[0140] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0141] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 882.59 g of phosphorus pentachloride was added in three equal batches at 40°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 hours.

[0142] S2-2. After the reaction is completed, 1321.38 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 440.46 ml of chlorobenzene. The combined organic phases are washed twice with 110.11 ml of water and dried over anhydrous sodium sulfate.

[0143] S2-3. 2 g of a chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 333.22 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone. HPLC: 98.7%, yield 93.37%.

[0144] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0145] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 331.05 g of morpholine, then heat to 122° C. and react for 4.5 h.

[0146] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. Chlorobenzene was removed at a vacuum of 5 kPa and a distillation temperature of 70°C to obtain 335.54 g of a yellow solid, 3-morpholino-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one, an intermediate of apixaban. HPLC analysis revealed a 94.75% yield and a 91.28% yield. Chlorobenzene (1339.60 g) was recovered, yielding 96%.

[0147] Example 8

[0148] This example provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. Unlike Example 1, the organic base used in this example is sodium tert-butoxide, and the other processes are the same as those in Example 1.

[0149] Follow these steps:

[0150] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0151] S1-1, 179.55g of p-nitroaniline (p-nitroaniline) was dissolved in 1256.71ml (1389.92g) of chlorobenzene, 157.71g of sodium tert-butoxide was added, and 201.52g of pentachlorovaleryl chloride was added dropwise at 20°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 40°C and the reaction was allowed to proceed for 6h.

[0152] S1-2. At a temperature of 20-40°C, 208.00 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at 35°C for 6 hours. After the reaction was completed, 897.65 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 718.12 ml of chlorobenzene. The combined organic phases were washed twice with 538.59 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 90°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0153] S1-3. 2 g of a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 269.71 g of 1-(4-nitrophenyl)-2-piperidone. HPLC: 97.9%, yield 94.25%.

[0154] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0155] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 882.59 g of phosphorus pentachloride was added in three equal batches at 50°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 hours.

[0156] S2-2. After the reaction is completed, 1321.38 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 440.46 ml of chlorobenzene. The combined organic phases are washed twice with 110.11 ml of water and dried over anhydrous sodium sulfate.

[0157] S2-3. 2 g of a chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 333.22 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone. HPLC: 98.7%, yield 93.37%.

[0158] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0159] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 331.05 g of morpholine, then heat to 124° C. and react for 4.5 h.

[0160] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. Chlorobenzene was removed at a vacuum of 3-5 kPa and a distillation temperature of 77°C to obtain 335.54 g of a yellow solid, 3-morpholino-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one, an intermediate of apixaban. HPLC analysis revealed a 94.75% yield, a 91.28% yield, and 1360.45 g of chlorobenzene was recovered, with a recovery rate of 98%.

[0161] Example 9

[0162] This example provides a method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone. Unlike Example 1, the organic base used in this example is sodium acetate, and the other processes are the same as those in Example 1.

[0163] Follow these steps:

[0164] S1. Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0165] S1-1, 179.55g of p-nitroaniline (p-nitroaniline) was dissolved in 1256.71ml (1389.92g) of chlorobenzene, 157.71g of sodium acetate was added, and 201.52g of pentachlorovaleryl chloride was added dropwise at 30°C. The addition time was controlled within 2h, and the mixture was added dropwise at a uniform rate. Then the temperature was raised to 38°C and the reaction was allowed to react for 6h.

[0166] S1-2. At a temperature of 20°C, 208.00 g of sodium hydroxide was added to the reaction solution in three equal batches, with an interval of one hour between each batch. The reaction was carried out at a temperature of 35°C for 6 hours. After the reaction was completed, 897.65 ml of water was added to the reaction solution and extracted once. The aqueous phase was extracted once with 718.12 ml of chlorobenzene. The combined organic phases were washed twice with 538.59 ml of water, dried over anhydrous sodium sulfate, and triethylamine was evaporated by atmospheric distillation at 90°C to obtain a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone.

[0167] S1-3. 2 g of a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 269.71 g of 1-(4-nitrophenyl)-2-piperidone. HPLC: 97.9%, yield 94.25%.

[0168] Synthesis of S2, 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone

[0169] S2-1. To the above-mentioned chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone, 882.59 g of phosphorus pentachloride was added in three equal batches at 50°C, with an interval of one hour between each batch, for a total of two hours. The temperature was then raised to 60°C and the reaction time was 3 hours.

[0170] S2-2. After the reaction is completed, 1321.38 ml of water is added to the reaction solution and extracted once. The aqueous phase is extracted once with 440.46 ml of chlorobenzene. The combined organic phases are washed twice with 110.11 ml of water and dried over anhydrous sodium sulfate.

[0171] S2-3. 2 g of a chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone was analyzed by HPLC to obtain 333.22 g of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone. HPLC: 98.7%, yield 93.37%.

[0172] S3. Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidinone

[0173] S3-1. To the above chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, add 331.05 g of morpholine, then heat to 130° C. and react for 4.5 h.

[0174] S3-2. After the reaction, the solvent was removed by distillation under reduced pressure. Chlorobenzene was removed at a vacuum of 5 kPa and a distillation temperature of 74°C to obtain 335.54 g of a yellow solid, 3-morpholino-1-(4-nitrobenzene)-5,6-dihydropiperidin-2(1-hydro)-one, an intermediate of apixaban. HPLC analysis revealed a 94.75% yield and a 91.28% yield. Chlorobenzene (1323.34 g) was recovered, yielding 95%.

[0175] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that it is still possible to modify the technical solutions described in the above embodiments, or to replace some or all of the technical features therein by equivalents. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention, and they should all be included in the scope of the claims and description of the present invention.

Claims

1. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, characterized in that: The following steps are involved: (1) dissolving p-nitroaniline in chlorobenzene, adding an organic base and pentachlorovaleryl chloride, and adding sodium hydroxide to continue the reaction until the p-nitroaniline reacts completely, and then adding water to obtain 1-(4-nitrophenyl)-2-piperidone; (2) adding phosphorus pentachloride to a chlorobenzene solution of 1-(4-nitrophenyl)-2-piperidone to react until the reaction of 1-(4-nitrophenyl)-2-piperidone is complete, and then adding water for treatment to obtain 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone; (3) Morpholine is added to a chlorobenzene solution of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone, and the mixture is refluxed until the reaction of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone is complete. After removing the solvent, the compound 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone is obtained.

2. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: The organic base used in step (1) includes any one of triethylamine, potassium tert-butoxide, sodium tert-butoxide, and sodium acetate.

3. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (1), the molar ratio of p-nitroaniline, pentachlorovaleryl chloride, organic base and sodium hydroxide is 1:(1-1.6):(0.5-1.5):(3-5); the amount ratio of chlorobenzene, water and p-nitroaniline is (5ml-20ml):(5ml-10ml):1g.

4. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (1), pentachlorovaleryl chloride is added dropwise at 20°C to 30°C, and then the temperature is raised to 20°C to 40°C to carry out chlorination reaction.

5. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (1), sodium hydroxide is added in batches.

6. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (2), the usage ratio of chlorobenzene, water and 1-(4-nitrophenyl)-2-piperidone is (5ml-20ml):(5ml-20ml):1g; the molar ratio of 1-(4-nitrophenyl)-2-piperidone to phosphorus pentachloride is 1:(2-5).

7. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (2), phosphorus pentachloride is added in batches.

8. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (3), triethylamine is recovered by atmospheric distillation at 90° C. to 130° C., and a fraction at 88° C. to 100° C. is received.

9. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: In step (3), the usage ratio of chlorobenzene to 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone is (3 ml to 20 ml):1 g; the molar ratio of 3,3-dichloro-1-(4-nitrophenyl)-2-piperidone to morpholine is 1:(2.5 to 10).

10. A method for synthesizing an apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone according to claim 1, characterized in that: The reaction temperature in step (3) is 120°C to 130°C.

11. An apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-piperidone, characterized in that: The compound is synthesized by the synthesis method according to any one of claims 1 to 10.

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