Apixaban intermediate and synthesis method thereof

Abstract

The invention discloses an apixaban intermediate and a synthesis method thereof, and relates to the technical field of pharmaceutical manufacturing intermediates. The synthesis method of the apixaban intermediate comprises the following steps: dissolving a compound as shown in a formula I in a solvent 1, adding an acid-binding agent and 5-chlorovaleryl chloride for reaction, and then adding an inorganic base 1 for reaction to obtain a compound as shown in a formula II; dissolving the compound as shown in the formula II in a solvent 2, adding a phase transfer catalyst, bromine and an inorganic base 2, and reacting to prepare a compound as shown in a formula III; dissolving the compound as shown in the formula III in a solvent 3, adding iron nitrate nonahydrate, a catalyst 1 and salt, and continuously introducing a catalyst 2 for reaction to prepare a compound as shown in a formula IV; dissolving the compound as shown in the formula IV in a solvent 4, adding morpholine and inorganic alkali 3, and reacting to obtain a compound as shown in a formula V; the invention solves the problems of harsh synthesis conditions and high cost of the existing apixaban intermediate.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical manufacturing intermediates, and particularly relates to an apixaban intermediate and a synthesis method thereof. Background Art

[0002] Apixaban has the chemical name of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, and the molecular formula of C 25 H 25 N5O4. Clinically, it is used for adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism events (VTE), and its chemical structural formula is as follows:

[0003]

[0005] Currently, the following several synthesis methods of apixaban have been reported:

[0006] US Patent US8884016 proposed a technical route for synthesizing apixaban from 1-(4-iodophenyl)piperidine-2,3-dione, and the reaction route is as follows:

[0007]

[0008] The key intermediate in this synthesis route, 1-(4-iodophenyl)piperidine-2,3-dione, was prepared in the prior art by decarboxylative hydrolysis of compound to remove group Z (carboxyl, ester group or cyano group). This method was only mentioned in US8884016 without a specific scheme, and compounds with group Z (carboxyl, ester group or cyano group) containing multiple carbonyl groups often need to be completed in a noble metal-catalyzed coupling reaction, with high costs and not suitable for large-scale production and preparation.

[0009] US Patent US2017015663 proposed a technical route for synthesizing apixaban from 1-(4-iodophenyl)piperidine-2,3-dione, and the reaction route is as follows:

[0010]

[0011] The starting route raw materials (p-iodoaniline and 5-bromovaleryl chloride) have high prices, the total yield of the route is only 1.3%, and the Ullmann coupling reaction requires high temperature and high pressure reaction, with harsh conditions and high costs, and is not suitable for industrial production.

[0012] In Chinese Patent CN101967145, p-nitroaniline is used as the starting material, and through amidation cyclization, dichlorination, elimination, cyclization elimination, catalytic hydrogenation reduction, and amidation cyclization in sequence, the target compound, the intermediate of apixaban, is obtained. The synthetic route is as follows:

[0013]

[0014] The total yield of this route is 35%. The synthetic yield is high, the raw materials are easily available, and the cost is lower. However, phosphorus pentachloride is used as a raw material, and the post-treatment cost is high and it is not environmentally friendly.

[0015] Chinese Patent CN 117486787 A reports a synthetic route for preparing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone using p-chloronitrobenzene as a raw material. The specific reaction formula is as follows:

[0016]

[0017] Using this method, the synthetic route is shorter and the yield is higher. However, the raw material in the first step is not easily synthesized; in the second step, 10 times the mass of dimethyl sulfoxide is used as the solvent, generating more three wastes; the expensive 2-iodoxybenzoic acid is used as an oxidant, resulting in a higher cost; and CeCl3·7H2O, a lanthanide heavy metal, is used as a catalyst, which is extremely difficult to remove from the product. Therefore, a new route for synthesizing 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone is needed.

[0018] Therefore, there is an urgent need to provide a synthetic method for the intermediate of apixaban with simple conditions, low synthesis cost, high yield, and environmental friendliness. Summary of the Invention

[0019] The technical problem to be solved by the present invention is that the existing intermediate of apixaban has problems such as harsh synthesis conditions and high costs. The purpose is to provide the intermediate of apixaban and its synthetic method, which solves the problems of harsh synthesis conditions and high costs of the existing intermediate of apixaban.

[0020] The present invention is achieved by the following technical solutions:

[0021] In the first aspect, the present invention provides a synthetic method for the intermediate of apixaban, comprising the following steps:

[0022] Dissolve the compound shown in formula I in solvent 1, add an acid-binding agent and 5-chlorovaleryl chloride to react, and then add inorganic base 1 to react to obtain the compound shown in formula II;

[0023] Dissolve the compound shown in formula II in solvent 2, add a phase transfer catalyst, bromine, and inorganic base 2, and react to obtain the compound shown in formula III;

[0024] Dissolve the compound shown in Formula III in Solvent 3, add ferric nitrate nonahydrate, Catalyst 1 and salt, and continuously introduce Catalyst 2 for reaction to obtain the compound shown in Formula IV;

[0025] Dissolve the compound shown in Formula IV in Solvent 4, add morpholine and Inorganic Base 3, and react to obtain the compound shown in Formula V;

[0026]

[0027] As a possible design, the compound shown in Formula I above is p-nitroaniline;

[0028] The compound shown in Formula II is 1-(4-nitrophenyl)-2-piperidone;

[0029] The compound shown in Formula III is 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one;

[0030] The compound shown in Formula IV is 1-(4-nitrophenyl)piperidine-2,3-dione;

[0031] The compound shown in Formula V is 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone.

[0032] As a possible design, the above-mentioned acid-binding agent includes triethylamine, pyridine, diethanolamine, sodium carbonate and / or potassium carbonate; the inorganic base 1 includes sodium hydroxide, potassium hydroxide, sodium carbonate and / or potassium carbonate;

[0033] The solution 1 includes one or more of dichloromethane, 1,2-dichloroethane, chlorobenzene and toluene.

[0034] As a possible design, the molar ratio of the above-mentioned acid-binding agent to the compound shown in Formula I is 0.5-1.2:1;

[0035] The molar ratio of the 5-chlorovaleryl chloride to the compound shown in Formula I is 1.1-1.5:1;

[0036] The molar ratio of the inorganic base 1 to the compound shown in Formula I is 3.0-5.0:1;

[0037] The mass ratio of the solvent 1 to the compound shown in Formula I is 5-15 mL:1 g;

[0038] The reaction temperature for adding the inorganic base 1 for reaction is 25-70 °C, and the reaction time is 2-16 h.

[0039] As a possible design, the above-mentioned solvent 2 includes one or more of water, dichloromethane and 1,2-dichloroethane; the phase transfer catalyst includes tetrabutylammonium bromide and / or benzyltriethylammonium chloride;

[0040] The inorganic base 2 includes potassium hydroxide and / or sodium hydroxide.

[0041] As a possible design, the mass ratio of the above-mentioned solvent 2 to the compound shown in Formula II is 5-15 mL: 1 g;

[0042] The phase transfer catalyst is 0.1%-0.5% of the mass of the compound shown in Formula II;

[0043] The molar ratio of bromine to the compound shown in Formula II is 1.0-2.0:1;

[0044] The molar ratio of the inorganic base 2 to the compound shown in Formula II is 2.6-6.0:1;

[0045] The reaction temperature for adding the phase transfer catalyst, bromine and inorganic base 2 to react is 5-70 °C, and the reaction time is 5-10 h.

[0046] As a possible design, the above-mentioned catalyst 1 includes inhibitor 701, 4-ACO-TEMPO or 4-Bz-TEMPO, wherein the structural formula of 4-ACO-TEMPO is;

[0047] The catalyst 2 includes air or oxygen;

[0048] The salt includes potassium chloride, potassium carbonate, sodium carbonate, sodium acetate and / or sodium sulfate;

[0049] The solvent 3 includes one or more of 1,2-dichloroethane, dichloromethane, carbon tetrachloride and toluene.

[0050] As a possible design, the mass ratio of the above-mentioned solvent 3 to the compound shown in Formula III is 15-40 mL: 1 g;

[0051] The molar ratio of ferric nitrate nonahydrate to the compound shown in Formula III is 0.1-1.0:1;

[0052] The molar ratio of the salt to the compound shown in Formula III is 0.1-1.0:1;

[0053] The molar ratio of the catalyst 1 to the compound shown in Formula III is 0.1-1.0:1;

[0054] The reaction temperature for adding ferric nitrate nonahydrate, catalyst 1 and salt and continuously introducing catalyst 2 to react is 20-50 °C, and the reaction time is 16-30 h;

[0055] The above-mentioned inorganic base 3 includes sodium carbonate and / or potassium carbonate;

[0056] The solvent 4 includes one or more of N,N-dimethylformamide (DMF), chlorobenzene, and toluene.

[0057] As a possible design, the molar ratio of the above-mentioned morpholine to the compound shown in Formula IV is 2.0 - 10.0:1;

[0058] The molar ratio of the inorganic base 3 to the compound shown in Formula IV is 2.0 - 5.0:1;

[0059] The mass ratio of the solvent 4 to the compound shown in Formula IV is 3 ml - 15 ml:1 g;

[0060] The reaction temperature for adding morpholine and inorganic base 3 to react is 30 - 80 °C, and the reaction time is 2 - 5 h.

[0061] In a second aspect, the present invention provides an apixaban intermediate, including the structure shown in Formula V:

[0062]

[0063] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0064] The present invention provides a synthesis method of apixaban intermediate 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone. In the synthesis process of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridone, solution 1 is used instead of dimethyl sulfoxide as the solvent, reducing the generation of three wastes; air or oxygen oxidation is used instead of the oxidant 2-iodoxybenzoic acid and the catalyst CeCl3·7H2O for oxidation, reducing the cost and heavy metal residues. The reaction temperature is very mild, reducing the synthesis difficulty, and the post-treatment operation is convenient. The obtained product has good quality and yield, and is easy to industrialize. Moreover, the whole synthesis route is simple, the raw materials are easily available and the cost is low, the reaction conditions are mild, and the operation is simple. Specific Embodiments

[0065] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention. For those not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0066] Since there are problems in the synthesis method of an existing apixaban intermediate, such as harsh synthesis conditions, high cost, low product yield, large environmental pollution, and high post-treatment cost, the present invention specifically provides a new synthesis method of apixaban intermediate to solve the above problems.

[0067] A synthetic method of an apixaban intermediate, comprising the following steps:

[0068] S1. Dissolve the compound shown in formula I in solvent 1, add an acid-binding agent and 5-chlorovaleryl chloride to react, and then add inorganic base 1 to react to obtain the compound shown in formula II. The compound shown in formula I undergoes an amidation reaction after adding 5-chlorovaleryl chloride, and finally undergoes a ring-closing reaction under the action of inorganic base 1.

[0069] In some embodiments of the present invention, the above-mentioned acid-binding agent includes triethylamine, pyridine, diethanolamine, sodium carbonate and / or potassium carbonate.

[0070] In some embodiments of the present invention, the compound shown in formula I is p-nitroaniline.

[0071] In some embodiments of the present invention, the above-mentioned inorganic base 1 includes sodium hydroxide, potassium hydroxide, sodium carbonate and / or potassium carbonate.

[0072] In some embodiments of the present invention, the above-mentioned solution 1 includes one or more of dichloromethane, 1,2-dichloroethane, chlorobenzene and toluene.

[0073] In some embodiments of the present invention, the molar ratio of the above-mentioned acid-binding agent to the compound shown in formula I is 0.5-1.2:1. The molar ratio of the acid-binding agent to the compound shown in formula I is any number within 0.5-1.2:1, including but not limited to 0.6:1, 0.7:1, 0.9:1, 0.95:1, 1.15:1 or other arbitrary values. Preferably, the molar ratio of the acid-binding agent to the compound shown in formula I is 0.7-1:1.

[0074] The molar ratio of the above-mentioned 5-chlorovaleryl chloride to the compound shown in formula I is 1.1-1.5:1. The molar ratio of 5-chlorovaleryl chloride to the compound shown in formula I is any number within 1.1-1.5:1, including but not limited to 1.15:1, 1.29:1, 1.37:1, 1.49:1 or other arbitrary values. Preferably, the molar ratio of 5-chlorovaleryl chloride to the compound shown in formula I is 1.2-1.4:1.

[0075] In some embodiments of the present invention, the molar ratio of the above-mentioned inorganic base 1 to the compound shown in formula I is 3.0-5.0:1. The molar ratio of inorganic base 1 to the compound shown in formula I is any number within 3.0-5.0:1, including but not limited to 3.2:1, 3.45:1, 3.8:1, 4.2:1, 4.5:1, 4.9:1 or other arbitrary values. Preferably, the molar ratio of inorganic base 1 to the compound shown in formula I is 3.5-4.5:1.

[0076] In some embodiments of the present invention, the mass ratio of the above-mentioned solvent 1 to the compound represented by Formula I is 5-15 mL:1 g. The mass ratio of solvent 1 to the compound represented by Formula I is any number within 5-15 mL:1 g, including but not limited to 6 mL:1 g, 8 mL:1 g, 9 mL:1 g, 12 mL:1 g, 14 mL:1 g, or any other arbitrary value. Preferably, the mass ratio of solvent 1 to the compound represented by Formula I is 8-12 mL:1 g.

[0077] In some embodiments of the present invention, the reaction temperature in the above step S1 is 25-70 °C, and the reaction time is 2-16 h.

[0078] S2. Dissolve the compound represented by Formula II in solvent 2, add a phase transfer catalyst, bromine, and inorganic base 2, and react to obtain the compound represented by Formula III.

[0079] In some embodiments of the present invention, the above-mentioned compound represented by Formula II is 1-(4-nitrophenyl)-2-piperidone.

[0080] In some embodiments of the present invention, the above-mentioned solvent 2 includes one or more of water, dichloromethane, and 1,2-dichloroethane.

[0081] In some embodiments of the present invention, the above-mentioned phase transfer catalyst includes tetrabutylammonium bromide and / or benzyltriethylammonium chloride.

[0082] In some embodiments of the present invention, the above-mentioned inorganic base 2 includes potassium hydroxide and / or sodium hydroxide.

[0083] In some embodiments of the present invention, the mass ratio of the above-mentioned solvent 2 to the compound represented by Formula II is 5-15 mL:1 g. The mass ratio of solvent 2 to the compound represented by Formula II is any number within 5-15 mL:1 g, including but not limited to 6 mL:1 g, 8 mL:1 g, 9 mL:1 g, 12 mL:1 g, 14 mL:1 g, or any other arbitrary value. Preferably, the mass ratio of solvent 2 to the compound represented by Formula II is 8-12 mL:1 g.

[0084] In some embodiments of the present invention, the above-mentioned phase transfer catalyst is 0.1%-0.5% of the mass of the compound represented by Formula II. Preferably, the phase transfer catalyst is any number within 0.1%-0.5% of the mass of the compound represented by Formula II, including but not limited to 0.2%, 0.3%, 0.4%, or any other arbitrary value. Preferably, the phase transfer catalyst is 0.2-0.4% of the mass of the compound represented by Formula II.

[0085] In some embodiments of the present invention, the molar ratio of the above-mentioned bromine to the compound shown in Formula II is 1.0 to 2.0:1. The molar ratio of bromine to the compound shown in Formula II is any number within 1.0 to 2.0:1, including but not limited to 1.2:1, 1.3:1, 1.53:1, 1.85:1 or any other arbitrary value. Preferably, the molar ratio of bromine to the compound shown in Formula II is 1.2 to 1.8:1.

[0086] In some embodiments of the present invention, the molar ratio of the above-mentioned inorganic base 2 to the compound shown in Formula II is 2.6 to 6.0:1. The molar ratio of inorganic base 2 to the compound shown in Formula II is any number within 2.6 to 6.0:1, including but not limited to 3:1, 2.8:1, 4.5:1, 5.7:1 or any other arbitrary value. Preferably, the molar ratio of inorganic base 2 to the compound shown in Formula II is 3.6 to 5.0:1.

[0087] In some embodiments of the present invention, the reaction temperature of the above-mentioned step S2 is 5 to 70 °C, and the reaction time is 5 to 10 h.

[0088] S3. Dissolve the compound shown in Formula III in Solvent 3, add ferric nitrate nonahydrate, Catalyst 1 and salt, and continuously introduce Catalyst 2 for reaction to obtain the compound shown in Formula IV.

[0089] In some embodiments of the present invention, the compound shown in Formula III is 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one.

[0090] In some embodiments of the present invention, the above-mentioned Catalyst 1 includes inhibitor 701, 4-ACO-TEMPO or 4-Bz-TEMPO, wherein the structural formula of 4-ACO-TEMPO is.

[0091] In some embodiments of the present invention, the above-mentioned Catalyst 2 includes air or oxygen.

[0092] In some embodiments of the present invention, the above-mentioned salt includes potassium chloride, potassium carbonate, sodium carbonate, sodium acetate and / or sodium sulfate.

[0093] In some embodiments of the present invention, the above-mentioned Solvent 3 includes one or more of 1,2-dichloroethane, dichloromethane, carbon tetrachloride and toluene.

[0094] In some embodiments of the present invention, the mass ratio of the above-mentioned Solvent 3 to the compound shown in Formula III is 15 to 40 mL:1 g. The mass ratio of Solvent 3 to the compound shown in Formula III is any number within 15 to 40 mL:1 g, including but not limited to 16 mL:1 g, 28 mL:1 g, 29 mL:1 g, 32 mL:1 g, 34 mL:1 g, or any other arbitrary value. Preferably, the mass ratio of Solvent 3 to the compound shown in Formula III is 20 to 35 mL:1 g.

[0095] In some embodiments of the present invention, the molar ratio of the above-mentioned ferric nitrate nonahydrate to the compound shown in Formula III is 0.1 to 1.0:1. The molar ratio of ferric nitrate nonahydrate to the compound shown in Formula III is any number within 0.1 to 1.0:1, including but not limited to 0.2:1, 0.3:1, 0.45:1, 0.55:1, 0.68:1, 0.79:1 or any other arbitrary value. Preferably, the molar ratio of ferric nitrate nonahydrate to the compound shown in Formula III is 0.3 to 0.8:1.

[0096] In some embodiments of the present invention, the molar ratio of the above-mentioned salt to the compound shown in Formula III is 0.1 to 1.0:1. The molar ratio of the salt to the compound shown in Formula III is any number within 0.1 to 1.0:1, including but not limited to 0.2:1, 0.3:1, 0.45:1, 0.55:1, 0.68:1, 0.79:1 or any other arbitrary value. Preferably, the molar ratio of the salt to the compound shown in Formula III is 0.3 to 0.8:1.

[0097] In some embodiments of the present invention, the molar ratio of the above-mentioned Catalyst 1 to the compound shown in Formula III is 0.1 to 1.0:1. The molar ratio of Catalyst 1 to the compound shown in Formula III is any number within 0.1 to 1.0:1, including but not limited to 0.2:1, 0.3:1, 0.45:1, 0.55:1, 0.68:1, 0.79:1 or any other arbitrary value. Preferably, the molar ratio of Catalyst 1 to the compound shown in Formula III is 0.3 to 0.8:1.

[0098] In some embodiments of the present invention, the reaction temperature of the above-mentioned step S3 is 20 to 50 °C, and the reaction time is 16 to 30 h.

[0099] S4. Dissolve the compound shown in Formula IV in Solvent 4, add morpholine and inorganic base 3, and react to obtain the compound shown in Formula V.

[0100] In some embodiments of the present invention, the above-mentioned compound shown in Formula IV is 1-(4-nitrophenyl)piperidine-2,3-dione.

[0101] In some embodiments of the present invention, the above-mentioned compound shown in Formula V is 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone.

[0102] In some embodiments of the present invention, the above-mentioned inorganic base 3 includes sodium carbonate and / or potassium carbonate.

[0103] In some embodiments of the present invention, the above-mentioned Solvent 4 includes one or more of N,N-dimethylformamide (DMF), chlorobenzene, and toluene.

[0104] In some embodiments of the present invention, the molar ratio of the above-mentioned morpholine to the compound shown in Formula IV is 2.0 to 10.0:1. The molar ratio of morpholine to the compound shown in Formula IV is any number within the range of 2.0 to 10.0:1, including but not limited to 5:1, 8:1, 9:1 or any other arbitrary value.

[0105] In some embodiments of the present invention, the molar ratio of the above-mentioned inorganic base 3 to the compound shown in Formula IV is 2.0 to 5.0:1. The molar ratio of inorganic base 3 to the compound shown in Formula IV is any number within the range of 2.0 to 5.0:1, including but not limited to 2.5:1, 3:1, 4.5:1 or any other arbitrary value.

[0106] In some embodiments of the present invention, the mass ratio of the above-mentioned solvent 4 to the compound shown in Formula IV is 3 ml to 15 ml:1 g. The mass ratio of solvent 4 to the compound shown in Formula IV is any number within the range of 3 ml to 15 ml:1 g, including but not limited to 8 ml:1 g, 13 ml:1 g, 14 ml:1 g or any other arbitrary value.

[0107] In some embodiments of the present invention, the reaction temperature of the above-mentioned step S4 is 30 to 80 °C, and the reaction time is 2 to 5 h.

[0108] The present invention also provides an apixaban intermediate, including the structure shown in Formula V:

[0109]

[0110] Preferably, the above-mentioned apixaban intermediate is 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone.

[0111] Example 1

[0112] Synthesis of 1-(4-nitrophenyl)-2-piperidone (the compound shown in Formula II):

[0113] (1) Add 138.12 g of p-nitroaniline, 80.9 g of triethylamine, and 966 mL of chlorobenzene to a 2000 mL three-necked flask. While maintaining the external temperature below 45 °C, add 186.02 g of 5-chlorovaleryl chloride dropwise. React at an external temperature of 45 °C for 2 h. Monitor the raw materials by HPLC and ensure that the raw materials are <1%. Lower the reaction solution to 20 - 30 °C, and while maintaining the internal temperature below 50 °C, add a total of 128 g of sodium hydroxide in three batches. React at an external temperature of 60 °C for 4 h. Monitor the raw materials by HPLC and ensure that the raw materials are <0.5%. Then stop the reaction;

[0114] (2) Add 691 mL of water to the reaction solution, let it stand for phase separation, and continue to add 276 mL of chlorobenzene to extract the aqueous phase; combine the organic phases, wash them twice with 276 mL×2 of water, continue to add 276 mL of chlorobenzene to extract the washing aqueous phase once, distill the solvent from the organic phase under vacuum at -0.09 MPa and an external temperature of 80 °C. Pulverize the crude product with 110 mL of methanol, dry it, and obtain 202.34 g of the yellowish-brown crystal product 1-(4-nitrophenyl)-2-piperidone, with a yield of 91.89% and an HPLC purity of 99.23%.

[0115] Example 2

[0116] Synthesis of 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one (the compound shown in Formula III):

[0117] (1) Add a mixture of 20 g of sodium hydroxide and 66 mL of water to a 500 mL three-necked flask containing 22.02 g of 1-(4-nitrophenyl)-2-piperidone, 132 mL of 1,2-dichloroethane, and 0.044 g of tetrabutylammonium bromide. While maintaining the internal temperature at 5 - 10 °C, dropwise add 17.58 g of bromine. After the addition is complete, maintain the internal temperature at 5 - 10 °C and react for 2 h, then set the external temperature at 50 °C and react for 5 h. Monitor the raw materials by HPLC, when the raw materials are <1%, stop the reaction;

[0118] (2) Cool to an internal temperature of 25 - 30 °C, let it stand for phase separation, add 33 mL of 1,2-dichloroethane to extract the aqueous phase, combine the organic phases and wash them twice with 45 mL×2 of 8% aqueous sodium bicarbonate solution; wash the aqueous phase with 25 mL of 1,2-dichloroethane for extraction once. Distill the solvent from the organic phase under vacuum at -0.09 MPa and an external temperature of 60 °C. Pulverize the crude product with 50 mL of a mixed solution of PE:EA = 3:1 at 60 °C, dry it, and obtain 17.7 g of the yellowish-brown solid product 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one, with a yield of 75% and an HPLC purity of 97.1%.

[0119] Example 3

[0120] This example is basically the same as Example 2, the difference lies in: the addition amount of sodium hydroxide.

[0121] Synthesis of 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one (the compound shown in Formula III):

[0122] (1) Add a mixture of 14 g of sodium hydroxide and 66 mL of water to a 500 mL three-necked flask containing 22.02 g of 1-(4-nitrophenyl)-2-piperidone, 132 mL of 1,2-dichloroethane, and 0.044 g of tetrabutylammonium bromide. While maintaining the internal temperature at 5 - 10 °C, dropwise add 17.58 g of bromine. After the addition is complete, maintain the internal temperature at 5 - 10 °C and react for 2 h, then set the external temperature at 50 °C and react for 5 h. Monitor the raw materials by HPLC, when the raw materials are <1%, stop the reaction;

[0123] (2) Cool to an internal temperature of 25 - 30 °C, let stand for phase separation. Add 33 mL of 1,2 - dichloroethane to the aqueous phase for extraction, and combine the organic phases. Wash the combined organic phases twice with 45 mL × 2 of 8% aqueous sodium bicarbonate solution; wash the aqueous phase with 25 mL of 1,2 - dichloroethane for extraction once. Distill the solvent from the organic phase under vacuum at -0.09 MPa and an external temperature of 60 °C. Pulp the crude product with 50 mL of a mixed solution of PE:EA = 3:1 at 60 °C, and dry to obtain 21.0 g of a yellowish - brown solid product, 3 - hydroxy - 1 - (4 - nitrophenyl)piperidin - 2 - one, with a yield of 88.91% and an HPLC purity of 98.3%.

[0124] Example 4

[0125] Synthesis of 1 - (4 - nitrophenyl)piperidine - 2,3 - dione (the compound shown in Formula Ⅳ):

[0126] Add 23.6 g of 3 - hydroxy - 1 - (4 - nitrophenyl)piperidin - 2 - one, 5.36 g of 4 - ACO - TEMPO, 0.75 g of potassium chloride (0.01 mol), 4.04 g of ferric nitrate nonahydrate, and 354 mL of 1,2 - dichloroethane. Continuously introduce compressed air and react at 35 - 40 °C for 18 h;

[0127] (2) After the reaction is completed, add 6N hydrochloric acid and stir for phase separation. Adjust the pH of the organic phase to 9 - 10 with 15% aqueous sodium carbonate solution. Wash the organic phase once more with 2% aqueous sodium carbonate solution. After combining the aqueous phases, continue to adjust the pH to 1 - 2 with 6N hydrochloric acid, and add 1,2 - dichloroethane for extraction twice. Combine the organic phases;

[0128] (3) Concentrate the organic phase under reduced pressure to obtain 20.61 g of a pale - yellow product, 1 - (4 - nitrophenyl)piperidine - 2,3 - dione, with a yield of 88% and an HPLC purity of 98.6%.

[0129] Example 5

[0130] This example is basically the same as Example 4, except that carbon tetrachloride is used to replace 1,2 - dichloroethane.

[0131] Synthesis of 1 - (4 - nitrophenyl)piperidine - 2,3 - dione (the compound shown in Formula Ⅳ):

[0132] Add 23.6 g of 3 - hydroxy - 1 - (4 - nitrophenyl)piperidin - 2 - one, 10.72 g of 4 - ACO - TEMPO, 0.75 g of potassium chloride, 4.04 g of ferric nitrate nonahydrate, and 354 mL of carbon tetrachloride. Continuously introduce compressed air and react at 35 - 40 °C for 16 h;

[0133] (2) After the reaction was completed, 6N hydrochloric acid was added and stirred to separate the phases. The organic phase was adjusted to pH 9 - 10 with 15% aqueous sodium carbonate solution. The organic phase was further washed once with 2% aqueous sodium carbonate solution, and the aqueous phases were combined. Then, the combined aqueous phases were adjusted to pH 1 - 2 with 6N hydrochloric acid, and extracted twice with 1,2 - dichloroethane. The organic phases were combined;

[0134] (3) The organic phase was concentrated under reduced pressure to obtain 20.4 g of a pale yellow product, 1 - (4 - nitrophenyl)piperidine - 2,3 - dione, with a yield of 87.11% and an HPLC purity of 98.3%.

[0135] Example 6

[0136] This example is basically the same as Example 4, except for the addition amount of 4 - ACO - TEMPO.

[0137] Synthesis of 1 - (4 - nitrophenyl)piperidine - 2,3 - dione (the compound shown in Formula IV):

[0138] 23.6 g of 3 - hydroxy - 1 - (4 - nitrophenyl)piperidin - 2 - one, 10.72 g of 4 - ACO - TEMPO, 1.38 g of potassium carbonate, 4.04 g of iron(III) nitrate nonahydrate, and 354 mL of 1,2 - dichloroethane were continuously bubbled with compressed air and reacted at 35 - 40 °C for 16 h;

[0139] (2) After the reaction was completed, 6N hydrochloric acid was added and stirred to separate the phases. The organic phase was adjusted to pH 9 - 10 with 15% aqueous sodium carbonate solution. The organic phase was further washed once with 2% aqueous sodium carbonate solution, and the aqueous phases were combined. Then, the combined aqueous phases were adjusted to pH 1 - 2 with 6N hydrochloric acid, and extracted twice with 1,2 - dichloroethane. The organic phases were combined;

[0140] (3) The organic phase was concentrated under reduced pressure to obtain 18.7 g of a pale yellow product, 1 - (4 - nitrophenyl)piperidine - 2,3 - dione, with a yield of 80% and an HPLC purity of 97.5%.

[0141] Example 7

[0142] Synthesis of 5,6 - dihydro - 3 - (4 - morpholinyl)-1 - (4 - nitrophenyl)-2(1H)-pyridinone (the compound shown in Formula V):

[0143] In a 250 mL three-necked flask, 23.4 g of 1-(4-nitrophenyl)piperidine-2,3-dione, 26.5 g of sodium carbonate, 26.14 g of morpholine and 117 mL of chlorobenzene were added, and the reaction was carried out at 50 °C for 3 h. The organic solvent and morpholine were removed by vacuum distillation at 80 °C. Then, it was washed twice with 75 mL×2 of water, filtered by suction, and the filter cake was recrystallized from toluene to obtain 27.3 g of a pale yellow powder product, 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone, with a yield of 90% and an HPLC purity of 98.5%.

[0144] Example 8

[0145] This example is basically the same as Example 7, except for: the addition amount of morpholine.

[0146] Synthesis of 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone (the compound shown in Formula V):

[0147] In a 250 mL three-necked flask, 23.4 g of 1-(4-nitrophenyl)piperidine-2,3-dione, 26.5 g of sodium carbonate, 43.56 g of morpholine and 117 mL of chlorobenzene were added, and the reaction was carried out at 50 °C for 2 h. The organic solvent and morpholine were removed by vacuum distillation at 80 °C. Then, it was washed twice with 75 mL×2 of water, filtered by suction, and the filter cake was recrystallized from toluene to obtain 25.78 g of a pale yellow powder product, 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone, with a yield of 85% and an HPLC purity of 97.1%.

[0148] Example 9

[0149] This example is basically the same as Example 7, except for: using toluene to replace chlorobenzene.

[0150] In a 250 mL three-necked flask, 23.4 g of 1-(4-nitrophenyl)piperidine-2,3-dione, 26.5 g of sodium carbonate, 26.14 g of morpholine and 117 mL of toluene were added, and the reaction was carried out at 110 °C for 2 h. The organic solvent and morpholine were removed by vacuum distillation at 80 °C. Then, it was washed twice with 75 mL×2 of water, filtered by suction, and the filter cake was recrystallized from toluene to obtain 21.23 g of a pale yellow powder product, 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone, with a yield of 70% and an HPLC purity of 95.4%.

[0151] The specific embodiments described above further elaborate on the object, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only the specific embodiments of the present invention and is not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing an apixaban intermediate, characterized in that, It includes the following steps: Dissolve the compound shown in Formula I in Solvent 1, add an acid-binding agent and 5-chlorovaleryl chloride to react, and then add inorganic base 1 to react to obtain the compound shown in Formula II; Dissolve the compound shown in Formula II in Solvent 2, add a phase transfer catalyst, bromine, and inorganic base 2, and react to prepare the compound shown in Formula III; Dissolve the compound shown in Formula III in Solvent 3, add iron(III) nitrate nonahydrate, Catalyst 1, and a salt, and continuously introduce Catalyst 2 to react to obtain the compound shown in Formula IV; Dissolve the compound shown in Formula IV in Solvent 4, add morpholine and inorganic base 3, and react to obtain the compound shown in Formula V; 2. The synthesis method of an apixaban intermediate according to claim 1, wherein, The compound shown in Formula I is p-nitroaniline; The compound shown in Formula II is 1-(4-nitrophenyl)-2-piperidone; The compound shown in Formula III is 3-hydroxy-1-(4-nitrophenyl)piperidin-2-one; The compound shown in Formula IV is 1-(4-nitrophenyl)piperidine-2,3-dione; The compound shown in Formula V is 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone.

3. A method for synthesizing an apixaban intermediate according to claim 1, characterized in that, The acid-binding agent includes triethylamine, pyridine, diethanolamine, sodium carbonate, and / or potassium carbonate; The inorganic base 1 includes sodium hydroxide, potassium hydroxide, sodium carbonate, and / or potassium carbonate; The Solvent 1 includes one or more of dichloromethane, 1,2-dichloroethane, chlorobenzene, and toluene.

4. A method for synthesizing an apixaban intermediate according to claim 1, characterized in that, The molar ratio of the acid-binding agent to the compound shown in Formula I is 0.5 - 1.2:1; The molar ratio of 5-chlorovaleryl chloride to the compound shown in Formula I is 1.1 - 1.5:1; The molar ratio of inorganic base 1 to the compound shown in Formula I is 3.0 - 5.0:1; The mass ratio of Solvent 1 to the compound shown in Formula I is 5 - 15 mL:1 g; The reaction temperature for adding inorganic base 1 to react is 25 - 70 °C, and the reaction time is 2 - 16 h.

5. The synthesis method of an apixaban intermediate according to claim 1, characterized in that, The Solvent 2 includes one or more of water, dichloromethane, and 1,2-dichloroethane; The phase transfer catalyst includes tetrabutylammonium bromide and / or benzyltriethylammonium chloride; The inorganic base 2 includes potassium hydroxide and / or sodium hydroxide.

6. The synthesis method of an apixaban intermediate according to claim 1, characterized in that, The mass ratio of Solvent 2 to the compound shown in Formula II is 5 - 15 mL:1 g; The phase transfer catalyst is 0.1% - 0.5% of the mass of the compound shown in Formula II; The molar ratio of bromine to the compound shown in Formula II is 1.0 - 2.0:1; The molar ratio of inorganic base 2 to the compound shown in Formula II is 2.6 - 6.0:1; The reaction temperature for adding the phase transfer catalyst, bromine, and inorganic base 2 to react is 5 - 70 °C, and the reaction time is 5 - 10 h.

7. A method for synthesizing an apixaban intermediate according to claim 1, characterized in that, The Catalyst 1 includes inhibitor 701, 4-ACO-TEMPO, or 4-Bz—TEMPO, where the structural formula of 4-ACO-TEMPO is; The Catalyst 2 includes air or oxygen; The salt includes potassium chloride, potassium carbonate, sodium carbonate, sodium acetate, and / or sodium sulfate; The Solvent 3 includes one or more of 1,2-dichloroethane, dichloromethane, carbon tetrachloride, and toluene.

8. A method for synthesizing an apixaban intermediate according to claim 1, characterized in that, The mass ratio of Solvent 3 to the compound shown in Formula III is 15 - 40 mL:1 g; The molar ratio of the iron(III) nitrate nonahydrate to the compound shown in Formula III is 0.1 to 1.0:1; The molar ratio of the salt to the compound shown in Formula III is 0.1 to 1.0:1; The molar ratio of the catalyst 1 to the compound shown in Formula III is 0.1 to 1.0:1; The reaction temperature for adding the iron(III) nitrate nonahydrate, catalyst 1 and salt and continuously introducing catalyst 2 for reaction is 20 to 50 °C, and the reaction time is 16 to 30 h.

9. The synthesis method of an apixaban intermediate according to claim 1, characterized in that, The inorganic base 3 includes sodium carbonate and / or potassium carbonate; The solvent 4 includes one or more of N,N-dimethylformamide (DMF), chlorobenzene and toluene; The molar ratio of the morpholine to the compound shown in Formula IV is 2.0 to 10.0:1; The molar ratio of the inorganic base 3 to the compound shown in Formula IV is 2.0 to 5.0:1; The mass ratio of the solvent 4 to the compound shown in Formula IV is 3 ml to 15 ml:1 g; The reaction temperature for adding the morpholine and inorganic base 3 for reaction is 30 to 80 °C, and the reaction time is 2 to 5 h.

10. An apixaban intermediate synthesized by the method according to any one of claims 1 to 9, characterized in that, It includes the structure shown in Formula V:

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