A kind of synthesis process of Apixaban

Abstract

The invention relates to the field of chemical pharmacy, and in particular to a synthesis process of apixaban, comprising the following steps: using 3-chloro-1-(4-(2-oxopiperidin-1-yl)phenyl-5,6-dihydropyridine-2(1H)-one (intermediate A) to react with oxalyl chloride monoester to obtain compound B, then reacting with p-methoxyphenylhydrazine hydrochloride to form a ring through condensation and coupling to obtain compound D, and finally preparing apixaban through amine ester exchange of compound D. Compared with the prior art, the invention has the advantages of: 1. The synthesis process is more efficient and mild, the operation is simple, and the raw materials are easy to obtain; 2. It avoids the use of expensive or toxic and irritating reagents; 3. The total yield is high and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical pharmacy, and in particular to a synthesis process of apixaban. Background Art

[0002] Apixaban, chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, and its structural formula is as follows:

[0003]

[0004] Apixaban is an oral anticoagulant jointly developed by Pfizer and Bristol-Myers Squibb. It is a factor Xa inhibitor and is now available in China, the United States and Europe. China has approved its use in adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism (VTE). In 2022, Pfizer / Bristol-Myers Squibb's global sales of Apixaban totaled US$18.269 billion, making it one of the world's best-selling drugs. It can be seen that the application market potential of Apixaban is huge, and it is particularly important to develop a more efficient synthesis process for Apixaban. At present, some common synthesis methods of Apixaban are as follows:

[0005] 1. Patent WO2010030983A2 published in 2010 provides a route for preparing apixaban:

[0006]

[0007] This route first uses p-iodoaniline and 5-bromovaleryl chloride as raw materials to prepare intermediate 2 through amidation-cyclization. 2 is subjected to dichloro substitution of α-active hydrogen with phosphorus pentachloride in chloroform, and condensation-elimination reaction is carried out in the presence of excess morpholine to obtain intermediate 3. p-Anisidine is used as the starting material, and then diazotized and reacted with ethyl 2-chloroacetoacetate to obtain compound 4. 4 and intermediate 3 are subjected to the [3+2] cyclization-elimination reaction strategy to generate compound 5. 5 is condensed with δ-valerolactam under conditions similar to the Ullmann reaction to generate compound 6. 6 is aminolyzed in an ethylene glycol solution of ammonia to obtain the target product. The expensive iodide and the low yield of 21% in the condensation reaction of 5 with δ-valerolactam make this route of low practical value.

[0008] 2. World Patent WO2003049681 A2 reports the synthesis route of apixaban as follows:

[0009]

[0010] This route uses δ-valerolactam as a raw material to obtain a dichloro compound of α-active hydrogen under the action of phosphorus pentachloride, and then eliminates a molecule of hydrogen chloride under the action of lithium carbonate to obtain compound 7. 7 reacts with morpholine in the presence of triethylamine to produce compound 8. 8 reacts with compound 4 to obtain compound 9. 9 and 10 react with potassium carbonate and cuprous iodide as a catalyst to obtain compound 11. 11 is reacted with isobutyl chloroformate to form a mixed anhydride and then ammonolyzed with excess ammonia water to obtain the target product. The total yield of this reaction is only 5.2%, and the operation is cumbersome, which limits its application.

[0011] 3. CN101967145A mentioned that p-nitroaniline and 5-chlorovaleryl chloride are used as starting materials, and the target compound apixaban is obtained by amidation-cyclization, dichloroation at the α position, condensation-elimination, sodium sulfide reduction, amidation-cyclization, [3+2] cyclization-elimination and high-pressure ammonolysis. The disadvantages of this route are: Compound 13 is reacted to prepare compound 14, and potassium tert-butoxide or sodium hydride is used as a condensing agent in the amidation and cyclization step, which has high production costs and high operating risks. The use of sodium sulfide in the conversion process from compound 12 to compound 13 is not environmentally friendly, and this step of reaction is prone to generate impurities, affecting the yield and purity of the product; the high-pressure ammonolysis reaction of compound 15 has high requirements for equipment, and the reaction process is not easy to monitor.

[0012]

[0013] 4. CN105732622A reports a synthesis process of apixaban, which uses p-nitroaniline and δ-valerolactone as raw materials, undergoes amidation ring opening under the action of AlMe3 to obtain compound 16, and compound 16 is reacted with methanesulfonyl chloride to obtain intermediate 17, which is then subjected to ring closure under the action of sodium ethoxide to obtain 1-(4-nitrophenyl)piperidone compound 18, which is dichloro at the α position and then subjected to condensation-elimination reaction with morpholine to obtain compound 19, and compound 19 and compound 4 undergo 1,3-dipolar cycloaddition ring closure reaction under the action of an acid binding agent and a phase transfer catalyst, and then morpholine is removed with hydrochloric acid to obtain compound 20, which is then subjected to nitro reduction to obtain compound 21, 21 is reacted with δ-valerolactone and ammonium chloride in AlMe3 in sequence to obtain compound 22, and compound 22 is reacted with methanesulfonyl chloride to obtain intermediate 23, and 23 is subjected to ring closure under the action of sodium ethoxide without separation to obtain apixaban. This route repeatedly uses dangerous and irritating reagents such as AlMe3 and methanesulfonyl chloride, which is not conducive to operation and production scale-up, and the reaction steps are too complicated.

[0014]

[0015] In summary, the following defects exist in the process of preparing apixaban: most of them use relatively expensive iodine-containing organic compounds, the intermediates used directly are not easy to obtain, and the amount of auxiliary reagents used is large; the reaction steps are generally long, the route is cumbersome, and the overall yield is low; the use of some dangerous and irritating reagents cannot be avoided, and some reactions are complicated and require harsh conditions. Summary of the invention

[0016] In order to solve the problems of the existing synthesis method, such as the long route, low raw material utilization rate, and the use of irritating reagents, the present invention provides a synthesis process of apixaban with a short route, simple operation, and high atom economy.

[0017] In order to achieve the above object, the technical solution of the present invention is: a synthesis process of apixaban, characterized in that it comprises the following steps:

[0018] Step (1) using intermediate A as a starting material and reacting it with oxalyl chloride monoester to obtain compound B;

[0019] Step (2) Compound B reacts with p-methoxyphenylhydrazine hydrochloride to obtain Compound C;

[0020] Step (3) Compound C is subjected to an intramolecular coupling reaction to obtain Compound D;

[0021] Step (4) Compound D is subjected to an aminolysis reaction to obtain apixaban, and the entire reaction route is as follows:

[0022]

[0023] R is selected from C 1～3 Alkyl, C 2～4 Alkenyl.

[0024] In step (1), intermediate A is used as a starting material and reacts with oxalyl chloride monoester to obtain intermediate B:

[0025]

[0026] The oxalyl chloride monoester is selected from oxalyl chloride monomethyl ester, oxalyl chloride monoethyl ester and oxalyl chloride monoallyl ester, preferably oxalyl chloride monomethyl ester and oxalyl chloride monoethyl ester.

[0027] The molar ratio of intermediate A to oxalyl chloride monoester is 1:1-2, preferably 1:1.3-1.5, and the solvent is selected from dichloromethane, chloroform, dichloroethane and the like, preferably dichloromethane.

[0028] In step (1), zinc powder, diiodomethane and cuprous salt are required, the molar ratio of intermediate A to zinc powder is 1:2-3, preferably 1:2-2.2, the molar ratio of intermediate A to diiodomethane is 1:1-1.2, preferably 1:1-1.1, the molar ratio of intermediate A to cuprous salt is 1:0.05-0.1, and the cuprous salt is selected from cuprous chloride, cuprous bromide, cuprous acetate, etc., preferably cuprous chloride. The reaction temperature is 0-40°C, and the reaction time is 4-8 hours.

[0029] During the reaction, zinc powder and cuprous salt need to be activated under nitrogen protection, then diiodomethane and intermediate A are added and stirred evenly, oxalyl chloride monoester is added dropwise at 0-5°C, and then the temperature is slowly raised to 40°C for reaction until the reaction is completed.

[0030] Step (2) Compound B reacts with p-methoxyphenylhydrazine hydrochloride to obtain Compound C;

[0031]

[0032] Compound B and p-methoxyphenylhydrazine undergo a condensation reaction under certain reaction conditions to obtain compound C, and p-methoxyphenylhydrazine is selected from commercially available p-methoxyphenylhydrazine hydrochloride. The molar ratio of compound B to p-methoxyphenylhydrazine hydrochloride is 1:1-1.2, preferably 1:1.1-1.2, the reaction solvent is a polar protic solvent selected from methanol, ethanol, isopropanol, tert-butanol and other solvents, preferably ethanol and isopropanol, the reaction temperature is 50-90°C, and the reaction time is 2-7 hours.

[0033] Step (3) Compound C is subjected to an intramolecular coupling reaction to obtain Compound D;

[0034]

[0035] In this reaction, it is necessary to add a base and a copper salt catalyst, the base is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, etc., preferably potassium carbonate. The copper salt catalyst is selected from copper trifluoromethanesulfonate, copper acetate, copper chloride, etc., preferably acetic acid ketone. The molar ratio of compound C to the base is 1:2-3, and the molar ratio of compound C to the copper salt is 1:0.1-0.2. The solvent is selected from DMSO, DMF, tetrahydrofuran, dioxane, acetonitrile, etc., preferably DMSO and DMF. The reaction temperature is 30-80°C, and the reaction time is 5-15 hours.

[0036] Step (4) Compound D is reacted to obtain Apixaban:

[0037]

[0038] In this step of the reaction, formamide is used as both a reaction raw material and a solvent, and an appropriate base needs to be added. The base is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc., preferably sodium methoxide and sodium ethoxide. When sodium methoxide is used as a base, methanol is selected as another solvent, and when sodium ethoxide is used as a base, ethanol is selected as another solvent. The molar ratio of compound D to the base is 1:2-3, preferably 1:2-2.5. The volume ratio of formamide and alcohol (methanol or ethanol) is 1:3-5, preferably 1:4. With formamide and alcohol as a mixed solvent, the mass volume ratio of compound D to the mixed solvent is 1g:5-10ml, preferably 1g:6-8ml. The reaction temperature is 50-70°C, and the reaction time is 3-8 hours. This method avoids the high temperature and high pressure in the traditional ester to amide conversion method, and the reaction is more gentle.

[0039] The reagents and raw materials used in the present invention are commercially available.

[0040] The beneficial effects of the present invention are:

[0041] 1. This route uses compound A as a starting material, reacts with oxalyl chloride monoester to obtain a β-chloro α-enone intermediate compound B, which is then reacted with p-methoxyphenylhydrazine hydrochloride to form an important parent ring 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine of apixaban through condensation and intramolecular coupling to form a ring, thereby avoiding the use of hydrazone (compound 4 in the background technology) in most routes for [3+2] cyclization-elimination reaction, making the reaction more simple and efficient. At the same time, the introduction of a simple piperidone ring in the form of a raw material in advance is also conducive to improving the overall yield.

[0042] 2. Avoid the use of expensive (such as iodobenzene derivatives in routes 1 and 2) or toxic and irritating reagents (such as PCl5, Na2S, NaH, AlMe3, MsCl in routes 1, 2, 3, and 4), thereby reducing the cost of the entire raw material and production operation.

[0043] 3. The method provided by the present invention has short steps, high atom economy, mild reaction conditions, few intermediate by-products obtained during the reaction, easy reaction handling, environmental friendliness, and industrial value. DETAILED DESCRIPTION

[0044] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0045] Example 1

[0046] Step 1, intermediate A reacts with monomethyl oxalyl chloride to obtain compound BI:

[0047]

[0048] 21.45g zinc powder, 1.62g cuprous chloride and 200ml dichloromethane were placed in a 1000ml reaction bottle, stirred and refluxed for 30 minutes under nitrogen protection, and then 43.93g diiodomethane was weighed into the reaction bottle, and refluxed for 1 hour. 50g intermediate A in 200ml dichloromethane solution was added to the reaction system, cooled to 0-5°C, and 30.14g oxalyl chloride monomethyl ester in 100ml dichloromethane solution was added dropwise under nitrogen protection, and the addition was completed in 15 minutes. The temperature was slowly raised to 25°C for reaction for 2 hours, and then heated to reflux for reaction for 2 hours. After the reaction, the reaction system was cooled to 0-5°C, 90 ml of 10% by mass dilute sulfuric acid was added dropwise, stirred for 10 minutes, filtered through diatomaceous earth, the filtrate was separated, the aqueous layer was washed with 2×100 ml of dichloromethane, the organic layers were combined, washed with 300 ml of saturated sodium bicarbonate, the dichloromethane layer was separated, dried and concentrated, and the crude product was purified with ethyl acetate / n-hexane to obtain 54.5 g of light brown solid with a yield of 85% and a HPLC purity of 94.3%.

[0049] MS (m / z): 391.82 [M+H]+; 1 H NMR(CDCl3,500MHz)δ7.50–7.45(m,2H),7.24–7.18(m,2H),4.45(t,J=5.5Hz,2H),3.82(s,3H),3.67 (t,J=5.6Hz,2H),2.40(t,J=5.6Hz,2H),2.21(t,J=6.0Hz,2H),1.95-1.89(m,2H),1.45-1.39(m,2H).

[0050] Example 2

[0051] Step 2, compound BI reacts with p-methoxyphenylhydrazine hydrochloride to obtain compound CI:

[0052]

[0053] 50g of compound BI prepared in Example 1, 22.34g of p-methoxyphenylhydrazine hydrochloride and 500ml of ethanol were added to a 1000ml reaction bottle, heated to 75°C, reacted for 3 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, most of the ethanol was concentrated under reduced pressure, 500ml of dichloromethane was added to dissolve and disperse, and 300ml of water was added to extract and separate the layers. The obtained water layer was washed with 2×200ml of dichloromethane, the organic phases were combined, dried and concentrated, and the obtained solid was refined with isopropyl acetate to obtain 58.8g of off-white solid, with a yield of 90% and a HPLC purity of 94.8%.

[0054] MS (m / z): 511.98 [M+H]+; 1 H NMR(CDCl3,500MHz).δ7.56–7.50(m,2H),7.51–7.45(m,2H),7.23–7.17(m,2H),7.27(s,1H),7.08–7.02(m,2H),4.45(t,J=5.5Hz,2H) ,3.84(s,3H),3.80(s,3H),3.67(t,J=5.6Hz,2H),2.40(t,J=5.6Hz,2H),2.21(t,J=6.0Hz,2H),1.95-1.89(m,2H),1.45-1.38(m,2H).

[0055] Example 3

[0056] Step 3, compound CI reacts with p-methoxyphenylhydrazine hydrochloride to obtain compound DI:

[0057]

[0058] 50g of compound CI prepared in Example 2 was dissolved in 350ml of DMSO, placed in a 500ml reaction bottle, 1.95g of copper acetate and 27.05g of potassium carbonate were added, stirred for reaction, heated to 70°C, reacted for 12 hours, and TLC detected that the raw material was completely converted. After the reaction, the reaction solution was cooled to room temperature, 1300ml of water and 500ml of ethyl acetate were added to the reaction solution, extracted and layered, the obtained water layer was washed with 2×150ml of ethyl acetate, the organic layers were combined, dried and concentrated, and the obtained solid was refined with tetrahydrofuran / n-hexane to obtain 40.8g of off-white solid, with a yield of 88% and a HPLC purity of 95.7%.

[0059] MS (m / z): 475.52 [M+H]+; 1 H NMR(CDCl3,500MHz).δ7.67–7.61(m,2H),7.55–7.49(m,2H),7.26–7.20(m,2H),7.13–7.07(m,2H),4.45(t,J=5.5Hz,2 H),3.99-3.94(m,5H),3.80(s,3H),3.30(t,J=5.7Hz,2H),2.21(t,J=6.0Hz,2H),1.96-1.90(m,2H),1.45-1.40m,2H).

[0060] Example 4

[0061] Step 4, compound DI is reacted to obtain apixaban:

[0062]

[0063] 30g of compound DI prepared in Example 3 was dissolved in 240ml of methanol, placed in a 500ml reaction bottle, 6.83g of sodium methoxide and 50ml of formamide were added, stirred for reaction, heated to 60°C, kept warm for 4 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, some solids were precipitated, most of the methanol was concentrated under reduced pressure, and 100ml of methanol was added, stirred at room temperature for 30 minutes, filtered, and the obtained solid was refined with ethanol to obtain 25.56g of white solid, with a yield of 88% and a HPLC purity of 99.7%.

[0064] MS (m / z): 460.51 [M+H]+; 1 H NMR(CDCl3,500MHz)δ7.66–7.60(m,2H),7.56–7.49(m,2H),7.25–7.19(m,2H),7.13–7.06(m,2H),6.32(s,2H),4.45(t,J=5.5H z,2H),3.96(t,J=5.7Hz,2H),3.80(s,3H),3.30(t,J=5.7Hz,2H),2.21(t,J=6.0Hz,2H),1.97-1.88(m,2H),1.46-1.42(m,2H).

[0065] Example 5

[0066] Step 1, intermediate A reacts with ethyl oxalyl chloride to obtain compound B-II:

[0067]

[0068] 32.18g zinc powder, 2.43g cuprous chloride and 300ml dichloromethane were placed in a 2000ml reaction bottle, stirred and refluxed for 30 minutes under nitrogen protection, and then 65.9g diiodomethane was weighed into the reaction bottle, and refluxed for 1 hour. 75g intermediate A in 300ml dichloromethane solution was added to the reaction system, cooled to 0-5°C, and 50.39g ethyl oxalyl chloride in 150ml dichloromethane solution was added dropwise under nitrogen protection, and the addition was completed in 20 minutes, and the temperature was slowly raised to 25°C for reaction for 2 hours, and then heated to reflux for reaction for 2 hours. After the reaction, the reaction system was cooled to 0-5°C, 135 ml of 10% by mass dilute sulfuric acid was added dropwise, stirred for 20 minutes, filtered through diatomaceous earth, the filtrate was separated, the aqueous layer was washed with 2×200 ml of dichloromethane, the organic layers were combined, washed with 400 ml of saturated sodium bicarbonate, the dichloromethane layer was separated, dried and concentrated, and the crude product was purified with ethyl acetate / n-hexane to obtain 87.67 g of light brown solid with a yield of 88% and a HPLC purity of 93.8%.

[0069] MS (m / z): 405.85 [M+H]+; 1 H NMR(CDCl3,500MHz)δ7.51–7.44(m,2H),7.26–7.19(m,2H),4.45(t,J=5.5Hz,2H),4.22(q,J=5.9Hz,2H),3.67(t,J=5 .6Hz,2H),2.40(t,J=5.6Hz,2H),2.21(t,J=6.0Hz,2H),1.96-1.89(m,2H),1.46-1.39(m,2H),1.31(t,J=5.9Hz,3H).

[0070] Example 6

[0071] Step 2, compound B-II reacts with p-methoxyphenylhydrazine hydrochloride to obtain compound C-II:

[0072]

[0073] 75g of compound B-II prepared in Example 5, 35.3g of p-methoxyphenylhydrazine hydrochloride and 750ml of isopropanol were added to a 2000ml reaction bottle, heated to 80°C, reacted for 2 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, most of the isopropanol was concentrated under reduced pressure, 800ml of dichloromethane was added to dissolve and disperse, and 500ml of water was added to extract and separate the layers. The obtained water layer was washed with 2×300ml of dichloromethane, the organic phases were combined, dried and concentrated, and the obtained solid was refined with isopropyl acetate to obtain 85.58g of off-white solid, with a yield of 88% and a HPLC purity of 94.7%.

[0074] MS (m / z): 526.01 [M+H]+; 1 H NMR(CDCl3,500MHz).δ7.56–7.45(m,4H),7.24–7.18(m,2H),7.08–7.02(m,2H),6.59(s,1H),4.45(t,J=5.5Hz,2H),4.24-4.19(m,2H),3.8 0(s,3H),3.67(t,J=5.6Hz,2H),2.40(t,J=5.6Hz,2H),2.21(t,J=6.0Hz,2H),1.95-1.88(m,2H),1.45-1.38(m,2H),1.30(t,J=5.9Hz,3H).

[0075] Example 7

[0076] Step 3, compound C-II reacts with p-methoxyphenylhydrazine hydrochloride to obtain compound D-II:

[0077]

[0078] 70g of compound C-II prepared in Example 6 was dissolved in 400ml of DMF, placed in a 1000ml reaction bottle, 2.66g of copper acetate and 36.8g of potassium carbonate were added, stirred for reaction, heated to 80°C, reacted for 7 hours, and TLC detected that the raw material was completely converted. After the reaction, the reaction solution was cooled to room temperature, 2000ml of water and 800ml of ethyl acetate were added to the reaction solution, extracted and separated, the obtained water layer was washed with 2×300ml of ethyl acetate, the organic layers were combined, dried and concentrated, and the obtained solid was refined with tetrahydrofuran / n-hexane to obtain 57.9g of off-white solid, with a yield of 89% and a HPLC purity of 97.2%.

[0079] MS (m / z): 489.55 [M+H]+; 1 H NMR(CDCl3,500MHz).δ7.75–7.69(m,2H),7.50–7.44(m,2H),7.37–7.31(m,2H),7.15–7.09(m,2H),4.45(t,J=5.9Hz,2H),4.34(q,J =5.9Hz,2H),3.96(t,J=5.8Hz,2H),3.80(s,3H),3.30(t,J=5.8Hz,2H),2.21(t,J=5.9Hz,2H),1.97–1.87(m,2H),1.47–1.33(m,5H).

[0080] Example 8

[0081] Step 4, compound D-II is reacted to obtain apixaban:

[0082]

[0083] 50g of compound D-II prepared in Example 7 was dissolved in 320ml of ethanol, placed in a 1000ml reaction bottle, 13.9g of sodium ethoxide and 80ml of formamide were added, stirred for reaction, heated to 60°C, kept warm for 5 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, some solids were precipitated, most of the ethanol was concentrated under reduced pressure, and 130ml of ethanol was added, stirred at room temperature for 30 minutes, filtered, and the obtained solid was refined with ethanol to obtain 42.32g of white solid, with a yield of 90% and a HPLC purity of 99.68%.

[0084] MS (m / z): 460.51 [M+H]+; 1H NMR(CDCl3,500MHz)δ7.66–7.60(m,2H),7.56–7.49(m,2H),7.25–7.19(m,2H),7.13–7.06(m,2H),6.32(s,2H),4.45(t,J=5.5H z,2H),3.96(t,J=5.7Hz,2H),3.80(s,3H),3.30(t,J=5.7Hz,2H),2.21(t,J=6.0Hz,2H),1.97-1.88(m,2H),1.46-1.42(m,2H).

[0085] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A synthesis process of apixaban, characterized in that, The steps include: In step (1), intermediate A is used as a starting material and reacted with oxalyl chloride monoester to obtain compound B; the solvent in step (1) is selected from one or more of dichloromethane, chloroform and dichloroethane; zinc powder, diiodomethane and cuprous salt need to be added in step (1), and the cuprous salt is selected from one or more of cuprous chloride, cuprous bromide and cuprous acetate; Step (2) Compound B reacts with p-methoxyphenylhydrazine hydrochloride to obtain Compound C; The reaction in step (2) requires the addition of a polar protic solvent, wherein the polar protic solvent is selected from one or more of methanol, ethanol, isopropanol, and tert-butanol; In step (3), compound C is subjected to an intramolecular coupling reaction to obtain compound D; a base and a copper salt catalyst need to be added in step (3); the base is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, and sodium ethoxide; the copper salt catalyst is selected from one or more of copper trifluoromethanesulfonate, copper acetate, and copper chloride; the reaction solvent of step (3) is selected from one or more of DMSO, DMF, tetrahydrofuran, dioxane, and acetonitrile; In step (4), compound D is subjected to an ammonolysis reaction to obtain apixaban. In step (4), formamide is added as a reaction raw material and a solvent at the same time, and an alcohol is added to the formamide to form a mixed solvent for the reaction, wherein the alcohol is selected from methanol or ethanol. In step (4), a suitable base is added, wherein the base is selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide. The entire reaction route is as follows: Where R is selected from C 1～3 Alkyl, C 2～4 Alkenyl.

2. The synthesis process according to claim 1, characterized in that In step (1), the molar ratio of intermediate A to oxalyl chloride monoester is 1:1-2, the reaction temperature of step (1) is 0-40°C, and the reaction time is 4-8 hours.

3. The synthesis process according to claim 1, characterized in that: The oxalyl chloride monoester is selected from oxalyl chloride monomethyl ester, oxalyl chloride monoethyl ester or oxalyl chloride monoallyl ester.

4. The synthesis process according to claim 1, characterized in that The molar ratio of intermediate A, zinc powder, diiodomethane and cuprous salt is 1:2-3:1-1.2:0.05-0.

1.

5. The synthesis process according to claim 1, characterized in that: The molar ratio of compound B to p-methoxyphenylhydrazine hydrochloride in step (2) is 1:1-1.2, the reaction temperature of step (2) is 50-90° C., and the reaction time is 2-7 hours.

6. The synthesis process according to claim 1, characterized in that: In step (3), the molar ratio of compound C to base is 1:2-3, and the molar ratio of compound C to copper salt is 1:0.1-0.

2.

7. The synthesis process according to claim 1, characterized in that: The reaction temperature of step (3) is 30-80°C and the reaction time is 5-15 hours.

8. The synthesis process according to claim 1, characterized in that: In step (4), the volume ratio of formamide to alcohol is 1:3-5, and the mass volume ratio of compound D to the mixed solvent is 1g:5-10ml.

9. The synthesis process according to claim 1, characterized in that: In step (4), the molar ratio of compound D to base is 1:2-3.

10. The synthesis process according to claim 1, characterized in that: The reaction temperature of step (4) is 50-70°C and the reaction time is 3-8 hours.

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