Preparation method of apixaban

Abstract

The invention relates to a preparation method of apixaban, which comprises the following steps: carrying out aldol condensation on ethyl methoxyacetate serving as a raw material and ethyl pyruvate to obtain an intermediate II, carrying out alkylation reaction on the intermediate II and 1, 2-dichloroethane to obtain an intermediate III, carrying out pyrazole synthesis reaction on the intermediate III and 4-methoxyphenylhydrazine to obtain an intermediate IV, carrying out alkylation reaction on the intermediate IV and 4-nitroaniline to obtain an intermediate V, and carrying out recrystallization on the intermediate V to obtain the apixaban. The preparation method comprises the following steps: carrying out ester group hydrolysis to prepare an intermediate VI, carrying out molecular lactamization in the presence of a condensing agent to prepare an intermediate VII, carrying out nitro reduction to prepare an intermediate VIII, carrying out amidation on the intermediate VIII and 5-bromovaleryl chloride under the action of an acid-binding agent, further carrying out an intramolecular alkylation reaction under the action of a strong alkali to prepare an intermediate IX, adding tert-butyl hydroperoxide and ammonia water, and carrying out a reaction under the action of a strong alkali to prepare the intermediate IX. Under the catalysis of iodine, carrying out oxidation amidation to prepare apixaban; the method has the advantages of cheap and easily available raw materials, easy realization of industrialization, high product purity, no dangerous process, simple equipment, novel route and short synthesis route.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing apixaban. Background Art

[0002] Apixaban (1) (trade name: Eliquis), chemically known as 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, is an oral, highly selective coagulation factor Xa inhibitor developed by Bristol-Myers Squibb (a global biopharmaceutical company). The drug is mainly used for the prevention and treatment of thromboembolic diseases.

[0003] There are four main methods for synthesizing apixaban: Scheme 1: 4-nitroaniline is reacted with 5-chlorovaleryl chloride through amidation, alkylation, chlorination, amine alkylation, nitro group reduction, amidation and alkylation with 5-chlorovaleryl chloride, followed by a [3+2] cyclization-elimination reaction with ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate, and finally amidation to produce apixaban. As described in patent CN101967145, this scheme utilizes readily available and inexpensive raw materials. However, sodium hydride is used twice in the reaction, making it a dangerous process. Furthermore, phosphorus pentachloride is used, requiring high equipment requirements, limiting production processes. The synthetic route for Scheme 1 is shown in Scheme 1.

[0004] Route 1: Scheme 2: 4-iodoaniline is used as the starting material, and then reacted with 5-chlorovaleryl chloride through amidation, alkylation, chlorination, and substitution. The product is then reacted with ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate via a [3+2] cyclization-elimination reaction, condensed under the catalysis of iodinated ketone, and finally aminolysis. This is described in patent WO2010030983. This scheme suffers from expensive starting materials, the use of phosphorus pentachloride, which is highly corrosive to equipment, and the diazotization reaction required for the synthesis of ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]acetate, which uses heavy metal catalysts. These factors limit its application. The synthetic route for Scheme 2 is shown in Scheme 2.

[0005] Route 2: Scheme three: using δ-valerolactam as starting material, chlorination, dehydrochlorination, reaction with morpholine, [3+2] cycloaddition-elimination reaction with (2Z)-chloro[(4-methoxyphenyl)hydrazono] acetic acid ethyl ester, condensation with N-(4-iodophenyl)-δ-valerolactam, hydrolysis, and finally aminolysis with isobutyl chloroformate to form anhydride, and then aminolysis to obtain. As in patent WO2003049681. The yield of this route is low, the reaction uses phosphorus pentachloride for chlorination, which requires high equipment, and the use of toxic isobutyl chloroformate and expensive iodine reagent limits its use. The synthetic route of scheme three is shown in route 3.

[0006] Route 3: Scheme four: still using 4-iodoaniline as starting material, reaction with 5-bromovaleryl chloride, then chlorination, dehydrochlorination, substitution, [3+2] cycloaddition-elimination reaction of (2Z)-chloro[(4-methoxyphenyl)hydrazono] acetic acid ethyl ester, condensation with δ-valerolactam in the presence of catalyst triphenylphosphine copper bromide, and finally aminolysis with ammonium formate in the presence of sodium methoxide to obtain. As in patent WO2003049681. The starting material of this synthetic route is expensive, the use of phosphorus pentachloride requires high equipment, and the use of expensive catalysts and heavy metals limits the use of the process. The synthetic route of scheme four is shown in route 4.

[0007] Route 4: Therefore, the present application proposes a preparation method of apixaban to solve the above problems. SUMMARY

[0008] The technical problem to be solved by the present application is to provide a preparation method of apixaban which is low in cost and easy to operate.

[0009] To solve the above technical problems, the technical scheme of the present application is as follows: a preparation method of apixaban, the innovation of which lies in that the reaction process of the preparation method comprises: Step 1: preparation of intermediate II: using ethyl methoxyacetate as raw material, and performing aldol condensation with ethyl pyruvate in the presence of a base to obtain intermediate II, i.e. ethyl 5-methoxyacetylpyruvate; Step 2: preparation of intermediate III: alkylating intermediate II with compound X in a solvent in the presence of a base to obtain intermediate III, i.e. ethyl 5-methoxy-3-(2-chloroethyl)acetylpyruvate; Step 3: preparation of intermediate IV: performing Knorr pyrazole synthesis reaction of intermediate III with compound XI 4-methoxyphenylhydrazine under acidic conditions to obtain intermediate IV, i.e. N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylic acid ethyl ester; step 4, preparation of intermediate V: under basic condition, intermediate IV was reacted with compound XII 4-nitroaniline via alkylation to give intermediate V, i.e. ethyl N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylate; step 5, preparation of intermediate VI: intermediate V was subjected to ester hydrolysis to give intermediate VI, i.e. N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid; step 6, preparation of intermediate VII: intermediate VI was subjected to intramolecular amidation in the presence of a condensing agent in a reaction solvent to give intermediate VII, i.e. N-(4-methoxyphenyl)-6-(4-nitrophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; step 7, preparation of intermediate VIII: intermediate VII was dissolved in ethanol and subjected to nitro reduction to give intermediate VIII, i.e. N-(4-methoxyphenyl)-6-(4-aminophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; step 8, preparation of intermediate IX: intermediate VIII was first subjected to amidation with compound XIII 5-bromopentanoyl chloride in the presence of an acid binding agent, and then subjected to intramolecular alkylation in the presence of a strong base to give intermediate IX, i.e. N-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-methoxymethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; step 9, preparation of Apixaban: intermediate IX was dissolved in a reaction solvent, and then subjected to oxidative amidation in the presence of tert-butyl hydroperoxide and ammonia under catalysis of iodine to give the finished product I, i.e. Apixaban; The synthetic route of the preparation method is shown as follows: Further, in the reaction of step 1, ethyl methoxyacetate and ethyl pyruvate were reacted in a molar ratio of 1:1.05, and the reaction was carried out under reflux conditions. The reaction base was sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride, and sodium ethoxide was preferred. The reaction solvent was methanol, ethanol, toluene, tetrahydrofuran or N,N-dimethylformamide DMF, and ethanol was preferred.

[0010] Further, in the reaction of step 2, the feeding ratio of ethyl 5-methoxyacetylpyruvate and 1,2-dichloroethane was 1:1.05, and the reaction was carried out under reflux conditions. The reaction base is sodium methoxide, sodium ethoxide, sodium hydride or potassium tert-butoxide, preferably sodium ethoxide; The reaction solvent is toluene, tetrahydrofuran, acetonitrile or toluene, preferably acetonitrile.

[0011] Furthermore, the acid in the reaction of step 3 is hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid or p-toluenesulfonic acid, preferably acetic acid.

[0012] Furthermore, NaI is added as a catalyst in the reaction of step 4; The reaction base is sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide, preferably potassium tert-butoxide; The reaction solvent is toluene, acetonitrile, tetrahydrofuran or 1,2-dichloroethane, preferably tetrahydrofuran.

[0013] Furthermore, in the reaction of step 5, the reaction base is sodium carbonate or sodium hydroxide, preferably sodium hydroxide; The reaction solvent is methanol or ethanol.

[0014] Furthermore, in the reaction of step 6, the condensing agent is CDI (N,N'-carbonyldiimidazole), EDCi (1-ethyl-(3-dimethylaminopropyl)carbodiimide) / HoBt (1-hydroxybenzotriazole), or DCC (dicyclohexylcarbodiimide) / HoBt (1-hydroxybenzotriazole), preferably CDI; The reaction solvent is tetrahydrofuran, acetonitrile, DMF, dichloromethane or 1,2-dichloromethane, preferably tetrahydrofuran.

[0015] Furthermore, in the reaction of step 7, the nitro reduction reaction is carried out by using Fe or Zn under acidic conditions, or by using Pd / C / H2 catalytic reduction, or by using a sulfiding agent, wherein the sulfiding agent is preferably Na2S.

[0016] Furthermore, in the reaction of step 8, the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate or triethylamine, preferably triethylamine; The strong base used in the reaction is sodium hydride, sodium methoxide, sodium hydroxide, sodium ethoxide or potassium tert-butoxide, preferably potassium tert-butoxide; The reaction solvent is dichloromethane, tetrahydrofuran or acetonitrile, preferably tetrahydrofuran.

[0017] Furthermore, in the reaction of step 9, the reaction solvent is tetrahydrofuran, acetonitrile or acetone, preferably tetrahydrofuran.

[0018] The advantages of the present invention are: (1) The raw material ethyl methoxyacetate used in the preparation method of apixaban of the present invention is cheap and easily available, the process can be easily industrialized, and the resulting final product has high purity.

[0019] (2) The preparation method of apixaban of the present invention has no hazardous process and simple equipment.

[0020] (3) The preparation method of apixaban of the present invention has a novel route and a short synthetic route. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0022] Figure 1 It is the hydrogen nuclear magnetic resonance spectrum of apixaban of the present invention.

[0023] Figure 2 It is the carbon-1NMR spectrum of Apixaban of the present invention. DETAILED DESCRIPTION

[0024] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined purpose of the invention, the specific implementation methods, structures, features and effects of the present invention are described in detail below in conjunction with the accompanying drawings and preferred embodiments.

[0025] Example 1 This embodiment provides a method for preparing apixaban, and the synthetic route is as follows: the reaction process comprises: Step 1, preparation of intermediate II; Ethyl methoxyacetate is used as the raw material and reacted with ethyl pyruvate under base catalysis to obtain intermediate II, namely ethyl 5-methoxyacetylacetonate; In the reaction, ethyl pyruvate acts as a nucleophile under alkaline conditions. Due to the electron-donating nature of the methoxy group, it is difficult for ethyl methoxylate to be dehydrogenated. Therefore, in the reaction, ethyl pyruvate removes hydrogen and acts as a nucleophile to attack ethyl methoxylate, thereby carrying out a condensation reaction.

[0026] The reaction formula is as follows (1): Formula (1): The detailed operation process is as follows: 118 g of ethyl methoxyacetate is dissolved in 200 ml of ethanol, 122 g of ethyl pyruvate is added, 102 g of sodium ethoxide is added, and the mixture is stirred at room temperature for 30 minutes. The system is slowly heated and refluxed for 4 hours. After the reaction is completed, the system is cooled to room temperature and then slowly poured into 300 ml of ice water. Extraction is performed with 400 ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent. The residue is distilled under reduced pressure to obtain 169.2 g of a colorless liquid, namely, intermediate II, with a yield of 90%.

[0027] The nuclear magnetic resonance hydrogen spectrum of the obtained intermediate II has resonance peaks at the following positions: 1HNMR (300 NHz, CDCl3): 1.26(m, 3H), 3.35(s, 3H), 4.14(m, 2H), 4.46(s, 2H), 4.82(s, 2H).

[0028] Step 2, preparation of intermediate III; Intermediate II is subjected to an alkylation reaction with 1,2-dichloroethane (compound X) in a solvent under base catalysis to obtain intermediate III, namely ethyl 5-methoxy-3-(2-chloroethyl) acetylacetonate; This reaction is a nucleophilic substitution reaction, and the reaction formula is as follows (2): Formula (2): The detailed operation process is as follows: 188 g of ethyl 5-methoxyacetylacetonate is dissolved in 300 ml of acetonitrile, 103 g of 1,2-dichloromethane is added, 82 g of sodium ethoxide is added under ice bath, and the mixture is stirred under ice bath for 30 minutes. Then, the system is heated and refluxed to react for 3 hours. After the reaction is completed, the system is cooled to room temperature and then slowly poured into ice water. The mixture is extracted with 400 ml of dichloromethane, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate is decompressed to recover the solvent. The residue is distilled under reduced pressure to obtain 230 g of a colorless liquid, namely, intermediate III, with a yield of 92%.

[0029] The nuclear magnetic resonance hydrogen spectrum of intermediate III obtained has resonance peaks at the following positions: 1 HNMR (300NHZ, CDCl3): 1.27(M, 3H), 2.14(m, 2H), 3.18(m, 1H)3.36(s, 3H), 3.72(m, 2H), 4.15(m, 2H), 4.58(s, 2H).

[0030] Step 3, preparation of intermediate IV; Under acidic conditions, intermediate III reacts with 4-methoxyphenylhydrazine (compound XI) via Knorr pyrazole synthesis to obtain intermediate IV, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylic acid ethyl ester. The Knorr reaction is an effective method for synthesizing pyrazoles. This method needs to be carried out under acidic conditions. The reaction formula is as follows: Formula (3): The detailed operation process is as follows: 250 g of ethyl 5-methoxy-3-(2-chloroethyl)acetylacetonate and 145 g of 4-methoxyphenylhydrazine are added to 500 ml of acetic acid, and the mixture is heated under reflux for 10 hours. After the reaction is completed, the system is cooled to room temperature. In an ice bath, 50% sodium bicarbonate solution is slowly added dropwise to the system until the pH value of the system reaches 4-6. The system is then extracted with 400 ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and filtered. The residue is then decompressed to recover ethyl acetate, and the residue is recrystallized from petroleum ether:ethyl acetate in a 1:1 ratio to obtain 295.68 g of a light yellow solid, namely, Intermediate IV, with a yield of 84%.

[0031] The nuclear magnetic resonance hydrogen spectrum of intermediate IV was obtained, which had resonance peaks at the following positions: 1 HNMR (300NHZ, CDCl3): 1.18 (m, 3H), 2.75 (m, 2H), 3.28 (s, 3H), 3.73 (m, 2H), 3.86 (s, 3H), 4.07 (s, 2H), 4.32 (m, 2H), 7.01-7.03 (m, 2H), 7.49-7.53(m, 2H).

[0032] Step 4, preparation of intermediate V; Under alkaline conditions, intermediate IV reacts with compound XII 4-nitroaniline through alkylation to obtain intermediate V, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid ethyl ester; This step is an N-alkylation reaction. Due to the limited activity of chlorine reaction, NaI is added as a catalyst in the reaction. The reaction formula is as follows (4): Formula (4): In this example, the detailed operation process for preparing intermediate V is as follows: 35.2 g of ethyl N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylate and 15 g of 4-nitroaniline are dissolved in 120 ml of tetrahydrofuran, 0.5 g of sodium iodide and 13.5 g of potassium tert-butoxide are added, and the system is stirred at room temperature for 10 minutes. The system is then heated and refluxed for 6 hours. After the reaction is completed, the system is cooled to room temperature, the reaction solution is slowly poured into ice water, stirred for 20 minutes, filtered, and the filter cake is washed with water until neutral. The filter cake is dried and recrystallized from 80% ethanol to obtain 41.31 g of a light yellow solid powder, namely intermediate V, with a yield of 91%.

[0033] The H NMR spectrum of intermediate V was obtained to have resonance peaks at the following positions: 1HNMR (300NHz, DMSO): 1.31(m, 3H), 2.66(m, 2H), 3.35(s, 3H), 3.52(m, 2H), 3.86(s, 3H), 4.09(s, 2H),4.28(m, 2H), 6.69-6.72(m, 2H), 7.01-7.03(m, 2H), 7.47-7.49(m, 2H), 7.96-8.02(m, 2H).

[0034] Step 5, preparation of intermediate VI; Intermediate V is subjected to ester hydrolysis to obtain intermediate VI, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid; The reaction formula is as follows (5): Formula (5): The detailed operation process is as follows: 45.4 g of ethyl N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylate was dissolved in 80 ml of methanol, 15 g of a 30% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 2 h. After the reaction was completed, the system was cooled to room temperature, the system was adjusted to neutrality with dilute hydrochloric acid, and stirred. A large amount of solid precipitated in the system, which was filtered, and the filter cake was washed with water until the end. The filter cake was dried and recrystallized from dichloromethane to obtain 40.89 g of a light yellow solid with a yield of 96%.

[0035] The H NMR spectrum of intermediate VI obtained has resonance peaks at the following positions: 1 HNMR (300NHZ, DMSO): 2.76 (m, 2H), 3.36 (s, 3H), 3.43 (m, 2H), 3.88 (s, 3H), 4.12 (s, 2H), 6.68-6.71 (m, 2H), 7.02-7.05 (m, 2H), 7.47-7.49(m, 2H), 8.02-8.03(m, 2H), 11.02(s, 1H).

[0036] Step 6, preparation of intermediate VII; Intermediate VI is subjected to intramolecular amide reaction in the presence of a condensing agent in a reaction solvent to obtain intermediate VII, namely N-(4-methoxyphenyl)-6-(4-nitrophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; This step is an amidation reaction, and the reaction formula is as follows (6): Formula (6): The detailed operation process is as follows: 42.6 g of N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid was dissolved in 120 ml of tetrahydrofuran, and 17 g of CDI was added. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the solvent was recovered under reduced pressure, and 200 ml of water was added to the residue, and the mixture was stirred for 1 h. A large amount of solid precipitated in the system. The solid was filtered, and the filter cake was washed three times with water. The filter cake was dried and recrystallized from methanol to obtain 35.5 g of a yellow solid, namely, intermediate VII, with a yield of 87%.

[0037] The nuclear magnetic resonance hydrogen spectrum of intermediate VII obtained has resonance peaks at the following positions: 1 HNMR (300NHZ, CDCl3): 3.14(m, 2H), 3.23(m, 2H), 3.32(s, 3H), 3.86(s, 3H), 4.13(s, 2H), 7.02-7.03(m,2H), 7.36-7.39(m, 2H), 7.53-7.54(m, 2H), 8.16-8.17(m, 2H).

[0038] Step 7, preparation of intermediate VIII; Intermediate VII is dissolved in ethanol and subjected to nitro reduction to obtain intermediate VIII, namely N-(4-methoxyphenyl)-6-(4-aminophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; This step is the nitro reduction reaction, and the reaction formula is as follows (7): Formula (7): The detailed operation process is as follows: 40.8 g of N-(4-methoxyphenyl)-6-(4-nitrophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine is dissolved in 100 ml of anhydrous ethanol and stirred to dissolve. A solution of 15.4 g of Na2S dissolved in 60 ml of water is added dropwise over about 30 minutes. The system is then heated to reflux for reaction. After the reaction is complete, the reaction solution is cooled to room temperature and the solvent is removed under reduced pressure. 150 ml of anhydrous ethanol is added to the residue, heated to dissolve, and filtered while hot. The filtrate is then decompressed to remove the solvent to obtain a yellow solid. The solid powder is recrystallized from chloroform to obtain 37 g of a light yellow solid, namely, intermediate VIII, with a yield of 98%.

[0039] The nuclear magnetic resonance hydrogen spectrum of intermediate VIII obtained has resonance peaks at the following positions: 1HNMR (300NHZ, CDCl3): 3.13(m, 2H), 2.32(m, 2H), 3.36(s, 3H), 3.88(s, 3H), 6.12(s, 2H), 6.63-6.66(m, 2H), 7.01-7.04(m, 2H), 7.12-7.13(m, 2H), 7.46-7.47(m, 2H).

[0040] Step 8, preparation of intermediate IX; First, intermediate VIII and chemical XIII 5-bromovaleryl chloride are amidated in the presence of an acid binder. After the reaction is complete, further intramolecular alkylation reaction is carried out in the presence of a strong base to obtain intermediate IX, namely N-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-methoxymethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; This reaction is actually a two-step reaction. The first step is the condensation of amino groups with acyl chlorides, which is carried out at low temperatures. The second step is the condensation of amides with halogenated hydrocarbons, which requires a strong base. The reaction formula is as follows (8): Formula (8): The detailed operation process is as follows: take 37.8 grams of N-(4-methoxyphenyl)-6-(4-aminophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, add 120 ml of tetrahydrofuran, add 11 grams of triethylamine, and slowly add 21 grams of 5-bromovaleryl chloride (dissolved in 30 ml of tetrahydrofuran) dropwise under ice bath. The temperature does not exceed 5° during the addition process. The addition is completed in 30 minutes, and then the temperature is kept warm for 30 minutes. Then the system is slowly heated to reflux for reaction, and the reaction is complete in 3 hours. Then, 1 g of NaI and 16.8 g of potassium tert-butoxide were added to the system, and the system was heated to reflux for 6 h. After the reaction, the solvent was removed under reduced pressure, 100 ml of ethyl acetate was added to the system, stirred to dissolve, 150 ml of ice water was added, stirred to disperse, the solution was separated, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to recover the solvent. The residue was recrystallized from chloroform to obtain 42.78 g of intermediate IX, with a yield of 93%.

[0041] The nuclear magnetic resonance hydrogen spectrum of intermediate IX obtained has resonance peaks at the following positions: 1HNMR (300NHZ, CDCl3): 1.65(m, 2H), 2.12-2.21(m, 4H), 3.06(m, 2H), 3.27-3.28(m, 2H), 3.36(s, 3H), 3.85(s, 3H), 4. 13(s, 2H), 4.38(m, 2H), 6.69-6.71(m, 2H), 7.01-7.04(m, 2H), 7.32-7.35(m, 2H), 7.53-7.54(m, 2H).

[0042] step9. Preparation of apixaban; The intermediate IX is dissolved in a reaction solvent, tert-butyl hydroperoxide and aqueous ammonia are added, and the product I, apixaban, is obtained by oxidative amidation under iodine catalysis; This step is an oxidative amidation reaction with mild reaction conditions. The reaction formula is as follows (9): Formula (9): The detailed operation process is as follows: 4.6 g of N-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-methoxymethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine is taken and dissolved in 15 ml of tetrahydrofuran, 20 ml of tert-butyl hydroperoxide is added, 20 ml of ammonia water is added, 1 gram of iodine is added, and the reaction is heated under reflux for 4 hours. After the reaction is completed, the solvent is recovered under reduced pressure, the residue is dissolved with 20 ml of ethyl acetate, 20 ml of water is added, the liquid is separated, the organic layer is dried over anhydrous sodium sulfate, filtered, the filtrate is decompressed and the solvent is recovered, and the residue is recrystallized with 95% ethanol to obtain 4.2 g of yellow solid powder, i.e., finished product I apixaban, with a yield of 92%. The nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum of apixaban are as follows: Figure 1 and Figure 2 shown.

[0043] Example 2 In this example, the intermediate V in Example 1 was prepared by the following method. The detailed operation process is as follows: 35.2 g of ethyl N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylate and 15 g of 4-nitroaniline were dissolved in 120 ml of tetrahydrofuran, and 0.5 g of sodium iodide and 8.2 g of sodium ethoxide were added. The system was stirred at room temperature for 10 minutes, then the system was heated and refluxed for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was slowly poured into ice water, stirred for 20 minutes, filtered, and the filter cake was washed with water until neutral, dried, and recrystallized from 80% ethanol to obtain 38.14 g of a light yellow solid powder, namely, intermediate V, with a yield of 84%.

[0044] Example 3 In this example, the intermediate V in Example 1 was prepared by the following method. The detailed operation process is as follows: 35.2 g of ethyl N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylate and 15 g of 4-nitroaniline were dissolved in 120 ml of tetrahydrofuran, and 0.5 g of sodium iodide and 6.5 g of sodium methoxide were added. The system was stirred at room temperature for 10 minutes, then the system was heated and refluxed for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was slowly poured into ice water, stirred for 20 minutes, filtered, and the filter cake was washed with water until neutral. The filter cake was dried and recrystallized from 80% ethanol to obtain 36.78 g of a light yellow solid powder, namely, intermediate V, with a yield of 81%.

[0045] The raw material ethyl methoxyacetate used in the preparation method of apixaban is cheap and easily available, the process is easy to industrialize, the obtained final product has high purity, there is no dangerous process, the equipment is simple, the synthesis route is novel and the synthesis route is short.

[0046] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as above in terms of a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can, without departing from the scope of the technical solution of the present invention, make some changes or modifications to equivalent embodiments using the technical contents disclosed above. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing apixaban, characterized in that: The reaction process of the preparation method comprises: Step 1, Preparation of Intermediate II: Using ethyl methoxyacetate as the raw material, it reacts with ethyl pyruvate under base catalysis to obtain Intermediate II, namely ethyl 5-methoxyacetylacetonate; Step 2, preparation of intermediate III: Intermediate II is subjected to an alkylation reaction with 1,2-dichloroethane in a solvent under base catalysis to obtain intermediate III, i.e., ethyl 5-methoxy-3-(2-chloroethyl) acetylacetonate; Step 3, Preparation of Intermediate IV: Under acidic conditions, intermediate III and 4-methoxyphenylhydrazine are reacted via Knorr pyrazole synthesis to obtain intermediate IV, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-chloroethyl)-pyrazole-5-carboxylic acid ethyl ester; Step 4, preparation of intermediate V: Under alkaline conditions, intermediate IV is subjected to alkylation reaction with 4-nitroaniline to obtain intermediate V, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid ethyl ester; Step 5, preparation of intermediate VI: Intermediate V is subjected to ester hydrolysis to obtain intermediate VI, namely N-(4-methoxyphenyl)-3-methoxymethyl-4-(2-(4-nitroanilino)ethyl)-pyrazole-5-carboxylic acid; Step 6, preparation of intermediate VII: Intermediate VI is subjected to intramolecular amide reaction in the presence of a condensing agent in a reaction solvent to obtain intermediate VII, namely N-(4-methoxyphenyl)-6-(4-nitrophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; Step 7, preparation of intermediate VIII: Intermediate VII is dissolved in ethanol and subjected to nitro reduction to obtain intermediate VIII, namely N-(4-methoxyphenyl)-6-(4-aminophenyl)-3-methoxymethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; Step 8, Preparation of Intermediate IX: First, intermediate VIII is amidated with 5-bromovaleryl chloride in the presence of an acid binding agent. After the reaction, further intramolecular alkylation reaction is carried out in the presence of a strong base to obtain intermediate IX, namely N-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-3-methoxymethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; Step 9. Preparation of apixaban: The intermediate IX is dissolved in a reaction solvent, tert-butyl hydroperoxide and aqueous ammonia are added, and the product I, i.e., apixaban, is obtained by oxidative amidation under iodine catalysis.

2. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 1, ethyl methoxyacetate and ethyl pyruvate are reacted in a molar ratio of 1:1.05, and the reaction is carried out under reflux conditions; The reaction base is sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; The reaction solvent is methanol, ethanol, toluene, tetrahydrofuran or N,N-dimethylformamide DMF.

3. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 2, the feed ratio of ethyl 5-methoxyacetylacetonate to 1,2-dichloroethane is 1:1.05, and the reaction is carried out under reflux conditions; The reaction base is sodium methoxide, sodium ethoxide, sodium hydride or potassium tert-butoxide; The reaction solvent is toluene, tetrahydrofuran, acetonitrile or toluene.

4. The method for preparing apixaban according to claim 1, wherein: The acid in the reaction of step 3 is hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid or p-toluenesulfonic acid.

5. The method for preparing apixaban according to claim 1, wherein: NaI is added as a catalyst in the reaction of step 4; The reaction base is sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide; The reaction solvent is toluene, acetonitrile, tetrahydrofuran or 1,2-dichloroethane.

6. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 5, the reaction base is sodium carbonate or sodium hydroxide; The reaction solvent is methanol or ethanol.

7. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 6, the condensing agent is CDI, EDCi / HoBt or DCC / HoBt; The reaction solvent is tetrahydrofuran, acetonitrile, DMF, dichloromethane or 1,2-dichloromethane.

8. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 7, the nitro group reduction reaction is carried out by using Fe or Zn under acidic conditions, or by using Pd / C / H2 catalytic reduction, or by using a sulfiding agent for reduction.

9. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 8, the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate or triethylamine; The strong base used in the reaction is sodium hydride, sodium methoxide, sodium hydroxide, sodium ethoxide or potassium tert-butoxide; The reaction solvent is dichloromethane, tetrahydrofuran or acetonitrile.

10. The method for preparing apixaban according to claim 1, wherein: In the reaction of step 9, the reaction solvent is tetrahydrofuran, acetonitrile or acetone.

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