Intermediates of apixaban and methods of preparation

Abstract

The present application relates to a kind of new intermediate of synthesis apixaban and preparation method thereof.The method specifically includes the following steps: 1) the aminolysis reaction of p-phenylenediamine and formula (1-a) compound is prepared to obtain formula (2) compound, 2) formula (2) compound is prepared to obtain formula (3) compound by substitution reaction, 3) formula (3) compound is prepared to obtain formula (4i) compound by substitution reaction, again by cyclization reaction and obtain formula (4) directly from formula (3) compound is prepared to obtain formula (4), 4) formula (4) compound is prepared to obtain formula (5) compound by cyclization reaction, 5) formula (5) compound is prepared to obtain formula (6) compound by hydrolysis reaction, 6) formula (6) compound is prepared to obtain formula (7) compound by reaction or by formula (6) compound first decarboxylation reaction obtains formula (6i) compound again by condensation reaction and obtains formula (7), reaction formula is as follows: the present application has the advantages of simple and easy to operate and the yield of each step reaction is higher, synthesis route is not only green environmental protection, with cost advantage simultaneously, be conducive to the industrialized production of implementation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemicals, specifically to a novel intermediate for the synthesis of apixaban and its preparation method. Background Technology

[0002] Apixaban is a new generation of oral antithrombotic drugs that exhibits high selectivity, good bioavailability, and high therapeutic efficacy among many factor Xa inhibitors. It is primarily used in adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolic events (VTE). Apixaban was initially discovered by Bristol-Myers Squibb in 2003, and its development was jointly undertaken with Pfizer in 2007. Since its market launch in 2011, sales have increased year by year. For BMS & Pfizer, Eliquis (apixaban) achieved total sales of $9.016 billion in the first three quarters of 2019, a year-on-year increase of 25%. Eliquis projects sales to reach $12 billion by 2025.

[0003]

[0004] Currently, there are many synthetic processes for apixaban on the market, but most of them are synthesized through its key intermediate 5,6-dihydro-3-(4-morpholino)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridone. Therefore, the synthetic research of this apixaban intermediate is crucial. The structural formula of this key intermediate is shown below:

[0005]

[0006] The following prior art reports a method for preparing this intermediate:

[0007] 1. A route proposed in Bristol-Myers Squibb's World Patent WO2003049681, published in 2003, involves using p-iodoaniline as a starting material, undergoing amidation-cyclization, dichlorination, and morpholine substitution to obtain a compound, which is then coupled with 2-piperidinone in the presence of the catalyst Cu(PPh3)3Br and cesium carbonate to yield compound I. This route uses p-nitroiodobenzene I as the starting material to introduce the piperidinone group. However, p-nitroiodobenzene is expensive, and the auxiliary reagent, triphenylphosphine copper bromide, is used in large quantities and is also expensive, limiting the application of this route.

[0008]

[0009] 2. East China University of Science and Technology, in its 2011 Chinese patent CN101967145, provided another process route: using p-nitroaniline and 5-chloropentanoyl chloride as raw materials, compound 2 is obtained through amidation-cyclization, dichlorination, elimination, and condensation reactions. Compound 2 is then reduced to the corresponding amino compound 4 by sodium sulfide. Compound 4 is then amidated and cyclized with 5-chloropentanoyl chloride to obtain compound I. In this route, p-nitroaniline is introduced to cyclize and form a piperidinone group. While p-nitroaniline has low raw material costs, the strong electron-withdrawing effect of the nitro group can hinder the acylation reaction. Furthermore, the reduction of the nitro group using basic sulfides is not thorough enough and can damage the amide bond, resulting in numerous byproducts and limiting the practical application of this route.

[0010]

[0011] 3. The Shanghai Institute of Pharmaceutical Industry improved upon the above two preparation methods and applied for Chinese patent CN103626689A in 2012, providing the following process route: using aniline as the starting material, compound 4 is obtained through amidation-cyclization, nitration, dichlorination, and morpholine substitution reactions. Compound 4 is reduced to the corresponding amino compound 3 by sodium sulfide. Compound 3 is then amidated and cyclized with 5-chloropentanoyl chloride to obtain compound 3. The starting materials in this route are inexpensive, but the nitration reaction in this route is rapidly exothermic, the reaction process is dangerous and introduces many impurities, and post-processing is difficult, making it unsuitable for industrial application.

[0012]

[0013] 4. Patent document CN101967145 discloses a method that uses p-nitroaniline as a starting material, and after amidation cyclization, phosphorus pentachloride chlorination elimination, sodium sulfide reduction, and acylation cyclization again, finally yielding 5,6-dihydro-3-(4-morpholino)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone. Due to the passivation of the nitro group, the overall yield of this method is relatively low.

[0014] 5. Patent CN110143914 uses p-chloroaniline as a starting material, and after acylation cyclization and chlorination, it reacts with morpholine and eliminates hydrogen chloride, and is coupled to 2-piperidinone to obtain 5,6-dihydro-3-(4-morpholino)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone.

[0015] 6. Patent CN104030972 uses p-diphenylamine as a raw material. After bilateral acylation cyclization, phosphorus pentachloride is unilaterally chlorinated, and then eliminated by reaction with morpholine to obtain 5,6-dihydro-3-(4-morpholino)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone. The selectivity of chlorination is a key issue in this method, which leads to unstable yield.

[0016] In summary, the current synthetic methods for preparing the apixaban intermediate 5,6-dihydro-3-(4-morpholino)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridone are largely the same. These similar processes all have many common problems and defects: poor reaction reproducibility; cumbersome post-processing; high equipment requirements; expensive starting materials and high costs.

[0017] Given the shortcomings of existing routes, it is necessary to further develop environmentally friendly routes for apixaban key intermediates suitable for commercial production. Summary of the Invention

[0018] This invention provides a novel intermediate for the synthesis of apixaban and its preparation method. This method has the advantages of being simple and easy to implement, with high yields in each step of the reaction. The synthetic route is environmentally friendly and reduces costs, making it convenient for industrial production.

[0019] To achieve the objectives of this invention, the following technical solution is provided:

[0020] In a first aspect, the present invention provides an intermediate for preparing apixaban of formula (1-a), with the following structural formula:

[0021]

[0022] In a second aspect, the present invention provides a method for preparing an intermediate of apixaban with the formula (1-a): tert-butanol undergoes an acylation reaction with oxaloyl chloride in an organic solvent under organic base catalysis, followed by an acylation reaction with phenol.

[0023] (1-a) The ammonolysis reaction has high selectivity when synthesizing (2);

[0024] The preferred method for preparing the intermediate of apixaban with formula (1-a) is as follows: the organic base is triethylamine, and triethylamine and tert-butanol are mixed in a molar ratio of 1:1 and added dropwise to the organic solvent of oxaloyl chloride; the addition of triethylamine and tert-butanol is controlled to be in equal amounts, which on the one hand ensures the stability of oxaloyl chloride, and on the other hand further reduces the generation of disubstituted products in the reaction.

[0025] Thirdly, an intermediate for preparing apixaban of formula (2) has the following structural formula:

[0026]

[0027] Fourthly, the present invention provides a method for preparing an apixaban intermediate of formula (2), characterized in that the compound of formula (2) is prepared by ammonolysis of phenylenediamine with a compound of formula (1-a), and the reaction formula is as follows:

[0028]

[0029] Fifthly, the present invention provides an intermediate for preparing apixaban of formula (3-1), with the following structural formula:

[0030]

[0031] In a sixth aspect, the present invention provides an intermediate for preparing apixaban of formula (4), with the following structural formula:

[0032]

[0033] R1 and R2 are each independently a C1-C6 aliphatic hydrocarbon, phenyl or substituted phenyl;

[0034] In this invention, "substituted phenyl" includes benzyl, benzene, halobenzene, nitrobenzene, alkoxybenzene, and benzyloxybenzene.

[0035] In a seventh aspect, the present invention provides an intermediate for preparing apixaban of formula (4i), with the following structural formula:

[0036]

[0037] Wherein, R1 and R2 are each independently aliphatic hydrocarbons, phenyl or substituted phenyl groups of C1-C6; X is a halogen, OSO2Ph-p-Me, OSO2Me or OSO2Ph.

[0038] In this invention, "substituted phenyl" includes benzyl, benzene, halobenzene, nitrobenzene, alkoxybenzene, and benzyloxybenzene.

[0039] Eighthly, the present invention provides a method for preparing an apixaban intermediate of formula (4), characterized in that the compound of formula (3) undergoes a substitution reaction to prepare a compound of formula (4i), which is then subjected to a cyclization reaction to obtain formula (4), or directly obtained from the compound of formula (4i) via a cyclization reaction.

[0040] The reaction formula is as follows:

[0041]

[0042] Wherein, R1 and R2 are each independently aliphatic hydrocarbons, phenyl or substituted phenyl groups of C1-C6; X is a halogen, OSO2Ph-p-Me, OSO2Me or OSO2Ph.

[0043] In this invention, "substituted phenyl" includes benzyl, benzene, halobenzene, nitrobenzene, alkoxybenzene, and benzyloxybenzene.

[0044] The compound of formula (4i) may or may not be separated.

[0045] In a ninth aspect, the present invention provides an intermediate for preparing apixaban of the formula (4i-1), with the following structural formula:

[0046]

[0047] In a tenth aspect, the present invention provides an intermediate for preparing apixaban of formula (4-1), with the following structural formula:

[0048]

[0049] Eleventhly, the present invention provides a method for preparing an apixaban intermediate of formula (4-1), characterized in that tert-butyl 4-bromobutyrate is reacted with a compound of formula (3) by a substitution reaction to obtain a compound of formula (4i-1), which is then subjected to a cyclization reaction to obtain formula (4-1), or formula (4-1) is prepared directly from formula (4i-1), as shown in the following reaction formula:

[0050]

[0051] The compound of formula (4i-1) may or may not be separated.

[0052] The preferred synthesis step of (4-1) is to prepare compound (4i-1) by substitution reaction of 3- and 4-bromobutyrate tert-butyl ester in an organic solvent under inorganic base catalysis at a temperature of 50-70°C, and then raise the temperature to 70-80°C for cyclization reaction to generate compound (4-1).

[0053] The inorganic base is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, and calcium carbonate.

[0054] This preferred method involves two reactions but can be completed in one step, which greatly simplifies reaction time and cost while ensuring yield and facilitating mass production.

[0055] Furthermore, the inorganic base is preferably potassium carbonate or cesium carbonate. Reactions catalyzed by these two inorganic bases can direct the reaction in the target direction and exhibit high selectivity.

[0056] The introduction of tert-butyl 4-bromobutyrate in section 4-1 is to ensure that there is a tert-butyl ester group after the 5-ring closure, which can guarantee a high yield of decarboxylation to 6.

[0057] In a twelfth aspect, the present invention provides a method for preparing an apixaban intermediate of formula (4-1), characterized in that the compound of formula (3) is reacted to obtain formula (4-1), and the reaction formula is as follows:

[0058]

[0059] In a thirteenth aspect, the present invention provides an intermediate for preparing apixaban of formula (5-1), with the following structural formula:

[0060]

[0061] In a fourteenth aspect, the present invention provides a method for preparing an apixaban intermediate of formula (5), characterized in that the compound of formula (4) is prepared by a cyclization reaction to obtain the compound of formula (5), as follows:

[0062]

[0063] R1 and R2 are each independently aliphatic hydrocarbons, phenyl or substituted phenyl groups of C1-C6.

[0064] In a fifteenth aspect, the present invention provides a method for preparing an apixaban intermediate of formula (5-1), characterized in that the compound of formula (4-1) is prepared by a cyclization reaction to obtain the compound of formula (5-1), the reaction formula being as follows:

[0065]

[0066] In a sixteenth aspect, the present invention provides an intermediate for preparing apixaban of formula (6), with the following structural formula:

[0067]

[0068] In a seventeenth aspect, the present invention provides a method for preparing an apixaban intermediate of formula (6), characterized in that the compound of formula (5-1) is prepared by a cyclization reaction to obtain the compound of formula (6), the reaction formula being as follows:

[0069]

[0070] In an eighteenth aspect, the present invention provides an intermediate for preparing apixaban of formula (6i), with the following structural formula:

[0071]

[0072] In a nineteenth aspect, the present invention provides a method for preparing an apixaban intermediate of formula (7), characterized in that the compound of formula (6) is prepared by a condensation reaction to obtain the compound of formula (7), or the compound of formula (6) is first decarboxylated to obtain the compound of formula (6i) and then condensed to obtain the compound of formula (70).

[0073] The reaction formula is as follows:

[0074]

[0075] In a twentieth aspect, the present invention provides a method for preparing apixaban intermediate formula 7, characterized by comprising the following steps:

[0076] 1) Compound (2) is prepared by ammonolysis of p-phenylenediamine with compound (1-a).

[0077] 2) Compound (2) is prepared by a substitution reaction to obtain compound (3).

[0078] 3) 4-Brominated tert-butyl ester is reacted with compound (3-1) to prepare compound (4i-1), which is then subjected to a cyclization reaction to obtain compound (4-1), or compound (3-1) is reacted directly to prepare compound (4-1).

[0079] 4) Compound of formula (4-1) was prepared by a cyclization reaction to obtain compound of formula (5-1).

[0080] 5) Compound (5-1) was prepared by hydrolysis to obtain compound (6).

[0081] 6) Compound (6) is prepared by condensation reaction to obtain compound (7), or compound (6) is obtained by decarboxylation reaction to obtain compound (6i) and then condensation reaction to obtain compound (70).

[0082] The reaction formula is as follows:

[0083]

[0084] In a twentieth aspect, the present invention provides a method for preparing apixaban intermediate formula 7, characterized by comprising the following steps:

[0085] 1) Compound (2) is prepared by ammonolysis of p-phenylenediamine with compound (1-a).

[0086] 2) Compound (2) is prepared by a substitution reaction to obtain compound (3).

[0087] 3) Compound (3) is prepared by substitution reaction to obtain compound (4i), and then by cyclization reaction to obtain compound (4), or compound (3) is directly prepared by reaction to obtain compound (4).

[0088] 4) Compound (4) was prepared by a cyclization reaction to obtain compound (5).

[0089] 5) Compound (5) was prepared by hydrolysis to obtain compound (6).

[0090] 6) Compound (6) is prepared by reaction to obtain compound (7), or compound (6) is obtained by decarboxylation reaction to obtain compound (6i) and then condensation reaction to obtain compound (7), as shown in the following reaction formulas:

[0091]

[0092] Compared with the prior art, the present invention provides a novel intermediate for the synthesis of apixaban and its preparation method, which have the following significant advancements:

[0093] (1) Simple and easy to implement: The initial raw materials containing tert-butyl ester in the synthetic route adopted in this invention have the advantage of being easy to prepare, and the stability of each step of the product is greatly increased. The transportation stability, storage stability and use stability during factory production are greatly increased, which makes the quality control of each intermediate in the reaction more convenient and reduces the requirements for equipment. In addition, there are no complex reactions in the synthetic route, so the entire synthetic route is simple and easy to operate.

[0094] (2) Low cost: No expensive catalysts or auxiliary reagents are used in the raw materials and reactions of the synthesis route of this invention, and expensive iodine-containing compounds are also avoided. This ensures that the three wastes generated in each process are less and easier to treat, which makes the reaction both green and environmentally friendly while greatly reducing costs.

[0095] (3) High yield: In the new intermediate of apixaban and its preparation method of the present invention, the yield of each reaction step can be above 85%, and the post-processing is simple and convenient, which is more conducive to the control during mass production. Detailed Implementation

[0096] The invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only and do not limit the scope of the claims.

[0097] Example 1: The preparation method of this apixaban precursor compound adopts the following specific process steps.

[0098] (1) Synthesis of compound 1-a:

[0099]

[0100] Dichloromethane (70 ml) and oxaloyl chloride (10.0 g, 0.079 mol) were added to a reaction flask. The mixture was stirred at -10 °C for 0.5 h. A mixed solution of tert-butanol (5.85 g, 0.079 mol): dichloromethane (10 ml): triethylamine (7.97 g, 0.079 mol) was added dropwise. After the addition was complete, the mixture was stirred at -10 °C for 0.5 h. Then, a mixed solution of phenol (7.43 g, 0.079 mol): dichloromethane (10 ml): triethylamine (7.97 g, 0.079 mol) was added dropwise. After the addition was complete, the mixture was stirred at -10 °C for 0.5 h. When HPLC and TLC showed the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the product (11.6 g, theoretical value 12.9 g, yield 90.2%). LCMS m / z 223 (M + +H,C 12 H 14 O4).

[0101] (2) Synthesis of compound 2:

[0102]

[0103] Ethyl acetate (100 ml), p-phenylenediamine (10.0 g, 0.093 mol), and tert-butyl oxalate (21.1 g, 0.095 mol) were added to a reaction flask. The mixture was stirred at 18 °C for 3.5 h. When HPLC and TLC showed that the reaction was complete, 50 g of water and concentrated hydrochloric acid (6.94 ml, 0.083 mol) were added for extraction and separation. The ethyl acetate layer was extracted and separated again with 100 g of water and concentrated hydrochloric acid (0.77 ml, 0.009 mol). The aqueous layers were combined, and sodium carbonate was added to adjust the pH to 7. The mixture was filtered, and the filter cake was washed with water and dried to obtain the product (19.7 g, theoretical value 21.8 g, yield 90.3%). LCMS m / z 236 (M + +H,C 12 H 16 N2O3).

[0104] (3) Synthesis of compound 3:

[0105]

[0106] Dichloromethane (100 ml) was added to a reaction flask, followed by compound 2 (10.0 g, 0.042 mol) and triethylamine (4.5 g, 0.044 mol). The mixture was cooled to 15 °C and stirred. While stirring, 5-chloropentanoyl chloride (6.9 g, 0.044 mol) was added dropwise. After the addition was complete, the mixture was kept at 15 °C for 0.5 h. When HPLC and TLC showed the reaction was complete, 40 g of water was added and stirred. The mixture was then filtered. Another 40 g of water was added to the filter cake, and the mixture was stirred and filtered again. The filter cake was washed with water and dried to obtain the product. The filtrates were mixed twice to separate the layers. The dichloromethane layer was recrystallized and dried to obtain the product. The product was mixed twice (14.3 g, theoretical value 15.0 g, yield 95.3%). LCMS m / z 355 (M + +H,C 17 H 23 ClN2O4).

[0107] (4) Synthesis of compound 4-1:

[0108]

[0109] Compound 3 (10.0 g, 0.028 mol), potassium carbonate (38.8 g, 0.282 mol), DMF (100 ml), and tert-butyl 4-bromobutyrate (7.55 g, 0.034 mol) were added to a reaction flask. The mixture was stirred at 55 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (11.6 g, theoretical value 12.9 g, yield 89.9%). LCMS m / z 461 (M + +H,C 25 H 36 N2O6).

[0110] (5) Synthesis of compound 5:

[0111]

[0112] Sodium tert-butoxide (2.71 g, 0.028 mol) was added to a reaction flask, followed by tetrahydrofuran (90 ml). The mixture was stirred at 65 °C, and then a tetrahydrofuran (30 ml) solution of compound 4-1 (10.0 g, 0.022 mol) was added. The reaction was maintained at this temperature for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 5 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (6.9 g, theoretical value 7.9 g, yield 87.3%). LCMS m / z 387 (M + +H,C21 H 26 N2O5).

[0113] (6) Synthesis of compound 6:

[0114]

[0115] Dichloromethane (70 ml), tetrahydrofuran (30 ml), and compound 5 (10.0 g, 0.026 mol) were added to a reaction flask. The mixture was kept at 20 °C with stirring, and hydrogen chloride gas was introduced to maintain the reaction temperature for 2.5 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Heptane (50 ml) was added at 20 °C and the mixture was stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (7.7 g, theoretical value 8.5 g, yield 90.5%). LCMS m / z 331 (M + +H,C 17 H 18 N2O5).

[0116] (7) Synthesis of compound 7:

[0117]

[0118] Compound 6 (10.0 g, 0.033 mol) was added to a reaction flask, along with acetonitrile (100 ml), morpholine (4.5 g, 0.052 mol), and acetic acid (3.1 g, 0.052 mol). The mixture was stirred at 80 °C for 4 h. When HPLC and TLC showed the reaction was complete, recrystallization yielded the product (9.7 g, theoretical value 10.7 g, yield 90.7%). LCMS m / z 356 (M). + +H,C 20 H 25 N3O3).

[0119] Example 2: Unlike Example 1, the preparation method of the apixaban precursor compound in this example adopts the following specific process steps.

[0120] (1) Synthesis of compound 1-a:

[0121] Dichloromethane (80 ml) and oxaloyl chloride (10.0 g, 0.079 mol) were added to a reaction flask. The mixture was stirred at -5°C for 0.5 h. A mixed solution of tert-butanol (5.85 g, 0.079 mol), dichloromethane (10 ml), and triethylamine (8.10 g, 0.080 mol) was added dropwise. After the addition was complete, the mixture was stirred at -10°C for 0.5 h. When the HPLC reaction was complete, a mixed solution of phenol (7.43 g, 0.079 mol), dichloromethane (10 ml), and triethylamine (8.10 g, 0.080 mol) was added dropwise. After the addition was complete, the mixture was stirred at -5°C for 0.5 h. When HPLC and TLC showed the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the product (11.5 g, theoretical value 12.9 g, yield 90.2%). LCMS m / z 223 (M + +H,C 12 H 14 O4).

[0122] (2) Synthesis of compound 2:

[0123] Ethyl acetate (100 ml), p-phenylenediamine (10.0 g, 0.093 mol), and tert-butyl oxalate (20.6 g, 0.093 mol) were added to a reaction flask. The mixture was stirred at 15 °C for 4 h. When HPLC and TLC showed that the reaction was complete, 40 g of water and concentrated hydrochloric acid (6.94 ml, 0.083 mol) were added for extraction and separation. The ethyl acetate layer was extracted and separated again by adding 90 g of water and concentrated hydrochloric acid (0.77 ml, 0.009 mol). The aqueous layers were combined, and the pH was adjusted to 8 by adding Na₂CO₃. The mixture was filtered, and the filter cake was washed with water and dried to obtain the product (19.3 g, theoretical value 21.8 g, yield 88.5%).

[0124] (3) Synthesis of compound 3:

[0125] Dichloromethane (100 ml) was added to the reaction flask, followed by compound 2 (10.0 g, 0.042 mol) and triethylamine (4.4 g, 0.043 mol). The mixture was cooled to 20 °C and stirred. While stirring, 5-chloropentanoyl chloride (6.69 g, 0.043 mol) was added dropwise. After the addition was complete, the mixture was kept at 20 °C for 0.5 h. When HPLC and TLC showed that the reaction was complete, 40 g of water was added and stirred. The mixture was then filtered. Another 40 g of water was added to the filter cake and stirred. The mixture was then filtered again. The filter cake was rinsed with water and dried to obtain the product. The filtrates were mixed twice to separate the layers. The dichloromethane layer was recrystallized and dried to obtain the product. The product was mixed twice (14.2 g, theoretical value 15.0 g, yield 94.6%).

[0126] (4) Synthesis of compound 4-1:

[0127] Compound 3 (10.0 g, 0.028 mol), potassium carbonate (38.8 g, 0.282 mol), DMF (90 ml), and tert-butyl 4-bromobutyrate (7.3 g, 0.033 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 11 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The concentrate was extracted with dichloromethane and water, and the organic layer was dried with anhydrous sodium sulfate. The product was then concentrated under reduced pressure to obtain 11.3 g (theoretical value 12.9 g, yield 87.5%).

[0128] (5) Synthesis of compound 5:

[0129] Sodium tert-butoxide (2.71 g, 0.028 mol) and tetrahydrofuran (80 ml) were added to a reaction flask and stirred at 60 °C. A tetrahydrofuran (20 ml) solution of compound 4-1 (10.0 g, 0.022 mol) was added and the reaction was maintained at this temperature for 0.5 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 0 °C, and the pH was adjusted to 3 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (6.8 g, theoretical value 7.9 g, yield 86.1%).

[0130] (6) Synthesis of compound 6:

[0131] Dichloromethane (80 ml), tetrahydrofuran (20 ml), and compound 5 (10.0 g, 0.026 mol) were added to a reaction flask. The mixture was kept at 15 °C with stirring, and hydrogen chloride gas was introduced to maintain the temperature for 2 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Heptane (45 ml) was added at 15 °C and the mixture was kept at 15 °C with stirring for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (7.5 g, theoretical value 8.5 g, yield 88.2%).

[0132] (7) Synthesis of compound 7:

[0133] Compound 6 (10.0 g, 0.033 mol) was added to a reaction flask, along with acetonitrile (90 ml), morpholine (4.4 g, 0.050 mol), and acetic acid (3.0 g, 0.050 mol). The mixture was stirred at 60 °C for 3 h. When HPLC and TLC showed that the reaction was complete, the product was recrystallized to obtain the product (9.3 g, theoretical value 10.7 g, yield 86.9%).

[0134] Example 3: Unlike Example 1, the preparation method of the apixaban precursor compound in this example adopts the following specific process steps.

[0135] (1) Synthesis of compound 1-a:

[0136] Dichloromethane (70 ml) and oxaloyl chloride (10.0 g, 0.079 mol) were added to a reaction flask. The mixture was stirred at 0 °C for 0.5 h. A mixed solution of tert-butanol (5.92 g, 0.08 mol): dichloromethane (10 ml): triethylamine (7.97 g, 0.079 mol) was added dropwise. After the addition was complete, the mixture was stirred at -10 °C for 0.5 h. When the HPLC reaction was complete, a mixed solution of phenol (7.53 g, 0.08 mol): dichloromethane (10 ml): triethylamine (7.97 g, 0.079 mol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 0.5 h. When HPLC and TLC showed the reaction was complete, the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the product (11.3 g, theoretical value 12.9 g, yield 87.5%). LCMS m / z 223 (M + +H,C 12 H 14 O4).

[0137] (2) Synthesis of compound 2:

[0138] Ethyl acetate (110 ml), p-phenylenediamine (10.0 g, 0.093 mol), and tert-butyl oxalate (21.6 g, 0.097 mol) were added to a reaction flask. The mixture was stirred at 20 °C for 4 h. When HPLC and TLC showed that the reaction was complete, 45 g of water and concentrated hydrochloric acid (7.5 ml, 0.09 mol) were added for extraction and separation. The ethyl acetate layer was extracted and separated by adding 95 g of water and concentrated hydrochloric acid (0.83 ml, 0.01 mol). The aqueous layers were combined, and the pH was adjusted to 7 by adding Na₂CO₃. The mixture was filtered, and the filter cake was washed with water and dried to obtain the product (19.5 g, theoretical value 21.8 g, yield 89.4%).

[0139] (3) Synthesis of compound 3:

[0140] Dichloromethane (100 ml) was added to a reaction flask, followed by compound 2 (10.0 g, 0.042 mol) and triethylamine (4.6 g, 0.045 mol). The mixture was cooled to 15 °C and stirred. While stirring, 5-chloropentanoyl chloride (6.98 g, 0.045 mol) was added dropwise. After the addition was complete, the mixture was kept at 15 °C for 0.5 h. When HPLC and TLC showed that the reaction was complete, 50 g of water was added and stirred. The mixture was then filtered. Another 50 g of water was added to the filter cake and stirred. The mixture was then filtered again. The filter cake was rinsed with water and dried to obtain the product. The filtrates were mixed twice to separate the layers. The dichloromethane layer was recrystallized and dried to obtain the product. The product was mixed twice (14.3 g, theoretical value 15.0 g, yield 95.3%).

[0141] (4) Synthesis of compound 4:

[0142] Compound 3 (10.0 g, 0.028 mol), potassium carbonate (42.8 g, 0.310 mol), DMF (110 ml), and tert-butyl 4-bromobutyrate (7.7 g, 0.035 mol) were added to a reaction flask. The mixture was stirred at 70 °C for 11 h, then heated to 70 °C and held for 4 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The concentrate was extracted with dichloromethane and water, and the organic layer was dried with anhydrous sodium sulfate. The product was then concentrated under reduced pressure to obtain the product (11.3 g, theoretical value 12.9 g, yield 87.5%).

[0143] (5) Synthesis of compound 5:

[0144] Sodium tert-butoxide (2.71 g, 0.031 mol) was added to a reaction flask, followed by tetrahydrofuran (100 ml). The mixture was stirred at 75 °C, and then a tetrahydrofuran (20 ml) solution of compound 4-1 (10.0 g, 0.022 mol) was added. The mixture was kept at this temperature for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 0 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried with anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (6.8 g, theoretical value 7.9 g, yield 86.1%).

[0145] (6) Synthesis of compound 6:

[0146] Dichloromethane (60 ml), tetrahydrofuran (40 ml), and compound 5 (10.0 g, 0.026 mol) were added to a reaction flask. The mixture was kept at 15 °C with stirring, and hydrogen chloride gas was introduced to maintain the temperature for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Heptane (55 ml) was added at 18 °C and the mixture was kept at 18 °C with stirring for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (7.8 g, theoretical value 8.5 g, yield 91.7%).

[0147] (7) Synthesis of compound 7:

[0148] Compound 6 (10.0 g, 0.033 mol) was added to a reaction flask, along with acetonitrile (90 ml), morpholine (4.6 g, 0.054 mol), and acetic acid (3.2 g, 0.054 mol). The mixture was stirred at 80 °C for 3 h. When HPLC and TLC showed that the reaction was complete, recrystallization yielded the product (9.4 g, theoretical value 10.7 g, yield 87.9%).

[0149] Example 4: Unlike Example 1, the preparation method of the apixaban precursor compound in this example adopts the following specific process steps.

[0150] (1) The synthesis of compound 1-a was the same as in Example 1, except for the following differences: acetonitrile was used as the organic solvent, and the temperature was maintained at -8°C to obtain the product (11.4 g, theoretical value 12.9 g, yield 88.3%), LCMS m / z 223 (M + +H,C 12 H 14 O4).

[0151] (2) The synthesis of compound 2 was the same as in Example 1 except for the following differences: Acetonitrile was used as the organic solvent, tert-butyl oxalate phenol ester (20.8 g, 0.094 mol) and concentrated hydrochloric acid (7.16 ml, 0.086 mol) were used to obtain the product (19.1 g, theoretical value 21.8 g, yield 87.6%).

[0152] (3) The synthesis of compound 3 is the same as in Example 1 except for the following differences: Acetonitrile was used as the organic solvent, and the ratio of compound 2: 5-chloropentanoyl chloride: triethylamine = 1.0:1.1:1.1 (moles) was used to obtain the product (14.0 g, theoretical value 15.0 g, yield 93.3%).

[0153] (4) Synthesis of compound 4i-1:

[0154]

[0155] Compound 3 (10.0 g, 0.028 mol), potassium carbonate (38.8 g, 0.282 mol), DMF (100 ml), and tert-butyl 4-bromobutyrate (7.55 g, 0.034 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (12.6 g, theoretical value 14.0 g, yield 90.0%). LCMS m / z 497 (M + +H,C 25 H 37 ClN2O6).

[0156] (5) Synthesis of compound 5:

[0157]

[0158] Sodium tert-butoxide (4.42 g, 0.046 mol) was added to a reaction flask, followed by tetrahydrofuran (90 ml). The mixture was stirred at 65 °C, and then a tetrahydrofuran (30 ml) solution of compound 4i-1 (10.0 g, 0.020 mol) was added and the reaction was maintained at this temperature for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 5 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (6.7 g, theoretical value 7.8 g, yield 85.8%). LCMS m / z 387 (M + +H,C 21 H 26 N2O5).

[0159] (6) Synthesis of compound 6: Tetrahydrofuran (100 ml) was added to a reaction flask, followed by compound 5 (10.0 g, 0.026 mol). The mixture was kept at 20 °C with stirring, and hydrogen chloride gas was introduced to maintain the temperature for 2.5 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure, 50 ml of ethyl acetate was added, and the mixture was filtered. Heptane (50 ml) was added at 20 °C and the mixture was kept at 20 °C with stirring for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (7.4 g, theoretical value 8.5 g, yield 87.1%).

[0160] (7) Synthesis of compound 6i:

[0161]

[0162] Acetonitrile (100 ml) was added to a reaction flask, followed by compound 6 (10.0 g, 0.026 mol). The mixture was stirred at 80 °C for 5 h. When HPLC and TLC showed that the reaction was complete, the product was concentrated under reduced pressure to obtain 8.4 g (theoretical value 8.6 g, yield 97.7%). LCMS m / z 287 (M + +H,C 16 H 18 N2O3).

[0163] (8) Synthesis of compound 7:

[0164]

[0165] Morpholine (4.5 g, 0.052 mol) and acetic acid (3.1 g, 0.052 mol) were added to a reaction flask and stirred for 0.5 h. Acetonitrile (100 ml) and compound 6i (10.0 g, 0.035 mol) were added. The mixture was kept at 80 °C and stirred for 4 h. When HPLC and TLC showed that the reaction was complete, the product was recrystallized to obtain the product (10.7 g, theoretical value 12.4 g, yield 86.3%).

[0166] The process route for preparing 6 in this invention can also be prepared by the following examples.

[0167] Example 5: The preparation method of preparation 6 in this invention adopts the following specific process steps.

[0168] (1) Synthesis of ethyl butyrate of compound 4-(2-ethoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide:

[0169]

[0170] 2-((4-(5-chloropentanamide)phenyl)amino)-2-oxoacetaminoethyl ester (10.0 g, 0.031 mol), potassium carbonate (42.2 g, 0.306 mol), DMF (100 ml), and ethyl 4-bromobutyrate (6.52 g, 0.034 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (11.1 g, theoretical value 12.4 g, yield 89.5%). LCMS m / z 405 (M + +H,C 21 H 28 N2O6).

[0171] (2) Synthesis of ethyl butyrate of compound 4-(2-ethoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide:

[0172]

[0173] 2-((4-(5-bromopentanamide)phenyl)amino)-2-oxoacetaminoethyl ester (10.0 g, 0.027 mol), potassium carbonate (37.3 g, 0.270 mol), DMF (100 ml), and ethyl 4-bromobutyrate (6.52 g, 0.034 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (11.2 g, theoretical value 12.4 g, yield 90.3%). LCMS m / z 405 (M + +H,C 21 H 28 N2O6).

[0174] (3) Synthesis of ethyl 1-(4-(2-oxopiperidin-1-yl)-phenyl)piperidine-2,3-dione-4-carboxylic acid:

[0175]

[0176] Sodium tert-butoxide (3.17 g, 0.033 mol) was added to a reaction flask, followed by tetrahydrofuran (90 ml). The mixture was stirred at 65 °C, and then a tetrahydrofuran (30 ml) solution of ethyl 4-(2-ethoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide)butanoate (10.0 g, 0.025 mol) was added. The mixture was stirred at 65 °C for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 5 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (7.8 g, theoretical value 8.9 g, yield 87.6%). LCMS m / z 359 (M + +H,C 19 H 22 N2O5).

[0177] (4) Synthesis of compound 6:

[0178]

[0179] Dichloromethane (70 ml), tetrahydrofuran (30 ml), and ethyl 1-(4-(2-oxopiridin-1-yl)phenyl)piperidin-2,3-dione-4-carboxylate (10.0 g, 0.028 mol) were added to a reaction flask. The mixture was stirred at 20 °C and incubated with hydrogen chloride gas for 2.5 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Heptane (50 ml) was added at 20 °C and stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (0.7 g, theoretical value 9.21 g, yield 7.6%). LCMS m / z 331 (M + +H,C 17 H 18 N2O5).

[0180] Example 6: The preparation method of preparation 6 in this invention adopts the following specific process steps.

[0181] (1) Synthesis of methyl 4-(2-methoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide)butyrate:

[0182]

[0183] 2-((4-(5-chloropentanamide)phenyl)amino)-2-oxoacetaminomethyl ester (10.0 g, 0.032 mol), potassium carbonate (44.2 g, 0.320 mol), DMF (100 ml), and methyl 4-bromobutyrate (6.84 g, 0.038 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (9.8 g, theoretical value 11.3 g, yield 86.7%). LCMS m / z 377 (M + +H,C 19 H 24 N2O6). OSO2Ph

[0184] (2) Synthesis of methyl 4-(2-methoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide)butyrate:

[0185]

[0186] 2-((4-(5-sulfonyl phenyl pentamide)phenyl)amino)-2-oxoacetaminomethyl ester (10.0 g, 0.023 mol), potassium carbonate (31.7 g, 0.230 mol), DMF (100 ml), and methyl 4-bromobutyrate (6.84 g, 0.038 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (7.6 g, theoretical value 8.7 g, yield 87.3%). LCMS m / z 377 (M + +H,C 19 H 24 N2O6).

[0187] (3) Synthesis of methyl 1-(4-(2-oxopiperidin-1-yl)-phenyl)piperidine-2,3-dione-4-carboxylic acid:

[0188]

[0189] Sodium tert-butoxide (3.11 g, 0.032 mol) was added to a reaction flask, followed by tetrahydrofuran (90 ml). The mixture was stirred at 65 °C, and then a tetrahydrofuran (30 ml) solution of methyl 4-(2-methoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide)butanoate (10.0 g, 0.027 mol) was added. The mixture was stirred at 65 °C for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 5 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (8.2 g, theoretical value 9.2 g, yield 89.1%). LCMS m / z 345 (M + +H,C 19 H 22 N2O5).

[0190] (4) Synthesis of compound 6:

[0191]

[0192] Dichloromethane (70 ml), tetrahydrofuran (30 ml), and methyl 1-(4-(2-oxopiridin-1-yl)phenyl)piperidin-2,3-dione-4-carboxylic acid (10.0 g, 0.029 mol) were added to a reaction flask. The mixture was stirred at 20 °C and incubated with hydrogen chloride gas for 2.5 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Heptane (50 ml) was added at 20 °C and stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed with heptane and dried to obtain the product (0.9 g, theoretical value 9.6 g, yield 9.3%). LCMS m / z 331 (M + +H,C 17 H 18 N2O5).

[0193] Example 7: The preparation method of preparation 6 in this invention adopts the following specific process steps.

[0194] (1) Synthesis of ethyl butyrate of compound 4-(2-tert-butoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide:

[0195]

[0196] Compound 3 (10.0 g, 0.028 mol), potassium carbonate (38.8 g, 0.282 mol), DMF (100 ml), and ethyl 4-bromobutyrate (6.56 g, 0.034 mol) were added to a reaction flask. The mixture was stirred at 50 °C for 12 h, then heated to 80 °C and held for 3 h. When HPLC and TLC showed that the reaction was complete, the mixture was filtered, concentrated under reduced pressure, and the concentrate was extracted with dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product (10.8 g, theoretical value 12.2 g, yield 88.5%). LCMS m / z 433 (M + +H,C 21 H 28 N2O6).

[0197] (2) Synthesis of methyl 1-(4-(2-oxopiperidin-1-yl)-phenyl)piperidine-2,3-dione-4-carboxylic acid:

[0198]

[0199] Sodium tert-butoxide (2.88 g, 0.030 mol) was added to a reaction flask, followed by tetrahydrofuran (90 ml). The mixture was stirred at 65 °C, and then a tetrahydrofuran (30 ml) solution of methyl 4-(2-tert-butoxy-2-oxo-N-(4-(2-oxopiridin-1-yl)-phenyl)acetamide)butanoate (10.0 g, 0.023 mol) was added. The mixture was stirred at 65 °C for 1 h. When HPLC and TLC showed that the reaction was complete, the mixture was concentrated under reduced pressure. Water (100 ml) and ethyl acetate (100 ml) were added at 5 °C, and the pH was adjusted to 2 with hydrochloric acid. The phases were separated, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure to obtain the product (7.0 g, theoretical value 8.0 g, yield 87.5%). LCMS m / z 345 (M + +H,C 19 H 22 N2O5).

[0200] (3) The synthesis of compound 6 is the same as in Example 5.

[0201] The foregoing general description of the invention and its specific embodiments should not be construed as limiting the technical solution of the invention. Those skilled in the art, based on the disclosure of this application, can add, reduce, or combine the disclosed technical features in the foregoing general description and / or embodiments without departing from the constituent elements of the invention, to form other technical solutions within the scope of protection of this application.

Claims

1. An intermediate for preparing apixaban of formula (6), with the following structural formula: 。 2. A method for preparing an apixaban intermediate of formula (6), characterized in that, Compound (5-1) was prepared by a detert-butylation reaction to give compound (6), as shown in the following reaction formula: 。 3. An intermediate for preparing apixaban of formula (6i), with the following structural formula: 。 4. A method for preparing an apixaban intermediate of formula (7), characterized in that, Compound (6) is prepared by condensation reaction to obtain compound (7), or compound (6i) is obtained by decarboxylation reaction and then condensation reaction to obtain compound (7), as shown in the following reaction formulas: ,or 。 5. A method for preparing an apixaban intermediate of formula (7), characterized in that, Includes the following steps: 1) Compound (2) is prepared by ammonolysis of p-phenylenediamine with compound (1-a). 2) Compound (2) is prepared by a substitution reaction to obtain compound (3). 3) 4-Bromobutyrate tert-butyl ester is reacted with compound (3) to prepare compound (4i-1), which is then cyclized to obtain compound (4-1) or directly reacted with compound (3) to obtain compound (4-1). 4) Compound of formula (4-1) was prepared by a cyclization reaction to obtain compound of formula (5-1). 5) Compound of formula (5-1) was prepared by a detert-butylation reaction to obtain compound of formula (6). 6) Compound (6) is prepared by reaction to obtain compound (7), or compound (6) is obtained by decarboxylation reaction to obtain compound (6i) and then condensation reaction to obtain compound (7); The reaction formula is as follows: 。

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