High purity apixaban and methods of making the same

Abstract

The application provides a high-purity apixaban and a preparation method thereof, and relates to the technical field of bulk drug synthesis. Specifically, compound 1 and compound 2 are used as raw materials, a phase catalyst is used, compound 1 is reacted with compound 2 in a reaction solvent under heterogeneous conditions, and amine ester exchange reaction is used to prepare crude apixaban; then the crude product is purified and crystallized to obtain apixaban products which are easy to prepare and high in purity. The raw material formula used in the application is simple, the amount of raw materials is small, the overall preparation method is simple and easy to operate, the requirements for equipment and energy consumption are low, and the application is especially suitable for large-scale industrial production. The prepared apixaban products are all above 99.94% in purity and above 98% in yield, and have the beneficial effects of high yield and high quality.

Description

Technical Field

[0001] This invention belongs to the field of active pharmaceutical ingredient synthesis technology, specifically relating to a high-purity apixaban and its preparation method. Background Technology

[0002] Apixaban is an oral serine protease inhibitor approved for marketing in the European Union in 2011, jointly developed by Pfizer and Bristol-Myers Squibb. Clinically, it is used to reduce the risk of stroke and thrombosis in patients with nonvalvular atrial fibrillation (NVAF), and to treat blood clots in the leg veins (deep vein thrombosis) or lungs (pulmonary embolism), reducing the risk of blood clot formation in the legs and lungs in people who have recently undergone hip or knee replacement surgery. In China, it is only used for the prevention of venous thrombosis after femoral head replacement surgery, and its treatment regimen has shown significant advantages over conventional heparin in record and advance trials.

[0003] Apixaban has the chemical formula 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-C]pyridine-3-carboxamide, CAS number 503612-47-3, and its structural formula is shown in Formula III:

[0004] Formula III

[0005] Currently, the disclosed synthesis processes for apixaban in the prior art include the following schemes:

[0006] (1) Patent application No. WOUS09056824 of 2010 discloses a synthetic route for apixaban, which uses p-iodoaniline and pentyrochloropentanoyl chloride as raw materials to synthesize apixaban. The specific synthetic route is shown in Formula IV. However, in this technical solution, the raw materials used are expensive, the process is complicated, the yield is low, and a lot of impurities are easily generated.

[0007] Formula IV.

[0008] (2) In 2003, Bristol-Myers Squibb disclosed a route for synthesizing apixaban using p-iodoaniline as a raw material in its world patent WO2003 / 04968. However, the yield was low and the cost was high. In 2007, Bristol-Myers Squibb disclosed a process patent for apixaban in US2006 / 0069258, replacing p-iodoaniline with p-nitroaniline. The specific synthetic route is shown in Formula V. However, in its scheme, expensive palladium on carbon was used to reduce the nitro group in the middle. Although the yield was improved, it was still not suitable for industrial production.

[0009] Formula V.

[0010] It is evident that existing apixaban production processes generally suffer from problems such as high raw material costs, low yields, and uncontrollable impurities leading to insufficient purity, severely limiting its industrial production. Therefore, obtaining high-purity apixaban products using inexpensive and readily available raw materials and simple processes is a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing high-purity apixaban. Using compounds 1 and 2 as raw materials, under heterogeneous conditions and with a phase catalyst, compounds 1 and 2 are reacted in a reaction solvent via an amino-ester exchange reaction to obtain crude apixaban. The crude product is then purified and crystallized to obtain an easily prepared apixaban product with high purity.

[0012] To achieve the above objectives, the present invention provides a method for preparing high-purity apixaban, specifically comprising the following steps:

[0013] Step S1: Add compound 1 and compound 2 to the reaction solvent, add the phase catalyst, stir to dissolve; slowly add sodium methoxide, stir to react, monitor the reaction until it is finished, add water to quench, filter, collect the filter cake, dry, and obtain crude apixaban.

[0014] Step S2: Add crude apixaban to the purification solvent, stir to dissolve, add activated carbon for decolorization, filter, collect the filtrate, cool to crystallize, dry, and obtain purified apixaban.

[0015] Step S3: Add the purified apixaban to a good solvent, heat to dissolve, crystallize in a poor solvent, cool to the crystal growth temperature, grow crystals, filter, and dry to obtain the purified apixaban.

[0016] In a preferred embodiment, compound 1 and compound 2 respectively have the structural formulas of formula I and formula II:

[0017] Formula I,

[0018] Formula II,

[0019] In a preferred embodiment, in step S1, the mass ratio of compound 1, compound 2 and sodium methoxide is 1:(0.9-2.3):(0.20-0.24), and more preferably, the mass ratio of compound 1, compound 2 and sodium methoxide is 1:2.3:0.23.

[0020] In this invention, compounds 1 and 2 are reactants, and sodium methoxide is the catalyst for their reaction. The addition of a phase catalyst utilizes the differences in solubility of different reactants and ions in the solvent, thereby enabling mass transfer (negative ion transfer) under heterogeneous conditions and thus increasing the reaction rate. Step 1 of this invention employs an amine-ester exchange reaction, which requires less investment than traditional processes, uses readily available and inexpensive raw materials, and is simple and easy to operate, making it suitable for industrialization. Furthermore, the amount of sodium methoxide used in this invention is relatively low, effectively reducing the amount of catalyst required.

[0021] In a preferred embodiment, in step S1, the reaction solvent includes one or more of formamide, toluene, and dichloromethane; more preferably, the reaction solvent is dichloromethane.

[0022] The solvent formamide selected in this invention is both a reactant and a solvent, resulting in less impurity synthesis; while the use of solvents such as toluene or dichloromethane is mainly due to the convenience of post-processing and recovery.

[0023] In a preferred embodiment, in step S1, the mass ratio of the reaction solvent to compound 1 is (2-10):1; more preferably, the mass ratio of the reaction solvent to compound 1 is (3-6):1.

[0024] If the amount of solvent is too small, the solid materials will not dissolve or disperse well, which is detrimental to the reaction; if the amount of solvent is too large, the reactant concentration will be low, the reaction will be slow, and the reaction will be incomplete. Therefore, the above-mentioned ratio is designed in this invention to improve the reaction effect.

[0025] In a preferred embodiment, in step S1, the phase catalyst comprises either a quaternary ammonium salt or a crown ether; more preferably, the quaternary ammonium salt comprises tetrabutylammonium bromide or tetrabutylammonium chloride.

[0026] In this invention, the selected phase catalyst can play a heterogeneous mass transfer or wetting role under heterogeneous conditions, thereby effectively improving the reaction rate.

[0027] In a preferred embodiment, in step S1, the molar ratio of the phase catalyst to compound 1 is (0-0.5):1; more preferably, the molar ratio of the phase catalyst to compound 1 is (0.001-0.5):1; and most preferably, the molar ratio of the phase catalyst to compound 1 is (0.01-0.1):1.

[0028] In a preferred embodiment, in step S1, the stirring and dissolving temperature is 20°C-90°C. At this temperature, it is beneficial for compound 1 and compound 2 to dissolve fully in the reaction solvent. Preferably, the stirring and dissolving temperature is 40°C-60°C.

[0029] In a preferred embodiment, in step S1, the sodium methoxide product can be in solid or sodium methoxide methanol solution. Both product states can achieve the technical solution of this invention, as long as the mass ratio of sodium methoxide to compound 1 and compound 2 is within the aforementioned range. In this invention, sodium methoxide serves as a catalyst for the reaction of compound 1 and compound 2, with a mass ratio of compound 1 to sodium methoxide of 1:0.20-0.24. Actual experimental investigations have shown that if the amount of sodium methoxide used is lower than this ratio, the reaction process is slower and compound 1 may not react completely, resulting in a lower product yield. If the amount of sodium methoxide used is higher than this ratio, although the reaction process will be faster, impurities will increase, which is detrimental to controlling product quality.

[0030] In a preferred embodiment, in step S1, when the sodium methoxide used is solid, it can be added in batches; when the sodium methoxide used is a sodium methoxide methanol solution, it can be added slowly dropwise. The sodium methoxide methanol solution is prepared by dissolving sodium methoxide in methanol. Preferably, the mass concentration of sodium methoxide in the solution is 15%-25%, more preferably, the mass concentration of sodium methoxide in the solution is 20%-25%.

[0031] In a preferred embodiment, in step S1, the monitoring of the end of the reaction is performed by TLC or HPLC monitoring until the reaction endpoint is reached, i.e., the starting material of compound 1 disappears or the reaction is complete.

[0032] In a preferred embodiment, in step S1, after collecting the filter cake, the filter cake can be rinsed with purified water to remove the reaction reagents.

[0033] In a preferred embodiment, in step S1, the drying conditions can be any apparatus and conditions known to those skilled in the art, and are not limited thereto in this invention. Preferably, the drying conditions are: treatment at 50℃-60℃ using a vacuum drying or forced-air drying apparatus for 1-2 hours.

[0034] In a preferred embodiment, in step S2, the purification solvent includes one or more of formamide, N,N-dimethylformamide, methanol, ethanol, isopropanol, acetonitrile, acetone, chloroform, dichloromethane, and water; preferably, the purification solvent includes N,N-dimethylformamide, dichloromethane, and a mixed solvent prepared from dichloromethane and water.

[0035] In a preferred embodiment, in step S2, the mass ratio of the purification solvent to crude apixaban is (3-20):1.

[0036] In a preferred embodiment, in step S2, the stirring and dissolving temperature is 20°C-90°C, at which temperature the crude apixaban has a higher solubility in the solvent. Preferably, the stirring and dissolving temperature is 40°C-60°C.

[0037] In a preferred embodiment, in step S2, the mass ratio of activated carbon to crude apixaban is (0.5%-10%):1, preferably, the mass ratio of activated carbon to crude apixaban is (1%-5%):1.

[0038] In a preferred embodiment, in step S2, the activated carbon decolorization temperature is 20-90°C, and the activated carbon decolorization time is more than 10 minutes.

[0039] In a preferred embodiment, in step S2, the cooling crystallization temperature is 0℃-30℃, and more preferably, the cooling crystallization temperature is 5℃-10℃.

[0040] In a preferred embodiment, in step S2, the drying conditions can be any apparatus and conditions known to those skilled in the art, and are not limited thereto in this invention. Preferably, the drying conditions are: treatment at 50℃-60℃ using a vacuum drying or forced-air drying apparatus for 1-2 hours.

[0041] In a preferred embodiment, in step S3, the benign solvent includes one or more of formamide, N,N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, acetone, chloroform, and dichloromethane.

[0042] In a preferred embodiment, in step S3, the mass ratio of the benign solvent to the purified apixaban is (3-30):1, preferably (5-10):1.

[0043] In a preferred embodiment, in step S3, the heating and dissolving temperature is 40℃-90℃, preferably 40℃-60℃.

[0044] In a preferred embodiment, in step S3, the undesirable solvent includes one or more of water, toluene, and ethyl acetate.

[0045] In a preferred embodiment, in step S3, the mass ratio of the undesirable solvent to the purified apixaban is (3-30):1, preferably (5-10):1.

[0046] In a preferred embodiment, in step S3, the mass ratio of the good solvent to the bad solvent is 1:(1-10), more preferably, the mass ratio of the good solvent to the bad solvent is 1:(1-2), and most preferably, the mass ratio of the good solvent to the bad solvent is 1:2.

[0047] In this invention, in step S3, recrystallization is carried out under two or more mixed solvent conditions. The purified apixaban obtained in step S2 is first dissolved in a solvent with high solubility (good solvent), and then a solvent with low solubility (bad solvent) is added to the solution to recrystallize apixaban and improve the purity of the product.

[0048] In a preferred embodiment, in step S3, the cooling rate is 20℃-30℃ / h.

[0049] In a preferred embodiment, in step S3, the crystal growth temperature is 5°C-30°C. The crystal growth time is 0.5-5 hours, and more preferably, the crystal growth temperature is 2-3 hours.

[0050] In a preferred embodiment, in step S3, the drying conditions can be any apparatus and conditions known to those skilled in the art, and are not limited thereto in this invention. Preferably, the drying conditions are: treatment at 50℃-60℃ using a vacuum drying or forced-air drying device for 2-6 hours.

[0051] Another objective of this invention is to provide a high-purity apixaban product prepared by any of the above methods. This invention uses a simplified formula and low-cost raw materials to prepare a high-quality apixaban product, resulting in good economic benefits. The crude apixaban obtained has a purity of over 98% and a yield of over 90%. The refined apixaban obtained has a purity of over 99.9%, a maximum single impurity of less than 0.05%, and a yield of over 90%.

[0052] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0053] 1. This invention employs heterogeneous reaction conditions and controls the addition of a phase catalyst to reduce reaction byproducts, resulting in a higher yield and better quality apixaban product.

[0054] 2. The raw material formula used in this invention is simplified and requires less quantity. The overall preparation method is simple and easy to operate, with low requirements for equipment and energy consumption, making it particularly suitable for large-scale industrial production. The apixaban products obtained have a purity of over 99.94% and a yield of over 98%, demonstrating the beneficial effects of high yield and high quality. Attached Figure Description

[0055] These and / or other aspects and advantages of the present invention will become clearer and more readily understood from the following detailed description of embodiments of the invention taken in conjunction with the accompanying drawings, wherein:

[0056] Figure 1 This is the HPLC chromatogram of the crude apixaban obtained in Example 1 of the present invention;

[0057] Figure 2 This is the HPLC chromatogram of the apixaban concentrate obtained in Example 1 of this invention;

[0058] Figure 3 This is the HPLC chromatogram of the crude apixaban obtained in Example 2 of the present invention;

[0059] Figure 4 This is the HPLC chromatogram of the apixaban concentrate obtained in Example 2 of this invention;

[0060] Figure 5 This is the HPLC chromatogram of the crude apixaban obtained in Example 3 of the present invention;

[0061] Figure 6 This is the HPLC chromatogram of the apixaban concentrate obtained in Example 3 of this invention;

[0062] Figure 7 This is the HPLC chromatogram of the crude apixaban obtained in Example 4 of the present invention;

[0063] Figure 8 This is the HPLC chromatogram of the apixaban concentrate obtained in Example 4 of this invention;

[0064] Figure 9 The X-ray diffraction pattern of the refined apixaban obtained in Example 4 of this invention;

[0065] Figure 10 The infrared spectrum of the apixaban concentrate obtained in Example 4 of this invention. Detailed Implementation

[0066] To enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. However, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments.

[0067] This invention provides a high-purity apixaban and its preparation method, solving the problems of expensive raw materials, low yield, and uncontrollable impurities leading to insufficient purity in the prior art.

[0068] The technical solution in this invention aims to solve the above problems, and the overall approach is as follows:

[0069] The technical solution of this application will be described in detail below through specific embodiments:

[0070] Unless otherwise specified, the technical means used in this invention are conventional means well known to those skilled in the art. All raw materials, reagents, instruments, and equipment used in this invention can be purchased commercially or prepared using existing methods. Unless otherwise specified, all reagents used in this invention are of analytical grade. In this invention, compound 1 is synthesized using existing technology, and compound 2 is purchased from Tianjin Damao Chemical Reagent Factory. In this invention, the room temperature is 25°C. Example

[0071] 10g of compound 1 and 23g of compound 2 were added to 50g of dichloromethane, followed by 2.5g of tetrabutylammonium bromide. The mixture was stirred at room temperature, and then 2.3g of sodium methoxide was slowly added while stirring. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and dried to obtain 9.33g of crude apixaban, with a yield of 93.3%. Figure 1 It can be seen that the purity of the crude apixaban obtained in this example is 98.39%.

[0072] 9.3g of crude apixaban was added to 100g of formamide, heated to 50°C to dissolve, 0.8g of activated carbon was added for decolorization, filtered, cooled to 5°C to crystallize, and dried to obtain 9.12g of purified apixaban, with a yield of 98.1%.

[0073] 9.1g of purified product was dissolved in 70g of DMF by heating, and crystals were precipitated in 70g of water. The solution was cooled to 15°C and allowed to crystallize for 3 hours. After filtration, the product was dried under vacuum at 55°C to obtain 8.86g of purified apixaban, with a yield of 97.4%. Figure 2 It can be seen that the purity of the apixaban obtained in this example is 99.94%.

[0074] Example

[0075] 10g of compound 1 and 23g of compound 2 were added to 30g of dichloromethane, followed by 2.5g of tetrabutylammonium bromide. The mixture was stirred at room temperature, and then 2.3g of sodium methoxide was slowly added while stirring. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and dried to obtain 9.38g of crude apixaban, with a yield of 93.8%. Figure 3 It can be seen that the purity of the crude apixaban obtained in this example is 98.98%.

[0076] 9.3g of crude apixaban was added to 100g of DMF, heated to 50°C to dissolve, 0.8g of activated carbon was added for decolorization, filtered, cooled to 5°C to crystallize, and dried to obtain 9.19g of purified apixaban, with a yield of 98.8%.

[0077] 9.1g of purified product was dissolved in 70g of DMF by heating, crystallized in 70g of water, cooled to 15°C, and allowed to crystallize for 3 hours. The crystals were then filtered and dried under vacuum at 55°C to obtain 8.91g of purified apixaban, with a yield of 97.9%. Figure 4 It can be seen that the purity of the apixaban obtained in this example is 99.94%. Example

[0078] 10g of compound 1 and 23g of compound 2 were added to 60g of dichloromethane, followed by 2.5g of tetrabutylammonium bromide. The mixture was stirred at room temperature, and then 2.3g of sodium methoxide was slowly added while stirring. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and dried to obtain 9.25g of crude apixaban, with a yield of 92.5%. Figure 5 It can be seen that the purity of the crude apixaban obtained in this example is 98.34%.

[0079] 9.2g of crude apixaban was added to 100g of DMF, heated to 50°C to dissolve, 0.8g of activated carbon was added for decolorization, filtered, cooled to 5°C to crystallize, and dried to obtain 9.10g of purified apixaban, with a yield of 98.9%.

[0080] 9.0 g of purified product was dissolved in 70 g of DMF by heating, and crystals were precipitated in 70 g of water. The solution was cooled to 15°C, and crystals were cultured for 3 hours. After filtration, the product was dried under vacuum at 55°C to obtain 8.8 g of purified apixaban, with a yield of 97.8%. Figure 6 It can be seen that the purity of the apixaban obtained in this example is 99.96%. Example

[0081] 10g of compound 1 and 23g of compound 2 were added to 50g of dichloromethane, followed by 2.5g of tetrabutylammonium chloride. The mixture was stirred at room temperature, and then 2.3g of sodium methoxide was slowly added while stirring. After the reaction was completed, water was added to quench the reaction, and the mixture was filtered. The filter cake was washed with water and dried to obtain 9.37g of crude apixaban, with a yield of 93.7%. Figure 7 It can be seen that the purity of the crude apixaban obtained in this example is 98.59%.

[0082] 9.3g of crude apixaban was added to 100g of formamide, heated to 50°C to dissolve, 0.8g of activated carbon was added for decolorization, filtered, cooled to 5°C to crystallize, and dried to obtain 9.02g of purified apixaban, with a yield of 97.0%.

[0083] 8.9g of purified product was dissolved in 70g of DMF by heating, and crystals were precipitated in 70g of water. The solution was cooled to 15°C and allowed to crystallize for 3 hours. After filtration, the product was dried under vacuum at 55°C to obtain 8.74g of purified apixaban, with a yield of 98.2%. Figure 8It can be seen that the purity of the apixaban obtained in this example is 99.97%.

[0084] Figure 9 The X-ray diffraction pattern of the refined apixaban obtained in this embodiment is shown. By comparing it with the standard pattern, it can be seen that the crystal form of the obtained apixaban is N-1. Figure 10 The infrared spectrum of the purified apixaban obtained in this example shows that the product has an N-H2 characteristic peak at 3400-3500 nm and a C=O characteristic peak at 1650-1700 nm, which proves that the product contains amide bonds. The HPLC chromatogram of the purified apixaban shows that the product has high purity and can be used for large-scale industrial production of high-quality apixaban products.

[0085] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing apixaban, characterized in that, Includes the following steps: Step S1: Add compound 1 and compound 2 to the reaction solvent, add the phase catalyst, stir to dissolve; slowly add sodium methoxide, stir to react, monitor the reaction until it is finished, add water to quench, filter, collect the filter cake, dry, and obtain crude apixaban. Step S2: Add crude apixaban to the purification solvent, stir to dissolve, add activated carbon for decolorization, filter, collect the filtrate, cool to crystallize, dry, and obtain purified apixaban. Step S3: Add the purified apixaban to a good solvent, heat to dissolve, crystallize in a poor solvent, cool to the crystal growth temperature, grow crystals, filter, and dry to obtain the purified apixaban. In step S1, compound 1 and compound 2 respectively have structural formulas of formula I and formula II: Formula I, Formula II The mass ratio of compound 1, compound 2, and sodium methoxide is 1:(0.9-2.3):(0.20-0.24). In step S1, the phase catalyst is a quaternary ammonium salt; the molar ratio of the phase catalyst to compound 1 is (0-0.5):1; In step S2, the purification solvent is formamide or N,N-dimethylformamide; the mass ratio of the purification solvent to crude apixaban is (3-20):

1. In step S3, the benign solvent is N,N-dimethylformamide; the mass ratio of the benign solvent to the purified apixaban is (3-30):1; In step S3, the unsuitable solvent is water; the mass ratio of the unsuitable solvent to the purified apixaban is (3-30):

1. The crude apixaban obtained has a purity of over 98% and a yield of over 90%. The refined apixaban obtained has a purity of over 99.9%, a maximum single impurity of less than 0.05%, and a yield of over 90%.

2. The method for preparing apixaban as described in claim 1, characterized in that, In step S1, the reaction solvent is one or more of formamide, toluene, and dichloromethane; The mass ratio of the reaction solvent to compound 1 is (2-10):

1.

3. The method for preparing apixaban as described in claim 1, characterized in that, In step S2, the mass ratio of activated carbon to crude apixaban is (0.5%-10%):1.

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