CN107955002B - Preparation method of apixaban and intermediate thereof - Google Patents
Preparation method of apixaban and intermediate thereof Download PDFInfo
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- CN107955002B CN107955002B CN201711444031.6A CN201711444031A CN107955002B CN 107955002 B CN107955002 B CN 107955002B CN 201711444031 A CN201711444031 A CN 201711444031A CN 107955002 B CN107955002 B CN 107955002B
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Abstract
The invention discloses a preparation method of apixaban and an intermediate thereof. The invention provides a preparation method of an apixaban intermediate I, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the apixaban intermediate II and p-fluoronitrobenzene to obtain the apixaban intermediate I. The preparation method has the advantages of short steps, simple and safe operation, simple post-treatment steps, environmental friendliness, high total yield, high purity of the prepared product, low production cost and high atom utilization rate, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of apixaban and an intermediate thereof.
Background
The novel antibacterial drug Apixaban (Apixaban, III) is a product developed and sold by combining shibabao with pfeiri global strategic cooperation. In 2011, the Chinese medicinal composition is firstly approved to be used for preventing venous thrombosis of adult patients who undergo selective hip joint or knee joint replacement surgery in 27 countries of European Union, Iceland and Norway; in 2013, 1 month, an imported drug license issued by the national food and drug administration of China is obtained, and the imported drug license is used for adult patients with hip joint or knee joint phase-selective replacement to prevent venous thromboembolic events, and is formally marketed in China in 2013, 4 months.
Apixaban is a novel oral anticoagulant drug, the recommended dose is 2.5mg, the drug is orally taken twice a day, the venous thromboembolism is effectively prevented, the bleeding risk is not increased, the conventional monitoring of the blood coagulation function is not needed, and the dose adjustment is also not needed.
The Apixaban intermediate I is an important intermediate for synthesizing Apixaban III. The methods for synthesizing the apixaban intermediate under the prior art conditions are reported in patent documents CN102675314A, CN103159670A and CN 103694237A.
The method reported in patent document CN102675314A and the like is obtained by condensation, cyclization, chlorination, dechlorination and condensation of p-nitroaniline. The steps are long, and sodium hydride is used, so that the operation risk is high; the phosphorus pentachloride has serious environmental pollution problem, and high temperature is required for dechlorination; the route has long steps, low yield (the total yield of the four steps is 43.7 percent) and high cost. Therefore, the prior art conditions are urgently needed to be changed, a method which is simple and convenient to operate and is suitable for the preparation of the apixaban intermediate is needed to be found, the steps are short, the operation is safe, and the requirements of industrial production are met.
Disclosure of Invention
The invention aims to solve the technical problems of long steps, high operational risk, serious environmental pollution, high requirements on production equipment, complex post-treatment process, low yield, high production cost, unsuitability for industrial production and the like of the preparation method of apixaban in the prior art. The preparation method has the advantages of short steps, simple and safe operation, simple post-treatment steps, environmental friendliness, high total yield, high purity of the prepared product, low production cost and high atom utilization rate, and is suitable for industrial production.
The invention provides a preparation method of an apixaban intermediate I, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the apixaban intermediate II and p-fluoronitrobenzene to obtain an apixaban intermediate I;
the preparation method of the apixaban intermediate I is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of the apixaban intermediate I, the organic solvent is preferably one or more of an ether solvent, an amide solvent, an acetal solvent and a sulfoxide solvent. The ether solvent is preferably one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and 1, 4-dioxane. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The acetal solvent is preferably N, N-dimethylformamide diethylacetal. The sulfoxide solvent is preferably dimethyl sulfoxide.
In the preparation method of the apixaban intermediate I, the volume-to-mass ratio of the organic solvent to the apixaban intermediate II is preferably 4mL/g to 20mL/g, more preferably 5mL/g to 10mL/g, such as 4mL/g, 5mL/g, 10mL/g, 15mL/g or 20 mL/g.
In the preparation method of the apixaban intermediate I, the alkali is preferably inorganic alkali; the inorganic base is preferably one or more of potassium tert-butoxide, sodium tert-butoxide, potassium trimethylsilanolate, sodium trimethylsilanolate, potassium tert-amylate and sodium tert-amylate.
In the preparation method of the apixaban intermediate I, the molar ratio of the alkali to the apixaban intermediate II is preferably 1-10, more preferably 2-10, such as 2, 3, 5,6 or 10.
In the preparation method of the apixaban intermediate I, the ratio of the p-fluoronitrobenzene to the apixaban intermediate II is preferably 1-10, and more preferably 1.5-10, such as 1.5, 2, 2.5, 5 or 10.
In the preparation method of the apixaban intermediate I, the temperature of the nucleophilic substitution reaction is preferably 20 to 80 ℃, more preferably 40 to 60 ℃, for example 40 to 50 ℃ or 50 to 60 ℃.
In the preparation method of apixaban intermediate I, the progress of the nucleophilic substitution reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally the end point of the reaction when apixaban intermediate II disappears, and the time of the nucleophilic substitution reaction is preferably 1 hour to 24 hours, and more preferably 2 hours to 24 hours, such as 2 hours, 3 hours, 4 hours, 12 hours or 24 hours.
The preparation method of the apixaban intermediate I preferably comprises the following steps: and adding alkali into a mixture formed by the apixaban intermediate II and an organic solvent, and then adding p-fluoronitrobenzene to carry out nucleophilic substitution reaction to obtain the apixaban intermediate I.
The preparation method of the apixaban intermediate I preferably adopts the following post-treatment steps: after the reaction is finished, quenching reaction, extracting, washing, drying, filtering and concentrating to obtain the apixaban intermediate I crude product. The quenching reaction is preferably carried out using a saturated ammonium chloride solution. The solvent adopted for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The number of times of extraction is preferably 1 to 3, for example 1. The washing is preferably carried out by sequentially using an inorganic alkali aqueous solution and a salt solution. The mass concentration of the inorganic alkaline aqueous solution is preferably 1 to 20 percent, for example 10 percent, and the mass concentration refers to the percentage of the mass of the inorganic alkali in the total mass of the inorganic alkaline aqueous solution. The inorganic base is preferably sodium bicarbonate. The mass concentration of the saline solution is preferably 1-20%, for example 15%, and the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution. The drying is preferably carried out by adopting a drying agent, and the drying agent is preferably anhydrous sodium sulfate. The filtration and concentration may be carried out by methods conventional in the art for such procedures. The concentration is preferably vacuum concentration, the vacuum degree of the vacuum concentration is preferably-0.01 MPa to-0.1 MPa, such as-0.085 MPa to-0.1 MPa, and the temperature of the vacuum concentration is preferably 45 ℃ to 55 ℃.
The apixaban intermediate I crude product is preferably recrystallized to obtain the apixaban intermediate I. The recrystallization preferably adopts a mixed solvent of an ester solvent and an ether solvent. The ester solvent is preferably ethyl acetate; the ether solvent is preferably cyclohexyl methyl ether; the volume ratio of the ester solvent to the ether solvent is preferably 1-5, for example 1.
The recrystallization preferably adopts the following steps: and (3) cooling, crystallizing and drying a solution formed by the apixaban intermediate I crude product and a solvent to obtain the apixaban intermediate I, wherein the solvent is a mixed solvent of an ester solvent and an ether solvent. The temperature of the solution formed by the apixaban intermediate I crude product and the solvent is preferably 75-85 ℃, the cooling crystallization temperature is preferably 0-5 ℃, and the cooling crystallization time is preferably 1-5 hours, such as 2 hours. The drying is preferably vacuum drying; the pressure of the vacuum drying is preferably-0.01 MPa to-0.1 MPa. The temperature of the vacuum drying is preferably 45-55 ℃, and the time of the vacuum drying is preferably 8-12 hours.
The preparation method of the apixaban intermediate I preferably further comprises a preparation method of an apixaban intermediate II, and the preparation method comprises the following steps: condensing 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate in an organic solvent in the presence of alkali to obtain the apixaban intermediate II;
the preparation method of the apixaban intermediate II is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of the apixaban intermediate II, the organic solvent is preferably one or more of an ester solvent, an aromatic hydrocarbon solvent and an ether solvent. The ester solvent is preferably one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate. The aromatic hydrocarbon solvent is preferably one or more of toluene, xylene and ethylbenzene. The ether solvent is preferably one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and 1, 4-dioxane.
In the preparation method of the apixaban intermediate II, the volume ratio of the organic solvent to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is preferably 10mL/g to 50mL/g, such as 10.1mL/g, 19.8mL/g, 29.7mL/g, 39.6mL/g or 49.5 mL/g.
In the preparation method of the apixaban intermediate II, the alkali is preferably organic alkali or inorganic alkali; the organic base is preferably one or more of triethylamine, diisopropylethylamine, tri-n-propylamine and tri-n-butylamine; the inorganic base is preferably one or more of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, and is further preferably potassium carbonate. When an inorganic base is used, the reaction is preferably carried out in the presence of a phase transfer catalyst, preferably tetra-n-butylammonium bromide, and the molar ratio of the phase transfer catalyst to the inorganic base is preferably 0.001 to 0.1, more preferably 0.01 to 0.05, for example 0.03.
In the preparation method of the apixaban intermediate II, the molar ratio of the alkali to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is preferably 1-10. When an organic base is used, the molar ratio of the base to 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridinone is further preferably 1 to 5, for example 1.5, 2 or 5; when an inorganic base is used, the molar ratio of the base to 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridinone is more preferably 3 to 10, for example 4 or 10.
In the method for preparing apixaban intermediate II, the molar ratio of the ethyl [ (4-methoxyphenyl) hydrazino ] chloroacetate to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is preferably 1 to 5, more preferably 1.2 to 5, such as 1.2, 1.5, 2, 2.5 or 5.
In the method for preparing the apixaban intermediate II, the temperature of the condensation reaction is preferably 65 to 115 ℃, more preferably 75 to 105 ℃, for example 75 to 85 ℃, 85 to 95 ℃ or 95 to 105 ℃.
In the process for preparing apixaban intermediate II, the time for the condensation reaction is preferably 1 hour to 30 hours, more preferably 12 hours to 24 hours, for example 12 hours, 16 hours, 20 hours or 24 hours.
The preparation method of the apixaban intermediate II preferably comprises the following steps: adding alkali into a mixture formed by organic solvent, 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate, and carrying out condensation reaction to obtain the apixaban intermediate II.
The preparation method of the apixaban intermediate II preferably adopts the following post-treatment steps: and after the reaction is finished, cooling, adding acid, stirring, quenching, reacting, extracting, concentrating and drying to obtain the apixaban intermediate II crude product. The acid is preferably an organic acid, and the organic acid is preferably trifluoroacetic acid. The stirring time is preferably 1 hour to 5 hours, for example, 2 hours. The quenching reaction preferably adopts inorganic alkaline aqueous solution, the mass concentration of the inorganic alkaline aqueous solution is preferably 1-30%, for example 10%, and the mass concentration refers to the mass percentage of the inorganic alkali in the total mass of the inorganic alkaline aqueous solution. The inorganic base is preferably sodium bicarbonate. The extraction, concentration, recrystallization and vacuum drying can be carried out by the conventional method in the field. The solvent used for extraction is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The number of times of extraction is preferably 1 to 3, for example 1. The washing is preferably performed by washing with an inorganic base and brine in this order. The mass percentage of the inorganic base is preferably 1% to 50%, more preferably 5% to 20%, for example 10%, and the mass percentage refers to the mass percentage of the inorganic base in the total mass of the inorganic base aqueous solution. The inorganic base is preferably sodium bicarbonate. The mass percentage of the saline solution is preferably 1% to 50%, more preferably 5% to 20%, for example 15%, and the mass percentage refers to the mass percentage of sodium chloride in the total mass of the saline solution. The number of washing is preferably 1 to 6, for example 2 or 4. The drying is preferably carried out by adopting a drying agent, and the drying agent is preferably anhydrous sodium sulfate.
And preferably, recrystallizing the apixaban intermediate II crude product, and drying in vacuum to obtain the apixaban intermediate II.
The recrystallization preferably adopts the following steps: and (3) cooling and crystallizing a solution formed by the apixaban intermediate II crude product and an organic solvent to obtain the apixaban intermediate II. The temperature of the solution of the apixaban intermediate II crude product and the organic solvent is preferably 60 to 90 ℃, for example 75 to 85 ℃. The temperature for cooling crystallization is preferably 0 ℃ to 5 ℃, and the time for cooling crystallization is preferably 1 hour to 5 hours, for example 2 hours. The organic solvent used for recrystallization is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The concentration is preferably vacuum concentration; the temperature of the vacuum concentration is preferably 45-55 ℃, and the pressure of the vacuum concentration is preferably-0.01 MPa to-0.1 MPa (for example, -0.085MPa to-0.1 MPa). The temperature of the vacuum drying is preferably 45-55 ℃, the time of the vacuum drying is preferably 8-12 hours, and the pressure of the vacuum drying is preferably-0.01 MPa-0.1 MPa.
In the invention, the preparation method of the apixaban intermediate I preferably adopts the following preparation route:
the invention also provides a preparation method of the apixaban intermediate IV, which comprises the following steps: after the apixaban intermediate I is prepared according to the preparation method, carrying out reduction reaction on the apixaban intermediate I and hydrogen in an organic solvent under the catalysis of palladium carbon to obtain an apixaban intermediate IV;
the preparation method of the apixaban intermediate IV can adopt the conventional method of the reduction reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the apixaban intermediate IV, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably ethanol.
In the preparation method of the apixaban intermediate IV, the volume-to-mass ratio of the organic solvent to the apixaban intermediate I is preferably 1mL/g to 50mL/g, more preferably 15mL/g to 30mL/g, such as 10 mL/g.
In the preparation method of the apixaban intermediate IV, the temperature of the reduction reaction is preferably 40-65 ℃, and more preferably 50-55 ℃.
In the method for preparing the apixaban intermediate IV, the pressure of the reduction reaction is preferably 0.1 to 0.5MPa, and more preferably 0.3 to 0.4 MPa.
In the preparation method of apixaban intermediate IV, the progress of the reduction reaction can be detected by a detection method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the time when the apixaban intermediate I disappears is used as the end point of the reaction, and the time of the reduction reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 6 hours, for example 4 hours.
The preparation method of the apixaban intermediate IV preferably adopts the following post-treatment steps: and after the reaction is finished, cooling, filtering, washing and vacuum concentrating to obtain the apixaban intermediate IV. The temperature of the vacuum concentration is preferably 45-55 ℃, and the pressure of the vacuum concentration is preferably-0.01 MPa to-0.1 MPa, such as-0.085 MPa to-0.1 MPa.
The invention also provides a preparation method of the apixaban intermediate V, which comprises the following steps: after the apixaban intermediate IV is prepared according to the preparation method, carrying out condensation reaction on the apixaban intermediate IV and 5-bromovaleryl chloride in an organic solvent in the presence of alkali to obtain an apixaban intermediate V;
the preparation method of the apixaban intermediate V can adopt the conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the apixaban intermediate V, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the preparation method of the apixaban intermediate V, the volume-to-mass ratio of the organic solvent to the apixaban intermediate IV is preferably 1mL/g to 50mL/g, more preferably 5mL/g to 15mL/g, for example 10 mL/g.
In the preparation method of the apixaban intermediate V, the alkali is preferably inorganic alkali; the inorganic base is preferably sodium hydroxide and/or potassium hydroxide.
In the preparation method of the apixaban intermediate V, the molar ratio of the alkali to the apixaban intermediate IV is preferably 1-10, more preferably 2-8, for example 5.2.
In the preparation method of the apixaban intermediate V, the molar ratio of the 5-bromovaleryl chloride to the apixaban intermediate IV is preferably 1 to 3, more preferably 1.1 to 1.5, for example 1.1.
In the process for preparing apixaban intermediate V, the temperature of the condensation reaction is preferably 10 to 50 ℃, more preferably 20 to 40 ℃, for example 30 to 35 ℃.
In the preparation method of apixaban intermediate V, the progress of the condensation reaction can be detected by a detection method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and generally the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 4 hours to 8 hours, for example 6 hours, when the apixaban intermediate IV disappears as a reaction endpoint.
The preparation method of the apixaban intermediate V preferably adopts the following post-treatment steps: and after the reaction is finished, quenching the reaction, extracting, concentrating and drying to obtain a crude product of the apixaban intermediate V. The quenching reaction preferably employs water. The extraction, concentration, recrystallization and vacuum drying can be carried out by the conventional method in the field. The solvent used for extraction is preferably halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The number of times of extraction is preferably 1 to 3, for example 1. The washing is preferably performed by washing with an inorganic base and brine in this order. The mass percentage of the inorganic base is preferably 1% to 50%, more preferably 5% to 20%, for example 10%, and the mass percentage refers to the mass percentage of the inorganic base in the total mass of the inorganic base aqueous solution. The inorganic base is preferably sodium bicarbonate. The mass percentage of the saline solution is preferably 1% to 50%, more preferably 5% to 20%, for example 15%, and the mass percentage refers to the mass percentage of sodium chloride in the total mass of the saline solution. The number of washing is preferably 1 to 6, for example 4. The drying is preferably carried out by adopting a drying agent, and the drying agent is preferably anhydrous sodium sulfate.
And preferably, recrystallizing the apixaban intermediate V crude product, and drying in vacuum to obtain the apixaban intermediate V.
The recrystallization preferably adopts the following steps: and (3) cooling and crystallizing a solution formed by the apixaban intermediate V crude product and an organic solvent to obtain the apixaban intermediate V. The temperature of the solution formed by the apixaban intermediate V crude product and the organic solvent is preferably 60-80 ℃, for example 75 ℃. The temperature for cooling crystallization is preferably 15-20 ℃, and the time for cooling crystallization is preferably 1-2 hours, such as 1 hour.
The organic solvent used for recrystallization is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The concentration is preferably vacuum concentration; the temperature of the vacuum concentration is preferably 45-55 ℃, and the pressure of the vacuum concentration is preferably-0.01 MPa to-0.1 MPa, such as-0.075 MPa to-0.09 MPa. The temperature of the vacuum drying is preferably 45-55 ℃, the time of the vacuum drying is preferably 8-12 hours, and the pressure of the vacuum drying is preferably-0.01 MPa-0.1 MPa.
The invention also provides a preparation method of apixaban III, which comprises the following steps: after the apixaban intermediate V is prepared according to the preparation method, carrying out condensation reaction on the apixaban intermediate V and formamide in an organic solvent in the presence of alkali to obtain apixaban III;
the preparation method of the apixaban III can adopt the conventional method of the condensation reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of Apixaban III, the organic solvent is preferably an amide solvent; the amide solvent is preferably N, N-dimethylformamide.
In the preparation method of apixaban III, the volume-mass ratio of the organic solvent to the apixaban intermediate V is preferably 1mL/g to 50mL/g, more preferably 5mL/g to 15mL/g, for example 10 mL/g.
In the preparation method of apixaban III, the alkali is preferably inorganic alkali; the inorganic base is preferably one or more of sodium methoxide, sodium ethoxide and potassium tert-butoxide.
In the preparation method of apixaban III, the molar ratio of the alkali to the apixaban intermediate V is preferably 1 to 30, more preferably 4 to 15, for example 8.5.
In the preparation method of apixaban III, the molar ratio of the formamide to the apixaban intermediate V is preferably 1 to 3, more preferably 1.1 to 1.5, such as 1.2.
In the method for preparing apixaban III, the temperature of the condensation reaction is preferably 0 to 40 ℃, more preferably 10 to 30 ℃, for example 15 to 20 ℃.
In the preparation method of apixaban intermediate V, the progress of the condensation reaction can be detected by a detection method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and generally the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 6 hours, for example 4 hours, when the apixaban intermediate V disappears as a reaction endpoint.
The preparation method of the apixaban III preferably adopts the following post-treatment steps: and after the reaction is finished, adding water, filtering and washing to obtain a crude apixaban III product. The filtration and washing may be carried out by methods conventional in the art for such procedures. The washing preferably adopts an ether solvent; the ether solvent is preferably methyl tert-butyl ether.
The Apixaban III crude product is preferably recrystallized and dried in vacuum to obtain the Apixaban III. The recrystallization preferably adopts the following steps: and (3) cooling and crystallizing a solution formed by the apixaban III crude product and an organic solvent to obtain the apixaban III. The temperature of the solution of the crude apixaban III with the organic solvent is preferably 60 ℃ to 80 ℃, for example 75 ℃. The temperature for cooling crystallization is preferably 5-10 ℃, and the time for cooling crystallization is preferably 1-2 hours, for example 1 hour. The organic solvent used for recrystallization is preferably a mixed solvent of an amide solvent and an ether solvent. The amide solvent is preferably N, N-dimethylformamide; the ether solvent is preferably methyl tert-butyl ether. The volume ratio of the ether solvent to the amide solvent is preferably 1 to 5, for example, 4. The temperature of the vacuum drying is preferably 45-55 ℃, the time of the vacuum drying is preferably 8-12 hours, and the pressure of the vacuum drying is preferably-0.01 MPa-0.1 MPa.
The preparation method of apixaban III in the invention preferably adopts the following synthetic route:
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method disclosed by the invention is mild in reaction conditions, simple in post-treatment steps, short in synthetic route, high in total yield (the highest yield reaches 67.3%), high in purity of the prepared apixaban intermediate I product, low in production cost, high in atom utilization rate and suitable for industrial production, and the purity of the prepared apixaban intermediate I product can reach more than 98%; and the Apixaban III (the purity is more than 99.5 percent and the single impurity is less than 0.1 percent) meeting the raw material drug standard can be prepared from the intermediate.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detailed Description
Example 1: preparation of Apixaban intermediate II
Under the protection of nitrogen, 18.2g of 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and 38.5g of [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate are added into 540mL of ethyl acetate, 20.3g of triethylamine is added under stirring, and the mixture is heated to react at 75-85 ℃ and stirred for 16 hours. Cooling to 15-25 ℃, filtering, then dropwise adding 32mL of trifluoroacetic acid, and stirring for 2 hours at 15-25 ℃. Adding 10% by mass of sodium bicarbonate aqueous solution to quench (the mass percentage refers to the mass percentage of the sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution), and then extracting with ethyl acetate for 1 time. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of sodium chloride in the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to obtain yellow solid. Adding 150mL of ethyl acetate into the yellow solid, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain light yellow solid 24.7g, wherein the yield is 78.3%, and the HPLC purity is 98.44%.
Example 2: preparation of Apixaban intermediate II
Under the protection of nitrogen, 18.2g of 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and 30.8g of [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate are added into 360mL of ethyl acetate, 19.4g of diisopropylethylamine is added under stirring, and the mixture is heated to 85-95 ℃ and stirred for 20 hours. Cooling to 15-25 ℃, filtering, dropwise adding 35mL of trifluoroacetic acid, and stirring for 2 hours at 15-25 ℃. Adding 10% sodium bicarbonate water solution to quench (the mass percentage refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate water solution, the same below), and extracting with ethyl acetate for 1 time. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of sodium chloride in the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to obtain yellow solid. Adding 150mL of ethyl acetate into the yellow solid, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, draining, and drying
Vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 deg.c for 8-12 hr to obtain light yellow solid 25.6g, yield 81.2% and HPLC purity 98.30%.
Example 3: preparation of Apixaban intermediate II
Under the protection of nitrogen, 18.2g of 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and 64.1g of [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate are added to 720mL of toluene, 92.6g of tri-n-butylamine is added under stirring, and the mixture is heated to 95-105 ℃ and stirred for 12 hours. Cooling to 15-25 ℃, filtering, then dropwise adding 50mL of trifluoroacetic acid, and stirring for 2 hours at 15-25 ℃. Adding 10% sodium bicarbonate water solution to quench (the mass percentage refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate water solution, the same below), and extracting with ethyl acetate for 1 time. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of sodium chloride in the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to obtain yellow solid. Adding 150mL of ethyl acetate into the yellow solid, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 23.2g of light yellow solid, wherein the yield is 73.6%, and the HPLC purity is 98.87%.
Example 4: preparation of Apixaban intermediate II
Under nitrogen protection, to 450mL of tetrahydrofuran were added 9.1g of 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and 64.2g of ethyl [ (4-methoxyphenyl) hydrazino ] chloroacetate, and to the mixture were added 69g of potassium carbonate and 0.49g of tetra-n-butylammonium bromide with stirring. Heating to react at 75-85 ℃ and stirring for 24 hours. Cooling to 15-25 ℃, filtering, dropwise adding 68mL of trifluoroacetic acid, and stirring for 2 hours at 15-25 ℃. Adding 10% sodium bicarbonate water solution to quench (the mass percentage refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate water solution, the same below), and extracting with ethyl acetate for 1 time. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of sodium chloride in the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to obtain yellow solid. And adding 75mL of ethyl acetate into the yellow solid, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and performing vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 11.5g of light yellow solid, wherein the yield is 72.9%, and the HPLC purity is 97.85%.
Example 5: preparation of Apixaban intermediate II
Under nitrogen protection, 9.1g of 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and 25.6g of [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate were added to 92mL of 1, 4-dioxane, and 11.3g of potassium hydroxide and 0.49g of tetra-n-butylammonium bromide were added with stirring. Heating to react at 95-105 ℃ and stirring for 20 hours. Cooling to 15-25 ℃, filtering, then dropwise adding 32mL of trifluoroacetic acid, and stirring for 2 hours at 15-25 ℃. Adding 10% by mass of sodium bicarbonate aqueous solution to quench (the mass percentage refers to the mass percentage of the sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution), and then extracting with ethyl acetate. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution (the mass percentage refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of the sodium chloride to the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to obtain yellow solid. And adding 75mL of ethyl acetate into the yellow solid, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and performing vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 11.8g of light yellow solid, wherein the yield is 74.8%, and the HPLC purity is 97.83%.
Example 6: preparation of Apixaban intermediate I
Adding 15.8g of Apixaban intermediate II (with HPLC purity of 98.44%) into 158mL of N, N-dimethylformamide under the protection of nitrogen, stirring at 0-10 ℃, adding 28.0g of potassium tert-butoxide, and stirring at 0-10 ℃ for 1-2 hours; stirring at 0-10 ℃, adding 17.6g of parafluoronitrobenzene, and stirring for 2 hours at 50-60 ℃. After cooling, it was quenched by addition of saturated ammonium chloride solution and extracted once with ethyl acetate. The organic phase was washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass sodium chloride solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain light yellow solid. Adding 50mL of ethyl acetate and 50mL of cyclohexyl methyl ether, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 17.7g of light yellow solid with the yield of 81.1% (the total yield of the two-step reaction is 63.5%) and the HPLC purity of 98.79%.
Example 7: preparation of Apixaban intermediate I
Adding 15.8g of Apixaban intermediate II (with HPLC purity of 98.30%) into 79mL of N, N-dimethylformamide under the protection of nitrogen, stirring at 10-20 ℃, adding 16.8g of potassium tert-butoxide, and stirring at 10-20 ℃ for 1-2 hours; stirring at 10-20 ℃, adding 14.1g of parafluoronitrobenzene, and stirring for 4 hours at 40-50 ℃. Quenched by addition of saturated ammonium chloride solution and extracted 1 time with ethyl acetate. The organic phase was washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass sodium chloride solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain light yellow solid. Adding 50mL of ethyl acetate and 50mL of cyclohexyl methyl ether, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and performing vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain light yellow solid 18.1g, wherein the yield is 82.9% (the total yield of the two-step reaction is 67.3%), and the HPLC purity is 98.89%.
Example 8: preparation of Apixaban intermediate I
Adding 15.8g of Apixaban intermediate II (with HPLC purity of 98.87%) into 63mL of dimethyl sulfoxide under the protection of nitrogen, stirring at 5-15 ℃, adding 9.6g of sodium tert-butoxide, and stirring at 5-15 ℃ for 1-2 hours; stirring at 5-15 ℃, adding 10.6g of parafluoronitrobenzene, and stirring for 3 hours at 50-60 ℃. Quenched by addition of saturated ammonium chloride solution and extracted 1 time with ethyl acetate. The organic phase was washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass sodium chloride solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain light yellow solid. Adding 50mL of ethyl acetate and 50mL of cyclohexyl methyl ether, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 17.5g of light yellow solid, wherein the yield is 80.2% (the total yield of the two-step reaction is 59.0%), and the HPLC purity is 98.73%.
Example 9: preparation of Apixaban intermediate I
Adding 7.9g of apixaban intermediate II (with the HPLC purity of 97.85%) into 158mL of tetrahydrofuran under the protection of nitrogen, stirring at 5-15 ℃, adding 27.5g of sodium tert-amylate, and stirring at 5-15 ℃ for 1-2 hours; stirring at 5-15 ℃, adding 35.2g of parafluoronitrobenzene, and stirring at 40-50 ℃ for 24 hours. Adding saturated ammonium chloride solution for quenching (the mass percentage refers to the mass percentage of the ammonium chloride in the total mass of the ammonium chloride aqueous solution), and then extracting with ethyl acetate for 1 time. The organic phase was washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass sodium chloride solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain light yellow solid. Adding 25mL of ethyl acetate and 25mL of cyclohexyl methyl ether, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 8.4g of light yellow solid, wherein the yield is 77.0% (the total yield of the two-step reaction is 56.1%), and the HPLC purity is 98.75%.
Example 10: preparation of Apixaban intermediate I
Adding 7.9g of apixaban intermediate II (with the HPLC purity of 97.83%) into 118mL of 1, 4-dioxane under the protection of nitrogen, stirring at 5-15 ℃, adding 18.9g of potassium tert-amyl alcohol, and stirring at 5-15 ℃ for 1-2 hours; stirring at 5-15 ℃, adding 17.6g of parafluoronitrobenzene, and stirring at 50-60 ℃ for 12 hours. Adding saturated ammonium chloride solution for quenching (the mass percentage refers to the mass percentage of the ammonium chloride in the total mass of the ammonium chloride aqueous solution), and then extracting with ethyl acetate. The organic phase was washed with a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 15% by mass sodium chloride solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the aqueous sodium chloride solution), and dried over anhydrous sodium sulfate. Filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain light yellow solid. Adding 25mL of ethyl acetate and 25mL of cyclohexyl methyl ether, heating to 75-85 ℃, stirring for 1 hour for dissolving, cooling to 0-5 ℃, stirring for 2 hours, filtering, washing with 0-5 ℃ ethyl acetate, drying, and vacuum-drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 7.7g of light yellow solid, wherein the yield is 76.3% (the total yield is 57.1%), and the HPLC purity is 98.39%.
Example 11: preparation of Apixaban III (method according to document CN 102675314A)
Adding 16.9g of apixaban intermediate I, 1.7g of palladium-carbon catalyst with the mass percentage of 5% (the mass percentage refers to the mass percentage of palladium in the total mass of palladium-carbon), and 170mL of ethanol into a hydrogenation kettle, and stirring for 4 hours at the hydrogen pressure of 0.3-0.4 MPa and the temperature of 50-55 ℃. Cooling, filtering, washing and vacuum concentrating (45-55 deg.C, -0.085 MPa-0.1 MPa) to obtain Apixaban intermediate IV15.7g with 100% yield.
Dissolving 15.7g of apixaban intermediate IV in 160mL of anhydrous dichloromethane, adding 4.0g of ground sodium hydroxide, dropwise adding 8.4g of 5-bromovaleryl chloride, adding 4.0g of ground sodium hydroxide after the addition is finished, and stirring for 6 hours at the temperature of 30-35 ℃. Quenched by addition of water and then extracted with dichloromethane. Washing the organic phase with 10% by mass of sodium bicarbonate aqueous solution (the mass percentage refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) and 15% by mass of sodium chloride aqueous solution (the mass percentage refers to the mass percentage of the sodium chloride to the total mass of the sodium chloride aqueous solution), and drying with anhydrous sodium sulfate. Filtering and vacuum concentrating (25-45 deg.C, -0.075 MPa-0.09 MPa), adding 96mL of ethyl acetate into the residue, heating to 75 deg.C to dissolve, slowly cooling to 15-20 deg.C, and stirring for 1 hr. Filtering, washing with ethyl acetate, drying under-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 9.52g of apixaban intermediate V with the yield of 50.4 percent.
Dissolving 9.52g of apixaban intermediate V in 95mL of N, N-dimethylformamide, adding 9.5mL of formamide, dropwise adding 27.0g of sodium methoxide methanol solution with the mass percentage of 30% (the mass percentage refers to the mass percentage of the sodium methoxide accounting for the total mass of the sodium methoxide methanol solution) at the temperature of 0-5 ℃, and stirring for 4 hours at the temperature of 15-20 ℃. Adding 190mL of water, stirring for 1 hour at 15-20 ℃, filtering, washing with methyl tert-butyl ether, draining, adding 24mL of N, N-dimethylformamide, heating to 75 ℃ to dissolve, slowly adding 96mL of methyl tert-butyl ether, cooling to 5-10 ℃, and stirring for 1 hour. Filtering, washing with methyl tert-butyl ether, vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 deg.c for 8-12 hr to obtain apixaban III in the yield of 70.3%, HPLC purity of 99.91% and maximum single impurity content of 0.056%.
Comparative example 1: preparation method of apixaban intermediate I
Apixaban intermediate I was prepared according to the method of patent document CN102675314A, with a total yield of 43.7% and product HPLC purity 97.54% in four steps.
To a reaction flask were added 40g of potassium carbonate, 30mL of water, 57.2g of p-nitroaniline, 272mL of tetrahydrofuran and 2.0g of tetra-n-butylammonium bromide, and 89.5g of 5-bromovaleryl chloride was added dropwise with stirring at room temperature. Stirring for 1 hour after the dripping is finished, adding 26.4g of potassium hydroxide, stirring for 4 hours at room temperature, adding 40mL of water and 60mL of ethyl acetate, stirring, standing for layering, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and vacuum concentrating (45-55 ℃, minus 0.085 MPa-minus 0.1MPa) to obtain a light yellow solid. Adding 100mL of ethyl acetate, stirring for 2 hours at room temperature, filtering, drying by pumping, and performing vacuum drying at-0.01 MPa to-0.1 MPa and 45-55 ℃ for 8-12 hours to obtain 76g of 1- (4-nitrophenyl) -2-piperidone with the yield of 90 percent.
To 19.2g of 1- (4-nitrophenyl) -2-piperidone, 100mL of chlorobenzene and 63.4g of phosphorus pentachloride were added, and the mixture was heated to 53 ℃ to react for 2 hours. Cooled to room temperature, added with 30mL of water dropwise, extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo (45-55 ℃ C., -0.085 MPa-0.1 MPa) to give 39.7g of 3, 3-dichloro-1- (4-nitrophenyl) -2-piperidone in 75% yield.
19.55g of 3, 3-dichloro-1- (4-nitrophenyl) -2-piperidone was added to 200mL of N, N-dimethylformamide and 2.94g of lithium chloride, and the mixture was heated to 105 ℃ and 54g of lithium carbonate was added in portions. Stirring was carried out at 105 ℃ for 4 hours. Cooling, adding water for quenching, filtering, extracting filtrate by dichloromethane, combining organic phases, drying by anhydrous sodium sulfate, filtering and vacuum concentrating (45-55 ℃ and minus 0.085MPa to minus 0.1MPa) to obtain 17.5g of 3-chloro-1- (4-nitrophenyl) -2-piperidine-3-ketene with the yield of 90 percent.
4.0g of 3-chloro-1- (4-nitrophenyl) -2-piperidin-3-enone was added 80mL of toluene and 4.87g of ethyl [ (4-methoxyphenyl) hydrazino ] chloroacetate, the mixture was heated to 96 ℃ and 4.6mL of triethylamine was slowly added, followed by stirring at 96 ℃ for 2 hours. Cooling, adding water for quenching, extracting with toluene, combining organic phases, drying by anhydrous sodium sulfate, filtering and vacuum concentrating (45-65 ℃, minus 0.085 MPa-minus 0.1MPa) to obtain 5.0g of apixaban intermediate I with the yield of 72 percent. The total yield of the four-step reaction is 43.7%.
Claims (9)
1. The preparation method of the apixaban intermediate I is characterized by comprising the following steps: in an organic solvent, in the presence of alkali, carrying out nucleophilic substitution reaction on the apixaban intermediate II and p-fluoronitrobenzene to obtain an apixaban intermediate I; the organic solvent is an amide solvent, and the amide solvent is N, N-dimethylformamide; the alkali is potassium tert-butoxide; the temperature of the nucleophilic substitution reaction is 40-60 ℃;
the preparation method of the apixaban intermediate I further comprises a preparation method of a crude product of the apixaban intermediate II, and comprises the following steps: condensing 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone and [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate in an organic solvent in the presence of alkali, cooling after the reaction is finished, adding acid, stirring, quenching the reaction, extracting, concentrating and drying to obtain the crude product of the apixaban intermediate II;
2. the process for the preparation of apixaban intermediate I according to claim 1, characterized in that:
the preparation method of the apixaban intermediate I is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the volume-mass ratio of the organic solvent to the apixaban intermediate II is 4 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the molar ratio of the alkali to the apixaban intermediate II is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the ratio of the p-fluoronitrobenzene to the apixaban intermediate II is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the time of the nucleophilic substitution reaction is 1 to 24 hours.
3. The process for the preparation of apixaban intermediate I according to claim 2, characterized in that:
when the preparation method of the apixaban intermediate I is carried out under the protection of protective gas; the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the volume-mass ratio of the organic solvent to the apixaban intermediate II is 5 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the molar ratio of the alkali to the apixaban intermediate II is 2-10;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the ratio of the p-fluoronitrobenzene to the apixaban intermediate II is 1.5-10;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate I, the time of the nucleophilic substitution reaction is 2 to 24 hours;
and/or the presence of a gas in the gas,
the preparation method of the apixaban intermediate I comprises the following steps: and adding alkali into a mixture formed by the apixaban intermediate II and an organic solvent, and then adding p-fluoronitrobenzene to carry out nucleophilic substitution reaction to obtain the apixaban intermediate I.
4. The process for the preparation of apixaban intermediate I according to claim 1, characterized in that:
the preparation method of the apixaban intermediate II is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the organic solvent is one or more of an ester solvent, an aromatic hydrocarbon solvent and an ether solvent;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the volume ratio of the organic solvent to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 10 mL/g-50 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the alkali is organic alkali or inorganic alkali;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the molar ratio of the alkali to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 1-10;
and/or the presence of a gas in the gas,
in the preparation method of the Apixaban intermediate II, the molar ratio of the [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the condensation reaction temperature is 65-115 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the condensation reaction time is 1-30 hours.
5. The process for the preparation of apixaban intermediate I according to claim 4, characterized in that:
when the preparation method of the apixaban intermediate II is carried out under the protection of protective gas, the protective gas is nitrogen and/or argon;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the ester solvent is one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert-butyl acetate;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the aromatic hydrocarbon solvent is one or more of toluene, xylene and ethylbenzene;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the ether solvent is one or more of tetrahydrofuran, dimethyl tetrahydrofuran, isopropyl ether and 1, 4-dioxane;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the organic base is one or more of triethylamine, diisopropylethylamine, tri-n-propylamine and tri-n-butylamine;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the inorganic base is one or more of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide; when inorganic base is used, the reaction is carried out in the presence of a phase transfer catalyst,
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, when organic alkali is adopted, the molar ratio of the alkali to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 1-5; when an inorganic base is adopted, the molar ratio of the base to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 3-10;
and/or the presence of a gas in the gas,
in the preparation method of the Apixaban intermediate II, the molar ratio of the [ (4-methoxyphenyl) hydrazino ] ethyl chloroacetate to the 5, 6-dihydro-3- (4-morpholinyl) -2(1H) -pyridone is 1.2-5;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the condensation reaction temperature is 75-105 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, the condensation reaction time is 12 to 24 hours.
6. The process for the preparation of apixaban intermediate I according to claim 5, characterized in that:
in the preparation method of the apixaban intermediate II, when inorganic base is adopted and the reaction is carried out in the presence of a phase transfer catalyst, the phase transfer catalyst is tetra-n-butylammonium bromide;
and/or the presence of a gas in the gas,
in the preparation method of the apixaban intermediate II, when inorganic base is adopted and the reaction is carried out in the presence of a phase transfer catalyst, the molar ratio of the phase transfer catalyst to the inorganic base is 0.001-0.1.
7. The preparation method of the apixaban intermediate IV is characterized by comprising the following steps: after the apixaban intermediate I is prepared by the preparation method according to any one of claims 1 to 6, carrying out reduction reaction on the apixaban intermediate I and hydrogen in an organic solvent under the catalysis of palladium carbon to obtain an apixaban intermediate IV;
8. the preparation method of the apixaban intermediate V is characterized by comprising the following steps: after the apixaban intermediate IV is prepared according to the preparation method of claim 7, carrying out a condensation reaction between the apixaban intermediate IV and 5-bromovaleryl chloride in an organic solvent in the presence of a base to obtain the apixaban intermediate V;
9. the preparation method of apixaban III is characterized by comprising the following steps: after the apixaban intermediate V is prepared according to the preparation method of claim 8, carrying out a condensation reaction between the apixaban intermediate V and formamide in an organic solvent in the presence of a base to obtain the apixaban III;
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| A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor;Narasimha Rao Nevuluri等;《Monatsh Chem》;20170421;第148卷;第1477-1482页 * |
| Alternate Synthesis of Apixaban (BMS-562247), an Inhibitor of Blood Coagulation Factor Xa;JIANG, Jian’an等;《Synthetic Communications》;20131231;第43卷(第1期);第72-79页 * |
| 阿哌沙班的合成工艺研究;陶海燕等;《中国药物化学杂志》;20131031;第23卷(第5期);第385-389页 * |
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