CN108558741B - Synthesis method of Apixaban intermediate - Google Patents
Synthesis method of Apixaban intermediate Download PDFInfo
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- CN108558741B CN108558741B CN201711449351.0A CN201711449351A CN108558741B CN 108558741 B CN108558741 B CN 108558741B CN 201711449351 A CN201711449351 A CN 201711449351A CN 108558741 B CN108558741 B CN 108558741B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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Abstract
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of an apixaban intermediate, which comprises the following steps: 4-R aniline and 5-chlorine valeryl chloride contact in an inert solvent in the presence of quaternary ammonium base to react to obtain an intermediate 1- (4-R phenyl) piperidine-2-ketone of apixaban, and the reaction formula is shown as formula I; the synthesis method improves the reaction efficiency and the conversion rate of the intermediate of apixaban, does not need to add tertiary amine organic base, does not use expensive NaH cyclization reagent, and saves the production cost.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method of an apixaban intermediate.
Background
Apixaban, whose british name is Apixaban (trade name: Eliquis), whose chemical name is 4,5,6, 7-tetrahydro-1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -1H-pyrazolo [3, 4-c ] pyridine-3-carboxamide, whose chemical structure is of formula II:
apixaban is a new generation of antithrombotic drug, is a novel factor Xa direct inhibitor jointly developed by behmeet-schGuibao and Hurrier company in the United states, is approved to be marketed in European Union 3 months in 2011, and is approved to be marketed in the United states by FDA 12 months in 2012. The product is currently used clinically to prevent Venous Thromboembolism (VTE) in adult patients undergoing phase selective hip or knee replacements.
Among them, 5, 6-dihydro-3- (4-morpholinyl) -1- [4- (2-oxo-1-piperidinyl) phenyl ] -2(1H) -pyridone (compound 1) and 1- (4-nitrophenyl) piperidin-2-one (compound 2) are important intermediates for synthesizing apixaban, and the related preparation methods are reported as follows:
patent document CN101967145 discloses a one-pot process for preparing an intermediate (compound 1), which comprises sequentially adding compound 3 and triethylamine to anhydrous tetrahydrofuran, slowly dropping a mixed solution of 5-chlorovaleryl chloride and an anhydrous solvent into the reaction mixed solution while keeping the reaction mixed solution under a cooling condition, and heating the reaction solution for reaction after dropping until the spots of compound 4 disappear; directly adding a cyclization condensing agent NaH into a reaction solution without purification, heating to 40-50 ℃ and reacting until intermediate state spots disappear; removing the solvent by rotary evaporation, adding water to precipitate a solid, and separating to obtain an intermediate compound 1.
Patent document CN101065379 uses p-nitroaniline as a raw material and 5-bromovaleryl chloride to obtain a compound 2 through an amidation-cyclization two-step method under an alkaline condition:
patent document CN104341336 discloses a process for preparing intermediate compounds 1 and 2, aromatic amine is reacted with 5-chloro valeryl chloride in an inert solvent by using potassium hydroxide, potassium carbonate, sodium bicarbonate and potassium bicarbonate as an acid-binding agent and a cyclization agent to directly obtain the intermediate compounds 1 and 2.
The technical solutions disclosed in the above patent documents mainly have the following problems:
1) the alkali adopted in the cyclization step is inorganic alkali such as NaH and the like, so that the cost is high, and the method is not suitable for industrial production;
2) in the reaction, triethylamine tertiary amine organic base is adopted to carry out amidation reaction firstly, and then sodium tert-butoxide, potassium tert-butoxide and sodium hydride with stronger alkalinity are used for cyclization reaction, so that the operation is complicated, the sodium hydride belongs to a dangerous reagent, great potential safety hazard exists, the post-treatment is complicated, and the product quality control is difficult;
3) inorganic bases such as potassium hydroxide, potassium carbonate, sodium bicarbonate and potassium bicarbonate have low solubility in inert organic solvents, so that the reaction efficiency is low and the reaction conversion rate is not high.
Therefore, the development of an intermediate synthesis method of apixaban with high reaction efficiency and high conversion rate is particularly urgent.
Disclosure of Invention
The invention aims to provide a synthesis method of an apixaban intermediate, aiming at the problems in the preparation of the apixaban intermediate in the prior art, the synthesis method improves the yield of the apixaban intermediate, does not need to add a tertiary amine organic base, does not use an expensive NaH cyclization reagent, and saves the production cost.
In order to achieve the above object, the present invention provides a method for synthesizing an intermediate of apixaban, comprising:
the 4-R aniline and 5-chlorine valeryl chloride contact in an inert solvent in the presence of quaternary ammonium base to react to obtain an intermediate 1- (4-R phenyl) piperidine-2-ketone of apixaban, and the reaction formula is shown as formula I:
in the formula I, R is selected from
A group and/or a nitro group.
According to the synthesis method provided by the invention, the intermediate 1- (4-Rylphenyl) piperidin-2-one of apixaban is selected from a compound 1 and/or a compound 2, wherein the structural formulas of the compound 1 and the compound 2 are as follows:
according to the synthesis method provided by the invention, preferably, the quaternary ammonium base is selected from one or more of tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, tetrapropyl ammonium hydroxide, tetrabutyl ammonium hydroxide, benzyl trimethyl ammonium hydroxide and benzyl triethyl ammonium hydroxide. More preferably, the quaternary ammonium base is selected from tetraethylammonium hydroxide.
According to the synthesis method provided by the invention, preferably, the inert solvent is selected from one or more of tetrahydrofuran, acetonitrile, dichloromethane and 1, 2-dichloroethane. More preferably, the inert solvent is selected from 1, 2-dichloroethane.
According to the synthesis method provided by the invention, preferably, the molar ratio of the 5-chlorovaleryl chloride to the 4-R-phenylamine is 1.0-2.0: 1, more preferably 1.0 to 1.2: 1.
preferably, the molar ratio of the quaternary ammonium base to the 4-R-phenylamine is 2.0-15.0: 1, more preferably 7.0 to 9.0: 1.
preferably, the mass ratio of the volume of the inert solvent to the reactants is 15 mL-30 mL: 1g, preferably 15mL to 20 mL: 1g of the total weight of the composition.
According to the synthesis method provided by the invention, preferably, the reaction temperature of the 5-chlorovaleryl chloride is-10 ℃ when the 5-chlorovaleryl chloride is added into a reaction system, and more preferably 0-5 ℃.
Preferably, after the 5-chlorovaleryl chloride is added, the reaction system is heated to the reflux temperature of the inert solvent; more preferably, the reflux temperature of the inert solvent is 80-90 ℃.
The technical scheme of the invention has the beneficial effects that:
1) in the synthesis method, tertiary amine organic alkali is not required to be added, and an expensive NaH cyclization reagent is not used, so that the production cost is saved;
2) the quaternary ammonium base adopted by the invention has triple functions of a cyclization agent, an acid-binding agent and a phase transfer catalyst in an inert solvent, thereby avoiding the adverse effect of a heterogeneous reaction system caused by inorganic base and improving the reaction conversion rate and the product yield; meanwhile, the synthesis method is a one-pot reaction, has mild conditions, is simple to operate, convenient to purify and environment-friendly, and is suitable for industrial production.
Detailed Description
In order that the technical features and contents of the present invention can be understood in detail, preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention have been described in the examples, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
The raw material sources are as follows:
the compound 3 is a compound of formula (I),
nanjing Kangman forest chemical industry Co., Ltd;
dichloromethane, alatin reagent;
triethylamine, alatin reagent company;
5-Chloropentanoyl chloride, Aladdin reagent;
tetraethylammonium hydroxide, alatin reagent.
Comparative example: preparation of Compound 1
Adding 250mL of dichloromethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding triethylamine (13.2g, 0.13mol), stirring in the ice bath for 10min, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol) at the temperature of 0-5 ℃. After finishing dripping, heating to room temperature (20-25 ℃) after ice-removing, reacting for 3 hours, when the reaction raw materials disappear, cooling the synthetic liquid to the room temperature, washing with 500mL of water, drying the organic phase with anhydrous sodium sulfate, concentrating to dryness, dissolving the residue with 500mL of acetonitrile, adding tetraethylammonium hydroxide (19.1g, 0.13mol), heating to reflux (80-85 ℃) for reacting for 5 hours, slowly cooling to 0-5 ℃, separating out a large amount of crystals, filtering, leaching the filter cake with 300mL of acetonitrile, and drying in vacuum to obtain 26.6g of compound 1 as a yellow solid, wherein the yield is as follows: 75 percent.
Example 1: preparation of Compound 1
Adding the compound 3(27.3g, 0.1mol) and 546mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring in the ice bath for 10min, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the reaction solution is heated to reflux (80-85 ℃), reacted for 5 hours, the reaction raw materials and intermediate states are monitored to disappear, the synthetic solution is cooled to room temperature, the room temperature is reduced, the synthetic solution is washed by 500mL of water, an organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and a residue is recrystallized by acetonitrile to obtain 31.6g of a yellow solid compound 1, wherein the yield is as follows: 89 percent.
Example 2: preparation of Compound 1
Adding the compound 3(27.3g, 0.1mol) and 546mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding benzyltriethylammonium hydroxide (146.3g, 0.7mol), stirring in the ice bath for 10min, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (80-85 ℃), the reaction is carried out for 5h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 31.2g of compound 1 as a yellow solid, wherein the yield is as follows: 88 percent.
Example 3: preparation of Compound 1
Adding the compound 3(27.3g, 0.1mol) and 546mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (132g, 0.9mol), stirring for 10min in the ice bath, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dripping is finished, the ice bath is removed and the temperature is raised to the reflux (80-85 ℃), the reaction is carried out for 5h, the reaction raw materials and the intermediate state are monitored to disappear, the synthetic liquid is cooled to the room temperature, the synthetic liquid is washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, the residue is recrystallized by acetonitrile to obtain 30.9g of compound 1 of yellow solid, and the yield is as follows: 87 percent.
Example 4: preparation of Compound 1
Adding 546mL of dichloromethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring in the ice bath for 10min, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), wherein the temperature is controlled to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (35-40 ℃), the reaction is carried out for 15h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 28.8g of compound 1 as a yellow solid, wherein the yield is as follows: 81 percent.
Example 5: preparation of Compound 1
Adding the compound 3(27.3g, 0.1mol) and 546mL of tetrahydrofuran into a three-necked flask, cooling the mixture to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring the mixture for 10min in the ice bath, and then dropwise adding 5-chlorovaleryl chloride (18.6g, 0.12mol) at the temperature of 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (35-40 ℃), the reaction is carried out for 15h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 27.7g of compound 1 as a yellow solid, wherein the yield is as follows: 78 percent.
Example 6: preparation of Compound 1
Adding the compound 3(27.3g, 0.1mol) and 546mL of acetonitrile into a three-necked flask, cooling the mixture to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring the mixture for 10min in the ice bath, and then dropwise adding 5-chlorovaleryl chloride (18.6g, 0.12mol) at the temperature of 0-5 ℃. After dripping, removing the ice bath, raising the temperature to reflux (80-85 ℃), reacting for 8 hours, monitoring the disappearance of reaction raw materials and intermediate states, slowly cooling the synthetic liquid to 0-5 ℃, separating out a large amount of crystals, filtering, leaching a filter cake with 300mL of acetonitrile, and drying in vacuum to obtain 29.5g of compound 1 as a yellow solid, wherein the yield is as follows: 83 percent.
Example 7: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring for 10min in the ice bath, then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (80-85 ℃), the reaction is carried out for 5h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 19.1g of compound 2 as a yellow solid, wherein the yield is as follows: 87 percent.
Example 8: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding benzyltriethylammonium hydroxide (146.3g, 0.7mol), stirring in the ice bath for 10min, and then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature at 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (80-85 ℃), the reaction is carried out for 5h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 18.4g of compound 2 as a yellow solid, wherein the yield is as follows: 84 percent.
Example 9: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of dichloroethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (132g, 0.9mol), stirring for 10min in the ice bath, then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (35-40 ℃), the reaction is carried out for 15h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 17.6g of compound 2 as a yellow solid, wherein the yield is as follows: 80 percent.
Example 10: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of dichloromethane into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring for 10min in the ice bath, then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (35-40 ℃), the reaction is carried out for 15h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 18.0g of compound 2 as a yellow solid, wherein the yield is as follows: 82 percent.
Example 11: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of tetrahydrofuran into a three-necked flask, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring for 10min in the ice bath, then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After the dropwise addition, the ice bath is removed and the reaction is carried out till the reflux (35-40 ℃), the reaction is carried out for 15h, the reaction raw materials and intermediate states are monitored to disappear, the synthetic liquid is cooled to room temperature and washed by 500mL of water, the organic phase is dried by anhydrous sodium sulfate and then concentrated to be dry, and the residue is recrystallized by acetonitrile to obtain 16.9g of compound 2 as a yellow solid, wherein the yield is as follows: 77 percent.
Example 12: preparation of Compound 2
Adding p-nitroaniline (13.8g, 0.1mol) and 276mL of acetonitrile into a three-necked bottle, cooling to 0 ℃ in an ice bath, adding tetraethylammonium hydroxide (103g, 0.7mol), stirring for 10min in the ice bath, then dropwise adding 5-chloropentanoyl chloride (18.6g, 0.12mol), and controlling the temperature to be 0-5 ℃. After dripping, removing the ice bath, raising the temperature to reflux (75-80 ℃), reacting for 8 hours, monitoring the disappearance of reaction raw materials and intermediate states, slowly cooling the synthetic liquid to 0-5 ℃, separating out a large amount of crystals, filtering, leaching a filter cake with 200mL of acetonitrile, and drying in vacuum to obtain 18.4g of compound 2 as a yellow solid, wherein the yield is as follows: 84 percent.
The comparison of the examples with the comparative examples shows that: in the synthesis method, inorganic base is not used, so that adverse effects caused by a heterogeneous reaction system are avoided; the quaternary ammonium base has the triple functions of the cyclization agent, the acid-binding agent and the phase transfer catalyst in an inert solvent, so that the product yield is improved.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (10)
1. A synthetic method of an apixaban intermediate is characterized by comprising the following steps:
the 4-R aniline and 5-chlorine valeryl chloride contact in an inert solvent in the presence of quaternary ammonium base to react to obtain an intermediate 1- (4-R phenyl) piperidine-2-ketone of apixaban, and the reaction formula is shown as formula I:
in the formula I, R is selected from
A group and/or a nitro group;
wherein the quaternary ammonium base is tetraethylammonium hydroxide or benzyltriethylammonium hydroxide; the inert solvent is 1, 2-dichloroethane; after the 5-chlorovaleryl chloride is added, heating the reaction system to the reflux temperature of the inert solvent, wherein the reflux temperature of the inert solvent is 80-90 ℃.
2. The process for the synthesis of intermediates of apixaban according to claim 1, wherein the quaternary ammonium base is tetraethylammonium hydroxide.
3. The method for synthesizing apixaban intermediates according to claim 1 or 2, wherein the molar ratio of the 5-chlorovaleryl chloride to the 4-R-phenylamine is 1.0 to 2.0: 1.
4. the method for synthesizing the apixaban intermediate according to claim 1 or 2, wherein the molar ratio of the quaternary ammonium base to the 4-R-phenylamine is 2.0-15.0: 1.
5. the synthesis method of the apixaban intermediate according to claim 1 or 2, characterized in that the mass ratio of the volume of the inert solvent to the reactants is 15-30 mL: 1g of the total weight of the composition.
6. The method for synthesizing the apixaban intermediate according to claim 1 or 2, wherein the reaction temperature of the 5-chlorovaleryl chloride is-10 to 10 ℃ when the 5-chlorovaleryl chloride is added into the reaction system.
7. The method for synthesizing the apixaban intermediate according to claim 3, wherein the molar ratio of the 5-chlorovaleryl chloride to the 4-R-phenylamine is 1.0-1.2: 1.
8. the method for synthesizing apixaban intermediates according to claim 4, wherein the molar ratio of the quaternary ammonium base to the 4-R-phenylamine is 7.0-9.0: 1.
9. the synthesis method of the apixaban intermediate according to claim 5, characterized in that the mass ratio of the volume of the inert solvent to the reactants is 15-20 mL: 1g of the total weight of the composition.
10. The method for synthesizing the apixaban intermediate according to claim 6, wherein the reaction temperature of the 5-chlorovaleryl chloride is 0-5 ℃ when the 5-chlorovaleryl chloride is added into the reaction system.
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| CN1518541A (en) * | 2001-01-19 | 2004-08-04 | Ĭ��ר���ɷ�����˾ | Phenyl derivatives |
| CN103626689A (en) * | 2012-08-24 | 2014-03-12 | 上海医药工业研究院 | Preparation method for apixaban intermediate |
| CN102320988B (en) * | 2011-06-03 | 2014-04-09 | 中国科学院上海有机化学研究所 | 4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof |
| CN104341336A (en) * | 2013-08-02 | 2015-02-11 | 上海科胜药物研发有限公司 | Novel method for synthesizing apixaban important intermediate |
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| CN1518541A (en) * | 2001-01-19 | 2004-08-04 | Ĭ��ר���ɷ�����˾ | Phenyl derivatives |
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| CN103626689A (en) * | 2012-08-24 | 2014-03-12 | 上海医药工业研究院 | Preparation method for apixaban intermediate |
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