CN113912598A - Synthesis method of apixaban and intermediate thereof - Google Patents
Synthesis method of apixaban and intermediate thereof Download PDFInfo
- Publication number
- CN113912598A CN113912598A CN202010643955.4A CN202010643955A CN113912598A CN 113912598 A CN113912598 A CN 113912598A CN 202010643955 A CN202010643955 A CN 202010643955A CN 113912598 A CN113912598 A CN 113912598A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- amidation
- cyclization
- phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of apixaban and an intermediate thereof, which takes nitroaniline and an amidation reagent as raw materials, and obtains a compound k, namely apixaban, through amidation, cyclization, dichlorization, elimination reaction, nucleophilic substitution reaction, reduction, amidation, cyclization reaction, [3+2] cyclization-elimination reaction and ammonolysis; or the compound d and the compound g are subjected to [3+2] cyclization-elimination reaction, amidation, cyclization reaction and ammonolysis to obtain a compound k, namely apixaban. The amidation reaction of the present invention uses catalyst without acid binding agent, and the process is suitable for continuous production and can reduce the discharge of three wastes obviously, so that the product cost is reduced obviously and the present invention is suitable for large scale industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to an industrialized synthesis method of apixaban and an intermediate thereof.
Background
In 2007, a global strategic cooperation agreement is formally executed by Baishiguibao and pfeiri, and an anticoagulant product apixaban is jointly developed and sold; in 2011, the Chinese medicinal composition is firstly approved to be used for preventing venous thrombosis of adult patients in selective hip joint or knee joint replacement surgery in 27 countries of European Union, Iceland and Norway; in 1 month 2013, an imported drug license issued by the national food and drug administration of China was obtained for adult patients with hip or knee joint elective replacement to prevent Venous Thromboembolic Events (VTE), and then was officially marketed in China in 4 months 2013 as a drug with the potential of "heavy-pound bombs".
Apixaban is a novel oral anticoagulant, is a novel oral factor Xa inhibitor, and is a drug for preventing and treating thrombus.
The recommended dose is 2.5mg, and the medicine is orally taken twice a day, so that the venous thromboembolism is effectively prevented, the bleeding risk is not increased, the blood coagulation function is not required to be monitored conventionally, and the dose is not required to be adjusted.
The existing synthesis method of apixaban mainly has the following obvious disadvantages: firstly, in the amidation reaction process of the p-nitroaniline, equivalent organic bases such as triethylamine, DIPEA and the like are needed to be used as acid-binding agents, a large amount of sewage with high COD/ammonia nitrogen is generated and is difficult to treat, and in addition, the triethylamine and the DIPEA also occupy cost with small proportion; secondly, in the method for closing the pyridone ring, a homogeneous reaction system with sodium tert-butoxide, DMSO and tetrahydrofuran as solvents as acid-binding agents is adopted, so that a large amount of high-COD/ammonia nitrogen sewage is generated, the treatment is difficult, and the cost is increased.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a novel industrialized synthesis method of apixaban and an intermediate thereof for the first time, the synthesis method takes paranitroaniline and an amidation reagent as raw materials, and the compound b is obtained through amidation and cyclization reaction (also called amidation-cyclization reaction); carrying out a dichlorination reaction on the compound b to obtain a compound c; carrying out elimination reaction and nucleophilic substitution reaction on the compound c to obtain a compound d; reducing the compound d by sodium sulfide to obtain a compound e; carrying out amidation on the compound e and an amidation reagent, and carrying out cyclization reaction to obtain a compound f; carrying out [3+2] cyclization-elimination reaction on the compound f and the compound g to obtain a compound j; aminolysis of the compound j to obtain a compound k, namely apixaban; the other route is as follows: carrying out [3+2] cyclization-elimination reaction on the compound d and the compound g to obtain a compound h; carrying out amidation-cyclization reaction on the compound h and an amidation reagent to obtain a compound j; and carrying out ammonolysis on the compound j to obtain a compound k, namely apixaban.
The invention is optimized in the aspect of the post-treatment operation of the amidation-cyclization reaction, and the amidation reaction does not need to use an acid-binding agent, so that the method has the advantages of low cost, short reaction time, high yield and suitability for large-scale industrial production; meanwhile, the ring closure reaction is carried out in a two-phase reaction system, and the continuous operation is very suitable for industrial production.
The synthesis route of the novel apixaban and the intermediate thereof is shown as the following route (A):
route (a);
the invention relates to a novel synthesis method of apixaban and an intermediate thereof, which comprises the following steps:
1) in an organic solvent, taking p-nitroaniline and an amidation reagent as raw materials, carrying out amidation reaction under the action of a catalyst, and then carrying out cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound b;
2) in an organic solvent, carrying out a dichlorination reaction on the compound b under the action of a chlorinated reagent to obtain a compound c;
3) in the reaction reagent, the compound c is subjected to elimination reaction and nucleophilic substitution reaction (namely elimination-nucleophilic substitution reaction) to obtain a compound d;
after the compound d is generated, a compound k, namely apixaban, can be obtained by two methods;
the method comprises the following steps:
4) in a solvent, reducing the compound d by a reducing agent to obtain a compound e;
5) in an organic solvent, carrying out amidation reaction on the compound e and an amidation reagent under the action of a catalyst, and carrying out cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound f;
6) in an organic solvent, under the action of alkali, a compound f and a compound g undergo a [3+2] cyclization-elimination reaction to obtain a compound j;
7) in a solvent, carrying out ammonolysis on the compound j to obtain a compound k, namely apixaban;
the second method comprises the following steps:
8) in an organic solvent, carrying out [3+2] cyclization-elimination reaction on a compound d and a compound g under the action of alkali to obtain a compound h;
9) carrying out amidation reaction on the compound h and an amidation reagent in an organic solvent under the action of a catalyst, and carrying out cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound j;
7) in a solvent, the compound j is aminolyzed to obtain a compound k, namely apixaban.
In the step 1), in the amidation reaction, the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane and the like; but are not limited to the above-mentioned organic solvents; preferably, it is xylene.
In the step 1), the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride, pivaloyl chloride and the like; preferably, it is 5-chlorovaleryl chloride.
In the step 1), in the amidation reaction, the catalyst is organic base supported by silica gel or free, and the organic base is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP, 4-pyrrolidinylpyridine and the like; preferably, imidazole.
In the step 1), in the amidation reaction, the molar ratio of the compound of formula a, the amidation reagent and the catalyst is 1: (1-5): (0.05-0.3); preferably, 1: 1.5:0.1.
In the step 1), the temperature of the amidation reaction is 80-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 1), the amidation reaction time is 2-12 h; preferably, it is 6 h.
In the step 1), the reaction operation is simple, the amidation reaction of the amidation reagent and the compound of the formula a is directly carried out under the action of the catalyst, the feeding types are few, and the reaction yield is high.
In the step 1), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent and is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane and the like; preferably, xylene; the other phase is an aqueous phase in which the inorganic base is dissolved, requiring additional additions.
The inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like, and preferably, potassium hydroxide.
In the step 1), the phase transfer catalyst used in the cyclization reaction is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6, 15-crown-5 and the like, and preferably tetrabutylammonium fluoride.
In the step 1), in the cyclization reaction, the molar ratio of the compound a, the inorganic base and the phase transfer catalyst is 1: (1-5): (0.05-0.3), preferably, 1: 5: 0.05.
in the step 1), the temperature of the cyclization reaction is 40-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 1), the time of the cyclization reaction is 2-12h, preferably 8 h.
In the step 1), after the compound of the formula b is obtained, a post-treatment process is also included, wherein the post-treatment process comprises liquid separation, water phase extraction, organic phase reflux water separation, reduced pressure concentration to a proper volume, and the compound can be directly put into the next reaction.
The amidation-cyclization method adopted in the step 1) is simple, efficient, mild in condition, capable of fully utilizing and applying a solvent, fully reacting a substrate, having a yield of more than 92%, generating less waste liquid, greatly reducing the material cost, scientific and environment-friendly, obvious in advantages and suitable for industrial amplification. In the cyclization reaction, the invention uses an organic solvent/water two-phase reaction system, avoids the use of strong bases such as sodium hydride, sodium tert-butoxide, potassium tert-butoxide and the like recorded in the prior literature to pull out the hydrogen on the amide to be carbanions, and also avoids the use of expensive solvents such as tetrahydrofuran and the like which are difficult to recycle and use, and has difficult operation and high cost; and step 5) and step 9) of the invention both use the method of step 1), further control the cost, it is the innovation point of the invention.
In step 2), the organic solvent is the same as the organic solvent mentioned in step 1), preferably xylene.
In the step 2), the chlorinated reagent is selected from one or more of phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfuryl chloride, thionyl chloride and the like; preferably, phosphorus pentachloride.
In the step 2), the mol/mass ratio of the compound b to the chlorinating reagent is 1: (2-10); preferably, 1: 5.
in the step 2), the temperature of the dichlorination reaction is 30-110 ℃; preferably 50 deg.c.
In step 2), the time of the chlorination reaction is 3-16h, preferably 4 h.
In the step 3), a solvent-free reaction is adopted, and the compound c directly carries out elimination-nucleophilic substitution reaction with a reaction reagent morpholine.
In the step 3), the mol/volume ratio of the compound c to the reaction reagent is 1: (4-20); preferably, 1: 8.
in the step 3), the temperature of the elimination-nucleophilic substitution reaction is 30-140 ℃; preferably 130 deg.c.
In the step 3), the time of the elimination-nucleophilic substitution reaction is 3-10 h; preferably, it is 6 h.
In step 4), the solvent is selected from one or more of dioxane, ethanol, DMF, methanol, isopropanol, water and the like, and preferably ethanol.
In the step 4), the reducing reagent is selected from sodium sulfide, sodium hydrosulfite, Fe/hydrochloric acid, Pd/C/H2One or more of the following; preferably, it is sodium sulfide.
In the step 4), the mol/mass ratio of the compound d to the reducing agent is 1: (5-20); preferably, 1: 6.
in the step 4), the temperature of the reduction reaction is 10-110 ℃; preferably, it is 80 ℃.
In the step 4), the time of the reduction reaction is 1-16 h; preferably, it is 8 h.
In the step 5), in the amidation reaction, the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane and the like; but are not limited to the above-mentioned organic solvents; preferably, it is xylene.
In the step 5), the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride, pivaloyl chloride and the like; preferably, it is 5-chlorovaleryl chloride.
In the step 5), in the amidation reaction, the catalyst is organic base supported on silica gel or free, and the organic base is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP, 4-pyrrolidinylpyridine and the like; preferably, imidazole.
In the step 5), in the amidation reaction, the molar ratio of the compound of formula e, the amidation reagent and the catalyst is 1: (1-5): (0.05-0.3); preferably, 1: 1.5:0.1.
In the step 5), the temperature of the amidation reaction is 80-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 5), the amidation reaction time is 2-12 h; preferably, it is 6 h.
In the step 5), the reaction operation is simple, the amidation reaction of the amidation reagent and the compound of the formula e is directly carried out under the action of the catalyst, the feeding types are few, and the reaction yield is high.
In the step 5), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent and is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane and the like; preferably, xylene; the other phase is an aqueous phase in which the inorganic base is dissolved, requiring additional additions.
The inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like, and preferably, potassium hydroxide.
In step 5), the phase transfer catalyst used in the cyclization reaction is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6, 15-crown-5 and the like, and preferably tetrabutylammonium fluoride.
In the step 5), in the cyclization reaction, the molar ratio of the compound e, the inorganic base and the phase transfer catalyst is 1: (1-5): (0.05-0.3), preferably, 1: 5: 0.05.
in the step 5), the temperature of the cyclization reaction is 40-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 5), the time of the cyclization reaction is 2-12h, preferably 8 h.
In the step 5), the method further comprises a post-treatment process after the compound of the formula f is obtained, wherein the post-treatment process comprises liquid separation, water phase extraction, organic phase reflux water separation, reduced pressure concentration to a proper volume, and direct input into the next reaction.
In step 6), the organic solvent is selected from one or more of dioxane, ethyl acetate, DMF, dichloromethane, toluene, 1, 2-dichloroethane, etc., preferably ethyl acetate.
In the step 6), the alkali is selected from one or more of triethylamine, trimethylamine, pyridine, diethylamine, DBU, DBN and the like; preferably, triethylamine.
In the step 6), the molar ratio of the compound f to the compound g to the base is 1: (1-8): (4-20); preferably, 1: 1.5: 5.
in the step 6), the temperature of the [3+2] cyclization-elimination reaction is 0-140 ℃; preferably, it is 60 ℃.
In the step 6), the time of the [3+2] cyclization-elimination reaction is 2-24 h; preferably, it is 10 h.
In step 7), the ammonia source for ammonolysis is one or more selected from ammonia methanol solution, ammonia ethanol solution, formamide, ammonia water and the like, and preferably, the ammonia water is used.
In step 7), the solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, water, etc., preferably methanol.
In step 7), the mol/volume of the compound j and the ammonia source is 1: (3-15); preferably, 1: 4.
in the step 7), the temperature of the ammonolysis reaction is-10-80 ℃; preferably 50 deg.c.
In the step 7), the ammonolysis reaction time is 5-36 h; preferably, it is 13 h.
In the step 8), the organic solvent is selected from one or more of dioxane, ethyl acetate, DMF, dichloromethane and the like; preferably, it is ethyl acetate.
In the step 8), the base is selected from one or more of triethylamine, trimethylamine, pyridine, diethylamine, DBU, DBN and the like, and preferably is triethylamine.
In the step 8), the molar ratio of the compound d to the compound g to the base is 1: (1-10); preferably, 1: 4.
in the step 8), the temperature of the [3+2] cyclization-elimination reaction is 0-110 ℃; preferably, it is 40 ℃.
In the step 8), the time of the [3+2] cyclization-elimination reaction is 0.5-10 h; preferably, it is 4 h.
In the step 9), in the amidation reaction, the organic solvent is one or more selected from dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane, and the like; but are not limited to the above-mentioned organic solvents; preferably, it is xylene.
In the step 9), the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride, pivaloyl chloride and the like; preferably, it is 5-chlorovaleryl chloride.
In the step 9), in the amidation reaction, the catalyst is organic base supported on silica gel or free, and the organic base is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP, 4-pyrrolidinylpyridine and the like; preferably, imidazole.
In the step 9), in the amidation reaction, the molar ratio of the compound of formula h, amidation reagent and catalyst is 1: (1-5): (0.05-0.3); preferably, 1: 1.5:0.1.
In the step 9), the temperature of the amidation reaction is 80-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 9), the amidation reaction time is 2-12 h; preferably, it is 6 h.
In the step 9), the reaction operation is simple, the amidation reaction of the amidation reagent and the compound of the formula h is directly carried out under the action of the catalyst, the feeding types are few, and the reaction yield is high.
In the step 9), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent and is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, dichloromethane, 1, 2-dichloroethane and the like; preferably, xylene; the other phase is an aqueous phase in which the inorganic base is dissolved, requiring additional additions.
The inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like, and preferably, potassium hydroxide.
In step 9), the phase transfer catalyst used in the cyclization reaction is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6, 15-crown-5 and the like, and preferably tetrabutylammonium fluoride.
In the step 9), in the cyclization reaction, the molar ratio of the compound h, the inorganic base and the phase transfer catalyst is 1: (1-5): (0.05-0.3), preferably, 1: 5: 0.05.
in the step 9), the temperature of the cyclization reaction is 40-160 ℃; preferably, it is reflux, wherein reflux means that the temperature of reflux is different when different solvents are used.
In the step 9), the time of the cyclization reaction is 2-12h, preferably 8 h.
In the step 9), after the compound of the formula j is obtained, a post-treatment process is also included, wherein the post-treatment process comprises liquid separation, water phase extraction, organic phase reflux water separation, reduced pressure concentration to a proper volume, and the compound can be directly put into the next reaction.
The invention is different from the prior art or the most main innovation points are as follows: 1. compared with the prior amidation-cyclization method, the amidation-cyclization method has the following remarkable advantages: (1) the acyl chloride is directly amidated under the action of a catalyst, so that the use of alkali acid-binding agents such as triethylamine, DIPEA, pyridine, n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide and the like is avoided; (2) benzene is used as a solvent, so that the recovery treatment is easy, the recovery rate is high, the reuse is facilitated, the use of expensive solvents such as tetrahydrofuran and the like which are difficult to recover is avoided, the generation of three wastes is reduced, and the cost is saved. 2. The cyclization method adopts a two-phase reaction system and a phase transfer catalyst method, has convenient reaction operation and low material cost, and is beneficial to industrialization.
In one embodiment, the industrial route of the novel apixaban and its intermediates according to the present invention is as follows:
route (A').
The invention has the beneficial effects that: firstly, organic bases such as triethylamine, DIPEA and the like are not needed to be used as acid-binding agents in the amidation reaction process of the paranitroaniline, so that a large amount of high COD/ammonia nitrogen sewage is avoided, the treatment is easy, and the cost is reduced; secondly, an organic solvent/water two-phase system is adopted in the cyclization (pyridone ring) reaction, and the first step and the second step are continuously operated, so that the production efficiency is greatly improved, the COD content in wastewater is reduced, the cost is reduced, and the industrialization is facilitated; finally, the Apixaban contains 2 identical piperidone rings, the technology is repeatedly used, in the amidation-ring closing operation, only temperature reduction is needed after the amidation reaction is finished, then an aqueous solution for dissolving inorganic base is directly added into the system to carry out the next reaction in two phases, and after the reaction is finished, the next reaction is directly carried out, so that the effects of simplifying the operation, reducing the three wastes and reducing the cost are very obvious.
Corresponding full-name corresponding table used for short names in the specification
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Synthesis of Compound b:
adding paranitroaniline (500g, 3.62mol), imidazole (catalyst) and xylene (5L) into a 100L reaction kettle connected with a tail gas absorption device, heating to reflux, dropwise adding 5-chlorovaleryl chloride (589g, 3.80mol), carrying out reflux reaction for 2-12h after the dropwise adding is finished, and detecting that the raw materials are completely reacted by TLC. Adding 4L of 50% potassium hydroxide solution, refluxing for 8h, detecting by TLC that the intermediate reaction is complete, cooling to room temperature, separating, extracting the aqueous phase with 2.5L of xylene, combining the organic phases, concentrating to a total volume of about 5L, and directly adding into the next reaction.
Adding paranitroaniline (500g, 3.62mol), imidazole DMAP (catalyst) and xylene (5L) into a 100L reaction kettle connected with a tail gas absorption device, heating to reflux, dropwise adding 5-chlorovaleryl chloride (589g, 3.80mol), carrying out reflux reaction for 2-12h after the dropwise adding is finished, and detecting that the raw materials are completely reacted by TLC. Adding 4L of 50% potassium hydroxide solution, refluxing for 8h, detecting by TLC that the intermediate reaction is complete, cooling to room temperature, separating, extracting the aqueous phase with 2.5L of xylene, combining the organic phases, concentrating to a total volume of about 5L, and directly adding into the next reaction.
Example 2
Synthesis of Compound c:
adding a dimethylbenzene (5L) solution of the compound b into the reaction kettle, adding phosphorus pentachloride (2148g, 10.3mol) under the protection of nitrogen, heating to 50 ℃, stirring for 4h, and detecting the complete reaction of the raw materials by TLC. Cooling to room temperature, pouring into 2L of ice water, stirring, filtering, separating liquid, putting the solid into an organic phase, separating water under negative pressure, recovering xylene under reduced pressure, cooling to 0 ℃ when about 1L of the solid is obtained, stirring, filtering, and drying in vacuum to obtain 880g of the product, wherein the yield of the two steps is 84.8%.
The specific operation steps for recovering the dimethylbenzene are as follows: adding water into the solution after reaction, wherein the volume ratio of the dimethylbenzene to the water is dimethylbenzene: stirring for 20 minutes with water of 5:1, standing, layering, and discarding the water phase; organic phase xylene, decompressing and steaming out about 1/10 xylene, cooling the rest xylene to room temperature, and mechanically applying; the 1/10 xylene distilled off was added up to 10 times, and then subjected to azeotropic dehydration to remove water for reuse.
Example 3
Synthesis of Compound d:
heating compound c (50.3g, 0.17mol) and morpholine (200ml) to 130 ℃ for reaction for about 1.5h, detecting that the raw materials are completely reacted by TLC, concentrating under reduced pressure to recover most of morpholine, cooling to room temperature, filtering, washing filter cakes by 50ml of water, and drying in vacuum to obtain 46.3g of yellow solid with the yield of 87.6%.
Example 4
Synthesis of Compound e:
sodium sulfide nonahydrate (9.6g, 0.04mol) is added into 20ml of water to be completely dissolved, then is dripped into ethanol (60ml) solution containing compound d (6.07g, 0.02mol), the temperature is raised to 50 ℃ to react for about 4 hours, TLC detects that the raw materials completely react, the solvent is removed by concentration under reduced pressure, the residue is added into 60ml of ethyl acetate to be stirred and pulped, and the product is filtered and dried in vacuum to obtain 4.92g of product with the yield of 90%.
Example 5
Synthesis of Compound f:
adding a compound e (98.9g, 0.362mol), DMAP (catalyst) and xylene (1L) into a reaction kettle connected with a tail gas absorption device, heating to reflux, dropwise adding 5-chlorovaleryl chloride (58.9g, 0.38mol), carrying out reflux reaction for 4h after the dropwise addition is finished, and detecting that the raw materials are completely reacted by TLC. Adding 0.8L of 50% potassium hydroxide solution, refluxing for 8h, detecting by TLC that the intermediate reaction is complete, cooling to room temperature, separating liquid, extracting the aqueous phase with 0.5L of dimethylbenzene, combining the organic phases, and concentrating to obtain 113.2g of product with 88.1% yield.
Example 6
Synthesis of Compound j:
triethylamine (32ml, 0.23mol), a compound f (64g, 0.18mol) and a compound g (45.5g, 0.15mol) are added into 500ml ethyl acetate, the mixture is heated to 80 ℃ to react for about 6h, TLC detects that raw materials completely react, the mixture is returned to room temperature, 60ml of 4N hydrochloric acid is added dropwise, the mixture is stirred for about 2h at room temperature, intermediate reaction is detected to be completely reacted, and the mixture is separated, washed and concentrated to obtain 58g and 79.1 percent of products.
Example 7
Synthesis of compound k (apixaban):
adding 25% ammonia water (1.5ml, 20mmol) and compound j (2.44g, 5.0mmol) into 50ml methanol, heating to 80 ℃ in a high-pressure reaction kettle, reacting for about 6h, detecting by TLC that the raw materials are completely reacted, then cooling to room temperature, pouring into 30ml ice water, cooling to 0 ℃, stirring, filtering, and drying in vacuum to obtain 2.09g and 91% of product.
Example 8
Synthesis of Compound h:
triethylamine (32ml, 0.23mol), a compound d (54.6g, 0.18mol) and a compound g (45.5g, 0.15mol) are added into 500ml ethyl acetate, the mixture is heated to 80 ℃ to react for about 6h, TLC detects that raw materials completely react, the mixture is returned to room temperature, 60ml of 4N hydrochloric acid is dripped into the mixture, the mixture is stirred for about 2h at room temperature, intermediate reaction is detected to be completely reacted, and the mixture is separated, washed by water and concentrated to obtain 49.1g and 75.1 percent of products.
Example 9
Synthesis of Compound j:
adding a compound e (158g, 0.362mol), DMAP (catalyst) and xylene (1.5L) into a reaction kettle connected with a tail gas absorption device, heating to reflux, dropwise adding 5-chlorovaleryl chloride (58.9g, 0.38mol), carrying out reflux reaction for 4h after the dropwise addition is finished, and detecting that the raw materials are completely reacted by TLC. Adding 1.2L of 50% potassium hydroxide solution, refluxing for 8h, detecting by TLC that the intermediate reaction is complete, cooling to room temperature, separating liquid, extracting the aqueous phase with 1L of xylene, combining the organic phases, and concentrating to obtain 155.2g of product with yield of 87.9%.
The specific operation steps for recovering the dimethylbenzene are as follows: adding water into the reacted solution, wherein the volume ratio of the dimethylbenzene to the water is dimethylbenzene: stirring for 20 minutes with water of 5:1, standing, layering, and discarding the water phase; organic phase xylene, decompressing and steaming out about 1/10 xylene, cooling the rest xylene to room temperature, and mechanically applying; the 1/10 xylene distilled off was added up to 10 times, and then subjected to azeotropic dehydration to remove water for reuse.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (13)
1. The synthesis method of apixaban and the intermediate thereof is characterized in that the synthesis route of the apixaban is shown as the following route (A),
the method comprises the following specific steps:
1) in an organic solvent, taking p-nitroaniline and an amidation reagent of a compound shown in the formula a as raw materials, and carrying out amidation reaction under the action of a catalyst; performing cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound b;
2) in an organic solvent, carrying out a dichlorination reaction on the compound b under the action of a chlorinated reagent to obtain a compound c;
3) in the reaction reagent, the compound c is subjected to elimination reaction and nucleophilic substitution reaction to obtain a compound d;
the method comprises the following steps:
4) in a solvent, reducing the compound d by a reducing agent to obtain a compound e;
5) in an organic solvent, carrying out amidation reaction on the compound e and an amidation reagent under the action of a catalyst, and carrying out cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound f;
6) in an organic solvent, under the action of alkali, a compound f and a compound g undergo a [3+2] cyclization-elimination reaction to obtain a compound j;
7) in a solvent, carrying out ammonolysis on the compound j to obtain a compound k, namely apixaban;
the second method comprises the following steps:
8) in an organic solvent, carrying out [3+2] cyclization-elimination reaction on a compound d and a compound g under the action of alkali to obtain a compound h;
9) carrying out amidation reaction on the compound h and an amidation reagent in an organic solvent under the action of a catalyst, and carrying out cyclization reaction in a two-phase reaction system under the action of a phase transfer catalyst to obtain a compound j;
7) in a solvent, the compound j is aminolyzed to obtain a compound k, namely apixaban.
2. The synthesis method according to claim 1, wherein in the amidation reaction in step 1), the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane, and dichloromethane; the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride and pivaloyl chloride; the catalyst is silica gel-supported or free organic alkali, and the organic alkali is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP and 4-pyrrolidinylpyridine; the molar ratio of the compound of the formula a to the amidation reagent to the catalyst is 1: (1-5): (0.05-0.3); the temperature of the amidation reaction is 80-160 ℃; the amidation reaction time is 2-12 h.
3. The synthesis method of claim 1, wherein in step 1), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane, and the other phase is an aqueous phase in which an inorganic base selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide is dissolved; in the cyclization reaction, the phase transfer catalyst is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6 and 15-crown-5; the molar ratio of the compound of the formula a to the inorganic base to the phase transfer catalyst is 1: (1-5): (0.05-0.3); the temperature of the cyclization reaction is 40-160 ℃; the time of the cyclization reaction is 2-12 h.
4. The synthesis method of claim 1, wherein in step 2), the chlorinated reagent is selected from one or more of phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, sulfuryl chloride and thionyl chloride; the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane; the mol/mass ratio of the compound b to the chlorinating reagent is 1: (2-10); the temperature of the dichlorination reaction is 30-110 ℃; the time of the chlorination reaction is 3-16 h.
5. The synthesis method of claim 1, wherein in the step 3), a solvent-free reaction is adopted, and the compound c directly performs elimination reaction and nucleophilic substitution reaction with a reaction reagent morpholine; wherein the molar/volume ratio of the compound c to the reaction reagent is 1: (4-20); the reaction temperature is 30-140 ℃; the reaction time is 3-10 h.
6. The synthesis method of claim 1, wherein in step 4), the solvent is selected from one or more of dioxane, ethanol, DMF, methanol, isopropanol and water; the reducing agent is selected from sodium sulfide, sodium hydrosulfite, Fe/hydrochloric acid, Pd/C/H2One or more of; the mol/mass ratio of the compound d to the reducing agent is 1: (5-20); the reduction reactionThe temperature is 10-110 ℃; the time of the reduction reaction is 1-16 h.
7. The synthesis method according to claim 1, wherein in the amidation reaction in step 5), the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane; the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride and pivaloyl chloride; the catalyst is silica gel-supported or free organic alkali, and the organic alkali is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP and 4-pyrrolidinylpyridine; the molar ratio of the compound of the formula e, the amidation reagent and the catalyst is 1: (1-5): (0.05-0.3); the temperature of the amidation reaction is 80-160 ℃; the amidation reaction time is 2-12 h.
8. The synthesis method of claim 1, wherein in the step 5), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane, and the other phase is an aqueous phase in which an inorganic base selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide is dissolved; in the cyclization reaction, the phase transfer catalyst is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6 and 15-crown-5; the molar ratio of the compound of the formula e, the inorganic base and the phase transfer catalyst is 1: (1-5): (0.05-0.3); the temperature of the cyclization reaction is 40-160 ℃; the time of the cyclization reaction is 2-12 h.
9. The synthesis method of claim 1, wherein in step 6), the organic solvent is selected from one or more of dioxane, ethyl acetate, DMF, dichloromethane, toluene and 1, 2-dichloroethane; the alkali is selected from one or more of triethylamine, trimethylamine, pyridine, diethylamine, DBU and DBN; the molar ratio of the compound f to the compound g to the base is 1: (1-8): (4-20); the temperature of the [3+2] cyclization-elimination reaction is 0-140 ℃; the time of the [3+2] cyclization-elimination reaction is 2-24 h.
10. The synthesis method according to claim 1, wherein in the step 7), the ammonia source for aminolysis is selected from one or more of ammonia methanol solution, ammonia ethanol solution, formamide and ammonia water; the solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol and water, and the mol/mass of the compound j and the ammonia source is 1: (3-15); the temperature of the ammonolysis reaction is-10-80 ℃; the time of the ammonolysis reaction is 5-36 h.
11. The synthesis method of claim 1, wherein in step 8), the organic solvent is selected from one or more of dioxane, ethyl acetate, DMF, dichloromethane, toluene and 1, 2-dichloroethane; and/or the base is selected from one or more of triethylamine, trimethylamine, pyridine, diethylamine, DBU and DBN; the molar ratio of the compound d to the compound g to the base is 1: (1-10); the temperature of the [3+2] cyclization-elimination reaction is 0-110 ℃; the time of the [3+2] cyclization-elimination reaction is 0.5-10 h.
12. The synthesis method according to claim 1, wherein in the amidation reaction in step 9), the organic solvent is selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane; the amidation reagent is selected from one or more of 5-chlorine valeryl chloride, acetyl chloride, propionyl chloride and pivaloyl chloride; the catalyst is silica gel-supported or free organic alkali, and the organic alkali is selected from one or more of DCC, EDCI, DBU, DBN, imidazole, N-methylimidazole, DMAP and 4-pyrrolidinylpyridine; the mol ratio of the compound of the formula h, the amidation reagent and the catalyst is 1: (1-5): (0.05-0.3); the temperature of the amidation reaction is 80-160 ℃; the amidation reaction time is 2-12 h.
13. The synthesis method of claim 1, wherein in the step 9), the cyclization reaction system is a two-phase reaction system, wherein one phase is an organic solvent selected from one or more of dioxane, DMAC, DMF, toluene, xylene, chlorobenzene, 1, 2-dichloroethane and dichloromethane, and the other phase is an aqueous phase in which an inorganic base selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium tert-butoxide and sodium tert-butoxide is dissolved; in the cyclization reaction, the phase transfer catalyst is selected from one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium fluoride, 18-crown-6 and 15-crown-5; the molar ratio of the compound of the formula h, the inorganic base and the phase transfer catalyst is 1: (1-5): (0.05-0.3); the temperature of the cyclization reaction is 40-160 ℃; the time of the cyclization reaction is 2-12 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010643955.4A CN113912598A (en) | 2020-07-07 | 2020-07-07 | Synthesis method of apixaban and intermediate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010643955.4A CN113912598A (en) | 2020-07-07 | 2020-07-07 | Synthesis method of apixaban and intermediate thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113912598A true CN113912598A (en) | 2022-01-11 |
Family
ID=79231377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010643955.4A Pending CN113912598A (en) | 2020-07-07 | 2020-07-07 | Synthesis method of apixaban and intermediate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113912598A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967145B (en) * | 2010-09-09 | 2012-07-04 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
| CN103694237B (en) * | 2014-01-07 | 2016-03-23 | 上海现代制药股份有限公司 | A kind of preparation method of anticoagulant apixaban and key intermediate |
| CN104045637B (en) * | 2014-04-18 | 2016-04-06 | 河北科技大学 | A kind of preparation method of Eliquis |
| CN110003206A (en) * | 2019-05-15 | 2019-07-12 | 江西国药有限责任公司 | A kind of preparation method of Eliquis |
| CN110041245A (en) * | 2019-04-29 | 2019-07-23 | 常州恒邦药业有限公司 | A kind of preparation of Eliquis and its intermediate |
-
2020
- 2020-07-07 CN CN202010643955.4A patent/CN113912598A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967145B (en) * | 2010-09-09 | 2012-07-04 | 华东理工大学 | Method for preparing antithrombotic medicament apixaban |
| CN103694237B (en) * | 2014-01-07 | 2016-03-23 | 上海现代制药股份有限公司 | A kind of preparation method of anticoagulant apixaban and key intermediate |
| CN104045637B (en) * | 2014-04-18 | 2016-04-06 | 河北科技大学 | A kind of preparation method of Eliquis |
| CN110041245A (en) * | 2019-04-29 | 2019-07-23 | 常州恒邦药业有限公司 | A kind of preparation of Eliquis and its intermediate |
| CN110003206A (en) * | 2019-05-15 | 2019-07-12 | 江西国药有限责任公司 | A kind of preparation method of Eliquis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN109180436A (en) | A kind of synthetic method of phloroglucin | |
| CN104387299B (en) | The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide | |
| CN113912598A (en) | Synthesis method of apixaban and intermediate thereof | |
| CN113667007B (en) | Liquid phase preparation method of cable Ma Lutai side chain | |
| CN106008316B (en) | A kind of method of synthesis Lei Dipawei chiral intermediates | |
| CN102417534A (en) | Synthesis technology of dutasteride | |
| CN105358529A (en) | Novel method for synthesizing key intermediate of apixaban | |
| CN116283654A (en) | Process for efficiently preparing dopamine hydrochloride bulk drug | |
| CN114436952A (en) | Synthesis method of 2-methoxy-3-amino-5-pyridine boronic acid pinacol ester and intermediate thereof | |
| CN105524001B (en) | A kind of N, N ＇ carbonic acyl radicals are double（The dioxygen ethylene imine of 4 ethyl 2,3）Preparation method | |
| CN112679365A (en) | Industrial preparation method of 6-bromonaphthalene-1, 2-diamine | |
| CN112225720A (en) | Production method of thiophene-2-acetyl chloride | |
| CN110878090B (en) | One-pot preparation process of NS5A protein inhibitor Daclatasvir | |
| CN115215835B (en) | Preparation method of 2- (2, 6-dioxopiperidin-3-yl) -1-oxyisoindoline-4-yl) acetic acid | |
| CN109970620A (en) | A method of preparing onglyza intermediate | |
| CN102417458A (en) | Preparation method of 9,9-bis(4-aminophenyl)fluorene | |
| CN113956268B (en) | 6-bromo-1-chlorobenzothiophene [2,3-c ] pyridine and synthetic method | |
| CN112920114B (en) | Synthetic method of hydroxychloroquine sulfate | |
| CN112079756B (en) | Preparation method of diallyl bisphenol S ether | |
| CN103554224B (en) | A kind of preparation method of VX-960 | |
| CN113773235B (en) | Synthesis method of clorsulon | |
| CN118479995A (en) | Sunitinib middle Process for preparing intermediate | |
| CN113387842A (en) | Method for synthesizing aromatic primary amine through OTf amine | |
| CN117510402A (en) | Optimized dabigatran etexilate key intermediate synthesis process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20220111 |