CN114085222A

CN114085222A - Preparation method of apixaban

Info

Publication number: CN114085222A
Application number: CN202111650550.4A
Authority: CN
Inventors: 姚红; 罗瑾
Original assignee: Hangzhou Huangsen Biological Technology Co ltd
Current assignee: Hangzhou Huangsen Biological Technology Co ltd
Priority date: 2021-12-30
Filing date: 2021-12-30
Publication date: 2022-02-25

Abstract

The invention discloses a preparation method of apixaban, which comprises the steps of carrying out ammonolysis on a compound 2 to obtain an apixaban compound 1, and carrying out ammonolysis in a mode of introducing ammonia gas; the specific operation steps are as follows: sequentially adding the compound 2 and an organic solvent into a reaction box, introducing ammonia gas into the reaction box from the top, driving a first partition plate to rotate reversely by the rotation of a stirring shaft, and introducing the ammonia gas into the solution to carry out an ammonolysis step; after the reaction is stopped, cooling the solution to room temperature, separating a second partition plate at the bottom of a first partition plate from the first partition plate, enabling the solution to leak from a first through hole on the first partition plate, leaving the particulate matters on the first partition plate, driving a movable ring to rotate by a stirring shaft after the solution is discharged, pushing the particulate matters on the first partition plate to move on the first partition plate by a first push plate on the movable ring, and enabling the particulate matters on the first partition plate to fall from a feeding hole and a discharging hole on the first partition plate to obtain a white solid, namely a compound 1; the organic solvent is selected from ethanol.

Description

Preparation method of apixaban

Technical Field

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of apixaban.

Background

Apixaban (apixaban, trade name Eliquis), chemical name: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-C ] pyridine-3-carboxamide; molecular formula is C25H25N5O 4; molecular weight 459.50; CAS registry number 503612-47-3, the chemical structure is:

for apixaban synthesis, it is mostly obtained by aminolysis of ethyl 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-C ] pyridine-3-carboxylate.

The preparation process of apixaban has the following defects: expensive organic compounds containing iodine are used, and the auxiliary reagent is large in dosage and expensive. The used reagent is inflammable and explosive, the reaction condition is harsh, the post-treatment is more complicated, the yield is low and the purity is low.

Disclosure of Invention

The invention provides a preparation method of apixaban for overcoming the defects of the prior art.

In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of apixaban comprises the steps of carrying out ammonolysis on a compound 2 to obtain an apixaban compound 1, and carrying out ammonolysis in a mode of introducing ammonia gas;

the specific operation steps are as follows: sequentially adding the compound 2 and an organic solvent into a reaction box, introducing ammonia gas into the reaction box from the top, driving a first partition plate to rotate reversely by the rotation of a stirring shaft, and introducing the ammonia gas into the solution to carry out an ammonolysis step; after the reaction is stopped, cooling the solution to room temperature, separating a second partition plate at the bottom of a first partition plate from the first partition plate, enabling the solution to leak from a first through hole on the first partition plate, leaving the particulate matters on the first partition plate, driving a movable ring to rotate by a stirring shaft after the solution is discharged, pushing the particulate matters on the first partition plate to move on the first partition plate by a first push plate on the movable ring, and enabling the particulate matters on the first partition plate to fall from a feeding hole and a discharging hole on the first partition plate to obtain a white solid, namely a compound 1; the organic solvent is selected from ethanol;

a twenty-fourth movable groove is formed in the inner wall of the blanking port, a sixteenth connecting spring is arranged on the inner wall of the twenty-fourth movable groove, a supporting plate is arranged at one end of the sixteenth connecting spring, a twenty-fifth movable groove is arranged above the twenty-fourth movable groove, a fifth push rod is arranged in the twenty-fifth movable groove in a penetrating manner, a fifth reset spring and a seventh connecting rope are arranged at one end of the fifth push rod, and one end of the seventh connecting rope is fixedly connected to the supporting plate; the fifth push rod penetrates through the second through hole; when the second partition plate descends for the first time, the sealing plate seals the second gas transmission cavity, the whole movable rod is pushed to descend by air pressure, the supporting plate is in an extending state at the moment, the first baffle plate abuts against the top of the supporting plate, the first supporting rod and the second supporting rod are separated from the bottom of the first baffle plate, the second partition plate descends relative to the first baffle plate, and the first baffle plate seals the discharging port; when the second baffle rises and seals first through-hole, the closing plate down moved for the movable rod, the second driving ring stretched out and promoted the fifth push rod and removed, the seventh is connected in rope pulling backup pad enters into the twenty-fourth activity inslot, drop on first bracing piece and second bracing piece behind the first baffle lost the holding power, first baffle forms the inclined plane, drive the movable ring rotation when the (mixing) shaft rotates and form vibrations, the particulate matter in the reaction box is discharged on first baffle simultaneously.

The ammonia gas is used for ammonolysis, the purity is higher than 97%, the by-products are few, the operation method is simple and convenient, the reaction process is easy to control, and meanwhile, the yield of the ammonolysis is higher than 91%. After two times of refining, the purity of apixaban is greatly improved, the purity reaches more than 99.6 percent, the single impurity is less than 0.1 percent, and the yield is more than 90 percent. The solvent used in the refining process has low toxicity, high safety, low cost and easy obtainment. The refining process is simple to operate, mild in reaction condition and low in cost, and is suitable for industrial production; the compound ammonolysis reaction and the filtering operation are carried out in the same reaction box, so that the raw material waste in the middle conveying process is reduced, the preparation of instruments and equipment is reduced, the preparation operation of apixaban is more convenient, and the raw material waste in the apixaban preparation process is reduced.

The first partition plate and the second partition plate are respectively arranged at the bottom of the reaction box, a plurality of first through holes are formed in the first partition plate, a plurality of first convex blocks corresponding to the first through holes are formed in the second partition plate, a first baffle plate is arranged in the feed opening, a plurality of first through grooves are formed in the second partition plate, a first connecting pipe and a second connecting pipe are arranged on the second partition plate, a first supporting spring is arranged at the bottom of the first connecting pipe, a first supporting rod is arranged at the top of the first supporting spring, a second supporting spring is arranged at the bottom of the second connecting pipe, a second supporting rod is arranged at the top of the second supporting spring, and the first supporting rod and the second supporting rod are made of magnets; when the compound 2 and the organic solvent are mixed in the reaction box, the second partition plate is abutted against the bottom of the first partition plate, the first bump is arranged in the first through hole in a penetrating manner, the first through hole is in a sealed state, the stirring shaft rotates to drive the first partition plate to rotate, ammonia gas is filled into the reaction box from the top of the reaction box, and ammonolysis reaction is carried out in the reaction box; after the solution reaction, the second baffle down moves for first baffle, first lug is deviate from in the first through-hole, first baffle still is in the feed opening, solution down drops from first through-hole department, the particulate matter is stayed on first baffle, the back is arranged to solution, first through-hole rotates to the position of being aligned with first lug, the first lug of second baffle up-motion is inserted in the first through-hole, first through-hole seals once more, the (mixing) shaft drives the loose ring and rotates, the second bracing piece down-motion drives first baffle one end down-motion, feed opening department forms the recess, first push pedal promotes the particulate matter and moves on first baffle, the particulate matter moves to feed opening department and rolls along first baffle surface and falls, do the collection to the particulate matter in the reaction box.

A first movable cavity is formed in the second partition plate, a first movable block and a second movable block are arranged in the first movable cavity, a first connecting spring is arranged on the side wall of one side of the first movable block, a second connecting spring is arranged on the side wall of the other side of the first movable block, one end of the first connecting spring is fixedly connected to the inner wall of the first movable cavity, a second movable block is arranged at one end of the second connecting spring, a first connecting rope is arranged on the second movable block, one end of the first connecting rope is fixedly connected to the bottom of the second supporting rod, a first connecting rod is hinged to the first movable block, one end of the first connecting rod is hinged to a second connecting rod, one end of the second connecting rod is hinged to the second movable block, and a second push plate used for pushing the first connecting rod and the second connecting rod to rotate is arranged at the bottom of the first movable cavity; after the reaction in the reaction box is finished, the second partition plate moves downwards relative to the first partition plate, the second push plate pushes the first connecting rod and the second connecting rod to rotate, after the first connecting rod and the second connecting rod rotate to form an inclined plane, the second connecting spring pulls the second movable block to move, and the first connecting rope pulls the second supporting rod to move downwards; after the solution in the reaction box is discharged, the first through hole is rotated to the position aligned with the first lug, the second partition plate moves upwards, the first lug is inserted into the first through hole to seal the first through hole, the first baffle falls on the first supporting rod and the second supporting rod, the first supporting rod and the second supporting rod have height difference, the first baffle falling on the first supporting rod and the second supporting rod forms an inclined plane, the particulate matters falling on the first baffle roll down along the surface of the first baffle, and the particulate matters in the reaction box are collected.

The stirring shaft is provided with a plurality of stirring rods, the stirring shaft is provided with an air inlet cavity, the stirring rods are provided with a first cavity communicated with the air inlet cavity, and the bottom of the first cavity is provided with a plurality of air outlet holes; the top of the reaction box is provided with a cover plate, the cover plate is provided with an air inlet corresponding to the air inlet cavity, the stirring shaft is provided with a second movable cavity, the second movable cavity is internally provided with a sleeve, the sleeve is provided with a second through groove corresponding to the first cavity, the bottom of the sleeve is provided with a third connecting spring, the cover plate is provided with an electric push rod, and a piston rod of the electric push rod is fixedly connected to the top of the sleeve; a movable rod is arranged in the air inlet cavity, a third connecting rod is arranged on the movable rod, a first movable groove matched with the third connecting rod is arranged on the side wall of the air inlet cavity, a third supporting spring is arranged at the bottom of the movable rod, and a second movable groove matched with the third connecting rod is arranged on the second partition plate; ammonia enters the air inlet cavity from the air inlet, the second through groove is aligned with the first cavity when the ammonolysis reaction is carried out in the reaction box, air in the air inlet cavity enters the first cavity through the second through groove, the air in the first cavity flows out from the air outlet, and the ammonia enters the solution to carry out the ammonolysis reaction; after the ammonolysis reaction in the reaction box is finished, the electric push rod drives the sleeve to move up, the second through groove is staggered with the first cavity, the first cavity is sealed, the movable rod is pushed to move down after the air pressure in the air inlet cavity is increased, the third connecting rod drives the second partition plate to move down, the first lug is separated from the first through hole, the first through hole is opened, the solution falls down from the first through hole, the particulate matters are left on the first partition plate, the solution is completely discharged, the first through hole is rotated to the position aligned with the first lug, the ammonia in the air inlet cavity is extracted, the second partition plate moves up, the first lug is inserted into the first through hole to seal the first through hole, and the stirring shaft is driven to rotate to collect the particulate matters on the first partition plate.

A third movable groove is formed in the inner wall of the second movable groove, a third movable block is arranged in the third movable groove, a fourth movable groove is formed in the third movable block, a first push block is arranged in the fourth movable groove, a fourth connecting spring is arranged on the side wall of the first push block, a second cavity is formed in the inner wall of the third movable groove, a third push plate is arranged in the second cavity, a fifth movable groove matched with the third push plate is formed in the third movable block, and a first reset spring is arranged on the third movable block; a second connecting rope is arranged on the third movable block, and one end of the second connecting rope is fixedly connected to the first movable block; a third cavity communicated with the second cavity is formed in the second partition plate, and a fourth push plate is arranged in the third cavity; after the solution in the reaction box is discharged, the second clapboard moves upwards, the first lug is inserted into the first through hole to close the first through hole, the fourth push plate pushes the air in the third cavity into the second cavity, the third push plate extends out of the second cavity, the third push plate is inserted into the fifth movable groove to push the first push block to extend out of the fourth movable groove, the stirring shaft drives the third connecting rod to contact with the first push block when rotating, the third connecting rod pushes the third movable block to move in the third movable groove, the second connecting rope pulls the first movable block to move, the first connecting rope pulls the second supporting rod to move, the third movable block moves to one end of the third movable groove, the first push block enters the fourth movable groove, the first return spring pulls the third movable block to move backwards, the first connecting spring pushes the first movable block to move backwards, the second supporting rod moves upwards, and then the third connecting rod contacts with the first push block again, first connecting rope pulling second bracing piece is discontinuous descends, produces vibrations on the second bracing piece, and first baffle shakes along with the vibrations of second bracing piece, shakes off the particulate matter on the first baffle.

A fourth cavity communicated with the third cavity is arranged below the third cavity, a first air conveying cavity communicated with the second cavity is arranged on the side wall of the fourth cavity, a fifth connecting spring is arranged at the bottom of the fourth push plate, a first push rod is arranged at the top of the fourth push plate, and a first connecting plate is arranged at the feed opening; a sixth connecting spring is arranged at the bottom of the fourth cavity, and a fifth push plate is arranged at the top end of the sixth connecting spring; a third movable cavity and a fourth movable cavity are arranged on the side wall of the first gas transmission cavity, a second baffle is arranged in the third movable cavity, a third baffle is arranged in the fourth movable cavity, a third through groove is formed in the second baffle, and a fourth through groove is formed in the third baffle; a sixth movable groove is formed in each of two sides of the third movable cavity, a fifth push block penetrates through the sixth movable groove, a first driving wheel used for driving the fifth push block and the second baffle is arranged on the inner wall of the sixth movable groove, a seventh movable groove is formed in the inner wall of the sixth movable groove, a seventh connecting spring is arranged on the inner wall of the seventh movable groove, a first limiting block is arranged at one end of the seventh connecting spring, and a first limiting groove matched with the first limiting block is formed in the side wall of the fifth push block; a fourth supporting spring is arranged at the bottom of the third baffle, a fifth movable cavity is arranged on the side wall of the fourth movable cavity, a second connecting plate is arranged on the side wall of the third baffle, a sixth push plate is arranged on the second connecting plate, and the sixth push plate is arranged in the third cavity in a penetrating manner; when the ammonolysis reaction is carried out in the reaction box, the second partition plate abuts against the bottom of the first partition plate, the first push rod abuts against the bottom of the first connecting plate, the fourth push plate pushes air in the third cavity to enter the fourth cavity, when the fourth push plate moves to the bottom of the third cavity, the fourth push plate pushes the sixth push plate to move downwards, the sixth push plate drives the third baffle plate to move downwards, at the moment, the second baffle plate seals the first air conveying cavity, and the air in the fourth cavity cannot enter the second cavity; after the ammonolysis reaction in the reaction box is completed, the second partition plate moves downwards relative to the first partition plate, the first lug is separated from the first through hole, the solution flows through the first through hole, the second partition plate moves to the bottom of the reaction box, the fifth push block moves upwards relative to the second partition plate after abutting against the bottom of the reaction box, the fifth push block drives the first driving wheel to rotate, the first driving wheel drives the second partition plate to move, the third through groove moves to a position corresponding to the first gas transmission cavity, the first limit block is embedded into the first limit groove to fix the fifth push block, and the third through groove keeps a position corresponding to the first gas transmission cavity; after the solution in the reaction box is discharged, the second partition plate moves upwards, the first push rod supports the bottom of the first connecting plate again, the fourth push plate moves downwards to extrude air in the third cavity, the fourth push plate pushes the sixth push plate to move downwards, the fourth through groove moves to the position aligned with the first air transmission cavity, the fifth push plate pushes the air in the fourth cavity to enter the second cavity through the first air transmission cavity, the third push plate pushes the fifth push block to stretch out from the fourth movable groove, and the third connecting rod rotates to drive the third movable block to move to form vibration on the first baffle plate.

An eighth movable groove is formed in the bottom of the first movable cavity, a seventh push plate is arranged in the eighth movable groove, an eighth connecting spring and a second push rod are arranged at the bottom of the seventh push plate, and the second push rod extends out of the eighth movable groove; a ninth movable groove is formed in the bottom of the first movable block, a tenth movable groove is formed in the bottom of the second movable block, the second push plate is arranged in the ninth movable groove and the tenth movable groove, and a third push rod and a second reset spring are arranged at the top of the second push plate; an eleventh movable groove is formed in the top of the first movable cavity, a ninth connecting spring is arranged at the top of the eleventh movable groove, an eighth push plate is arranged at the bottom end of the ninth connecting spring, a third connecting rope is arranged on the eighth push plate, and one end of the third connecting rope is fixedly connected to the first limiting block; a twelfth movable groove is formed in the side wall of the seventh push plate, a tenth connecting spring is arranged in the twelfth movable groove, a second limiting block is arranged at one end of the tenth connecting spring, a second limiting groove matched with the second limiting block is formed in the inner wall of the eighth movable groove, and a cambered surface is formed in the second limiting block; when the second partition plate moves downwards to the bottom of the reaction box, the second push rod abuts against the bottom of the reaction box, the seventh push plate pushes the second push plate to move upwards, the third push rod abuts against the joint of the first connecting rod and the second connecting rod, after the middle parts of the first connecting rod and the second connecting rod are arched, the second connecting spring pulls the second movable block to move towards the first movable block, and the first connecting rope pulls the second supporting rod to move downwards; after the solution reacts in the reaction box, ammonia gas is introduced into the eleventh movable groove, the eighth push plate moves downwards to push the first connecting rod and the second connecting rod to move downwards, and the first connecting rod and the second connecting rod rotate to be horizontal to push the second movable block to move, so that the second support rod is reset; when the eighth push plate moves downwards, the third connecting rope pulls the first limiting block to enter the seventh movable groove, the first limiting block is separated from the first limiting groove, the fifth push block moves downwards, and the second baffle plate closes the first air conveying cavity again.

A fourth connecting rod is arranged on the inner wall of the reaction box, a first connecting ring is arranged on the fourth connecting rod, the stirring shaft is arranged in the first connecting ring in a penetrating manner, a second through hole is formed in the first partition plate, the stirring shaft is arranged in the second through hole in a penetrating manner, and the movable ring is rotatably connected to the bottom of the first connecting ring; a fifth connecting rod is arranged at the bottom of the movable ring, a second connecting ring is arranged at the bottom of the fifth connecting rod, a first driving ring and a second driving wheel are rotatably connected to the bottom of the second connecting ring, and the stirring shaft is in transmission fit with the first driving ring through the second driving wheel; a thirteenth movable groove is formed in the inner wall of the second through hole, a third driving wheel is arranged in the thirteenth movable groove, a fourteenth movable groove is formed in the bottom of the thirteenth movable groove, and a third limiting block is arranged in the fourteenth movable groove; when the solution is subjected to ammonolysis reaction in the reaction box, the second limiting block abuts against the bottom of the third driving wheel, the first driving ring is driven to rotate reversely when the stirring shaft rotates, the first driving ring drives the third driving wheel to rotate, the third driving wheel drives the whole first partition plate to rotate together, and the first partition plate rotates relative to the stirring rod to complete the ammonolysis reaction of the solution; the ammonolysis reaction in the reaction box is accomplished, the solution discharge back in the reaction box is moved down with the second baffle, the first through-hole is sealed in the upward movement of second baffle, electric push rod driving sleeve is in the state of rising this moment, the third stopper enters into the fourteenth activity inslot, third stopper and third drive wheel throw off the contact, when the (mixing) shaft drove first drive ring and rotates, first drive ring drove the relative first baffle rotation of third drive wheel, the (mixing) shaft drove the activity ring and rotates, first push pedal rotates the granule roll that promotes on the first baffle on first baffle, the particulate matter drops to feed opening department and does the collection to the particulate matter.

A plurality of fifteenth movable grooves are formed in the side wall of the stirring shaft, a sixth connecting rod is arranged in each fifteenth movable groove, a second transmission ring is arranged on each sixth connecting rod, a second air conveying cavity is formed in each movable rod, a sixth movable cavity is arranged at the bottom of each second air conveying cavity, a fifth through groove corresponding to each fifteenth movable groove is formed in the bottom of each sixth movable cavity, a sealing plate is arranged in each sixth movable cavity, the inner diameter of each sixth movable cavity is larger than that of each second air conveying cavity, and a plurality of sixth through grooves are formed in each sealing plate; a through cavity is formed in the bottom of the sixth movable cavity, a third support rod penetrates through the through cavity, a sixteenth movable groove is formed in the inner wall of the through cavity, an eleventh connecting spring is arranged on the inner wall of the sixteenth movable groove, a fourth limiting block is arranged at one end of the eleventh connecting spring, a third limiting groove and a fourth limiting groove which are matched with the fourth limiting block are formed in the third support rod, the fourth limiting groove is formed above the third limiting groove, and the third support rod is made of an electromagnet; a seventeenth movable groove is formed in the bottom of the movable rod, a fourth push rod is arranged in the seventeenth movable groove, a third reset spring and a fourth connecting rope are arranged on the fourth push rod, and one end of the fourth connecting rope is fixedly connected to the fourth limiting block; when the solution reacts in the reaction box, the second partition plate is abutted against the bottom of the first partition plate, the fourth limiting block is inserted into the third limiting groove, and the supporting rod is abutted against the bottom of the sealing plate; after the reaction in the reaction box is finished, the electric push rod drives the sleeve to move upwards, the sleeve seals the first cavity, the movable rod is pushed to move downwards after the air pressure in the air inlet cavity is increased, the support rod provides supporting force for the sealing plate, the movable rod integrally moves downwards, the second partition plate moves downwards along with the movable rod, after the movable rod moves to the bottom of the air inlet cavity, the fourth push rod pushes against the bottom of the air inlet cavity and moves upwards relative to the movable rod, and the fourth connecting rope pulls the fourth limiting block to enter a sixteenth movable groove; after the solution in the reaction box is exhausted, the ammonia gas in the air inlet cavity is exhausted, the movable rod drives the second partition plate to move upwards, the third support rod is adsorbed at the bottom of the air inlet cavity, when the second partition plate abuts against the bottom of the first partition plate, the fourth limit groove on the third support rod moves to one side of the fourth limit block, the fourth limit block is inserted into the fourth limit groove, and at the moment, a gap exists between the sealing plate and the third support rod; let in the ammonia toward the intake chamber, first cavity is still in the encapsulated situation, the third bracing piece provides the holding power for the movable rod, atmospheric pressure promotes the closing plate and down moves for the movable rod, the closing plate gets into fifth logical groove department from the second defeated gas chamber bottom and moves away the back ammonia, the ammonia promotes the sixth connecting rod and stretches out, the second driving ring stretches out and contacts with the fifth connecting rod, third stopper does not contact with the third drive wheel this moment, when the (mixing) shaft drives the second driving ring and rotates, the second driving ring drives the second go-between and rotates, the movable ring rotates along with the second go-between, first push rod promotes the particulate matter removal on the first baffle, the particulate matter drops out from feed opening department and collects it.

An eighteenth movable groove is formed in the top of the sixth movable cavity, a second push block is arranged in the eighteenth movable groove, a fourth reset spring is arranged on the second push block, a fifth cavity communicated with the eighteenth movable groove is formed above the eighteenth movable groove, a third connecting plate is arranged in the fifth cavity, a twelfth connecting spring and a fifth connecting rope are arranged on the third connecting plate, and one end of the fifth connecting rope is fixedly connected to the top of the fourth push rod; a nineteenth movable groove is formed in the second push block, a seventh through groove is formed in the top of the nineteenth movable groove, a thirteenth connecting spring is arranged on the inner wall of the nineteenth movable groove, and a third push block is arranged on the thirteenth connecting spring; a twenty-first movable groove is formed in the inner wall of the twentieth movable groove, a fifteenth connecting spring is arranged in the twenty-first movable groove, a fifth limiting block is arranged at one end of the fifteenth connecting spring, and a fifth limiting groove matched with the fifth limiting block is formed in the fourth pushing block; a third connecting ring is arranged on the third limiting block, a twenty-second movable groove is arranged on the side wall of the fourteenth movable groove, an eighth through groove is arranged on the third connecting ring, a twenty-third movable groove is arranged on the inner wall of the eighth through groove, a connecting block is arranged in the twenty-third movable groove, a sixth connecting rope is arranged on the connecting block, one end of the sixth connecting rope is fixedly connected to the fifth limiting block, a connecting belt is arranged on the connecting block, a ninth push plate is arranged in the twenty-second movable groove, and the ninth push plate extends out of the twenty-second movable groove; the stirring shaft is provided with a ring groove, a tenth push plate is arranged in the ring groove, and the tenth push plate is fixedly connected to the bottom of the sleeve through a seventh connecting rod; the tenth push plate is arranged at the bottom of the ninth push plate; after the second partition plate moves downwards and is separated from the first partition plate, the third limiting block moves towards the bottom of the fourteenth movable groove, the fourth pushing block moves towards the outside of the twentieth movable groove, and the fifth limiting block is inserted into the fifth limiting groove to fix the fourth pushing block; when the second partition plate moves upwards, the fourth pushing block is pushed to move upwards, the fourth pushing block drives the third limiting block to move upwards, and the third limiting block abuts against the third driving wheel to fix the third driving wheel; when the electric push rod drives the sleeve to move upwards, the sleeve drives the tenth push plate to move upwards, the tenth push plate pushes the ninth push plate to move, the ninth push plate pushes the connecting belt to move, the connecting block pulls the fifth limiting block to enter the twenty-first movable groove when moving, after the fifth limiting block is separated from the fifth limiting groove, the third limiting block moves downwards relative to the fourth push block, the third limiting block is separated from the third driving wheel, the stirring shaft rotates relative to the first partition plate, and particles in the reaction box are collected; after the particulate matter in the reaction box is collected, the ammonia in the inlet chamber is discharged, the closing plate resets toward sixth activity chamber top, the third ejector pad stretches out from nineteenth activity inslot this moment, the closing plate up moves and promotes the third ejector pad removal, the third ejector pad drives the second ejector pad removal, the air of second ejector pad extrusion eighteenth activity inslot enters into the fifth cavity, atmospheric pressure promotes the third connecting plate and removes, fifth connecting rope pulling fourth push rod removes, the fourth stopper is deviate from the fourth spacing inslot, the third bracing piece loses up after inferior magnetic force, the fourth stopper inserts the third spacing inslot after the third spacing groove removes to fourth stopper one side, the third bracing piece supports at the fixed closing plate bottom of the closing plate, accomplish closing plate and third bracing piece that resets.

The invention has the following advantages: the ammonia gas is used for ammonolysis, the purity is higher than 97%, the by-products are few, the operation method is simple and convenient, the reaction process is easy to control, and meanwhile, the yield of the ammonolysis is higher than 91%. After two times of refining, the purity of apixaban is greatly improved, the purity reaches more than 99.6 percent, the single impurity is less than 0.1 percent, and the yield is more than 90 percent. The solvent used in the refining process has low toxicity, high safety, low cost and easy obtainment. The refining process is simple to operate, mild in reaction condition and low in cost, and is suitable for industrial production; the compound ammonolysis reaction and the filtering operation are carried out in the same reaction box, so that the raw material waste in the middle conveying process is reduced, the preparation of instruments and equipment is reduced, the preparation operation of apixaban is more convenient, and the raw material waste in the apixaban preparation process is reduced.

Drawings

FIG. 1 is a schematic view of the structure of a reaction tank of the present invention.

FIG. 2 is a front view of the reaction chamber of the present invention.

Fig. 3 is a cross-sectional view taken along line B-B of fig. 2.

Fig. 4 is an enlarged view of a portion a in fig. 3.

Fig. 5 is an enlarged view of fig. 3 at B.

Fig. 6 is an enlarged view of fig. 3 at C.

Fig. 7 is an enlarged view of fig. 3 at D.

Fig. 8 is an enlarged view of fig. 4 at E.

Fig. 9 is an enlarged view of fig. 6 at F.

Fig. 10 is a cross-sectional view taken along line E-E of fig. 2.

Fig. 11 is an enlarged view at G in fig. 10.

Fig. 12 is a cross-sectional view taken along G-G in fig. 2.

Fig. 13 is an enlarged view of fig. 12 at H.

Fig. 14 is an enlarged view at I in fig. 12.

FIG. 15 is a right side view of the reaction chamber of the present invention.

Fig. 16 is a cross-sectional view taken along line H-H of fig. 15.

Fig. 17 is an enlarged view at J in fig. 16.

Fig. 18 is an enlarged view at K in fig. 16.

Fig. 19 is an enlarged view at L in fig. 18.

Fig. 20 is a cross-sectional view taken along line I-I of fig. 15.

Fig. 21 is an enlarged view of fig. 20 at M.

Fig. 22 is an enlarged view of fig. 21 at N.

Fig. 23 is a cross-sectional view taken along J-J in fig. 15.

Fig. 24 is an enlarged view at O in fig. 23.

Fig. 25 is a cross-sectional view taken along line M-M of fig. 15.

Fig. 26 is an enlarged view at P in fig. 25.

Fig. 27 is an enlarged view at Q in fig. 26.

Fig. 28 is a cross-sectional view taken along line K-K of fig. 15.

Fig. 29 is an enlarged view of fig. 28 at R.

Fig. 30 is an enlarged view of fig. 29 at S.

Fig. 31 is a cross-sectional view taken along L-L in fig. 15.

Fig. 32 is an enlarged view at T in fig. 31.

Detailed Description

As shown in figures 1-32, a method for preparing apixaban, comprising the steps of aminolysis of a compound 2 to obtain an apixaban compound 1, and ammonolysis by introducing ammonia gas;

the specific operation steps are as follows: sequentially adding the compound 2 and an organic solvent into a reaction box 1, introducing ammonia gas into the reaction box 1 from the top, driving a first partition plate 3 to rotate reversely by rotating a stirring shaft 11, and introducing the ammonia gas into a solution to carry out an ammonolysis step; after the reaction is stopped, cooling the solution to room temperature, separating the second partition plate 4 at the bottom of the first partition plate 3 from the first partition plate 3, allowing the solution to leak out of the first through hole on the first partition plate 3, allowing the particles to remain on the first partition plate 3, after the solution is discharged, driving the movable ring 142 to rotate by the stirring shaft 11, pushing the particles on the first partition plate 3 to move on the first partition plate 3 by the first push plate 147 on the movable ring 142, and allowing the particles on the first partition plate 3 to fall from the feeding and discharging hole of the first partition plate 3 to obtain a white solid, namely compound 1; the organic solvent is selected from ethanol; when the ammonolysis reaction is carried out in the reaction, the reaction pressure is kept between 0.3 and 0.4 MPa; the mass and the volume of the organic solvent of the compound 2 are 1g to 20-50mL, the temperature when ammonia gas is introduced is 30-120 ℃, and the reaction time is 4-12 h.

The first partition plate 3 and the second partition plate 4 are respectively arranged at the bottom of the reaction box 1, a plurality of first through holes are formed in the first partition plate 3, a plurality of first protruding blocks corresponding to the first through holes are formed in the second partition plate 4, a first baffle plate 31 is arranged in the feed opening, a plurality of first through grooves are formed in the second partition plate 4, a first connecting pipe 41 and a second connecting pipe 42 are arranged on the second partition plate 4, a first supporting spring 412 is arranged at the bottom of the first connecting pipe 41, a first supporting rod 411 is arranged at the top of the first supporting spring 412, a second supporting spring 422 is arranged at the bottom of the second connecting pipe 42, a second supporting rod 421 is arranged at the top of the second supporting spring 422, and the first supporting rod 411 and the second supporting rod 421 are made of magnets; when the compound 2 and the organic solvent are mixed in the reaction box 1, the second partition plate 4 is abutted against the bottom of the first partition plate 3, the first bump is arranged in the first through hole in a penetrating manner, the first through hole is in a sealed state, the stirring shaft 11 rotates to drive the first partition plate 3 to rotate, ammonia gas is filled into the reaction box 1 from the top of the reaction box 1, and ammonolysis reaction is carried out in the reaction box 1; after the solution reaction, second baffle 4 down moves for first baffle 3, first lug is deviate from in the first through-hole, first baffle 31 still is in the feed opening, solution down drops from first through-hole, the particulate matter is stayed on first baffle 3, the back is arranged to solution, first through-hole rotates to the position of being aligned with first lug, the first lug of second baffle 4 up moving inserts in the first through-hole, first through-hole seals once more, (mixing) shaft 11 drives the activity ring 142 and rotates, second bracing piece 421 down moves and drives first baffle 31 one end down, feed opening department forms the recess, first push pedal 147 promotes the particulate matter and moves on first baffle 3, the particulate matter moves to feed opening department and rolls along first baffle 31 surface and falls, do the collection to the particulate matter in the reaction box 1.

A first movable cavity is arranged on the second clapboard 4, a first movable block 49 and a second movable block 410 are arranged in the first movable cavity, a first connecting spring 492 is arranged on the side wall of one side of the first movable block 49, a second connecting spring 493 is arranged on the side wall of the other side, one end of the first connecting spring 492 is fixedly connected to the inner wall of the first movable cavity, one end of the second connecting spring 493 is provided with a second movable block 410, the second movable block 410 is provided with a first connecting rope, one end of the first connecting rope is fixedly connected to the bottom of the second support bar 421, a first connecting rod 491 is hinged on the first movable block 49, one end of the first connecting rod 491 is hinged with a second connecting rod 4101, one end of the second connecting rod 4101 is hinged to the second movable block 410, and a second push plate 420 for pushing the first connecting rod 491 and the second connecting rod 4101 to rotate is arranged at the bottom of the first movable cavity; after the reaction in the reaction box 1 is finished, the second partition plate 4 moves downwards relative to the first partition plate 3, the second push plate 420 pushes the first connecting rod 491 and the second connecting rod 4101 to rotate, after the first connecting rod 491 and the second connecting rod 4101 rotate to form an inclined plane, the second connecting spring 493 pulls the second movable block 410 to move, and the first connecting rope pulls the second supporting rod 421 to move downwards; after the solution in the reaction box 1 is discharged, the first through hole rotates to the position aligned with the first bump, the second partition plate 4 moves upwards, the first bump is inserted into the first through hole to close the first through hole, the first baffle 31 falls on the first support rod 411 and the second support rod 421, the first support rod 411 and the second support rod 421 have a height difference, the first baffle 31 falling on the first support rod 411 and the second support rod 421 forms an inclined plane, particulate matters falling on the first baffle 31 roll down along the surface of the first baffle 31, and the particulate matters in the reaction box 1 are collected.

A plurality of stirring rods 111 are arranged on the stirring shaft 11, an air inlet cavity is arranged on the stirring shaft 11, a first cavity communicated with the air inlet cavity is arranged on the stirring rods 111, and a plurality of air outlet holes are formed in the bottom of the first cavity; the top of the reaction box 1 is provided with a cover plate 2, the cover plate 2 is provided with an air inlet corresponding to the air inlet cavity, the stirring shaft 11 is provided with a second movable cavity, the second movable cavity is internally provided with a sleeve 112, the sleeve 112 is provided with a second through groove corresponding to the first cavity, the bottom of the sleeve 112 is provided with a third connecting spring 113, the cover plate 2 is provided with an electric push rod 21, and a piston rod of the electric push rod 21 is fixedly connected to the top of the sleeve 112; a movable rod 15 is arranged in the air inlet cavity, a third connecting rod 153 is arranged on the movable rod 15, a first movable groove matched with the third connecting rod 153 is arranged on the side wall of the air inlet cavity, a third supporting spring 1510 is arranged at the bottom of the movable rod 15, and a second movable groove matched with the third connecting rod 153 is arranged on the second partition plate 4; ammonia enters the air inlet cavity from the air inlet, the second through groove is aligned with the first cavity when the ammonolysis reaction is carried out in the reaction box 1, air in the air inlet cavity enters the first cavity through the second through groove, air in the first cavity flows out from the air outlet, and the ammonia enters the solution to carry out the ammonolysis reaction; after the ammonolysis reaction in the reaction box 1 is finished, the electric push rod 21 drives the sleeve 112 to move upwards, the second through groove is staggered with the first cavity, the first cavity is sealed, the air pressure in the air inlet cavity is increased to push the movable rod 15 to move downwards, the third connecting rod 153 drives the second partition plate 4 to move downwards, the first lug is separated from the first through hole, the first through hole is opened, the solution falls from the first through hole, the particulate matters are left on the first partition plate 3, the solution is completely discharged, the first through hole is rotated to the position aligned with the first lug, the ammonia gas in the air inlet cavity is extracted, the second partition plate 4 moves upwards, the first lug is inserted into the first through hole to seal the first through hole, and the stirring shaft 11 drives the movable ring 142 to rotate to collect the particulate matters on the first partition plate 3.

A third movable groove is formed in the inner wall of the second movable groove, a third movable block 43 is arranged in the third movable groove, a fourth movable groove is formed in the third movable block 43, a first push block 431 is arranged in the fourth movable groove, a fourth connecting spring is arranged on the side wall of the first push block 431, a second cavity is formed in the inner wall of the third movable groove, a third push plate 490 is arranged in the second cavity, a fifth movable groove matched with the third push plate 490 is formed in the third movable block 43, and a first reset spring is arranged on the third movable block 43; a second connecting rope is arranged on the third movable block 43, and one end of the second connecting rope is fixedly connected to the first movable block 49; a third cavity communicated with the second cavity is formed in the second partition plate 4, and a fourth push plate 44 is arranged in the third cavity; after the solution in the reaction box 1 is discharged, the second partition plate 4 moves upwards, the first bump is inserted into the first through hole to close the first through hole, the fourth push plate 44 pushes the air in the third cavity into the second cavity, the third push plate 490 extends from the second cavity, the third push plate 490 is inserted into the fifth movable groove to push the first push block 431 to extend from the fourth movable groove, the stirring shaft 11 drives the third connecting rod 153 to rotate and contact with the first push block 431, the third connecting rod 153 pushes the third movable block 43 to move in the third movable groove, the second connecting rope pulls the first movable block 49 to move, the first connecting rope pulls the second supporting rod 421 to move, after the third movable block 43 moves to one end of the third movable groove, the first push block 431 enters the fourth movable groove, the first return spring pulls the third movable block 43 to move back, the first connecting spring 492 pushes the first movable block 49 to move back, the second support rod 421 moves upward, and then the third connecting rod 153 contacts with the first push block 431 again, the first connecting rope pulls the second support rod 421 to descend discontinuously, vibration is generated on the second support rod 421, and the first baffle 31 vibrates along with the second support rod 421 to shake off the particles on the first baffle 31.

A fourth cavity communicated with the third cavity is arranged below the third cavity, a first air conveying cavity communicated with the second cavity is arranged on the side wall of the fourth cavity, a fifth connecting spring 442 is arranged at the bottom of the fourth push plate 44, a first push rod 441 is arranged at the top of the fourth push plate, and a first connecting plate 48 is arranged at the feed opening; a sixth connecting spring 471 is arranged at the bottom of the fourth cavity, and a fifth push plate 47 is arranged at the top end of the sixth connecting spring 471; a third movable cavity and a fourth movable cavity are arranged on the side wall of the first gas transmission cavity, a second baffle 46 is arranged in the third movable cavity, a third baffle 45 is arranged in the fourth movable cavity, a third through groove is formed in the second baffle 46, and a fourth through groove is formed in the third baffle 45; sixth movable grooves are respectively formed in two sides of the third movable cavity, a fifth push block 460 penetrates through the sixth movable grooves, a first driving wheel 470 used for driving the fifth push block 460 and the second baffle 46 is arranged on the inner wall of the sixth movable groove, a seventh movable groove is formed in the inner wall of the sixth movable groove, a seventh connecting spring 4801 is arranged on the inner wall of the seventh movable groove, a first limiting block 480 is arranged at one end of the seventh connecting spring 4801, and a first limiting groove matched with the first limiting block 480 is formed in the side wall of the fifth push block 460; a fourth supporting spring 451 is arranged at the bottom of the third baffle plate 45, a fifth movable cavity is arranged on the side wall of the fourth movable cavity, a second connecting plate 452 is arranged on the side wall of the third baffle plate 45, a sixth pushing plate 453 is arranged on the second connecting plate 452, and the sixth pushing plate 453 is arranged in the third cavity in a penetrating manner; when the ammonolysis reaction is carried out in the reaction box 1, the second partition plate 4 abuts against the bottom of the first partition plate 3, the first push rod 441 abuts against the bottom of the first connecting plate 48, the fourth push plate 44 pushes the air in the third cavity to enter the fourth cavity, when the fourth push plate 44 moves to the bottom of the third cavity, the fourth push plate 44 pushes the sixth push plate 453 to move downwards, the sixth push plate 453 drives the third baffle plate 45 to move downwards, at the moment, the second baffle plate 46 seals the first air conveying cavity, and the air in the fourth cavity cannot enter the second cavity; after the ammonolysis reaction in the reaction box 1 is completed, the second partition plate 4 moves downwards relative to the first partition plate 3, the first bump is separated from the first through hole, the solution flows through the first through hole, the second partition plate 4 moves to the bottom of the reaction box 1, the fifth push block 460 abuts against the bottom of the reaction box 1 and then moves upwards relative to the second partition plate 4, the fifth push block 460 drives the first driving wheel 470 to rotate, the first driving wheel 470 drives the second partition plate 46 to move, the third through groove moves to a position corresponding to the first gas transmission cavity, the first limiting block 480 is embedded into the first limiting groove to fix the fifth push block 460, and the third through groove keeps a position corresponding to the first gas transmission cavity; after the solution in the reaction box 1 is discharged, the second partition plate 4 moves upwards, the first push rod 441 abuts against the bottom of the first connecting plate 48 again, the fourth push plate 44 moves downwards to extrude the air in the third cavity, the fourth push plate 44 pushes the sixth push plate 453 to move downwards, the fourth through groove moves to the position aligned with the first air transmission cavity, the fifth push plate 47 pushes the air in the fourth cavity to enter the second cavity through the first air transmission cavity, the third push plate 490 pushes the fifth push block 460 to extend out of the fourth through groove, and the third connecting rod 153 rotates to drive the third movable block 43 to move on the first baffle plate 31 to form vibration; under the arrangement of the second baffle and the third baffle, even if the first baffle and the second baffle are abutted together, air cannot enter the second cavity to push the third push plate to move when the reaction in the reaction box is carried out.

An eighth movable groove is formed in the bottom of the first movable cavity, a seventh push plate 430 is arranged in the eighth movable groove, an eighth connecting spring 4301 and a second push rod 4302 are arranged at the bottom of the seventh push plate 430, and the second push rod 4302 extends out of the eighth movable groove; a ninth movable groove is formed in the bottom of the first movable block 49, a tenth movable groove is formed in the bottom of the second movable block 410, the second push plate 420 is arranged in the ninth movable groove and the tenth movable groove, a third push rod 4202 and a second return spring 4201 are arranged on the top of the second push plate 420, one end of the second return spring is fixedly connected to the ninth movable groove, and the other end of the second return spring is not fixedly connected to the tenth movable groove; an eleventh movable groove is formed in the top of the first movable cavity, a ninth connecting spring 4401 is arranged at the top of the eleventh movable groove, an eighth push plate 440 is arranged at the bottom end of the ninth connecting spring 4401, a third connecting rope is arranged on the eighth push plate 440, and one end of the third connecting rope is fixedly connected to the first limiting block 480; a twelfth movable groove is formed in the side wall of the seventh push plate 430, a tenth connecting spring 4304 is arranged in the twelfth movable groove, a second limiting block 4303 is arranged at one end of the tenth connecting spring 4304, a second limiting groove matched with the second limiting block 4303 is formed in the inner wall of the eighth movable groove, and a cambered surface is formed on the second limiting block 4303; when the second partition plate 4 moves downwards to the bottom of the reaction box 1, the second push rod 4302 abuts against the bottom of the reaction box 1, the seventh push plate 430 pushes the second push plate 420 to move upwards, the third push rod 4202 abuts against the joint of the first connecting rod 491 and the second connecting rod 4101, after the middle parts of the first connecting rod 491 and the second connecting rod 4101 arch up, the second connecting spring 493 pulls the second movable block 410 to move towards the first movable block 49, and the first connecting rope pulls the second supporting rod 421 to move downwards; after the solution reacts in the reaction chamber 1, ammonia gas is introduced into the eleventh movable groove, the eighth push plate 440 moves downward to push the first connecting rod 491 and the second connecting rod 4101 to move downward, and the first connecting rod 491 and the second connecting rod 4101 rotate to be horizontal to push the second movable block 410 to move, so that the resetting of the second support rod 421 is completed; when the eighth push plate 440 moves downward, the third connecting rope pulls the first limiting block 480 to enter the seventh movable groove, the first limiting block 480 is separated from the first limiting groove, the fifth push block 460 moves downward, and the second baffle 46 closes the first air transmission cavity again.

A fourth connecting rod 141 is arranged on the inner wall of the reaction box 1, a first connecting ring 14 is arranged on the fourth connecting rod 141, the stirring shaft 11 is arranged in the first connecting ring 14 in a penetrating manner, a second through hole is arranged on the first partition plate 3, the stirring shaft 11 is arranged in the second through hole in a penetrating manner, and the movable ring 142 is rotatably connected to the bottom of the first connecting ring 14; the bottom of the movable ring 142 is provided with a fifth connecting rod 143, the bottom of the fifth connecting rod 143 is provided with a second connecting ring 144, the bottom of the second connecting ring 144 is rotatably connected with a first driving ring 145 and a second driving wheel 146, and the stirring shaft 11 is in driving fit with the first driving ring 145 through the second driving wheel 146; a thirteenth movable groove is formed in the inner wall of the second through hole, a third driving wheel 34 is arranged in the thirteenth movable groove, a fourteenth movable groove is formed in the bottom of the thirteenth movable groove, and a third limiting block 36 is arranged in the fourteenth movable groove; when the solution is subjected to ammonolysis reaction in the reaction box 1, the second limiting block 4303 abuts against the bottom of the third transmission wheel 34, the stirring shaft 11 drives the first transmission ring 145 to rotate reversely, the first transmission ring 145 drives the third transmission wheel 34 to rotate, the third transmission wheel 34 drives the whole first partition plate 3 to rotate together, and the first partition plate 3 rotates relative to the stirring rod 111 to complete the ammonolysis reaction of the solution; the ammonolysis reaction in the reaction box 1 is completed, after the solution in the reaction box 1 is discharged by the downward movement of the second partition plate 4, the upward movement of the second partition plate 4 seals the first through hole, at the moment, the electric push rod 21 drives the sleeve 112 to be in a lifting state, the third limit block 36 enters the fourteenth movable groove, the third limit block 36 is separated from the third driving wheel 34, when the stirring shaft 11 drives the first driving ring 145 to rotate, the first driving ring 145 drives the third driving wheel 34 to rotate relative to the first partition plate 3, the stirring shaft 11 drives the movable ring 142 to rotate, the first push plate 147 rotates on the first partition plate 3 to push the particles on the first partition plate 3 to roll, and the particles fall to the discharge opening to collect the particles.

A plurality of fifteenth movable grooves are formed in the side wall of the stirring shaft 11, a sixth connecting rod 159 is arranged in each fifteenth movable groove, a second transmission ring 1591 is arranged on each sixth connecting rod 159, a second air transmission cavity is formed in each movable rod 15, a sixth movable cavity is arranged at the bottom of each second air transmission cavity, a fifth through groove corresponding to each fifteenth movable groove is formed in the bottom of each sixth movable cavity, a sealing plate 151 is arranged in each sixth movable cavity, the inner diameter of each sixth movable cavity is larger than that of each second air transmission cavity, and a plurality of sixth through grooves are formed in each sealing plate 151; a through cavity is formed in the bottom of the sixth movable cavity, a third support rod 152 penetrates through the through cavity, a sixteenth movable groove is formed in the inner wall of the through cavity, an eleventh connecting spring 1531 is arranged on the inner wall of the sixteenth movable groove, a fourth limiting block 153 is arranged at one end of the eleventh connecting spring 1531, a third limiting groove and a fourth limiting groove which are matched with the fourth limiting block 153 are formed in the third support rod 152, the fourth limiting groove is formed above the third limiting groove, and the third support rod 152 is made of an electromagnet; a seventeenth movable groove is formed in the bottom of the movable rod 15, a fourth push rod 154 is arranged in the seventeenth movable groove, a third return spring and a fourth connecting rope are arranged on the fourth push rod 154, and one end of the fourth connecting rope is fixedly connected to the fourth limiting block 153; when the solution reacts in the reaction box 1, the second partition plate 4 abuts against the bottom of the first partition plate 3, at this time, the fourth limiting block 153 is inserted into the third limiting groove, and the support rod abuts against the bottom of the sealing plate 151; after the reaction in the reaction box 1 is finished, the electric push rod 21 drives the sleeve 112 to move upwards, the sleeve 112 closes the first cavity, the movable rod 15 is pushed to move downwards after the air pressure in the air inlet cavity is increased, the support rod provides support force for the sealing plate 151, the movable rod 15 integrally moves downwards, the second partition plate 4 moves downwards along with the movable rod 15, the fourth push rod 154 moves upwards relative to the movable rod 15 after abutting against the bottom of the air inlet cavity after the movable rod 15 moves to the bottom of the air inlet cavity, and the fourth connecting rope pulls the fourth limiting block 153 to enter a sixteenth movable groove; after the solution in the reaction box 1 is exhausted, the ammonia gas in the air inlet cavity is exhausted, the movable rod 15 drives the second partition plate 4 to move upwards, the third support rod 152 is adsorbed at the bottom of the air inlet cavity, when the second partition plate 4 abuts against the bottom of the first partition plate 3, the fourth limit groove on the third support rod 152 moves to one side of the fourth limit block 153, the fourth limit block 153 is inserted into the fourth limit groove, and at the moment, a gap exists between the sealing plate 151 and the third support rod 152; the ammonia gas is introduced into the air inlet cavity, the first cavity is still in a closed state, the third support rod 152 provides a supporting force for the movable rod 15, the sealing plate 151 is pushed by air pressure to move downwards relative to the movable rod 15, the ammonia gas enters the fifth through groove after the sealing plate 151 is moved away from the bottom of the second air delivery cavity, the ammonia gas pushes the sixth connecting rod 159 to extend out, the second transmission ring 1591 extends out to contact with the fifth connecting rod 143, at the moment, the third limiting block 36 does not contact with the third driving wheel 34, when the stirring shaft 11 drives the second transmission ring 1591 to rotate, the second transmission ring 1591 drives the second connecting ring 144 to rotate, the movable ring 142 rotates along with the second connecting ring 144, the first push rod 441 pushes the particulate matters on the first partition plate 3 to move, and the particulate matters fall out from the blanking opening to be collected.

An eighteenth movable groove is formed in the top of the sixth movable cavity, a second push block 158 is arranged in the eighteenth movable groove, a fourth reset spring 1581 is arranged on the second push block 158, a fifth cavity communicated with the eighteenth movable groove is formed above the eighteenth movable groove, a third connecting plate 157 is arranged in the fifth cavity, a twelfth connecting spring 1571 and a fifth connecting rope are arranged on the third connecting plate 157, and one end of the fifth connecting rope is fixedly connected to the top of the fourth push rod 154; a nineteenth movable groove is formed in the second push block 158, a seventh through groove is formed in the top of the nineteenth movable groove, a thirteenth connecting spring 1582 is arranged on the inner wall of the nineteenth movable groove, and a third push block 1583 is arranged on the thirteenth connecting spring 1582; a twentieth movable groove is formed in the bottom of the third limiting block 36, a fourteenth connecting spring 361 is arranged on the inner wall of the twentieth movable groove, a fourth pushing block 362 is arranged at the bottom end of the fourteenth connecting spring 361, a twenty-first movable groove is formed in the inner wall of the twentieth movable groove, a fifteenth connecting spring 365 is arranged in the twenty-first movable groove, a fifth limiting block 364 is arranged at one end of the fifteenth connecting spring 365, and a fifth limiting groove matched with the fifth limiting block 364 is formed in the fourth pushing block 362; a third connecting ring 363 is arranged on the third limiting block 36, a twenty-second movable groove is arranged on the side wall of the fourteenth movable groove, an eighth through groove is arranged on the third connecting ring 363, a twenty-third movable groove is arranged on the inner wall of the eighth through groove, a connecting block 366 is arranged in the twenty-third movable groove, a sixth connecting rope is arranged on the connecting block 366, one end of the sixth connecting rope is fixedly connected to the fifth limiting block 364, a connecting belt 367 is arranged on the connecting block 366, a ninth push plate 35 is arranged in the twenty-second movable groove, and the ninth push plate 35 extends out of the twenty-second movable groove; an annular groove is formed in the stirring shaft 11, a tenth push plate 114 is arranged in the annular groove, and the tenth push plate 114 is fixedly connected to the bottom of the sleeve 112 through a seventh connecting rod; the tenth push plate 114 is arranged at the bottom of the ninth push plate 35; after the second partition plate 4 moves downwards to be separated from the first partition plate 3, the third limiting block 36 moves towards the bottom of the fourteenth movable groove, the fourth pushing block 362 moves towards the outside of the twentieth movable groove, and the fifth limiting block 364 is inserted into the fifth limiting groove to fix the fourth pushing block 362; when the second partition board 4 moves upwards, the fourth pushing block 362 is pushed to move upwards, the fourth pushing block 362 drives the third limiting block 36 to move upwards, and the third limiting block 36 abuts against the third driving wheel 34 to fix the third driving wheel 34; when the electric push rod 21 drives the sleeve 112 to move upwards, the sleeve 112 drives the tenth push plate 114 to move upwards, the tenth push plate 114 pushes the ninth push plate 35 to move, the ninth push plate 35 pushes the connecting strip 367 to move, the connecting block 366 pulls the fifth limiting block 364 to enter the twenty-first movable groove when moving, after the fifth limiting block 364 is separated from the fifth limiting groove, the third limiting block 36 moves downwards relative to the fourth push block 362, the third limiting block 36 is separated from the third driving wheel 34, and the stirring shaft 11 rotates relative to the first partition plate 3 to collect particles in the reaction box 1; after the particulate matters in the reaction box 1 are collected, the ammonia gas in the air inlet cavity is discharged, the sealing plate 151 resets towards the top of the sixth movable cavity, at the moment, the third push block 1583 extends out of the nineteenth movable groove, the sealing plate 151 moves upwards to push the third push block 1583 to move, the third push block 1583 drives the second push block 158 to move, the second push block 158 extrudes the air in the eighteenth movable groove and enters the fifth cavity, the air pressure pushes the third connecting plate 157 to move, the fifth connecting rope pulls the fourth push rod 154 to move, the fourth limit block 153 is separated from the fourth limit groove, the third support rod 152 moves upwards after losing the secondary magnetic force, the fourth limit block 153 is inserted into the third limit groove after the third limit groove moves to one side of the fourth limit block 153, the third support rod 152 abuts against the sealing plate 151 to fix the sealing plate 151 at the bottom of the sealing plate 151, and the resetting of the third support rod 152 is completed.

A twenty-fourth movable groove is formed in the inner wall of the feed opening, a sixteenth connecting spring 321 is arranged on the inner wall of the twenty-fourth movable groove, a supporting plate 32 is arranged at one end of the sixteenth connecting spring, a twenty-fifth movable groove is formed above the twenty-fourth movable groove, a fifth push rod 33 is arranged in the twenty-fifth movable groove in a penetrating mode, a fifth reset spring 331 and a seventh connecting rope are arranged at one end of the fifth push rod, and one end of the seventh connecting rope is fixedly connected to the supporting plate; the fifth push rod penetrates through the second through hole; when the second partition plate descends for the first time, the sealing plate seals the second gas transmission cavity, the whole movable rod is pushed to descend by air pressure, the supporting plate is in an extending state at the moment, the first baffle plate abuts against the top of the supporting plate, the first supporting rod and the second supporting rod are separated from the bottom of the first baffle plate, the second partition plate descends relative to the first baffle plate, the first baffle plate seals the discharging port, and particulate matters are prevented from directly falling into the discharging port; when the second baffle rises and seals first through-hole, the closing plate down moves for the movable rod, the second driving ring stretches out and promotes the fifth push rod and removes, the seventh is connected the rope pulling backup pad and is entered into the twenty-fourth movable groove, drop on first bracing piece and second bracing piece after first baffle loses the holding power, first baffle forms the inclined plane under first bracing piece and second bracing piece effect, drive the movable ring rotation and form vibrations on first baffle simultaneously when the (mixing) shaft rotates, so that do the collection to the particulate matter in the reaction box.

A fourth connecting ring is arranged at the top of the third connecting rod, a groove matched with the fourth connecting ring is formed in the top of the second movable groove, a third air conveying cavity is formed in the fourth connecting ring, a fourth air conveying cavity communicated with the third air conveying cavity is formed in the top of the movable rod, an electromagnetic valve is arranged in the fourth air conveying cavity, and a fifth air conveying cavity communicated with the eleventh movable groove is formed in the top of the groove; after the particulate matters in the reaction box are discharged, the electromagnetic valve is opened to open the fourth gas transmission cavity, part of ammonia enters the eleventh movable groove through the fifth gas transmission cavity to push the eighth push plate to move downwards, and the eighth push plate pushes the first connecting rod and the second connecting rod to move downwards to complete the resetting of the first baffle and the second baffle.

The bottom of the reaction box is provided with a cushion block 12 which is arranged so as to push a fifth push block and other parts to move when the second partition plate descends; and a fifth supporting spring 13 is arranged at the bottom of the second partition plate and provides auxiliary resetting capability for the second partition plate.

After the second partition plate descends, the stirring shaft can drive the first partition plate to rotate by a specified angle so that the first through hole and the first bump are staggered, and the first partition plate and the second partition plate are in a separated state.

The third stopper, the sealing plate, the fifth push block and other parts related to resetting are all provided with springs for driving the stirring shaft to rotate, and the motors are arranged at the bottom of the reaction box and are conventional technical means, so that the details are not repeated.

Be equipped with the discharge gate on the reaction box lateral wall, discharge gate department is equipped with sealing door 16, is equipped with the locator on the first baffle lateral wall, guarantees that the feed opening all aligns with the discharge gate when the reaction box is ejection of compact at every turn.

The drawings in the present application are only schematic and the specific dimensions thereof are subject to practical implementation.

Claims

1. A preparation method of apixaban comprises the steps of carrying out ammonolysis on a compound 2 to obtain an apixaban compound 1, and carrying out ammonolysis in a mode of introducing ammonia gas; the method is characterized in that:

the specific operation steps are as follows: sequentially adding the compound 2 and an organic solvent into a reaction box (1), introducing ammonia gas into the reaction box (1) from the top, driving a first partition plate (3) to rotate in the reverse direction by rotating a stirring shaft (11), and introducing the ammonia gas into the solution to carry out an ammonolysis step; after the reaction is stopped, cooling the solution to room temperature, separating a second partition plate (4) at the bottom of a first partition plate (3) from the first partition plate (3), leaking the solution from a first through hole on the first partition plate (3), leaving the particles on the first partition plate (3), after the solution is discharged, driving a movable ring (142) to rotate by a stirring shaft (11), pushing the particles on the first partition plate (3) to move on the first partition plate (3) by a first push plate (147) on the movable ring (142), and dropping the particles on the first partition plate (3) from a feeding and discharging hole on the first partition plate (3) to obtain a white solid, namely a compound 1; the organic solvent is selected from ethanol;

a twenty-fourth movable groove is formed in the inner wall of the blanking port, a sixteenth connecting spring (321) is arranged on the inner wall of the twenty-fourth movable groove, a supporting plate (32) is arranged at one end of the sixteenth connecting spring (321), a twenty-fifth movable groove is arranged above the twenty-fourth movable groove, a fifth push rod (33) penetrates through the twenty-fifth movable groove, a fifth reset spring (331) and a seventh connecting rope are arranged at one end of the fifth push rod (33), and one end of the seventh connecting rope is fixedly connected to the supporting plate (32); the fifth push rod penetrates through the second through hole; when the second partition plate descends for the first time, the sealing plate seals the second gas transmission cavity, the whole movable rod is pushed to descend by air pressure, the supporting plate is in an extending state at the moment, the first baffle plate abuts against the top of the supporting plate, the first supporting rod and the second supporting rod are separated from the bottom of the first baffle plate, the second partition plate descends relative to the first baffle plate, and the first baffle plate seals the discharging port; when the second baffle rises and seals first through-hole, the closing plate down moved for the movable rod, the second driving ring stretched out and promoted the fifth push rod and removed, the seventh is connected in rope pulling backup pad enters into the twenty-fourth activity inslot, drop on first bracing piece and second bracing piece behind the first baffle lost the holding power, first baffle forms the inclined plane, drive the movable ring rotation when the (mixing) shaft rotates and form vibrations, the particulate matter in the reaction box is discharged on first baffle simultaneously.

2. The process for the preparation of apixaban according to claim 1, characterized in that: the first partition plate (3) and the second partition plate (4) are respectively arranged at the bottom of the reaction box (1), a plurality of first through holes are arranged on the first clapboard (3), a plurality of first convex blocks corresponding to the first through holes are arranged on the second clapboard (4), a first baffle (31) is arranged in the feed opening, a plurality of first through grooves are arranged on the second clapboard (4), a first connecting pipe (41) and a second connecting pipe (42) are arranged on the second clapboard (4), a first supporting spring (412) is arranged at the bottom of the first connecting pipe (41), a first supporting rod (411) is arranged at the top of the first supporting spring (412), a second supporting spring (422) is arranged at the bottom of the second connecting pipe (42), a second supporting rod (421) is arranged at the top of the second supporting spring (422), the first supporting rod (411) and the second supporting rod (421) are both made of magnets; when the compound 2 and the organic solvent are mixed in the reaction box (1), the second partition plate (4) is abutted against the bottom of the first partition plate (3), the first bump is arranged in the first through hole in a penetrating mode, the first through hole is in a sealed state, the stirring shaft (11) rotates to drive the first partition plate (3) to rotate, ammonia gas is filled into the reaction box (1) from the top of the reaction box (1), and ammonolysis reaction is carried out in the reaction box (1); after the solution reaction, second baffle (4) down moves for first baffle (3), first lug is deviate from in the first through-hole, first baffle (31) still are in the feed opening, solution down drops from first through-hole, the particulate matter is stayed on first baffle (3), the back is arranged to solution, first through-hole rotates to the position of being aligned with first lug, second baffle (4) up move first lug and insert in the first through-hole, first through-hole seals once more, (mixing) shaft (11) drive loose ring (142) and rotate, second bracing piece (421) down move and drive first baffle (31) one end down and move, feed opening department forms the recess, first push pedal (147) promote the particulate matter and move on first baffle (3), the particulate matter moves to feed opening department and rolls along first baffle (31) surface and falls, do the particulate matter collection to the reaction box (1) in the particulate matter.

3. The process for the preparation of apixaban according to claim 2, characterized in that: a first movable cavity is arranged on the second partition plate (4), a first movable block (49) and a second movable block (410) are arranged in the first movable cavity, a first connecting spring (492) is arranged on the side wall of one side of the first movable block (49), a second connecting spring (493) is arranged on the side wall of the other side of the first movable block, one end of the first connecting spring (492) is fixedly connected to the inner wall of the first movable cavity, a second movable block (410) is arranged at one end of the second connecting spring (493), a first connecting rope is arranged on the second movable block (410), one end of the first connecting rope is fixedly connected to the bottom of the second supporting rod (421), a first connecting rod (491) is hinged to the first movable block (49), a second connecting rod (4101) is hinged to one end of the first connecting rod (491), one end of the second connecting rod (4101) is hinged to the second movable block (410), a second push plate (420) for pushing the first connecting rod (491) and the second connecting rod (4101) to rotate is arranged at the bottom of the first movable cavity; after the reaction in the reaction box (1) is finished, the second partition plate (4) moves downwards relative to the first partition plate (3), the second push plate (420) pushes the first connecting rod (491) and the second connecting rod (4101) to rotate, after the first connecting rod (491) and the second connecting rod (4101) rotate to form an inclined plane, the second connecting spring (493) pulls the second movable block (410) to move, and the first connecting rope pulls the second supporting rod (421) to move downwards; after the solution in the reaction box (1) is discharged, the first through hole rotates to the position aligned with the first lug, the second partition plate (4) moves upwards, the first lug is inserted into the first through hole to seal the first through hole, the first baffle (31) falls on the first supporting rod (411) and the second supporting rod (421), the first supporting rod (411) and the second supporting rod (421) have height difference, the first baffle (31) falling on the first supporting rod (411) and the second supporting rod (421) forms an inclined plane, particles falling on the first baffle (31) roll down along the surface of the first baffle (31), and the particles in the reaction box (1) are collected.

4. The process for the preparation of apixaban according to claim 3, characterized in that: a plurality of stirring rods (111) are arranged on the stirring shaft (11), an air inlet cavity is arranged on the stirring shaft (11), a first cavity communicated with the air inlet cavity is arranged on the stirring rods (111), and a plurality of air outlet holes are formed in the bottom of the first cavity; a cover plate (2) is arranged at the top of the reaction box (1), an air inlet corresponding to the air inlet cavity is formed in the cover plate (2), a second movable cavity is formed in the stirring shaft (11), a sleeve (112) is arranged in the second movable cavity, a second through groove corresponding to the first cavity is formed in the sleeve (112), a third connecting spring (113) is arranged at the bottom of the sleeve (112), an electric push rod (21) is arranged on the cover plate (2), and a piston rod of the electric push rod (21) is fixedly connected to the top of the sleeve (112); a movable rod (15) is arranged in the air inlet cavity, a third connecting rod (153) is arranged on the movable rod (15), a first movable groove matched with the third connecting rod (153) is arranged on the side wall of the air inlet cavity, a third supporting spring (1510) is arranged at the bottom of the movable rod (15), and a second movable groove matched with the third connecting rod (153) is arranged on the second partition plate (4); ammonia enters the air inlet cavity from the air inlet, the second through groove is aligned with the first cavity when the ammonolysis reaction is carried out in the reaction box (1), air in the air inlet cavity enters the first cavity through the second through groove, air in the first cavity flows out from the air outlet, and the ammonia enters the solution to carry out the ammonolysis reaction; after the ammonolysis reaction in reaction box (1) is finished, electric push rod (21) drive sleeve (112) up move, the second leads to groove and staggers mutually with first cavity, first cavity is sealed, promote movable rod (15) down move after the atmospheric pressure in the intake chamber increases, third connecting rod (153) drive second baffle (4) down move, first lug is deviate from in the first through-hole, first through-hole is opened and is seen, the solution falls from first through-hole, the particulate matter is stayed on first baffle (3), after the solution is all discharged, first through-hole rotates to on the position of being aligned with first lug, the ammonia in the intake chamber is taken out, second baffle (4) up move, first lug inserts first through-hole of closed in the first through-hole, (11) drive movable ring (142) and rotate and do the collection to the particulate matter on first baffle (3).

5. The process for the preparation of apixaban according to claim 4, characterized in that: a third movable groove is formed in the inner wall of the second movable groove, a third movable block (43) is arranged in the third movable groove, a fourth movable groove is formed in the third movable block (43), a first push block (431) is arranged in the fourth movable groove, a fourth connecting spring is arranged on the side wall of the first push block (431), a second cavity is formed in the inner wall of the third movable groove, a third push plate (490) is arranged in the second cavity, a fifth movable groove matched with the third push plate (490) is formed in the third movable block (43), and a first reset spring is arranged on the third movable block (43); a second connecting rope is arranged on the third movable block (43), and one end of the second connecting rope is fixedly connected to the first movable block (49); a third cavity communicated with the second cavity is formed in the second partition plate (4), and a fourth push plate (44) is arranged in the third cavity; after the solution in the reaction box (1) is discharged, the second partition plate (4) moves upwards, the first bump is inserted into the first through hole to close the first through hole, the fourth push plate (44) pushes the air in the third cavity into the second cavity, the third push plate (490) extends out of the second cavity, the third push plate (490) is inserted into the fifth movable groove to push the first push block (431) to extend out of the fourth movable groove, the stirring shaft (11) drives the third connecting rod (153) to contact with the first push block (431) when rotating, the third connecting rod (153) pushes the third movable block (43) to move in the third movable groove, the second connecting rope pulls the first movable block (49) to move, the first connecting rope pulls the second supporting rod (421) to move, the third movable block (43) moves to one end of the third movable groove, the first push block (431) enters the fourth movable groove, the first return spring pulls the third movable block (43) to move back, the first connecting spring (492) pushes the first movable block (49) to move back, the second supporting rod (421) moves upwards, then the third connecting rod (153) is contacted with the first pushing block (431) again, the first connecting rope pulls the second supporting rod (421) to descend discontinuously, vibration is generated on the second supporting rod (421), and the first baffle (31) vibrates along with the second supporting rod (421) to shake off particles on the first baffle (31).

6. The process for the preparation of apixaban according to claim 5, characterized in that: a fourth cavity communicated with the third cavity is arranged below the third cavity, a first air conveying cavity communicated with the second cavity is arranged on the side wall of the fourth cavity, a fifth connecting spring (442) is arranged at the bottom of the fourth push plate (44), a first push rod (441) is arranged at the top of the fourth push plate, and a first connecting plate (48) is arranged at the feed opening; a sixth connecting spring (471) is arranged at the bottom of the fourth cavity, and a fifth push plate (47) is arranged at the top end of the sixth connecting spring (471); a third movable cavity and a fourth movable cavity are arranged on the side wall of the first gas transmission cavity, a second baffle (46) is arranged in the third movable cavity, a third baffle (45) is arranged in the fourth movable cavity, a third through groove is formed in the second baffle (46), and a fourth through groove is formed in the third baffle (45); sixth movable grooves are respectively formed in two sides of the third movable cavity, a fifth push block (460) penetrates through the sixth movable grooves, a first transmission wheel (470) used for transmitting the fifth push block (460) and the second baffle (46) is arranged on the inner wall of the sixth movable groove, a seventh movable groove is formed in the inner wall of the sixth movable groove, a seventh connecting spring (4801) is arranged on the inner wall of the seventh movable groove, a first limiting block (480) is arranged at one end of the seventh connecting spring (4801), and a first limiting groove matched with the first limiting block (480) is formed in the side wall of the fifth push block (460); a fourth supporting spring (451) is arranged at the bottom of the third baffle plate (45), a fifth movable cavity is arranged on the side wall of the fourth movable cavity, a second connecting plate (452) is arranged on the side wall of the third baffle plate (45), a sixth pushing plate (453) is arranged on the second connecting plate (452), and the sixth pushing plate (453) penetrates through the third cavity; when ammonolysis reaction is carried out in the reaction box (1), the second partition plate (4) abuts against the bottom of the first partition plate (3), the first push rod (441) abuts against the bottom of the first connecting plate (48), the fourth push plate (44) pushes air in the third cavity to enter the fourth cavity, when the fourth push plate (44) moves to the bottom of the third cavity, the fourth push plate (44) pushes the sixth push plate (453) to move downwards, the sixth push plate (453) drives the third baffle plate (45) to move downwards, at the moment, the second baffle plate (46) seals the first air conveying cavity, and air in the fourth cavity cannot enter the second cavity; after the ammonolysis reaction in the reaction box (1) is completed, the second partition plate (4) moves downwards relative to the first partition plate (3), the first bump is separated from the first through hole, the solution flows through the first through hole, the second partition plate (4) moves to the bottom of the reaction box (1), the fifth push block (460) abuts against the bottom of the reaction box (1) and moves upwards relative to the second partition plate (4), the fifth push block (460) drives the first transmission wheel (470) to rotate, the first transmission wheel (470) drives the second baffle (46) to move, the third through groove moves to a position corresponding to the first gas transmission cavity, the first limiting block (480) is embedded into the first limiting groove to fix the fifth push block (460), and the third through groove maintains a position corresponding to the first gas transmission cavity; after the solution in the reaction box (1) is discharged, the second partition plate (4) moves upwards, the first push rod (441) abuts against the bottom of the first connecting plate (48) again, the fourth push plate (44) moves downwards to extrude air in the third cavity, the fourth push plate (44) pushes the sixth push plate (453) to move downwards, the fourth through groove moves to the position aligned with the first air transmission cavity, the fifth push plate (47) pushes the air in the fourth cavity to enter the second cavity through the first air transmission cavity, the third push plate (490) pushes the fifth push block (460) to extend out of the fourth through groove, and the third connecting rod (153) rotates to drive the third movable block (43) to move on the first baffle (31) to form vibration.

7. The process for the preparation of apixaban according to claim 6, characterized in that: an eighth movable groove is formed in the bottom of the first movable cavity, a seventh push plate (430) is arranged in the eighth movable groove, an eighth connecting spring (4301) and a second push rod (4302) are arranged at the bottom of the seventh push plate (430), and the second push rod (4302) extends out of the eighth movable groove; a ninth movable groove is formed in the bottom of the first movable block (49), a tenth movable groove is formed in the bottom of the second movable block (410), the second push plate (420) is arranged in the ninth movable groove and the tenth movable groove, and a third push rod (4202) and a second return spring (4201) are arranged on the top of the second push plate (420); an eleventh movable groove is formed in the top of the first movable cavity, a ninth connecting spring (4401) is arranged at the top of the eleventh movable groove, an eighth push plate (440) is arranged at the bottom end of the ninth connecting spring (4401), a third connecting rope is arranged on the eighth push plate (440), and one end of the third connecting rope is fixedly connected to the first limiting block (480); a twelfth movable groove is formed in the side wall of the seventh push plate (430), a tenth connecting spring (4304) is arranged in the twelfth movable groove, a second limiting block (4303) is arranged at one end of the tenth connecting spring (4304), a second limiting groove matched with the second limiting block (4303) is formed in the inner wall of the eighth movable groove, and a cambered surface is formed in the second limiting block (4303); when the second partition plate (4) moves downwards to the bottom of the reaction box (1), the second push rod (4302) abuts against the bottom of the reaction box (1), the seventh push plate (430) pushes the second push plate (420) to move upwards, the third push rod (4202) abuts against the joint of the first connecting rod (491) and the second connecting rod (4101), after the middle parts of the first connecting rod (491) and the second connecting rod (4101) are arched, the second connecting spring (493) pulls the second movable block (410) to move towards the direction of the first movable block (49), and the first connecting rope pulls the second supporting rod (421) to move downwards; after the solution reacts in the reaction box (1), ammonia gas is introduced into the eleventh movable groove, the eighth push plate (440) moves downwards to push the first connecting rod (491) and the second connecting rod (4101) to move downwards, and the first connecting rod (491) and the second connecting rod (4101) rotate to the horizontal state to push the second movable block (410) to move, so that the resetting of the second supporting rod (421) is completed; when the eighth push plate (440) moves downwards, the third connecting rope pulls the first limiting block (480) to enter the seventh movable groove, the first limiting block (480) is separated from the first limiting groove, the fifth push block (460) moves downwards, and the second baffle (46) closes the first air conveying cavity again.

8. The process for the preparation of apixaban according to claim 4, characterized in that: a fourth connecting rod (141) is arranged on the inner wall of the reaction box (1), a first connecting ring (14) is arranged on the fourth connecting rod (141), the stirring shaft (11) is arranged in the first connecting ring (14) in a penetrating manner, a second through hole is formed in the first partition plate (3), the stirring shaft (11) is arranged in the second through hole in a penetrating manner, and the movable ring (142) is rotatably connected to the bottom of the first connecting ring (14); a fifth connecting rod (143) is arranged at the bottom of the movable ring (142), a second connecting ring (144) is arranged at the bottom of the fifth connecting rod (143), a first transmission ring (145) and a second transmission wheel (146) are rotatably connected to the bottom of the second connecting ring (144), and the stirring shaft (11) is in transmission fit with the first transmission ring (145) through the second transmission wheel (146); a thirteenth movable groove is formed in the inner wall of the second through hole, a third driving wheel (34) is arranged in the thirteenth movable groove, a fourteenth movable groove is formed in the bottom of the thirteenth movable groove, and a third limiting block (36) is arranged in the fourteenth movable groove; when the solution is subjected to ammonolysis reaction in the reaction box (1), the second limiting block (4303) abuts against the bottom of the third transmission wheel (34), the stirring shaft (11) drives the first transmission ring (145) to rotate in the reverse direction, the first transmission ring (145) drives the third transmission wheel (34) to rotate, the third transmission wheel (34) drives the whole first partition plate (3) to rotate together, the first partition plate (3) rotates relative to the stirring rod (111), and the ammonolysis reaction of the solution is completed; the ammonolysis reaction in the reaction box (1) is completed, the second partition plate (4) moves downwards to discharge the solution in the reaction box (1), the second partition plate (4) moves upwards to seal the first through hole, the electric push rod (21) drives the sleeve (112) to be in a lifting state at the moment, the third limiting block (36) enters the fourteenth movable groove, the third limiting block (36) and the third driving wheel (34) are separated from each other and are in contact, when the stirring shaft (11) drives the first driving ring (145) to rotate, the first driving ring (145) drives the third driving wheel (34) to rotate relative to the first partition plate (3), the stirring shaft (11) drives the movable ring (142) to rotate, the first push plate (147) rotates on the first partition plate (3) to push particles on the first partition plate (3) to roll, and the particles fall to a discharge port to be collected.

9. The process for the preparation of apixaban according to claim 8, characterized in that: a plurality of fifteenth movable grooves are formed in the side wall of the stirring shaft (11), a sixth connecting rod (159) is arranged in each fifteenth movable groove, a second transmission ring (1591) is arranged on each sixth connecting rod (159), a second air conveying cavity is formed in each movable rod (15), a sixth movable cavity is arranged at the bottom of each second air conveying cavity, a fifth through groove corresponding to each fifteenth movable groove is formed in the bottom of each sixth movable cavity, a sealing plate (151) is arranged in each sixth movable cavity, the inner diameter of each sixth movable cavity is larger than that of each second air conveying cavity, and a plurality of sixth through grooves are formed in each sealing plate (151); a through cavity is formed in the bottom of the sixth movable cavity, a third support rod (152) penetrates through the through cavity, a sixteenth movable groove is formed in the inner wall of the through cavity, an eleventh connecting spring (1531) is arranged on the inner wall of the sixteenth movable groove, a fourth limiting block (153) is arranged at one end of the eleventh connecting spring (1531), a third limiting groove and a fourth limiting groove which are matched with the fourth limiting block (153) are formed in the third support rod (152), the fourth limiting groove is formed above the third limiting groove, and the third support rod (152) is made of an electromagnet; a seventeenth movable groove is formed in the bottom of the movable rod (15), a fourth push rod (154) is arranged in the seventeenth movable groove, a third reset spring and a fourth connecting rope are arranged on the fourth push rod (154), and one end of the fourth connecting rope is fixedly connected to the fourth limiting block (153); when the solution reacts in the reaction box (1), the second partition plate (4) is pressed against the bottom of the first partition plate (3), the fourth limiting block (153) is inserted into the third limiting groove, and the supporting rod is pressed against the bottom of the sealing plate (151); after the reaction in the reaction box (1) is finished, the electric push rod (21) drives the sleeve (112) to move upwards, the sleeve (112) seals the first cavity, the movable rod (15) is pushed to move downwards after the air pressure in the air inlet cavity is increased, the support rod provides supporting force for the sealing plate (151), the movable rod (15) integrally moves downwards, the second partition plate (4) moves downwards along with the movable rod (15), the movable rod (15) moves to the bottom of the air inlet cavity, the fourth push rod (154) pushes against the bottom of the air inlet cavity and moves upwards relative to the movable rod (15), and the fourth connecting rope pulls the fourth limiting block (153) to enter a sixteenth movable groove; after the solution in the reaction box (1) is exhausted, the ammonia gas in the air inlet cavity is exhausted, the movable rod (15) drives the second partition plate (4) to move upwards, the third support rod (152) is adsorbed at the bottom of the air inlet cavity, when the second partition plate (4) abuts against the bottom of the first partition plate (3), the fourth limit groove on the third support rod (152) moves to one side of the fourth limit block (153), the fourth limit block (153) is inserted into the fourth limit groove, and at the moment, a gap exists between the sealing plate (151) and the third support rod (152); introducing ammonia gas into the air inlet cavity, keeping the first cavity in a closed state, providing a supporting force for the movable rod (15) by the third supporting rod (152), pushing the sealing plate (151) to move downwards relative to the movable rod (15) by air pressure, enabling the ammonia gas to enter the fifth through groove after the sealing plate (151) is moved away from the bottom of the second air delivery cavity, pushing the sixth connecting rod (159) to extend by the ammonia gas, enabling the second transmission ring (1591) to extend to be in contact with the fifth connecting rod (143), enabling the third limiting block (36) not to be in contact with the third transmission wheel (34) at the moment, and enabling the stirring shaft (11) to drive the second transmission ring (1591) to rotate, the second transmission ring (1591) drives the second connecting ring (144) to rotate, the movable ring (142) rotates along with the second connecting ring (144), the first push rod (441) pushes the particles on the first clapboard (3) to move, and the particles fall out from the feed opening to be collected.

10. The process for the preparation of apixaban according to claim 9, characterized in that: an eighteenth movable groove is formed in the top of the sixth movable cavity, a second push block (158) is arranged in the eighteenth movable groove, a fourth reset spring (1581) is arranged on the second push block (158), a fifth cavity communicated with the eighteenth movable groove is formed above the eighteenth movable groove, a third connecting plate (157) is arranged in the fifth cavity, a twelfth connecting spring (1571) and a fifth connecting rope are arranged on the third connecting plate (157), and one end of the fifth connecting rope is fixedly connected to the top of the fourth push rod (154); a nineteenth movable groove is formed in the second pushing block (158), a seventh through groove is formed in the top of the nineteenth movable groove, a thirteenth connecting spring (1582) is arranged on the inner wall of the nineteenth movable groove, and a third pushing block (1583) is arranged on the thirteenth connecting spring (1582); a twentieth movable groove is formed in the bottom of the third limiting block (36), a fourteenth connecting spring (361) is arranged on the inner wall of the twentieth movable groove, a fourth push block (362) is arranged at the bottom end of the fourteenth connecting spring (361), a twenty-first movable groove is formed in the inner wall of the twentieth movable groove, a fifteenth connecting spring (365) is arranged in the twenty-first movable groove, a fifth limiting block (364) is arranged at one end of the fifteenth connecting spring (365), and a fifth limiting groove matched with the fifth limiting block (364) is formed in the fourth push block (362); a third connecting ring (363) is arranged on the third limiting block (36), a twenty-second movable groove is arranged on the side wall of the fourteenth movable groove, an eighth through groove is arranged on the third connecting ring (363), a twenty-third movable groove is arranged on the inner wall of the eighth through groove, a connecting block (366) is arranged in the twenty-third movable groove, a sixth connecting rope is arranged on the connecting block (366), one end of the sixth connecting rope is fixedly connected to the fifth limiting block (364), a connecting belt (367) is arranged on the connecting block (366), a ninth push plate (35) is arranged in the twenty-second movable groove, and the ninth push plate (35) extends out of the twenty-second movable groove; an annular groove is formed in the stirring shaft (11), a tenth push plate (114) is arranged in the annular groove, and the tenth push plate (114) is fixedly connected to the bottom of the sleeve (112) through a seventh connecting rod; the tenth push plate (114) is arranged at the bottom of the ninth push plate (35); after the second partition plate (4) moves downwards and is separated from the first partition plate (3), the third limiting block (36) moves towards the bottom of the fourteenth movable groove, the fourth push block (362) moves towards the outside of the twentieth movable groove, and the fifth limiting block (364) is inserted into the fifth limiting groove to fix the fourth push block (362); when the second partition plate (4) moves upwards, the fourth pushing block (362) is pushed to move upwards, the fourth pushing block (362) drives the third limiting block (36) to move upwards, and the third limiting block (36) abuts against the third driving wheel (34) to fix the third driving wheel (34); when the electric push rod (21) drives the sleeve (112) to move upwards, the sleeve (112) drives the tenth push plate (114) to move upwards, the tenth push plate (114) pushes the ninth push plate (35) to move, the ninth push plate (35) pushes the connecting band (367) to move, the connecting block (366) pulls the fifth limiting block (364) to enter the twenty-first movable groove when moving, after the fifth limiting block (364) is separated from the fifth limiting groove, the third limiting block (36) moves downwards relative to the fourth push block (362), the third limiting block (36) is separated from contact with the third driving wheel (34), the stirring shaft (11) rotates relative to the first partition plate (3), and particulate matters in the reaction box (1) are collected; after the particles in the reaction box (1) are collected, ammonia gas in the air inlet cavity is exhausted, the sealing plate (151) resets towards the top of the sixth movable cavity, at the moment, the third push block (1583) extends out of the nineteenth movable groove, the sealing plate (151) moves upwards to push the third push block (1583) to move, the third push block (1583) drives the second push block (158) to move, the second push block (158) extrudes air in the eighteenth movable groove to enter the fifth cavity, air pressure pushes the third connecting plate (157) to move, the fifth connecting rope pulls the fourth push rod (154) to move, the fourth limiting block (153) is separated from the fourth limiting groove, the third supporting rod (152) moves upwards after losing secondary magnetic force, the third limiting groove moves to the side of the fourth limiting block (153), the fourth limiting block (153) is inserted into the third limiting groove, the third supporting rod (152) abuts against the bottom of the sealing plate (151) to fix the sealing plate (151), and the resetting of the sealing plate (151) and the third supporting rod (152) is completed.