CN106986864A - The preparation facilities and preparation method of a kind of Azilsartan - Google Patents
The preparation facilities and preparation method of a kind of Azilsartan Download PDFInfo
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- CN106986864A CN106986864A CN201710213267.2A CN201710213267A CN106986864A CN 106986864 A CN106986864 A CN 106986864A CN 201710213267 A CN201710213267 A CN 201710213267A CN 106986864 A CN106986864 A CN 106986864A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
A kind of preparation facilities of Azilsartan disclosed by the invention, the invention also discloses the method that Azilsartan preparation is carried out using the device, method selection prepared by Azilsartan is with 3 amino 2 [(base of 2 ' cyanobiphenyl 4) methyl] Methyl anthranilate, tetraethyl orthocarbonates etc. for raw material, Azilsartan crude product is reacted to obtain through the step of cyclization, addition, condensation, cyclization, hydrolysis etc. five, then through being refining to obtain the synthetic route of Azilsartan finished product.The preparation facilities and preparation method of a kind of Azilsartan of the present invention, disclose a kind of preparation facilities and preparation method that it is particularly applicable to Workshop Production of unlisted medicinal chemicals Azilsartan, specific operation and technical support are provided for actual drug production, there is good practical value.
Description
Technical field
The invention belongs to medicine preparing technical field, and in particular to a kind of preparation facilities of Azilsartan, and the present invention is also related to
And the method that Azilsartan preparation is carried out using said apparatus.
Background technology
Azilsartan is the angiotensin II receptor antagonist medicine for treating vascular hypertension, is used for treating hypertension
Disease, is also currently the only angiotensin II receptor antagonist (husky smooth class) medicine in late-stage clinical.But the country has no medicine
Factory produces the medicine in batches.
The content of the invention
It is raw there is provided can apply to factory's batch it is an object of the invention to provide a kind of preparation facilities of Azilsartan
The preparation facilities of Azilsartan is produced, is actually the put into production specific operation of offer and technical support.
It is another object of the present invention to the method for Azilsartan preparation is carried out using said apparatus.
The technical solution adopted in the present invention is, a kind of preparation facilities of Azilsartan, including the first ring being sequentially connected
Close process preparation facilities, addition process preparation facilities, condensation process preparation facilities, the second cyclization process preparation facilities, hydrolysis work
Sequence preparation facilities and refining step preparation facilities.
It is of the invention to be further characterized in that,
First cyclization process preparation facilities include be sequentially connected the first blending tank, the first cyclization kettle, the first line pump and
Washing, filtering and drying machine, the first cyclization kettle is connected with the first vacuum feeder, and washing, filtering and drying machine is prepared with addition process and filled
Put connection；
Addition process preparation facilities includes the second vacuum feeder, addition kettle, the second line pump, the first knot being sequentially connected
Brilliant kettle, the first bag type filtering machine, the first neutralization kettle, the 3rd line pump, MGM tubular membranes filter, second neutralize kettle, cross diafiltration
Machine, back flow reaction kettle, the second bag type filtering machine, the 3rd vacuum feeder and the first microwave vacuum dryer are washed, second neutralizes kettle
The 4th vacuum feeder is connected with, the second vacuum feeder is connected with washing, filtering and drying machine；
Being condensed process preparation facilities includes the 5th vacuum feeder, the second blending tank, condensation kettle, the 4th line pump, first
Extractor, the 5th line pump, the second extractor, the 3rd extractor and the kettle that is concentrated under reduced pressure, the discharging opening of the first extractor pass through pipe
Road is connected with the charging aperture of the 3rd extractor, and the 5th vacuum feeder is connected with the first microwave vacuum dryer；
Second cyclization process preparation facilities includes feed pump, the second cyclization kettle and the filtering drying machine being sequentially connected, charging
Pump is connected with concentration kettle；
It is true that hydrolyzing process preparation facilities includes the 6th vacuum feeder, hydrolysis kettle, the 3rd bag type filtering machine and the second microwave
Empty drying machine, the 6th vacuum feeder is connected with filtering drying machine；
The 7th vacuum feeder that refining step preparation facilities includes being sequentially connected, decolouring kettle, microwave decarburization filter, the
Two crystallization kettles, the 6th line pump, centrifuge, the 8th vacuum feeder and double conic rotary vacuum dryer, the 7th vacuum feeder
It is connected with the second microwave vacuum dryer.
Another technical scheme of the present invention is, a kind of preparation method of Azilsartan, using a kind of Azilsartan
Preparation facilities, comprise the following steps：
Step 1, the first cyclization process：3- amino -2- [(2 '-cyanobiphenyl -4- bases) is sequentially added into the first cyclization kettle
Methyl] Methyl anthranilate, tetraethyl orthocarbonate and glacial acetic acid, stirring the first ring-closure reaction kettle in reaction solution it is heated up
To after 75-85 DEG C, then temperature control reaction 4h is cooled to 10 DEG C, 5N hydrogen-oxygens is added dropwise into the first ring-closure reaction kettle at such a temperature
Change sodium solution, obtained reaction solution is input in washing, filtering and drying machine and filtered, obtain AZ-6 filter cakes, cleaning AZ-6 filters
Cake, AZ-6 filter cakes are dried in vacuo under the conditions of 70~90 DEG C and obtain solid AZ-6；
Step 2, addition process：Dimethyl sulfoxide (DMSO), AZ-6, hydroxylamine hydrochloride, sodium acid carbonate are sequentially added into addition kettle, is risen
Temperature is reacted 22~26h, the reaction solution in addition kettle is input in the first crystallization kettle, after it is down to room temperature to 75~85 DEG C
Crystallization；Material in first crystallization kettle is filtered by the first bag type filtering machine, filtrate is collected, obtained filter cake and water is added to
In first neutralization reaction kettle, stirring, be added dropwise concentration mass fraction be 36% hydrochloric acid into the first neutralization reaction kettle, regulation pH value to
3, the reaction solution in the first neutralization reaction kettle is driven into MGM tubular membranes filters and filtered, filtrate is collected；Filtrate is conveyed
Neutralized to second in kettle, then sodium carbonate solid, regulation pH value to 11 are added into the second neutralization kettle；Second is neutralized the thing in kettle
Material is transported to agitation and filtration in filtration washing machine, obtains filter cake；Filter cake is sequentially added into back flow reaction kettle and volume fraction is
95% ethanol solution, is warming up to backflow, stirs 1.5~2.5h, and the material in back flow reaction kettle is transported to second bag by cooling
Filter, the filter cake in the second bag type filtering machine is added in the first microwave vacuum dryer, at 50~70 DEG C in formula filter
Under the conditions of be dried in vacuo, obtain AZ-7；
Step 3, condensation process：AZ-7, triethylamine, dichloromethane are sequentially added into condensation kettle, chloromethane is then added dropwise again
Acetoacetic ester -- dichloromethane solution, time for adding is 2.5~3.5h, continues to react 3~5h, and controlling reaction temperature, will at 25 DEG C
Reaction solution in condensation kettle is transported in the first extractor to be extracted with water, then arrives the water conveying in the first extractor
In second extractor, then into the second extractor add dichloromethane extracted；By the organic phase in the first extractor and the
Organic phase in two extractors is transported in the 3rd extractor, then into the 3rd extractor, addition water is extracted, and retains the 3rd
Organic phase in extractor, is transported to and is concentrated under reduced pressure in kettle, and decompression, which is distillated, obtains AZ-8；
Step 4, the second cyclization process：Sequentially added into the second cyclization kettle volume fraction be 95% ethanol solution and
AZ-8, is heated to backflow, reacts 9~11h；Then the reaction solution in the second cyclization kettle is transported in filtering drying machine and filtered,
Filtrate is collected, filter cake is dried in vacuo under the conditions of 60 DEG C, AZ-9 is obtained；
Step 5, hydrolyzing process：The sodium hydroxide that AZ-9, methanol and mass fraction are 10% is sequentially added into hydrolysis kettle
The aqueous solution, 1~1.5h of temperature rising reflux, stirring is added dropwise 1N salt acid for adjusting pH to 3, the material in hydrolysis kettle is transported into the 3rd bag
Filtered in formula filter, obtain filter cake；Filter cake is added in the second microwave vacuum dryer, is dried in vacuo under the conditions of 60 DEG C,
Obtain Azilsartan crude product；
Step 6, refining step：Azilsartan crude product, activated carbon and absolute ethyl alcohol are sequentially added into decolouring kettle, is heated up,
Flowed back 2~3h, and the material in decolouring kettle is transported in micropore decarbonization filtering machine and filtered, and the material after filtering is transported to the second knot
In brilliant kettle, 5 DEG C, stirring, crystallization are cooled to；Material in second crystallization kettle is transported in centrifuge and filtered, filtrate is collected；Will
Filter cake in centrifuge is added in double conic rotary vacuum dryer, under the conditions of 60 DEG C be dried in vacuo, obtain Azilsartan into
Product.
It is of the invention to be further characterized in that,
In step 1,3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] Methyl anthranilate per 1kg needs original
The consumption of carbonic acid tetra-ethyl ester is：0.83~0.88L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] aminobenzene per 1kg
Methyl formate needs the consumption of glacial acetic acid to be：0.16~0.21L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) first per 1kg
Base] Methyl anthranilate needs the consumption of 5N sodium hydroxide solutions to be：1.19~1.23L；The dropwise addition of 5N sodium hydroxide solutions
Time is 3~5h.
In step 2, the AZ-6 per 1kg needs the consumption of dimethyl sulfoxide (DMSO) to be：3.56~3.6L；AZ-6 and hydroxylamine hydrochloride
Mass ratio is：1：1.1~1：1.2；The mass ratio of AZ-6 and sodium acid carbonate is：1：0.98~1：1.02；AZ-6 per 1kg needs
The consumption of concentrated hydrochloric acid is：0.15~0.2L；The mass ratio of AZ-6 and sodium carbonate is：1：0.85~1：0.95；AZ-6 per 1kg is needed
The consumption for wanting the ethanol solution that volume fraction is 95% is：3.63~3.72L.
In step 3, dichloromethane is added in three times：The consumption of the dichloromethane solution of addition is for the first time：Per 1kg
AZ-7 needs the consumption of dichloromethane to be：1.5~1.6L, second of addition is ethyl chloroformate -- dichloromethane solution, often
1kg AZ-7 needs ethyl chloroformate -- and the consumption of dichloromethane solution is：0.89~1.01L, ethyl chloroformate -- dichloromethane
Alkane solution is mixed to get using ethyl chloroformate with dichloromethane, wherein the volume proportion of ethyl chloroformate and dichloromethane
For 1：4~1：4.5；The consumption of the dichloromethane solution of addition is for the third time：AZ-7 per 1kg needs the consumption of dichloromethane
For：0.75~0.8L；AZ-7 per 1kg needs the consumption of triethylamine to be：0.36~0.4L.
In step 4, the volume ratio for the ethanol solution that AZ-8 is 95% with volume fraction is 1：4.8~1：5.
In step 5, the AZ-9 per 1kg needs the consumption of methanol to be 5.3~5.9L；AZ-9 per 1kg needs mass fraction
It is 2.2~2.3L for the consumption of 10% sodium hydrate aqueous solution.
In step 6, wherein the mass ratio of Azilsartan crude product and activated carbon is 1：0.09~1：0.11, wherein per 1kg Ah
Qi Shatan crude products need the consumption for the ethanol solution that volume fraction is 95% to be 4.58~5.34L.
The beneficial effects of the invention are as follows：A kind of preparation method of Azilsartan of the present invention devises a kind of unlistedization
The preparation method that bulk drug Azilsartan is applied to Workshop Production is learned, specific operation and technology branch are provided for actual drug production
Hold, there is good practical value.
Brief description of the drawings
Fig. 1 be a kind of Azilsartan of the invention preparation method in the first cyclization process and addition process flow chart；
Fig. 2 be a kind of Azilsartan of the invention preparation method in condensation process and the second cyclization process flow chart；
Fig. 3 be a kind of Azilsartan of the invention preparation method in hydrolyzing process and refining step flow chart.
In figure, 1. first blending tanks, 2. first cyclization kettles, 3. first line pumps, 4. washing, filtering and drying machines, 5. additions
Kettle, 6. second line pumps, 7. first crystallization kettles, 8. first bag type filtering machines, 9. first neutralization kettles, 10. the 3rd line pumps,
11.MGM tubular membranes filters, 12. second neutralize kettle, 13. filtration washing machines, 14. back flow reaction kettles, 15. second pocket type mistakes
Filter, 16. first microwave vacuum dryers, 17. second blending tanks, 18. condensation kettles, 19. the 4th line pumps, 20. first extractions
Device, 21. second extractors, 22. the 3rd extractors, 23. the 5th line pumps, 24. are concentrated under reduced pressure kettle, 25. feed pumps, 26. second
Cyclization kettle, 27. filtering drying machines, 28. hydrolysis kettles, 29. the 3rd bag type filtering machines, 30. second microwave vacuum dryers, 31. take off
Color kettle, 32. microwave decarburization filters, 33. second crystallization kettles, 34. the 6th line pumps, 35. centrifuges, 36. bipyramid rotary vacuum
Drying machine, 37. first vacuum feeders, 38. second vacuum feeders, 39. the 3rd vacuum feeders, 40. the 4th vacuum feedings
Machine, 41. the 5th vacuum feeders, 42. the 6th vacuum feeders, 43. the 7th vacuum feeders, 44. the 8th vacuum feeders.
Embodiment
With reference to the drawings and specific embodiments are combined, the present invention is described in detail.
A kind of preparation facilities of Azilsartan of the present invention, as shown in Figure 1, Figure 2 and Figure 3, the first cyclization work being sequentially connected
Sequence preparation facilities, addition process preparation facilities, condensation process preparation facilities, the second cyclization process preparation facilities, hydrolyzing process system
Standby device and refining step preparation facilities.
First cyclization process preparation facilities includes the first blending tank 1, the first cyclization kettle 2, the first line pump 3 being sequentially connected
And washing, filtering and drying machine 4, the first cyclization kettle 2 is connected with the first vacuum feeder 37, washing, filtering and drying machine 4 and addition process
Preparation facilities is connected；
The second vacuum feeder 38 that addition process preparation facilities includes being sequentially connected, addition kettle 5, the second line pump 6, the
One crystallization kettle 7, the first bag type filtering machine 8, first are neutralized in kettle 9, the 3rd line pump 10, MGM tubular membranes filter 11, second
With kettle 12, filtration washing machine 13, back flow reaction kettle 14, the second bag type filtering machine 15, the 3rd vacuum feeder 39 and the first microwave
Vacuum drier 16, the second neutralization kettle 12 is connected with the 4th vacuum feeder 40, and the second vacuum feeder 38 is filtered dry with washed
Dry machine 4 is connected；
Being condensed process preparation facilities includes the 5th vacuum feeder 41, the second blending tank 17, condensation kettle 18, the 4th line pump
19th, the first extractor 20, the 5th line pump 23, the second extractor 21, the 3rd extractor 22 and the kettle 24 that is concentrated under reduced pressure, the first extraction
The discharging opening of device 20 is connected by pipeline with the charging aperture of the 3rd extractor 22, the 5th vacuum feeder 41 and the first microwave vacuum
Drying machine 16 is connected；
Second cyclization process preparation facilities includes feed pump 25, the second cyclization kettle 26 and the filtering drying machine being sequentially connected
27, feed pump 25 is connected with concentration kettle 24；
Hydrolyzing process preparation facilities includes the 6th vacuum feeder 42, hydrolysis kettle 28, the 3rd bag type filtering machine 29 and second
Microwave vacuum dryer 30, the 6th vacuum feeder 42 is connected with filtering drying machine 27；
Refining step preparation facilities includes the 7th vacuum feeder 43, decolouring kettle 31, microwave the decarburization filtering being sequentially connected
Machine 32, the second crystallization kettle 33, the 6th line pump 34, centrifuge 35, the 8th vacuum feeder 44 and double conic rotary vacuum dryer
36, the 7th vacuum feeder 43 is connected with the second microwave vacuum dryer 30.
A kind of preparation method of Azilsartan, using a kind of preparation facilities of Azilsartan, comprises the following steps：
Step 1, the first cyclization process：3- amino -2- [(2 '-cyanobiphenyl -4- are sequentially added into the first cyclization kettle 2
Base) methyl] Methyl anthranilate, tetraethyl orthocarbonate and glacial acetic acid, stirring the first ring-closure reaction kettle 2 in reaction solution make it
It is warming up to after 75-85 DEG C, then temperature control reaction 4h is cooled to 10 DEG C, 5N is added dropwise into the first ring-closure reaction kettle 2 at such a temperature
Sodium hydroxide solution, obtained reaction solution is input in washing, filtering and drying machine 4 and filtered, and obtains AZ-6 filter cakes, cleans AZ-
6 filter cakes, AZ-6 filter cakes are dried in vacuo under the conditions of 70~90 DEG C and obtain solid AZ-6；
Step 2, addition process：Dimethyl sulfoxide (DMSO), AZ-6, hydroxylamine hydrochloride, sodium acid carbonate are sequentially added into addition kettle 5,
75~85 DEG C are warming up to, 22~26h is reacted, the reaction solution in addition kettle 5 is input in the first crystallization kettle 7, treats that it is down to room
Crystallization after temperature；Material in first crystallization kettle 7 is filtered by the first bag type filtering machine 8, filtrate is collected, by obtained filter cake and water
Be added in the first neutralization reaction kettle 9, stir, be added dropwise concentration mass fraction be 36% hydrochloric acid into the first neutralization reaction kettle 9, adjust
PH value is saved to 3, the reaction solution in the first neutralization reaction kettle 9 is driven into MGM tubular membranes filter 11 and filtered, filter is collected
Liquid；Filtrate is transported in the second neutralization kettle 12, then sodium carbonate solid, regulation pH value to 11 are added into the second neutralization kettle 12；
The material in kettle 12 is neutralized by second and is transported to agitation and filtration in filtration washing machine 13, obtains filter cake；Into back flow reaction kettle 14 according to
Secondary filter cake and the volume fraction of adding is 95% ethanol solution, is warming up to backflow, stirs 1.5~2.5h, cooling, by back flow reaction
Material in kettle 14 is transported in the second bag type filtering machine 15 and filtered, and the filter cake in the second bag type filtering machine 15 is added into first
In microwave vacuum dryer 16, it is dried in vacuo under the conditions of 50~70 DEG C, obtains AZ-7；
Step 3, condensation process：AZ-7, triethylamine, dichloromethane are sequentially added into condensation kettle 18, chlorine is then added dropwise again
Ethyl formate -- dichloromethane solution, time for adding be 2.5~3.5h, continue react 3~5h, controlling reaction temperature at 25 DEG C,
Reaction solution in condensation kettle 18 is transported in the first extractor 20 and extracted with water, then by the water in the first extractor 20
Mutually it is transported in the second extractor 21, then dichloromethane is added into the second extractor 21 and is extracted；By the first extractor 20
In organic phase and the second extractor 21 in organic phase be transported in the 3rd extractor 22, then added into the 3rd extractor 22
Water is extracted, and is retained the organic phase in the 3rd extractor 22, is transported to and is concentrated under reduced pressure in kettle 24, and decompression, which is distillated, to be obtained
AZ-8；
Step 4, the second cyclization process：Sequentially added into the second cyclization kettle 26 volume fraction be 95% ethanol solution and
AZ-8, is heated to backflow, reacts 9~11h；Then the reaction solution in the second cyclization kettle 26 is transported to mistake in filtering drying machine 27
Filter, collects filtrate, filter cake is dried in vacuo under the conditions of 60 DEG C, AZ-9 is obtained；
Step 5, hydrolyzing process：The hydroxide that AZ-9, methanol and mass fraction are 10% is sequentially added into hydrolysis kettle 28
1N salt acid for adjusting pH is added dropwise to 3 in sodium water solution, 1~1.5h of temperature rising reflux, stirring, and the material in hydrolysis kettle 28 is transported into the
Filtered in three bag type filtering machines 29, obtain filter cake；Filter cake is added in the second microwave vacuum dryer 30, it is true under the conditions of 60 DEG C
Sky is dried, and obtains Azilsartan crude product；
Step 6, refining step：Azilsartan crude product, activated carbon and absolute ethyl alcohol are sequentially added into decolouring kettle 31, is risen
Temperature, flowed back 2~3h, and the material in decolouring kettle 31 is transported in micropore decarbonization filtering machine 32 and filtered, the material conveying after filtering
Into the second crystallization kettle 33,5 DEG C, stirring, crystallization are cooled to；Material in second crystallization kettle 33 is transported to mistake in centrifuge 35
Filter, collects filtrate；Filter cake in centrifuge 35 is added in double conic rotary vacuum dryer 36, vacuum is done under the conditions of 60 DEG C
It is dry, obtain Azilsartan finished product.
In step 1,3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] Methyl anthranilate per 1kg needs original
The consumption of carbonic acid tetra-ethyl ester is：0.83~0.88L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] aminobenzene per 1kg
Methyl formate needs the consumption of glacial acetic acid to be：0.16~0.21L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) first per 1kg
Base] Methyl anthranilate needs the consumption of 5N sodium hydroxide solutions to be：1.19~1.23L；The dropwise addition of 5N sodium hydroxide solutions
Time is 3~5h.
In step 2, the AZ-6 per 1kg needs the consumption of dimethyl sulfoxide (DMSO) to be：3.56~3.6L；AZ-6 and hydroxylamine hydrochloride
Mass ratio is：1：1.1~1：1.2；The mass ratio of AZ-6 and sodium acid carbonate is：1：0.98~1：1.02；AZ-6 per 1kg needs
The consumption of concentrated hydrochloric acid is：0.15~0.2L；The mass ratio of AZ-6 and sodium carbonate is：1：0.85~1：0.95；AZ-6 per 1kg is needed
The consumption for wanting the ethanol solution that volume fraction is 95% is：3.63~3.72L.
In step 3, dichloromethane is added in three times：The consumption of the dichloromethane solution of addition is for the first time：Per 1kg
AZ-7 needs the consumption of dichloromethane to be：1.5~1.6L, second of addition is ethyl chloroformate -- dichloromethane solution, often
1kg AZ-7 needs ethyl chloroformate -- and the consumption of dichloromethane solution is：0.89~1.01L, ethyl chloroformate -- dichloromethane
Alkane solution is mixed to get using ethyl chloroformate with dichloromethane, wherein the volume proportion of ethyl chloroformate and dichloromethane
For 1：4~1：4.5；The consumption of the dichloromethane solution of addition is for the third time：AZ-7 per 1kg needs the consumption of dichloromethane
For：0.75~0.8L；AZ-7 per 1kg needs the consumption of triethylamine to be：0.36~0.4L.
In step 4, the volume ratio for the ethanol solution that AZ-8 is 95% with volume fraction is 1：4.8~1：5.
In step 5, the AZ-9 per 1kg needs the consumption of methanol to be 5.3~5.9L；AZ-9 per 1kg needs mass fraction
It is 2.2~2.3L for the consumption of 10% sodium hydrate aqueous solution.
9. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 6, wherein Ah
The mass ratio of Qi Shatan crude products and activated carbon is 1：0.09~1：0.11, wherein needing volume fraction per 1kg Azilsartan crude products
It is 4.58~5.34L for the consumption of 95% ethanol solution.
Embodiment 1
1st, the first cyclization process
Step 1.1, to the first cyclization kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add through electronics
The weighed AZ-5 of scale, then the glacial acetic acid of the tetraethyl orthocarbonate from storage tank, storage tank is squeezed into by the first cyclization by measuring pump
In kettle, stirring is warming up to after 75 DEG C, temperature control reaction 4h, is cooled to 10 DEG C, 5N is slowly added dropwise by measuring pump at this temperature in holding
From the first blending tank sodium hydroxide solution, 3h is added dropwise；3- amino -2- [(2 '-cyanobiphenyl -4- bases) first wherein per 1kg
Base] Methyl anthranilate needs the tetraethyl orthocarbonate consumption to be：0.83L；Per 1kg 3- amino -2- [(2 '-cyanobiphenyl -
4- yls) methyl] Methyl anthranilate needs the consumption of glacial acetic acid to be：0.16L；[(2 '-cyano group joins 3- amino -2- per 1kg
Benzene -4- bases) methyl] Methyl anthranilate needs the consumption of 5N sodium hydroxide solutions to be：1.19L；
After step 1.2, reaction terminate, reaction solution is squeezed into washing, filtering and drying machine by the first line pump and filtered, filter
Liquid send municipal processing, then adds purifying water wash through common conduit, obtains AZ-6 filter cakes, filter cake is dried in vacuo under the conditions of 70 DEG C
Obtain faint yellow solid AZ-6.
2nd, addition process
Step 2.1, to addition kettle carry out early stage vacuumize, after cleaning, sequentially added by vacuum feeder through electronics
The AZ-6 that the load weighted sodium acid carbonate of scale, hydroxylamine hydrochloride, step 1 are obtained, it is using measuring pump that the dimethyl sulfoxide (DMSO) in storage tank is defeated
It is sent in addition kettle, stirring and dissolving, is warming up to 75 DEG C, reacts 22 hours；Reaction solution in addition kettle is passed through into the second line pump
The first crystallization kettle is squeezed into, room temperature, crystallization is down to；AZ-6 per 1kg needs the consumption of dimethyl sulfoxide (DMSO) to be：3.56L；AZ-6 and salt
The mass ratio of sour azanol is：1：1.1；The mass ratio of AZ-6 and sodium acid carbonate is：1：0.98.
Step 2.2, the material in the first crystallization kettle filtered into the first bag type filtering machine through pipeline, collect filter
Liquid, reclaims dimethyl sulfoxide (DMSO), filter cake is manually added in the first neutralization kettle, purified water is added in first through common conduit
In kettle, stirring, then be added drop-wise to mass fraction in the first neutralization kettle for 36% hydrochloric acid with measuring pump is slow, regulation pH value to 3
Afterwards, reaction solution is squeezed into MGM tubular membranes filters by the 3rd line pump and filtered, filter residue send municipal processing, collect filtrate；
Filtrate is neutralized in kettle through pipeline to second, is added through the load weighted sodium carbonate solid of electronic scale, stirred by vacuum feeder
Mix, regulation pH value to 11；By second neutralize kettle in material through pipeline the agitation and filtration into filtration washing machine, obtain AZ-7 filter
Cake, filtrate send municipal processing.Again through common conduit purifying water washing, filtrate send Sewage Disposal to handle, wherein per 1kg
AZ-6 needs the consumption of concentrated hydrochloric acid to be：0.15L；The mass ratio of AZ-6 and sodium carbonate is：1：0.85；
Step 2.3, the filter cake in filtration washing machine is manually added in back flow reaction kettle, then body is squeezed into by measuring pump
Fraction is 95% ethanol solution, is warming up to backflow, stirs 1.5h, and cooling is defeated through pipeline by the material in back flow reaction kettle
It is sent in the second bag type filtering machine and filters, collects filtrate, the filter cake in the second bag type filtering machine is added by vacuum feeder
Into the first microwave vacuum dryer, it is dried in vacuo under the conditions of 50 DEG C, obtains AZ-7, reclaims the ethanol (rate of recovery in filtrate
For 95%), residue send municipal processing, wherein the AZ-6 per 1kg needs the consumption of ethanol solution that volume fraction is 95% to be：
3.63L。
3rd, it is condensed process
Step 3.1, early stage is carried out to condensation kettle vacuumize, after cleaning, step is added by vacuum feeder and obtained
AZ-7, the dichloromethane of the triethylamine from storage tank, storage tank is sequentially added by measuring pump, the dichloromethane solution this time added
Consumption be：AZ-7 per 1kg needs the consumption of dichloromethane to be：1.5L, then be slowly added dropwise by measuring pump mixed from second
Closing the ethyl chloroformate in tank -- dichloromethane solution is into condensation kettle, ethyl chloroformate -- the dichloromethane solution this time added
Consumption be：Ethyl chloroformate is needed per 1kg AZ-7 -- the consumption of dichloromethane solution is：0.89L, wherein chloro-carbonic acid second
Ester -- dichloromethane solution is mixed to get using ethyl chloroformate with dichloromethane, wherein ethyl chloroformate and dichloromethane
Volume proportion be 1：4；2.5h is added dropwise at 25 DEG C in controlling reaction temperature, continues to react 3h；AZ-7 per 1kg needs triethylamine
Consumption be：0.36L.
Step 3.2, the reaction solution in condensation kettle is driven into the first extractor by the 4th line pump, then through public pipe
Road adds purified water extraction；Aqueous phase in first extractor is squeezed into the second extractor through the 5th line pump, then through measuring pump
The dichloromethane extraction from storage tank is squeezed into, the consumption of the dichloromethane solution this time added is：AZ-7 per 1kg needs dichloro
The consumption of methane is：0.75L；；First extractor and the organic phase of the second extractor outflow are through pipeline to the 3rd extractor
In, then through common conduit addition purified water extraction；Collecting aqueous phase send Sewage Disposal to handle；
Step 3.3, by the organic phase in the 3rd extractor through pipeline to being concentrated under reduced pressure in kettle, subtract under the conditions of 30 DEG C
Concentration and recovery dichloromethane is pressed, distillate is the 3/4 of organic phase volume, obtains light yellow oil AZ-8.
4th, the second cyclization process
Step 4.1, early stage is carried out to the second cyclization kettle vacuumize, after cleaning, squeezed into successively by feed pump from subtracting
The ethanol solution for pressing the AZ-8 in concentration kettle, the volume fraction in storage tank to be 95%, is heated to backflow, reacts 9h, wherein AZ-8
The volume ratio for the ethanol solution for being 95% with volume fraction is 1：4.8；
Step 4.2, the reaction solution in the second cyclization kettle filtered into filtering drying machine through pipeline, collects filtrate,
By filter cake, it is dried in vacuo under the conditions of 60 DEG C, obtains AZ-9, reclaims the ethanol in filtrate, residue send municipal processing.
5th, hydrolyzing process
Step 5.1, to hydrolysis kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add claim through electronic scale
Measured AZ-9, then sequentially add by measuring pump 10% sodium hydrate aqueous solution of the methanol from storage tank, storage tank, heating
Flow back 1h, and stirring is lower to be added dropwise the 1N salt acid for adjusting pH from storage tank to 3 by measuring pump；AZ-9 per 1kg needs the use of methanol
Measure as 5.3L；AZ-9 per 1kg needs the consumption of 10% sodium hydrate aqueous solution to be 2.2L；
Step 5.2, the material in hydrolysis kettle filtered into the 3rd bag type filtering machine through pipeline, collect filtrate, filter
Liquid send Sewage Disposal to handle；
Step 5.3, the filter cake in the 3rd bag type filtering machine by vacuum feeder is added to the second micro-wave vacuum
In machine, it is dried in vacuo under the conditions of 60 DEG C, obtains Azilsartan crude product (content 90%).
6th, refining step
Step 6.1, early stage is carried out to decolouring kettle vacuumize, after cleaning, added by vacuum feeder from second micro-
After the Azilsartan crude product of ripple vacuum drier, manually add through the load weighted activated carbon of electronic scale, then added through pump from storage
The volume fraction of tank is 95% ethanol solution, heating, backflow 2h；Wherein the mass ratio of Azilsartan crude product and activated carbon is 1：
0.09, the consumption that the ethanol solution that volume fraction is 95% is needed per 1kg Azilsartan crude products is 4.58L；
Step 6.2, the material in decolouring kettle filtered into microwave decarburization filter through pipeline, the material after filtering
Through pipeline to crystallization kettle, 5 DEG C, stirring, crystallization are slowly cooled to；Material in second crystallization kettle is beaten through the 6th line pump
Enter in centrifuge and filter, collect filtrate；
Step 6.3, by the filter cake in centrifuge by vacuum feeder add double conic rotary vacuum dryer in, at 60 DEG C
Under the conditions of be dried in vacuo, obtain Azilsartan finished product, reclaim the ethanol (rate of recovery is 95%) in filtrate, residue send municipal place
Reason.
Embodiment 2
1st, the first cyclization process
Step 1.1, to the first cyclization kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add through electronics
The weighed AZ-5 of scale, then the glacial acetic acid of the tetraethyl orthocarbonate from storage tank, storage tank is squeezed into by the first cyclization by measuring pump
In kettle, stirring is warming up to after 80 DEG C, temperature control reaction 4h, is cooled to 10 DEG C, 5N is slowly added dropwise by measuring pump at this temperature in holding
From the first blending tank sodium hydroxide solution, 4h is added dropwise；3- amino -2- [(2 '-cyanobiphenyl -4- bases) first wherein per 1kg
Base] Methyl anthranilate needs the tetraethyl orthocarbonate consumption to be：0.86L；Per 1kg 3- amino -2- [(2 '-cyanobiphenyl -
4- yls) methyl] Methyl anthranilate needs the consumption of glacial acetic acid to be：0.19L；[(2 '-cyano group joins 3- amino -2- per 1kg
Benzene -4- bases) methyl] Methyl anthranilate needs the consumption of 5N sodium hydroxide solutions to be：1.2L；
After step 1.2, reaction terminate, reaction solution is squeezed into washing, filtering and drying machine by the first line pump and filtered, filter
Liquid send municipal processing, then adds purifying water wash through common conduit, obtains AZ-6 filter cakes, filter cake is dried in vacuo under the conditions of 80 DEG C
Obtain faint yellow solid AZ-6.
2nd, addition process
Step 2.1, to addition kettle carry out early stage vacuumize, after cleaning, sequentially added by vacuum feeder through electronics
The AZ-6 that the load weighted sodium acid carbonate of scale, hydroxylamine hydrochloride, step 1 are obtained, it is using measuring pump that the dimethyl sulfoxide (DMSO) in storage tank is defeated
It is sent in addition kettle, stirring and dissolving, is warming up to 80 DEG C, reacts 24 hours；Reaction solution in addition kettle is passed through into the second line pump
The first crystallization kettle is squeezed into, room temperature, crystallization is down to；AZ-6 per 1kg needs the consumption of dimethyl sulfoxide (DMSO) to be：3.58L；AZ-6 and salt
The mass ratio of sour azanol is：1：1.15；The mass ratio of AZ-6 and sodium acid carbonate is：1：1；
Step 2.2, the material in the first crystallization kettle filtered into the first bag type filtering machine through pipeline, collect filter
Liquid, reclaims dimethyl sulfoxide (DMSO), filter cake is manually added in the first neutralization kettle, purified water is added in first through common conduit
In kettle, stirring, then be added drop-wise to mass fraction in the first neutralization kettle for 36% hydrochloric acid with measuring pump is slow, pH value is adjusted to 3,
The first reaction solution for neutralizing kettle will be neutralized filtering in MGM tubular membranes filters is squeezed into by the 3rd line pump, filter residue send municipal administration
Processing, collects filtrate；Filtrate is neutralized in kettle through pipeline to second, is added by vacuum feeder load weighted through electronic scale
Sodium carbonate solid, stirring, regulation pH value to 11；The material second neutralized in kettle is stirred into filtration washing machine through pipeline
Filtering, obtains AZ-7 filter cakes, filtrate send municipal processing.Again through common conduit purifying water washing, filtrate send Sewage Disposal to handle,
AZ-6 wherein per 1kg needs the consumption of concentrated hydrochloric acid to be：0.17L；The mass ratio of AZ-6 and sodium carbonate is：1：0.88；
Step 2.3, the filter cake in filtration washing machine is manually added in back flow reaction kettle, then body is squeezed into by measuring pump
Fraction is 95% ethanol solution, is warming up to backflow, stirs 2h, cooling, by the material in back flow reaction kettle through pipeline
Filtered into the second bag type filtering machine, collect filtrate, the filter cake in the second bag type filtering machine is added to by vacuum feeder
In first microwave vacuum dryer, it is dried in vacuo under the conditions of 60 DEG C, obtains AZ-7, (rate of recovery is the ethanol for reclaiming in filtrate
95%), residue send municipal processing, wherein the AZ-6 per 1kg needs the consumption of ethanol solution that volume fraction is 95% to be：
3.67L。
3rd, it is condensed process
Step 3.1, early stage is carried out to condensation kettle vacuumize, after cleaning, step is added by vacuum feeder and obtained
AZ-7, the dichloromethane of the triethylamine from storage tank, storage tank is sequentially added by measuring pump, the dichloromethane solution this time added
Consumption be：AZ-7 per 1kg needs the consumption of dichloromethane to be：1.55L, then be slowly added dropwise by measuring pump mixed from second
Closing the ethyl chloroformate in tank -- dichloromethane solution is into condensation kettle, ethyl chloroformate -- the dichloromethane solution this time added
Consumption be：Ethyl chloroformate is needed per 1kg AZ-7 -- the consumption of dichloromethane solution is：0.95L, wherein chloro-carbonic acid second
Ester -- dichloromethane solution is mixed to get using ethyl chloroformate with dichloromethane, wherein ethyl chloroformate and dichloromethane
Volume proportion be 1：4.25；3h is added dropwise at 25 DEG C in controlling reaction temperature, continues to react 4h；AZ-7 per 1kg needs triethylamine
Consumption be：0.38L.
Step 3.2, the reaction solution in condensation kettle is driven into the first extractor by the 4th line pump, then through public pipe
Road adds purified water extraction；Aqueous phase in first extractor is squeezed into the second extractor through the 5th line pump, then through measuring pump
The dichloromethane extraction from storage tank is squeezed into, the consumption of the dichloromethane solution this time added is：AZ-7 per 1kg needs dichloro
The consumption of methane is：0.77L；First extractor and the organic phase of the second extractor outflow are through pipeline to the 3rd extractor
In, then through common conduit addition purified water extraction；Collecting aqueous phase send Sewage Disposal to handle；
Step 3.3, by the organic phase in the 3rd extractor through pipeline to being concentrated under reduced pressure in kettle, subtract under the conditions of 30 DEG C
Concentration and recovery dichloromethane is pressed, distillate is the 3/4 of organic phase volume, obtains light yellow oil AZ-8.
4th, the second cyclization process
Step 4.1, early stage is carried out to the second cyclization kettle vacuumize, after cleaning, squeezed into successively by feed pump from subtracting
The ethanol solution for pressing the AZ-8 in concentration kettle, the volume fraction in storage tank to be 95%, is heated to backflow, reacts 10h, wherein AZ-8
The volume ratio for the ethanol solution for being 95% with volume fraction is 1：4.9；
Step 4.2, the reaction solution in the second cyclization kettle filtered into filtering drying machine through pipeline, collects filtrate,
By filter cake, it is dried in vacuo under the conditions of 60 DEG C, obtains AZ-9, reclaim the ethanol in filtrate, residue send municipal processing.
5th, hydrolyzing process
Step 5.1, to hydrolysis kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add claim through electronic scale
Measured AZ-9, then sequentially add by measuring pump 10% sodium hydrate aqueous solution of the methanol from storage tank, storage tank, heating
Flow back 1.25h, and stirring is lower to be added dropwise the 1N salt acid for adjusting pH from storage tank to 3 by measuring pump；AZ-9 per 1kg needs methanol
Consumption is 5.6L；AZ-9 per 1kg needs the consumption of 10% sodium hydrate aqueous solution to be 2.25L；
Step 5.2, the material in hydrolysis kettle filtered into the 3rd bag type filtering machine through pipeline, collect filtrate, filter
Liquid send Sewage Disposal to handle；
Step 5.3, the filter cake in the 3rd bag type filtering machine by vacuum feeder is added to the second micro-wave vacuum
In machine, it is dried in vacuo under the conditions of 60 DEG C, obtains Azilsartan crude product (content 90%).
6th, refining step
Step 6.1, early stage is carried out to decolouring kettle vacuumize, after cleaning, added by vacuum feeder from second micro-
After the Azilsartan crude product of ripple vacuum drier, manually add through the load weighted activated carbon of electronic scale, then added through pump from storage
The volume fraction of tank is 95% ethanol solution, heating, backflow 2.5h；The mass ratio of wherein Azilsartan crude product and activated carbon is
1：0.1, wherein the consumption that the ethanol solution that volume fraction is 95% is needed per 1kg Azilsartan crude products is 5.0L；
Step 6.2, the material in decolouring kettle filtered into microwave decarburization filter through pipeline, the material after filtering
Through pipeline to crystallization kettle, 5 DEG C, stirring, crystallization are slowly cooled to；Material in second crystallization kettle is beaten through the 6th line pump
Enter in centrifuge and filter, collect filtrate；
Step 6.3, by the filter cake in centrifuge by vacuum feeder add double conic rotary vacuum dryer in, at 60 DEG C
Under the conditions of be dried in vacuo, obtain Azilsartan finished product, reclaim the ethanol (rate of recovery is 95%) in filtrate, residue send municipal place
Reason.
Embodiment 3
1st, the first cyclization process
Step 1.1, to the first cyclization kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add through electronics
The weighed AZ-5 of scale, then the glacial acetic acid of the tetraethyl orthocarbonate from storage tank, storage tank is squeezed into by the first cyclization by measuring pump
In kettle, stirring is warming up to after 85 DEG C, temperature control reaction 4h, is cooled to 10 DEG C, 5N is slowly added dropwise by measuring pump at this temperature in holding
From the first blending tank sodium hydroxide solution, 5h is added dropwise；3- amino -2- [(2 '-cyanobiphenyl -4- bases) first wherein per 1kg
Base] Methyl anthranilate needs the tetraethyl orthocarbonate consumption to be：0.88L；Per 1kg 3- amino -2- [(2 '-cyanobiphenyl -
4- yls) methyl] Methyl anthranilate needs the consumption of glacial acetic acid to be：0.21L；[(2 '-cyano group joins 3- amino -2- per 1kg
Benzene -4- bases) methyl] Methyl anthranilate needs the consumption of 5N sodium hydroxide solutions to be：1.23L；
After step 1.2, reaction terminate, reaction solution is squeezed into washing, filtering and drying machine by the first line pump and filtered, filter
Liquid send municipal processing, then adds purifying water wash through common conduit, obtains AZ-6 filter cakes, filter cake is dried in vacuo under the conditions of 90 DEG C
Obtain faint yellow solid AZ-6.
2nd, addition process
Step 2.1, to addition kettle carry out early stage vacuumize, after cleaning, sequentially added by vacuum feeder through electronics
The AZ-6 that the load weighted sodium acid carbonate of scale, hydroxylamine hydrochloride, step 1 are obtained, it is using measuring pump that the dimethyl sulfoxide (DMSO) in storage tank is defeated
It is sent in addition kettle, stirring and dissolving, is warming up to 85 DEG C, reacts 26 hours；Reaction solution in addition kettle is passed through into the second line pump
The first crystallization kettle is squeezed into, room temperature, crystallization is down to；AZ-6 per 1kg needs the consumption of dimethyl sulfoxide (DMSO) to be：3.6L；AZ-6 and salt
The mass ratio of sour azanol is：1：1.2；The mass ratio of AZ-6 and sodium acid carbonate is：1：1.02；
Step 2.2, the material in the first crystallization kettle filtered into the first bag type filtering machine through pipeline, collect filter
Liquid, reclaims dimethyl sulfoxide (DMSO), filter cake is manually added in the first neutralization kettle, purified water is added in first through common conduit
In kettle, stirring, then be added drop-wise to mass fraction in the first neutralization kettle for 36% hydrochloric acid with measuring pump is slow, pH value is adjusted to 3,
The first reaction solution for neutralizing kettle will be neutralized filtering in MGM tubular membranes filters is squeezed into by the 3rd line pump, filter residue send municipal administration
Processing, collects filtrate；Filtrate is neutralized in kettle through pipeline to second, is added by vacuum feeder load weighted through electronic scale
Sodium carbonate solid, stirring, regulation pH value to 11；The material second neutralized in kettle is stirred into filtration washing machine through pipeline
Filtering, obtains AZ-7 filter cakes, filtrate send municipal processing.Again through common conduit purifying water washing, filtrate send Sewage Disposal to handle,
AZ-6 wherein per 1kg needs the consumption of concentrated hydrochloric acid to be：0.2L；The mass ratio of AZ-6 and sodium carbonate is：1:0.95；
Step 2.3, the filter cake in filtration washing machine is manually added in back flow reaction kettle, then body is squeezed into by measuring pump
Fraction is 95% ethanol solution, is warming up to backflow, stirs 2.5h, and cooling is defeated through pipeline by the material in back flow reaction kettle
It is sent in the second bag type filtering machine and filters, collects filtrate, the filter cake in the second bag type filtering machine is added by vacuum feeder
Into the first microwave vacuum dryer, it is dried in vacuo under the conditions of 50 DEG C, obtains AZ-7, reclaims the ethanol (rate of recovery in filtrate
For 95%), residue send municipal processing, wherein the AZ-6 per 1kg needs the consumption of ethanol solution that volume fraction is 95% to be：
3.72L。
3rd, it is condensed process
Step 3.1, early stage is carried out to condensation kettle vacuumize, after cleaning, step is added by vacuum feeder and obtained
AZ-7, the dichloromethane of the triethylamine from storage tank, storage tank is sequentially added by measuring pump, the dichloromethane solution this time added
Consumption be：AZ-7 per 1kg needs the consumption of dichloromethane to be：1.6L, amount pump is slowly added dropwise in the second blending tank
Ethyl chloroformate -- dichloromethane solution is into condensation kettle, ethyl chloroformate -- the consumption of dichloromethane solution this time added
For：Ethyl chloroformate is needed per 1kg AZ-7 -- the consumption of dichloromethane solution is：1.01L, wherein ethyl chloroformate -- dichloro
Dichloromethane is mixed to get using ethyl chloroformate with dichloromethane, and the volume of wherein ethyl chloroformate and dichloromethane is matched somebody with somebody
Than for 1：4.5；Controlling reaction temperature is added dropwise 3.5 and continues to react 5h at 25 DEG C；AZ-7 per 1kg needs the consumption of triethylamine to be：
0.4L。
Step 3.2, the reaction solution in condensation kettle is driven into the first extractor by the 4th line pump, then through public pipe
Road adds purified water extraction；Aqueous phase in first extractor is squeezed into the second extractor through the 5th line pump, then through measuring pump
The dichloromethane extraction from storage tank is squeezed into, the consumption of the dichloromethane solution this time added is：AZ-7 per 1kg needs dichloro
The consumption of methane is：0.8L；；First extractor and the organic phase of the second extractor outflow are through pipeline to the 3rd extractor
In, then through common conduit addition purified water extraction；Collecting aqueous phase send Sewage Disposal to handle；
Step 3.3, by the organic phase in the 3rd extractor through pipeline to being concentrated under reduced pressure in kettle, subtract under the conditions of 30 DEG C
Concentration and recovery dichloromethane is pressed, distillate is the 3/4 of organic phase volume, obtains light yellow oil AZ-8.
4th, the second cyclization process
Step 4.1, early stage is carried out to the second cyclization kettle vacuumize, after cleaning, squeezed into successively by feed pump from subtracting
The ethanol solution for pressing the AZ-8 in concentration kettle, the volume fraction in storage tank to be 95%, is heated to backflow, reacts 11h, wherein AZ-8
The volume ratio for the ethanol solution for being 95% with volume fraction is 1：5；
Step 4.2, the reaction solution in the second cyclization kettle filtered into filtering drying machine through pipeline, collects filtrate,
By filter cake, it is dried in vacuo under the conditions of 60 DEG C, obtains AZ-9, reclaims the ethanol in filtrate, residue send municipal processing.
5th, hydrolyzing process
Step 5.1, to hydrolysis kettle carry out early stage vacuumize, after cleaning, by vacuum feeder add claim through electronic scale
Measured AZ-9, then sequentially add by measuring pump 10% sodium hydrate aqueous solution of the methanol from storage tank, storage tank, heating
Flow back 1.5h, and stirring is lower to be added dropwise the 1N salt acid for adjusting pH from storage tank to 3 by measuring pump；AZ-9 per 1kg needs methanol
Consumption is 5.9L；AZ-9 per 1kg needs the consumption of 10% sodium hydrate aqueous solution to be 2.3L；
Step 5.2, the material in hydrolysis kettle filtered into the 3rd bag type filtering machine through pipeline, collect filtrate, filter
Liquid send Sewage Disposal to handle；
Step 5.3, the filter cake in the 3rd bag type filtering machine by vacuum feeder is added to the second micro-wave vacuum
In machine, it is dried in vacuo under the conditions of 60 DEG C, obtains Azilsartan crude product (content 90%).
6th, refining step
Step 6.1, early stage is carried out to decolouring kettle vacuumize, after cleaning, added by vacuum feeder from second micro-
After the Azilsartan crude product of ripple vacuum drier, manually add through the load weighted activated carbon of electronic scale, then added through pump from storage
The volume fraction of tank is 95% ethanol solution, heating, backflow 3h；Wherein the mass ratio of Azilsartan crude product and activated carbon is 1：
0.11, the consumption that the ethanol solution that volume fraction is 95% is needed per 1kg Azilsartan crude products is 5.34L；
Step 6.2, the material in decolouring kettle filtered into microwave decarburization filter through pipeline, the material after filtering
Through pipeline to crystallization kettle, 5 DEG C, stirring, crystallization are slowly cooled to；Material in second crystallization kettle is beaten through the 6th line pump
Enter in centrifuge and filter, collect filtrate；
Step 6.3, by the filter cake in centrifuge by vacuum feeder add double conic rotary vacuum dryer in, at 60 DEG C
Under the conditions of be dried in vacuo, obtain Azilsartan finished product, reclaim the ethanol (rate of recovery is 95%) in filtrate, residue send municipal place
Reason.
Feed purity specification such as table 1 used in embodiment 1-3：
Table 1. prepares the specification of material in each workshop section of Azilsartan
A kind of preparation method of Azilsartan of the present invention has the following advantages：The present invention devises a kind of unlisted chemistry
Bulk drug Azilsartan is applied to the preparation method of Workshop Production, and specific operation and technology branch are provided for actual drug production
Hold, there is good practical value.
Claims (9)
1. a kind of preparation facilities of Azilsartan, it is characterised in that including the first cyclization process preparation facilities for being sequentially connected plus
Into process preparation facilities, condensation process preparation facilities, the second cyclization process preparation facilities, hydrolyzing process preparation facilities and refined work
Sequence preparation facilities.
2. a kind of preparation facilities of Azilsartan according to claim 1, it is characterised in that the first cyclization process system
Standby device includes the first blending tank (1), the first cyclization kettle (2), the first line pump (3) and the washing, filtering and drying machine being sequentially connected
(4), the first cyclization kettle (2) is connected with the first vacuum feeder (37), the washing, filtering and drying machine (4) and addition process
Preparation facilities is connected；
The addition process preparation facilities includes the second vacuum feeder (38), addition kettle (5), the second line pump being sequentially connected
(6), the first crystallization kettle (7), the first bag type filtering machine (8), first neutralize kettle (9), the 3rd line pump (10), MGM tubular membranes
Filter (11), second neutralize kettle (12), filtration washing machine (13), back flow reaction kettle (14), the second bag type filtering machine (15), the
Three vacuum feeders (39) and the first microwave vacuum dryer (16), the second neutralization kettle (12) are connected with the 4th vacuum feeding
Machine (40), second vacuum feeder (38) is connected with washing, filtering and drying machine (4)；
The condensation process preparation facilities includes the 5th vacuum feeder (41), the second blending tank (17), condensation kettle (18), the 4th
Line pump (19), the first extractor (20), the 5th line pump (23), the second extractor (21), the 3rd extractor (22) and decompression
Concentration kettle (24), the discharging opening of first extractor (20) is connected by pipeline with the charging aperture of the 3rd extractor (22), institute
The 5th vacuum feeder (41) is stated to be connected with the first microwave vacuum dryer (16)；
The second cyclization process preparation facilities includes feed pump (25), the second cyclization kettle (26) and the filtration drying being sequentially connected
Machine (27), the feed pump (25) is connected with concentration kettle (24)；
The hydrolyzing process preparation facilities includes the 6th vacuum feeder (42), hydrolysis kettle (28), the 3rd bag type filtering machine (29)
And second microwave vacuum dryer (30), the 6th vacuum feeder (42) is connected with filtering drying machine (27)；
The refining step preparation facilities includes the 7th vacuum feeder (43), decolouring kettle (31), microwave decarburization being sequentially connected
Filter (32), the second crystallization kettle (33), the 6th line pump (34), centrifuge (35), the 8th vacuum feeder (44) and bipyramid
Rotary vacuum dryer (36), the 7th vacuum feeder (43) is connected with the second microwave vacuum dryer (30).
3. a kind of preparation method of Azilsartan, it is characterised in that using a kind of system of Azilsartan as claimed in claim 1
Standby device, comprises the following steps：
Step 1, the first cyclization process：3- amino -2- [(2 '-cyanobiphenyl -4- bases) is sequentially added into the first cyclization kettle (2)
Methyl] Methyl anthranilate, tetraethyl orthocarbonate and glacial acetic acid, stirring the first ring-closure reaction kettle (2) in reaction solution make it
It is warming up to after 75-85 DEG C, then temperature control reaction 4h is cooled to 10 DEG C, is added dropwise at such a temperature into the first ring-closure reaction kettle (2)
5N sodium hydroxide solutions, obtained reaction solution is input in washing, filtering and drying machine (4) and filtered, AZ-6 filter cakes are obtained, clearly
AZ-6 filter cakes are washed, AZ-6 filter cakes are dried in vacuo under the conditions of 70~90 DEG C and obtain solid AZ-6；
Step 2, addition process：Dimethyl sulfoxide (DMSO), AZ-6, hydroxylamine hydrochloride, sodium acid carbonate are sequentially added into addition kettle (5), is risen
Temperature reacts 22~26h, the reaction solution in addition kettle (5) is input in the first crystallization kettle (7), treats that it is down to 75~85 DEG C
Crystallization after room temperature；Material in first crystallization kettle (7) is filtered by the first bag type filtering machine (8), filtrate is collected, by obtained filter
Cake and water are added in the first neutralization reaction kettle (9), stirring, and it is 36% hydrochloric acid to the first neutralization reaction that concentration mass fraction, which is added dropwise,
In kettle (9), the reaction solution in the first neutralization reaction kettle (9) is driven into MGM tubular membranes filter (11) by regulation pH value to 3
Middle filtering, collects filtrate；Filtrate is transported in the second neutralization kettle (12), then addition sodium carbonate in kettle (12) is neutralized to second and is consolidated
Body, regulation pH value to 11；Material in second neutralization kettle (12) is transported to agitation and filtration in filtration washing machine (13), must be filtered
Cake；It is 95% ethanol solution that filter cake and volume fraction are sequentially added into back flow reaction kettle (14), is warming up to backflow, is stirred
Material in back flow reaction kettle (14) is transported to filtering in the second bag type filtering machine (15), by second by 1.5~2.5h, cooling
Filter cake in bag type filtering machine (15) is added in the first microwave vacuum dryer (16), and vacuum is done under the conditions of 50~70 DEG C
It is dry, obtain AZ-7；
Step 3, condensation process：AZ-7, triethylamine, dichloromethane are sequentially added into condensation kettle (18), chloromethane is then added dropwise again
Acetoacetic ester -- dichloromethane solution, time for adding is 2.5~3.5h, continues to react 3~5h, and controlling reaction temperature, will at 25 DEG C
Reaction solution in condensation kettle (18) is transported in the first extractor (20) and extracted with water, then by the first extractor (20)
Water conveying extracted into the second extractor (21), then to dichloromethane is added in the second extractor (21)；By first
Organic phase in extractor (20) is transported in the 3rd extractor (22) with the organic phase in the second extractor (21), then to the 3rd
Water is added in extractor (22) to be extracted, and is retained the organic phase in the 3rd extractor (22), is transported to the kettle that is concentrated under reduced pressure
(24) in, decompression, which is distillated, obtains AZ-8；
Step 4, the second cyclization process：Sequentially added into the second cyclization kettle (26) volume fraction be 95% ethanol solution and
AZ-8, is heated to backflow, reacts 9~11h；Then the reaction solution in the second cyclization kettle (26) is transported to filtering drying machine (27)
Middle filtering, collects filtrate, filter cake is dried in vacuo under the conditions of 60 DEG C, AZ-9 is obtained；
Step 5, hydrolyzing process：The sodium hydroxide that AZ-9, methanol and mass fraction are 10% is sequentially added into hydrolysis kettle (28)
1N salt acid for adjusting pH is added dropwise to 3 in the aqueous solution, 1~1.5h of temperature rising reflux, stirring, and the material in hydrolysis kettle (28) is transported into the
Filtered in three bag type filtering machines (29), obtain filter cake；Filter cake is added in the second microwave vacuum dryer (30), in 60 DEG C of conditions
Lower vacuum drying, obtains Azilsartan crude product；
Step 6, refining step：Azilsartan crude product, activated carbon and absolute ethyl alcohol are sequentially added into decolouring kettle (31), is heated up,
Flowed back 2~3h, and the material in decolouring kettle (31) is transported into filtering in micropore decarbonization filtering machine (32), the material conveying after filtering
Into the second crystallization kettle (33), 5 DEG C, stirring, crystallization are cooled to；Material in second crystallization kettle (33) is transported to centrifuge
(35) filtered in, collect filtrate；Filter cake in centrifuge (35) is added in double conic rotary vacuum dryer (36), at 60 DEG C
Under the conditions of be dried in vacuo, obtain Azilsartan finished product.
4. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 1, the 3- per 1kg
Amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] Methyl anthranilate needs the consumption of tetraethyl orthocarbonate to be：0.83~
0.88L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] Methyl anthranilate per 1kg needs the consumption of glacial acetic acid
For：0.16~0.21L；3- amino -2- [(2 '-cyanobiphenyl -4- bases) methyl] Methyl anthranilate per 1kg needs 5N hydrogen
The consumption of sodium hydroxide solution is：1.19~1.23L；The time for adding of 5N sodium hydroxide solutions is 3~5h.
5. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 2, the AZ- per 1kg
6 need the consumption of dimethyl sulfoxide (DMSO) to be：3.56~3.6L；The mass ratio of AZ-6 and hydroxylamine hydrochloride is：1：1.1~1：1.2；AZ-6
Mass ratio with sodium acid carbonate is：1：0.98~1：1.02；AZ-6 per 1kg needs the consumption of concentrated hydrochloric acid to be：0.15~0.2L；
The mass ratio of AZ-6 and sodium carbonate is：1：0.85~1：0.95；AZ-6 per 1kg needs the ethanol solution that volume fraction is 95%
Consumption be：3.63~3.72L.
6. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 3, dichloromethane point
Three additions：The consumption of the dichloromethane solution of addition is for the first time：AZ-7 per 1kg needs the consumption of dichloromethane to be：1.5
~1.6L, second -- dichloromethane solution, the AZ-7 per 1kg needs ethyl chloroformate -- dichloro that is ethyl chloroformate added
The consumption of dichloromethane is：0.89~1.01L, ethyl chloroformate -- dichloromethane solution are to use ethyl chloroformate and dichloromethane
What alkane was mixed to get, wherein the volume proportion of ethyl chloroformate and dichloromethane is 1：4~1：4.5；The dichloro that third time is added
The consumption of dichloromethane is：AZ-7 per 1kg needs the consumption of dichloromethane to be：0.75~0.8L；AZ-7 per 1kg needs three
The consumption of ethamine is：0.36~0.4L.
7. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 4, AZ-8 and volume
The volume ratio for the ethanol solution that fraction is 95% is 1：4.8~1：5.
8. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 5, the AZ- per 1kg
9 need the consumption of methanol for 5.3~5.9L；AZ-9 per 1kg needs the use for the sodium hydrate aqueous solution that mass fraction is 10%
Measure as 2.2~2.3L.
9. the preparation method of a kind of Azilsartan according to claim 3, it is characterised in that in step 6, wherein A Qisha
The mass ratio of smooth crude product and activated carbon is 1：0.09~1：0.11, wherein needing the volume fraction to be per 1kg Azilsartan crude products
The consumption of 95% ethanol solution is 4.58~5.34L.
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| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
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| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
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| 束蓓艳，等: "阿奇沙坦的合成", 《中国医药工业杂志》 * |
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| CN108003058A (en) * | 2017-12-12 | 2018-05-08 | 淄博鑫泉医药技术服务有限公司 | The process for purification of sartanbiphenyl |
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