CN108456160A - A kind of synthesis technology of Amlodipine Besylate Tablet - Google Patents
A kind of synthesis technology of Amlodipine Besylate Tablet Download PDFInfo
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- CN108456160A CN108456160A CN201810212857.8A CN201810212857A CN108456160A CN 108456160 A CN108456160 A CN 108456160A CN 201810212857 A CN201810212857 A CN 201810212857A CN 108456160 A CN108456160 A CN 108456160A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
The problem of the invention discloses a kind of synthesis technologies of Amlodipine Besylate Tablet, are related to medical synthesis technical field, and the product purity for solving existing synthesis technology preparation is low, product quality poor controllability.The present invention controls the parameter of synthesis technology using phthalic anhydride as raw material, shortens technological process, reduces synthesis cost, and product yield is up to 91%, Amlodipine Besylate Tablet purity obtained is up to 99.5%；The present invention further prepares Amlodipine Besylate Tablet using homemade Amlodipine as raw material, reduces product cost, and product quality controllability is strong.
Description
Technical field
The present invention relates to medical synthesis technical fields, more specifically, it relates to a kind of synthesis of Amlodipine Besylate Tablet
Technique.
Background technology
Amlodipine Besylate Tablet is dihydropyridine type calcium antagonists (calcium ion antagonist or slow channel blocking agent).Cardiac muscle and
The contraction of smooth muscle enters cell dependent on extracellular calcium by specific ion channel.This product selective depression calcium ion
Cross-film enters smooth muscle cell and cardiac muscle cell, is more than cardiac muscle to the effect of smooth muscle.
A kind of preparation of amlodipine benzenesulphonate is disclosed in the Chinese invention patent of Publication No. CN1263525A
Method, by Amlodipine elder generation and organic or inorganic acid forming salt, then again with alkali metal benzene sulfonate in water-alcohol in the mixed solvent
Reaction is made, and yield is 81~90%.
It needs, first by Amlodipine at salt, then to react with benzene sulfonate again, which increase reactions to walk when preparing due to it
Suddenly, and to industrial production increase cost.In addition this method is using metathesis reaction due to preparing amlodipine benzenesulphonate, because
This raw material Amlodipine in obtained amlodipine benzenesulphonate is difficult to completely eliminate, and purity is low, the quality control to product
It is unfavorable to make.
Invention content
In view of the deficiencies of the prior art, the present invention intends to provide a kind of synthesis work of Amlodipine Besylate Tablet
Skill, with rate of recovery height, product purity is high, the strong advantage of product quality controllability.
To achieve the above object, the present invention provides following technical solutions：
A kind of synthesis technology of Amlodipine Besylate Tablet, includes the following steps：
Step 1, the preparation of N- (2- ethoxys)-phthalimide：
In retort, toluene is put into, phthalic anhydride is added under agitation, be warming up to 60-80 DEG C, ethanol amine is added dropwise, after adding
It is warming up to 110 DEG C, reflux dewatering 12 hours or more is cooled to 20 ± 5 DEG C, centrifugal filtration washs filter residue with toluene, dries, and does
Dry, discharging obtains N- (2- ethoxys)-phthalimide；
Step 2, the preparation of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, toluene, stirring heating are put into, toluene distillation maintains the reflux for a point water after liquid is full of in water knockout drum,
Sampling and measuring divides water, when phegma moisture content≤0.2%, changes back stream as distillation, distills out toluene, stirs lower cooling, wait in tank
When temperature is down to 45 DEG C, retort nitrogen charging is given, continues to be cooled to 0 ± 5 DEG C, is added with stirring N- (2- ethoxys)-O-phthalic
Acid imide is subsequently added into sodium hydride, finishes, and covers tightly cover, is stirred under the conditions of 0 ± 5 DEG C, and 4- chloracetyls are pumped into measuring tank
Ethyl acetate, toluene are simultaneously uniformly mixed, and the toluene that 4- chloroacetyl acetacetic esters are added dropwise into retort under the conditions of 0 ± 5 DEG C is molten
Liquid, time for adding control at 4 hours, finish, continue to be stirred to react, and slowly heat up, reacting liquid temperature is made slowly to be risen in 5 hours
To 35 ± 3 DEG C, the 12 hours reaction time or more is warming up to 48 ± 3 DEG C and continues to keep the temperature, and until the reaction is complete, cooling controls interior temperature
30 ± 5 DEG C, acetic acid on the rocks finishes, and continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds water at 30 ± 5 DEG C,
It stands, water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred in retort, to quality is added in water washing tank
The brine that score is 25% stirs, and stands, and branch vibration layer obtains 4- [(2- phthalimides) ethyoxyl] acetoacetate second
The toluene solution of ester；
Step 3, the preparation of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, the toluene solution of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into, at 70 DEG C
It is evaporated under reduced pressure below, water knockout drum is made to be full of, then proceed to reduced-pressure backflow, until moisture content≤0.2% in phegma, is cooled to 30
± 5 DEG C, 2- chlorobenzaldehydes are added, maintains interior 30 ± 5 DEG C of temperature, hexahydropyridine is added, stir 30 minutes, depressurized under the conditions of 65 DEG C
Reflux water-dividing 12 hours or more is cooled to 30 ± 5 DEG C, and water is added, and stirs, and stands, layering, lower aqueous layer recovery processing, upper layer
The toluene solution of as 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate；
Step 4, the preparation of phthalyl Amlodipine crude product：
In retort, the first of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Benzole soln is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, and n-hexane is added, and stirring is cooled to 30 ± 5 DEG C, stands, and extraction is just
Hexane rinse, the remaining n-hexane of vacuum distillation removing under the conditions of 30 ± 5 DEG C, is added glacial acetic acid, and stirring makes material dissolution, adds
Enter METHYL 3 AMINO CROTONATE, maintains interior 30 ± 5 DEG C of temperature, be stirred to react 65 hours or more, centrifugal filtration, filter is washed with glacial acetic acid
Slag, drying are dried to loss on drying≤5% under the conditions of 65 ± 5 DEG C, are cooled to room temperature, discharge, with obtaining O-phthalic amide nitrogen
Flat crude product；
Step 5, the purification of phthalyl Amlodipine：
In retort, methanol is added, stirring is warming up to 70 ± 3 DEG C, and phthalyl Amlodipine crude product is added, and reflux 4 is small
When, 35 ± 5 DEG C are cooled to, is stirred 3 hours, centrifugal filtration washs filter residue with methanol, drying, dry 8 under the conditions of 70 ± 5 DEG C
Hour or more, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine；
Step 6, the preparation of Amlodipine：
Methylamine solution is added into reaction kettle, is added with stirring phthalyl Amlodipine, maintains 30 ± 5 DEG C of stirrings of temperature
20 hours or more, 25 ± 5 DEG C are cooled to, filtering is filtered with water washing filter residue is drunk up to water outlet pH≤10, then with purifying water wash
Slag is filtered dry, dry under the conditions of 65 ± 5 DEG C, until moisture≤1.5%, is cooled to room temperature, is discharged, is obtained Amlodipine；
Step 7, the preparation of Amlodipine Besylate Tablet crude product：
Benzene sulfonic acid, purified water are added in benzene sulfonic acid dissolution kettle, activated carbon is added after stirring and dissolving, under the conditions of 35 ± 5 DEG C
Stirring decoloration, filtering obtain benzene sulfonic acid solution, and Amlodipine, purified water are added in reaction kettle and are stirred, and under stirring, remain anti-
35 ± 5 DEG C of temperature in kettle is answered, benzene sulfonic acid solution is added dropwise, finishes, continues to stir under the conditions of 35 ± 5 DEG C, is filtered, with purifying water washing
Until water outlet pH >=3, dry under the conditions of 75 DEG C, until loss on drying≤3.5% discharges, it is thick to obtain Amlodipine Besylate Tablet
Product；
Step 8, the preparation of Amlodipine Besylate Tablet：
Methanol is added into dissolution kettle, is added with stirring Amlodipine Besylate Tablet crude product, is warming up to 60 ± 5 DEG C, heat preservation keeps its molten
Solution is complete, and filtering washs dissolution kettle and filter with methanol, and filtrate and cleaning solution enter crystallization kettle, starts crystallization kettle stirring, subtracts
Pressure concentration, recycle methanol, be added ethyl acetate, carry out azeotropic distillation, when in crystallization kettle temperature rise to 65 DEG C or more when stop
Distillation is first cooled to 30 DEG C, keeps the temperature 3 hours, then is cooled to 5 DEG C of interior temperature and stirs 3 hours, centrifugal filtration, filter residue ethyl acetate
Washing, drying is dry under the conditions of 75 DEG C, until loss on drying≤0.5%, discharging, obtain white Amlodipine Besylate Tablet；
The synthesis technology is carried out by following reaction formula：
Further preferably, the step 2 specifically includes：In retort, toluene is put into, first is distilled in stirring heating
Benzene maintains the reflux for point water 60 minutes after liquid is full of in water knockout drum, sampling and measuring divide water, when phegma moisture content≤
0.2%, stream is changeed back as distillation, distills out toluene, is stirred lower cooling and is given retort nitrogen charging when temperature in tank is down to 45 DEG C, after
It is continuous to be cooled to 0 ± 5 DEG C, it is added with stirring N- (2- ethoxys)-phthalimide, sodium hydride is subsequently added into, finishes, cover tightly
Cover stirs under the conditions of 0 ± 5 DEG C, and 4- chloroacetyl acetacetic esters, toluene are pumped into measuring tank and is uniformly mixed, 0 ± 5
The toluene solution of 4- chloroacetyl acetacetic esters is added dropwise under the conditions of DEG C into retort, time for adding is controlled at 4 hours, is finished, after
It is continuous to be stirred to react, it slowly heats up, reacting liquid temperature is made to be slowly increased to 35 ± 3 DEG C in 5 hours, reaction time >=12 hour rise
Temperature continues to keep the temperature to 48 ± 3 DEG C, until the reaction is complete, cooling, control in 30 ± 5 DEG C of temperature, acetic acid on the rocks finishes, and continues to stir
Keep material stirring in reaction solution uniform, interior temperature control system adds water at 30 ± 5 DEG C, finishes, and continues stirring 30 minutes, stops nitrogen charging, stops
It only stirs, stands, water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred in retort, add into retort
Enter toluene, stir, stands, water layer is separated into barrelling, then toluene layer is transferred to water washing tank, water layer is transferred in retort, to anti-
It answers and toluene is added in tank, stir, stand, water layer is separated, toluene layer merging is transferred in water washing tank, to matter is added in water washing tank
The brine that score is 25% is measured, stirs 15 minutes, stands 30 minutes, branch vibration layer obtains 4- [(2- phthalimides) ethoxies
Base] ethyl acetoacetate toluene solution.
Further preferably, the pressure in the step 3 when reduced-pressure backflow is -0.07~-0.09Mpa.
Further preferably, the addition mass ratio of 2- chlorobenzaldehydes and hexahydropyridine is 27 in the step 3：1.5.
Further preferably, the step 4 specifically includes：In retort, [(2- is adjacent by input 2- (support of 2- chlorine Bians) -4-
Phthalimide) ethyoxyl] ethyl acetoacetate toluene solution, at 65 DEG C or less be evaporated under reduced pressure, recycle toluene, be added just
Hexane, stirring are cooled to 30 ± 5 DEG C, stand, and extract n-hexane washing lotion out, add n-hexane, stirred under the conditions of 30 ± 5 DEG C,
It stands, then extracts n-hexane washing lotion out, glacial acetic acid, stirring is added in the remaining n-hexane of vacuum distillation removing under the conditions of 30 ± 5 DEG C
Make material dissolution, METHYL 3 AMINO CROTONATE be added, maintains interior 30 ± 5 DEG C of temperature, be stirred to react 65 hours or more, centrifugal filtration,
Filter residue is washed with glacial acetic acid, is dried, is dried to loss on drying≤5% under the conditions of 65 ± 5 DEG C, is cooled to room temperature, discharges, obtains adjacent
Phenyl-diformyl Amlodipine crude product.
Further preferably, method dry in the step 1 is：In 65-70 DEG C, the condition that vacuum degree is -0.1MPa
Lower drying, is cooled to room temperature, discharging.
Compared with prior art, the invention has the advantages that：
(1) present invention is using phthalic anhydride as raw material, and controls the parameter of synthesis technology, shortens technological process, reduces synthesis cost, and
And product yield is up to 91%, Amlodipine Besylate Tablet purity obtained is up to 99.5%；
(2) present invention further prepares Amlodipine Besylate Tablet using homemade Amlodipine as raw material, reduces product cost,
Product quality controllability is strong.
Specific implementation mode
With reference to embodiment, the present invention will be described in detail.Unless stated otherwise, it is tried used in following embodiment
Agent and instrument are commercially available product and laboratory conventional instrument.
Embodiment 1：A kind of synthesis technology of Amlodipine Besylate Tablet, includes the following steps：
Step 1, the preparation of N- (2- ethoxys)-phthalimide：
In retort, 133kg toluene is put into, 40kg phthalic anhydrides are added under agitation, is warming up to 60 DEG C, 16.4kg second is added dropwise
Hydramine, is warming up to 110 DEG C after adding, reflux dewatering 12 hours or more is cooled to 15 DEG C, and centrifugal filtration washs filter residue with toluene,
Drying, it is dry, 65 DEG C, vacuum degree be -0.1MPa under conditions of it is dry, be cooled to room temperature, discharge, obtain the N- (2- of 51kg
Ethoxy)-phthalimide, yield 99%, purity 98.5%；
Step 2, the preparation of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, 350kg toluene, stirring heating are put into, toluene distillation maintains the reflux for after liquid is full of in water knockout drum
Divide water 60 minutes, sampling and measuring divides water, when phegma moisture content≤0.2%, changes back stream as distillation, toluene is distilled out, under stirring
Cooling gives retort nitrogen charging, continues to be cooled to -5 DEG C, be added with stirring N- (the 2- hydroxyls of 40kg when temperature in tank is down to 45 DEG C
Ethyl)-phthalimide, 20kg sodium hydrides are subsequently added into, are finished, cover is covered tightly, are stirred under the conditions of -5 DEG C, are being measured
It is pumped into 38.4kg 4- chloroacetyl acetacetic esters, 45kg toluene in tank and is uniformly mixed, is added dropwise into retort under the conditions of -5 DEG C
The toluene solution of 4- chloroacetyl acetacetic esters, time for adding control at 4 hours, finish, continue to be stirred to react 2 hours, slowly rise
Temperature makes reacting liquid temperature be slowly increased to 32 DEG C in 5 hours, 12 hours reaction time or more, and being warming up to 45 DEG C, to continue heat preservation 1 small
When, until the reaction is complete, cooling controls interior 25 DEG C of temperature, adds 61kg glacial acetic acid, finish, and continue stirring makes in reaction solution for 60 minutes
Material stirring is uniform, and interior temperature control system adds water at 25 DEG C, stands, water layer is separated barrelling, toluene layer is transferred to water washing tank, by water
Layer is transferred in retort, to the brine that 100kg mass fractions are 25% is added in water washing tank, is stirred, is stood, branch vibration layer obtains
The toluene solution of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate；
Step 3, the preparation of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, the toluene solution of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into, at 70 DEG C
It is evaporated under reduced pressure below, water knockout drum is made to be full of, then proceed to reduced-pressure backflow, until moisture content≤0.2% in phegma, is cooled to 25
DEG C, be added 27kg 2- chlorobenzaldehydes, maintain in temperature 25 DEG C, be added 1.5kg hexahydropyridines, stir 30 minutes, 65 DEG C ,-
Reduced-pressure backflow divides water 12 hours or more under the conditions of 0.07Mpa, is cooled to 25 DEG C, and 120kg water is added, and stirring stands 30 minutes, point
Layer, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] acetoacetate
The toluene solution of ethyl ester；
Step 4, the preparation of phthalyl Amlodipine crude product：
In retort, the first of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Benzole soln is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, 56kg n-hexanes are added, stir 25 minutes, be cooled to 25 DEG C, stands
15 minutes, extract n-hexane washing lotion out, the remaining n-hexane of vacuum distillation removing, is added 240kg glacial acetic acid, stirs under the conditions of 25 DEG C
Mixing makes material dissolution, and 64kg METHYL 3 AMINO CROTONATEs are added, and maintains interior 25 DEG C of temperature, is stirred to react 65 hours or more, centrifuged
Filter, filter residue is washed with 50kg glacial acetic acid, is dried, and is dried to loss on drying≤5% under the conditions of 60 DEG C, is cooled to room temperature, is discharged,
Obtain phthalyl Amlodipine crude product, yield 63.8%, purity 98.5%；
Step 5, the purification of phthalyl Amlodipine：
In retort, 245kg methanol is added, stirring is warming up to 67 DEG C, and 72kg phthalyl Amlodipine crude products are added, and returns
Stream 4 hours is cooled to 30 DEG C, stirs 3 hours, and centrifugal filtration washs filter residue with 60kg methanol, and drying is done under the conditions of 65 DEG C
Dry 8 hours or more, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine, yield 89.9%, purity 99.0%；
Step 6, the preparation of Amlodipine：
290kg methylamine solutions are added into reaction kettle, are added with stirring 59kg phthalyl Amlodipines, maintain temperature 25
DEG C stirring 20 hours or more, is cooled to 20 DEG C, filtering, is drenched with drinking water washing filter residue until water outlet pH≤10, then with purified water
Filter wash slag, is filtered dry, dry under the conditions of 60 DEG C, until moisture≤1.5%, is cooled to room temperature, discharges, obtains Amlodipine, receives
Rate 91.6%, purity 99.0%；
Step 7, the preparation of Amlodipine Besylate Tablet crude product：
25kg benzene sulfonic acids, 175kg purified waters are added in benzene sulfonic acid dissolution kettle, 1kg activated carbons are added after stirring and dissolving, 30
Decoloration is stirred under the conditions of DEG C, filtering obtains benzene sulfonic acid solution, and 40kg Amlodipines, 250kg purified waters are added in reaction kettle and are stirred
It mixes, under stirring, maintains 30 DEG C of temperature in reaction kettle, benzene sulfonic acid solution is added dropwise, finishes, continues to stir under the conditions of 30 DEG C, filter, use
Purifying water washing is dry under the conditions of 75 DEG C until water outlet pH >=3, until loss on drying≤3.5% discharges, obtains benzene sulfonic acid ammonia
Flordipine crude product, yield 101.0%, purity 99.1%；
Step 8, the preparation of Amlodipine Besylate Tablet：
260kg methanol is added into dissolution kettle, is added with stirring 44.3kg Amlodipine Besylate Tablet crude products, is warming up to 55 DEG C, protects
Temperature makes it dissolve completely for 30 minutes, and filtering washs dissolution kettle and filter, filtrate and cleaning solution enter crystallization with 50kg methanol
Kettle starts crystallization kettle stirring, is concentrated under reduced pressure, recycle methanol, 270kg ethyl acetate is added, azeotropic distillation carried out, when in crystallization kettle
Temperature rise is first cooled to 30 DEG C to distillation is stopped at 65 DEG C or more, keeps the temperature 3 hours, then is cooled to 5 DEG C of interior temperature and stirs 3 hours,
Centrifugal filtration, filter residue are washed with 60kg ethyl acetate, drying, dry under the conditions of 75 DEG C, until loss on drying≤0.5%, goes out
Material, obtains white Amlodipine Besylate Tablet, yield 91%, purity 99.5%.
Above-mentioned synthesis technology is carried out by following reaction formula：
Embodiment 2：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 2 tool
Body includes：In retort, 350kg toluene, stirring heating are put into, toluene distillation is kept back after liquid is full of in water knockout drum
Flow point water 60 minutes, sampling and measuring divide water, when phegma moisture content≤0.2%, change back stream as distillation, distill out toluene, stir
Lower cooling gives retort nitrogen charging, continues to be cooled to 5 DEG C, be added with stirring the N- (2- of 40kg when temperature in tank is down to 45 DEG C
Ethoxy)-phthalimide, 20kg sodium hydrides are subsequently added into, are finished, cover is covered tightly, stirs, is counting under the conditions of 5 DEG C
It is pumped into 38.4kg 4- chloroacetyl acetacetic esters, 45kg toluene in measuring tank and is uniformly mixed, is dripped into retort under the conditions of 5 DEG C
Add the toluene solution of 4- chloroacetyl acetacetic esters, time for adding was controlled at 4 hours, was finished, and continued to be stirred to react 2 hours, slowly
Heating, makes reacting liquid temperature be slowly increased to 38 DEG C in 5 hours, 12 hours reaction time or more is warming up to 51 DEG C and continues heat preservation 1
Hour, until the reaction is complete, cooling controls interior 35 DEG C of temperature, adds 61kg glacial acetic acid, finish, and continuing stirring makes reaction solution in 60 minutes
Middle material stirring is uniform, and interior temperature control system adds 180kg water, finish at 35 DEG C, continues stirring 30 minutes, stops nitrogen charging, stops stirring
It mixes, stands, water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred in retort, is added into retort
75kg toluene stirs, and stands, water layer is separated barrelling, then toluene layer is transferred to water washing tank, water layer is transferred in retort, to
75kg toluene is added in retort, stirs, stands, water layer is separated, toluene layer merging is transferred in water washing tank, in water washing tank
The brine that 100kg mass fractions are 25% is added, stirs 15 minutes, stands 30 minutes, branch vibration layer obtains 4- [(2- O-phthalics
Acid imide) ethyoxyl] ethyl acetoacetate toluene solution；The yield 91.1% of Amlodipine Besylate Tablet, purity 99.3%.
Embodiment 3：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 4 tool
Body includes：In retort, input 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate
Toluene solution is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, 56kg n-hexanes are added, stirs 25 minutes, be cooled to 25 DEG C, quiet
It sets 15 minutes, extracts n-hexane washing lotion out, add 56kg n-hexanes, stirred under the conditions of 25 DEG C, stand, then extract n-hexane out and wash
Liquid, the remaining n-hexane of vacuum distillation removing under the conditions of 25 DEG C, is added 240kg glacial acetic acid, and stirring makes material dissolution, is added
64kg METHYL 3 AMINO CROTONATEs maintain interior 25 DEG C of temperature, are stirred to react 65 hours or more, centrifugal filtration is washed with 50kg glacial acetic acid
Filter residue is washed, is dried, is dried to loss on drying≤5% under the conditions of 60 DEG C, is cooled to room temperature, discharges, obtains O-phthalic amide nitrogen
Horizon crude product, yield 64.2%, purity 98.7%；The yield 90.9% of Amlodipine Besylate Tablet, purity 99.4%.
Embodiment 4：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 1
For：In retort, 133kg toluene is put into, 40kg phthalic anhydrides are added under agitation, is warming up to 70 DEG C, 16.4kg second is added dropwise
Hydramine, is warming up to 110 DEG C after adding, reflux dewatering 12 hours or more is cooled to 20 DEG C, and centrifugal filtration washs filter residue with toluene,
Drying, it is dry, 70 DEG C, vacuum degree be -0.1MPa under conditions of it is dry, be cooled to room temperature, discharge, obtain the N- (2- of 51kg
Ethoxy)-phthalimide, yield 99%, purity 98.6%；The yield 91% of Amlodipine Besylate Tablet, purity
99.5%.
Embodiment 5：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 1
For：In retort, 133kg toluene is put into, 40kg phthalic anhydrides are added under agitation, is warming up to 80 DEG C, 16.4kg second is added dropwise
Hydramine, is warming up to 110 DEG C after adding, reflux dewatering 12 hours or more is cooled to 25 DEG C, and centrifugal filtration washs filter residue with toluene,
Drying, it is dry, 70 DEG C, vacuum degree be -0.1MPa under conditions of it is dry, be cooled to room temperature, discharge, obtain the N- (2- of 51kg
Ethoxy)-phthalimide, yield 99%, purity 98.5%；The yield 91.2% of Amlodipine Besylate Tablet, purity
99.5%.
Embodiment 6：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 2
For：In retort, 350kg toluene, stirring heating are put into, toluene distillation maintains the reflux for point after liquid is full of in water knockout drum
Water 60 minutes, sampling and measuring divide water, when phegma moisture content≤0.2%, change back stream as distillation, distill out toluene, stirring declines
Temperature gives retort nitrogen charging, continues to be cooled to 0 DEG C, be added with stirring N- (the 2- hydroxyl second of 40kg when temperature in tank is down to 45 DEG C
Base)-phthalimide, 20kg sodium hydrides are subsequently added into, are finished, cover is covered tightly, are stirred under the conditions of 0 DEG C, in measuring tank
Middle suction 38.4kg 4- chloroacetyl acetacetic esters, 45kg toluene are simultaneously uniformly mixed, and 4- is added dropwise into retort under the conditions of 0 DEG C
The toluene solution of chloroacetyl acetacetic ester, time for adding control at 4 hours, finish, continue to be stirred to react 2 hours, slowly heat up,
Reacting liquid temperature is set to be slowly increased to 35 DEG C in 5 hours, 12 hours reaction time or more is warming up to 48 DEG C and continues heat preservation 1 hour,
Until the reaction is complete, cool down, control interior 30 DEG C of temperature, add 61kg glacial acetic acid, finish, continuing stirring makes material in reaction solution in 60 minutes
It stirring evenly, interior temperature control system adds 180kg water, finishes at 30 DEG C, continues stirring 30 minutes, stops nitrogen charging, stops stirring, stands,
Water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred in retort, 75kg toluene is added into retort,
Stirring stands, water layer is separated barrelling, then toluene layer is transferred to water washing tank, water layer is transferred in retort, adds into retort
Enter 75kg toluene, stir, stand, water layer is separated, toluene layer merging is transferred in water washing tank, to 100kg is added in water washing tank
The brine that mass fraction is 25% stirs 15 minutes, stands 30 minutes, branch vibration layer obtains 4- [(2- phthalimides) second
Oxygroup] ethyl acetoacetate toluene solution；The yield 91% of Amlodipine Besylate Tablet, purity 99.6%.
Embodiment 7：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 3
For：In retort, put into 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate toluene solution, 70 DEG C with
Lower vacuum distillation, makes water knockout drum be full of, then proceedes to reduced-pressure backflow, until moisture content≤0.2% in phegma, is cooled to 30
DEG C, be added 27kg 2- chlorobenzaldehydes, maintain in temperature 30 DEG C, be added 1.5kg hexahydropyridines, stir 30 minutes, 65 DEG C ,-
Reduced-pressure backflow divides water 12 hours or more under the conditions of 0.08Mpa, is cooled to 30 DEG C, and 120kg water is added, and stirring stands 30 minutes, point
Layer, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] acetoacetate
The toluene solution of ethyl ester；The yield 91.1% of Amlodipine Besylate Tablet, purity 99.5%.
Embodiment 8：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 3
For：In retort, put into 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate toluene solution, 70 DEG C with
Lower vacuum distillation, makes water knockout drum be full of, then proceedes to reduced-pressure backflow, until moisture content≤0.2% in phegma, is cooled to 35
DEG C, be added 27kg 2- chlorobenzaldehydes, maintain in temperature 35 DEG C, be added 1.5kg hexahydropyridines, stir 30 minutes, 65 DEG C ,-
Reduced-pressure backflow divides water 12 hours or more under the conditions of 0.09Mpa, is cooled to 35 DEG C, and 120kg water is added, and stirring stands 30 minutes, point
Layer, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] acetoacetate
The toluene solution of ethyl ester；The yield 91.2% of Amlodipine Besylate Tablet, purity 99.5%.
Embodiment 9：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 4
For：In retort, the toluene of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Solution is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, 56kg n-hexanes are added, stir 25 minutes, be cooled to 30 DEG C, stands 15
Minute, it extracts n-hexane washing lotion out, adds 56kg n-hexanes, stirred under the conditions of 25 DEG C, stand, then extract n-hexane washing lotion out,
Vacuum distillation removes remaining n-hexane under the conditions of 30 DEG C, and 240kg glacial acetic acid is added, and stirring makes material dissolution, and 64kg is added
METHYL 3 AMINO CROTONATE maintains interior 30 DEG C of temperature, is stirred to react 65 hours or more, centrifugal filtration, filter is washed with 50kg glacial acetic acid
Slag, drying are dried to loss on drying≤5% under the conditions of 65 DEG C, are cooled to room temperature, discharge, obtain phthalyl Amlodipine
Crude product, yield 64.2%, purity 98.6%；The yield 91% of Amlodipine Besylate Tablet, purity 99.4%.
Embodiment 10：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 4
For：In retort, the toluene of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Solution is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, 56kg n-hexanes are added, stir 25 minutes, be cooled to 35 DEG C, stands 15
Minute, it extracts n-hexane washing lotion out, adds 56kg n-hexanes, stirred under the conditions of 25 DEG C, stand, then extract n-hexane washing lotion out,
Vacuum distillation removes remaining n-hexane under the conditions of 35 DEG C, and 240kg glacial acetic acid is added, and stirring makes material dissolution, and 64kg is added
METHYL 3 AMINO CROTONATE maintains interior 35 DEG C of temperature, is stirred to react 65 hours or more, centrifugal filtration, filter is washed with 50kg glacial acetic acid
Slag, drying are dried to loss on drying≤5% under the conditions of 70 DEG C, are cooled to room temperature, discharge, obtain phthalyl Amlodipine
Crude product, yield 64.2%, purity 98.6%；The yield 91.1% of Amlodipine Besylate Tablet, purity 99.4%.
Embodiment 11：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 5
For：In retort, 245kg methanol is added, stirring is warming up to 70 DEG C, and 72kg phthalyl Amlodipine crude products are added, and returns
Stream 4 hours is cooled to 35 DEG C, stirs 3 hours, and centrifugal filtration washs filter residue with 60kg methanol, and drying is done under the conditions of 70 DEG C
Dry 8 hours or more, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine, yield 89.9%, purity 99.1%；Benzene sulfonic acid
The yield 91.3% of Amlodipine, purity 99.6%.
Embodiment 12：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 5
For：In retort, 245kg methanol is added, stirring is warming up to 73 DEG C, and 72kg phthalyl Amlodipine crude products are added, and returns
Stream 4 hours is cooled to 40 DEG C, stirs 3 hours, and centrifugal filtration washs filter residue with 60kg methanol, and drying is done under the conditions of 75 DEG C
Dry 8 hours or more, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine, yield 89.9%, purity 99.1%；Benzene sulfonic acid
The yield 91.2% of Amlodipine, purity 99.4%.
Embodiment 13：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 6
For：290kg methylamine solutions are added into reaction kettle, are added with stirring 59kg phthalyl Amlodipines, maintain temperature 30
DEG C stirring 20 hours or more, is cooled to 25 DEG C, filtering, is drenched with drinking water washing filter residue until water outlet pH≤10, then with purified water
Filter wash slag, is filtered dry, dry under the conditions of 65 DEG C, until moisture≤1.5%, is cooled to room temperature, discharges, obtains Amlodipine, receives
Rate 91.6%, purity 99.2%；The yield 91.2% of Amlodipine Besylate Tablet, purity 99.3%.
Embodiment 14：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 6
For：290kg methylamine solutions are added into reaction kettle, are added with stirring 59kg phthalyl Amlodipines, maintain temperature 35
DEG C stirring 20 hours or more, is cooled to 30 DEG C, filtering, is drenched with drinking water washing filter residue until water outlet pH≤10, then with purified water
Filter wash slag, is filtered dry, dry under the conditions of 70 DEG C, until moisture≤1.5%, is cooled to room temperature, discharges, obtains Amlodipine, receives
Rate 91.6%, purity 99.1%；The yield 91.3% of Amlodipine Besylate Tablet, purity 99.6%.
Embodiment 15：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 7
For：25kg benzene sulfonic acids, 175kg purified waters are added in benzene sulfonic acid dissolution kettle, 1kg activated carbons are added after stirring and dissolving, 35
Decoloration is stirred under the conditions of DEG C, filtering obtains benzene sulfonic acid solution, and 40kg Amlodipines, 250kg purified waters are added in reaction kettle and are stirred
It mixes, under stirring, maintains 35 DEG C of temperature in reaction kettle, benzene sulfonic acid solution is added dropwise, finishes, continues to stir under the conditions of 35 DEG C, filter, use
Purifying water washing is dry under the conditions of 75 DEG C until water outlet pH >=3, until loss on drying≤3.5% discharges, obtains benzene sulfonic acid ammonia
Flordipine crude product, yield 101.0%, purity 99.1%；
Step 8 is：260kg methanol is added into dissolution kettle, is added with stirring 44.3kg Amlodipine Besylate Tablet crude products, heats up
To 60 DEG C, heat preservation makes it dissolve completely for 30 minutes, and filtering washs dissolution kettle and filter, filtrate and cleaning solution with 50kg methanol
Into crystallization kettle, crystallization kettle stirring is started, is concentrated under reduced pressure, methanol is recycled, 270kg ethyl acetate is added, carries out azeotropic distillation, when
Temperature rise is first cooled to 30 DEG C to distillation is stopped at 65 DEG C or more in crystallization kettle, keeps the temperature 3 hours, then be cooled to 5 DEG C of interior temperature and stir
It mixes 3 hours, centrifugal filtration, filter residue is washed with 60kg ethyl acetate, drying, dry under the conditions of 75 DEG C, until loss on drying≤
0.5%, discharging obtains white Amlodipine Besylate Tablet, yield 91%, purity 99.4%.
Embodiment 16：A kind of synthesis technology of Amlodipine Besylate Tablet, difference from example 1 is that, step 7
For：25kg benzene sulfonic acids, 175kg purified waters are added in benzene sulfonic acid dissolution kettle, 1kg activated carbons are added after stirring and dissolving, 40
Decoloration is stirred under the conditions of DEG C, filtering obtains benzene sulfonic acid solution, and 40kg Amlodipines, 250kg purified waters are added in reaction kettle and are stirred
It mixes, under stirring, maintains 40 DEG C of temperature in reaction kettle, benzene sulfonic acid solution is added dropwise, finishes, continues to stir under the conditions of 40 DEG C, filter, use
Purifying water washing is dry under the conditions of 75 DEG C until water outlet pH >=3, until loss on drying≤3.5% discharges, obtains benzene sulfonic acid ammonia
Flordipine crude product, yield 101.0%, purity 99.2%；
Step 8 is：260kg methanol is added into dissolution kettle, is added with stirring 44.3kg Amlodipine Besylate Tablet crude products, heats up
To 65 DEG C, heat preservation makes it dissolve completely for 30 minutes, and filtering washs dissolution kettle and filter, filtrate and cleaning solution with 50kg methanol
Into crystallization kettle, crystallization kettle stirring is started, is concentrated under reduced pressure, methanol is recycled, 270kg ethyl acetate is added, carries out azeotropic distillation, when
Temperature rise is first cooled to 30 DEG C to distillation is stopped at 65 DEG C or more in crystallization kettle, keeps the temperature 3 hours, then be cooled to 5 DEG C of interior temperature and stir
It mixes 3 hours, centrifugal filtration, filter residue is washed with 60kg ethyl acetate, drying, dry under the conditions of 75 DEG C, until loss on drying≤
0.5%, discharging obtains white Amlodipine Besylate Tablet, yield 91%, purity 99.6%.
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (6)
1. a kind of synthesis technology of Amlodipine Besylate Tablet, which is characterized in that include the following steps：
Step 1, the preparation of N- (2- ethoxys)-phthalimide：
In retort, toluene is put into, phthalic anhydride is added under agitation, be warming up to 60-80 DEG C, ethanol amine is added dropwise, after adding
It is warming up to 110 DEG C, reflux dewatering 12 hours or more is cooled to 20 ± 5 DEG C, centrifugal filtration washs filter residue with toluene, dries, and does
Dry, discharging obtains N- (2- ethoxys)-phthalimide；
Step 2, the preparation of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, toluene, stirring heating are put into, toluene distillation maintains the reflux for a point water after liquid is full of in water knockout drum,
Sampling and measuring divides water, when phegma moisture content≤0.2%, changes back stream as distillation, distills out toluene, stirs lower cooling, wait in tank
When temperature is down to 45 DEG C, retort nitrogen charging is given, continues to be cooled to 0 ± 5 DEG C, is added with stirring N- (2- ethoxys)-O-phthalic
Acid imide is subsequently added into sodium hydride, finishes, and covers tightly cover, is stirred under the conditions of 0 ± 5 DEG C, and 4- chloracetyls are pumped into measuring tank
Ethyl acetate, toluene are simultaneously uniformly mixed, and the toluene that 4- chloroacetyl acetacetic esters are added dropwise into retort under the conditions of 0 ± 5 DEG C is molten
Liquid, time for adding control at 4 hours, finish, continue to be stirred to react, and slowly heat up, reacting liquid temperature is made slowly to be risen in 5 hours
To 35 ± 3 DEG C, the 12 hours reaction time or more is warming up to 48 ± 3 DEG C and continues to keep the temperature, and until the reaction is complete, cooling controls interior temperature
30 ± 5 DEG C, acetic acid on the rocks finishes, and continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds water at 30 ± 5 DEG C,
It stands, water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred in retort, to quality is added in water washing tank
The brine that score is 25% stirs, and stands, and branch vibration layer obtains 4- [(2- phthalimides) ethyoxyl] acetoacetate second
The toluene solution of ester；
Step 3, the preparation of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate：
In retort, the toluene solution of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into, at 70 DEG C
It is evaporated under reduced pressure below, water knockout drum is made to be full of, then proceed to reduced-pressure backflow, until moisture content≤0.2% in phegma, is cooled to 30
± 5 DEG C, 2- chlorobenzaldehydes are added, maintains interior 30 ± 5 DEG C of temperature, hexahydropyridine is added, stir 30 minutes, depressurized under the conditions of 65 DEG C
Reflux water-dividing 12 hours or more is cooled to 30 ± 5 DEG C, and water is added, and stirs, and stands, layering, lower aqueous layer recovery processing, upper layer
The toluene solution of as 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate；
Step 4, the preparation of phthalyl Amlodipine crude product：
In retort, the first of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Benzole soln is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, and n-hexane is added, and stirring is cooled to 30 ± 5 DEG C, stands, and extraction is just
Hexane rinse, the remaining n-hexane of vacuum distillation removing under the conditions of 30 ± 5 DEG C, is added glacial acetic acid, and stirring makes material dissolution, adds
Enter METHYL 3 AMINO CROTONATE, maintains interior 30 ± 5 DEG C of temperature, be stirred to react 65 hours or more, centrifugal filtration, filter is washed with glacial acetic acid
Slag, drying are dried to loss on drying≤5% under the conditions of 65 ± 5 DEG C, are cooled to room temperature, discharge, with obtaining O-phthalic amide nitrogen
Flat crude product；
Step 5, the purification of phthalyl Amlodipine：
In retort, methanol is added, stirring is warming up to 70 ± 3 DEG C, and phthalyl Amlodipine crude product is added, and reflux 4 is small
When, 35 ± 5 DEG C are cooled to, is stirred 3 hours, centrifugal filtration washs filter residue with methanol, drying, dry 8 under the conditions of 70 ± 5 DEG C
Hour or more, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine；
Step 6, the preparation of Amlodipine：
Methylamine solution is added into reaction kettle, is added with stirring phthalyl Amlodipine, maintains 30 ± 5 DEG C of stirrings of temperature
20 hours or more, 25 ± 5 DEG C are cooled to, filtering is filtered with water washing filter residue is drunk up to water outlet pH≤10, then with purifying water wash
Slag is filtered dry, dry under the conditions of 65 ± 5 DEG C, until moisture≤1.5%, is cooled to room temperature, is discharged, is obtained Amlodipine；
Step 7, the preparation of Amlodipine Besylate Tablet crude product：
Benzene sulfonic acid, purified water are added in benzene sulfonic acid dissolution kettle, activated carbon is added after stirring and dissolving, under the conditions of 35 ± 5 DEG C
Stirring decoloration, filtering obtain benzene sulfonic acid solution, and Amlodipine, purified water are added in reaction kettle and are stirred, and under stirring, remain anti-
35 ± 5 DEG C of temperature in kettle is answered, benzene sulfonic acid solution is added dropwise, finishes, continues to stir under the conditions of 35 ± 5 DEG C, is filtered, with purifying water washing
Until water outlet pH >=3, dry under the conditions of 75 DEG C, until loss on drying≤3.5% discharges, it is thick to obtain Amlodipine Besylate Tablet
Product；
Step 8, the preparation of Amlodipine Besylate Tablet：
Methanol is added into dissolution kettle, is added with stirring Amlodipine Besylate Tablet crude product, is warming up to 60 ± 5 DEG C, heat preservation keeps its molten
Solution is complete, and filtering washs dissolution kettle and filter with methanol, and filtrate and cleaning solution enter crystallization kettle, starts crystallization kettle stirring, subtracts
Pressure concentration, recycle methanol, be added ethyl acetate, carry out azeotropic distillation, when in crystallization kettle temperature rise to 65 DEG C or more when stop
Distillation is first cooled to 30 DEG C, keeps the temperature 3 hours, then is cooled to 5 DEG C of interior temperature and stirs 3 hours, centrifugal filtration, filter residue ethyl acetate
Washing, drying is dry under the conditions of 75 DEG C, until loss on drying≤0.5%, discharging, obtain white Amlodipine Besylate Tablet；
The synthesis technology is carried out by following reaction formula：
2. the synthesis technology of Amlodipine Besylate Tablet according to claim 1, which is characterized in that the step 2 is specifically wrapped
It includes：In retort, toluene, stirring heating are put into, toluene distillation maintains the reflux for point water 60 after liquid is full of in water knockout drum
Minute, sampling and measuring divides water, when phegma moisture content≤0.2%, changes back stream as distillation, distills out toluene, stirs lower cooling, wait for
When temperature is down to 45 DEG C in tank, retort nitrogen charging is given, continues to be cooled to 0 ± 5 DEG C, is added with stirring the adjacent benzene of N- (2- ethoxys)-
Dicarboximide is subsequently added into sodium hydride, finishes, and covers tightly cover, is stirred under the conditions of 0 ± 5 DEG C, and 4- chlorine is pumped into measuring tank
Ethyl acetoacetate, toluene are simultaneously uniformly mixed, and the first of 4- chloroacetyl acetacetic esters is added dropwise into retort under the conditions of 0 ± 5 DEG C
Benzole soln, time for adding control at 4 hours, finish, continue to be stirred to react, and slowly heat up, and reacting liquid temperature is made to delay in 5 hours
Slowly 35 ± 3 DEG C are risen to, reaction time >=12 hour are warming up to 48 ± 3 DEG C and continue to keep the temperature, and until the reaction is complete, cool down, in control
30 ± 5 DEG C of temperature, acetic acid on the rocks finishes, and continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds at 30 ± 5 DEG C
Water finishes, and continues stirring 30 minutes, stops nitrogen charging, stops stirring, stands, water layer is separated barrelling, toluene layer is transferred to washing
Water layer is transferred in retort by tank, and toluene is added into retort, is stirred, and is stood, and water layer is separated barrelling, then by toluene layer
It is transferred to water washing tank, water layer is transferred in retort, toluene is added into retort, is stirred, stands, water layer is separated, by toluene
It is laminated and be transferred in water washing tank, to the brine that mass fraction is 25% is added in water washing tank, stirs 15 minutes, stand 30 minutes,
Branch vibration layer obtains the toluene solution of 4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate.
3. the synthesis technology of Amlodipine Besylate Tablet according to claim 1, which is characterized in that depressurized in the step 3
Pressure when reflux is -0.07~-0.09Mpa.
4. the synthesis technology of Amlodipine Besylate Tablet according to claim 1, which is characterized in that 2- chlorine in the step 3
The addition mass ratio of benzaldehyde and hexahydropyridine is 27：1.5.
5. the synthesis technology of Amlodipine Besylate Tablet according to claim 1, which is characterized in that the step 4 is specifically wrapped
It includes：In retort, the toluene of 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethyoxyl] ethyl acetoacetate is put into
Solution is evaporated under reduced pressure at 65 DEG C or less, recycles toluene, and n-hexane is added, and stirring is cooled to 30 ± 5 DEG C, stands, extraction just oneself
Alkane washing lotion, adds n-hexane, is stirred under the conditions of 30 ± 5 DEG C, stands, then extract n-hexane washing lotion out, under the conditions of 30 ± 5 DEG C
Vacuum distillation removes remaining n-hexane, and glacial acetic acid is added, and stirring makes material dissolution, and METHYL 3 AMINO CROTONATE is added, and maintains
30 ± 5 DEG C of interior temperature, is stirred to react 65 hours or more, centrifugal filtration, and filter residue is washed with glacial acetic acid, drying, under the conditions of 65 ± 5 DEG C
It is dry to be cooled to room temperature to loss on drying≤5%, it discharges, obtains phthalyl Amlodipine crude product.
6. the synthesis technology of Amlodipine Besylate Tablet according to claim 1, which is characterized in that dry in the step 1
Method be：In 65-70 DEG C, vacuum degree to be dried under conditions of -0.1MPa, it is cooled to room temperature, is discharged.
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| CN109456251A (en) * | 2018-12-17 | 2019-03-12 | 苏州华道生物药业股份有限公司 | A kind of synthetic method of 2- benzene two (first) acylimino ethanesulfonyl chloride |
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