CN108358833A - A kind of synthesis technology of amlodipine maleate - Google Patents
A kind of synthesis technology of amlodipine maleate Download PDFInfo
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- CN108358833A CN108358833A CN201810212405.XA CN201810212405A CN108358833A CN 108358833 A CN108358833 A CN 108358833A CN 201810212405 A CN201810212405 A CN 201810212405A CN 108358833 A CN108358833 A CN 108358833A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—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
Abstract
The invention discloses a kind of synthesis technologies of amlodipine maleate, are related to medical synthesis technical field, solve the problems, such as that existing synthesis technology by-product and impurity in industrialized production are on the high side.The present invention reduces impurity content by the parameter of control synthesis technology, and amlodipine maleate purity obtained is up to 99.5%；The present invention further prepares amlodipine maleate 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 maleate
Technique.
Background technology
Hypertension and angina pectoris are common disease, frequently-occurring disease, it seriously endangers the life and health of the mankind, and patient need to connect throughout one's life
Continuous medication, therefore the development of such drug is always the focus of global pharmaceutical sector.Amlodipine maleate is mainly used for treating high blood
The diseases such as pressure and angina pectoris.Amlodipine maleate is dihydropyridine calcium channel blocker, is hindered with usually used calcium channel
Stagnant dose is compared, it has the characteristics that, and antihypertensive effect is steady, onset time is long and few side effects.It as peripheral arterial expander,
Vascular smooth muscle is directly acted on, peripheral vascular resistance is reduced, to reduce blood pressure；Can also by expand periphery parteriole and
Coronary artery reduces Total peripheral vascular resistance, releases coronarospasm, reduces the afterload of heart, to allevating angina pectoris.
Amlodipine maleate is widely used in clinic due to its unique advantage.
European patent EP 89167 makes public for the first time the technique for preparing amlodipine maleate, it is to dissolve Amlodipine
In ethyl acetate or ethyl alcohol, solid maleic acid is added, then Amlodipine maleic acid just precipitates.This salt using
It filters and is recrystallized in 1: 1 mixture of ethyl acetate or acetone/ethyl acetate, obtain the sterling of the salt.But the technique is in industry
By-product and impurity problem on the high side are encountered in metaplasia production.It is, therefore, desirable to provide a kind of new technique is to solve the above problems.
Invention content
In view of the deficiencies of the prior art, the present invention intends to provide a kind of synthesis work of amlodipine maleate
Skill, with product purity height, 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 maleate, 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 finishes, continues stirring 30 minutes, stop nitrogen charging, stop stirring, stand, water layer is separated into barrelling, toluene layer is transferred to water washing tank,
Water layer is transferred in retort, toluene is added into retort, is stirred, stands, water layer is separated into barrelling, then toluene layer is transferred to
Water layer is transferred in retort by water washing tank, and toluene is added into retort, is stirred, and stands, water layer is separated, and toluene is laminated
And be transferred in water washing tank, the brine for being added that mass fraction is 25% is given in water washing tank, is stirred 15 minutes, stands 30 minutes, divides and goes
Water 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 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 dries, dry, is cooled to room temperature, discharges, obtains phthalyl Amlodipine 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 maleate crude product：
Amlodipine, water are added in eggplant-shape bottle, are stirred at room temperature, maleic acid is soluble in water, and 30 DEG C of constant temperature is dripped with dropping funel
It adds in the Amlodipine solution in eggplant-shape bottle, finishes, continue stirring 4 hours, filter, filter cake is washed with water 2-3 times, in 65 DEG C of items
It is dried in vacuo 8 hours or more under part, obtains the amlodipine maleate crude product of white chunks, yield 91%, purity 99.2%；
Step 8, amlodipine maleate refine：
Amlodipine maleate crude product is taken, is added in eggplant-shape bottle, then methanol is added into eggplant-shape bottle, is heated to 60 DEG C, stirring makes
Material is completely dissolved, and is cooled to 50 DEG C, and activated carbon is added, and stirring is warming up to 65 DEG C, stirs 30min, and heat filtering removes deactivation
Charcoal, and methanol is added to clean eggplant-shape bottle, vacuum distillation steams to the half of volume of material, ethyl acetate is added, carries out azeotropic distillation,
Volume 50ml is steamed, room temperature is cooled to, then is down to 0 DEG C, is stirred, is filtered, is dried under reduced pressure, obtains amlodipine maleate, yield
91.5%, purity 99.5%；
The synthesis technology is carried out by following reaction formula：
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.
Further preferably, the pressure in the step 3 when reduced-pressure backflow is -0.07~-0.09Mpa.
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, it is dry, it is cooled to room temperature, discharges, obtains phthalyl Amlodipine crude product.
Further preferably, drying means is in the step 4：Under the conditions of 65 ± 5 DEG C dry to loss on drying≤
5%.
Further preferably, in the step 7, primary drying case is smoked per 2h in the drying process and volatilized with removing
Steam.
Compared with prior art, the invention has the advantages that：
(1) present invention reduces impurity content by the parameter of control synthesis technology, and amlodipine maleate purity obtained is up to
99.5%；
(2) present invention further prepares amlodipine maleate 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 maleate, 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 is cooled to room temperature, discharges, obtain N- (the 2- hydroxyl second of 51kg in 65 DEG C, vacuum degree to be dried under conditions of -0.1MPa
Base)-phthalimide；
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, distills out 45kg toluene (work
For the retarder thinner of 4- chloroacetyl acetacetic esters), it stirs lower cooling and gives retort nitrogen charging when temperature in tank is down to 45 DEG C, after
It is continuous to be cooled to -5 DEG C, it is added with stirring N- (2- ethoxys)-phthalimide of 40kg, is subsequently added into 20kg sodium hydrides,
It finishes, covers tightly cover, stirred under the conditions of -5 DEG C, 4- chloroacetyl acetacetic esters, the 45kg first of 38.4kg are pumped into measuring tank
Benzo is uniformly mixed, and the toluene solution of 4- chloroacetyl acetacetic esters, time for adding control is added dropwise into retort under the conditions of -5 DEG C
System finished at 4 hours, and continued to be stirred to react, and slowly heated up, and reacting liquid temperature is made to be slowly increased to 32 DEG C in 5 hours, when reaction
Between 12 hours or more, be warming up to 45 DEG C and continue to keep the temperature, until the reaction is complete, cooling, control in temperature 25 DEG C, add 61kg glacial acetic acid,
It finishes, continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds 180kg water, finish at 25 DEG C, continues stirring 30
Minute, stop nitrogen charging, stop stirring, stands, water layer is separated into barrelling, toluene layer is transferred to water washing tank, water layer is transferred to reaction
In tank, 75kg toluene is added into retort, stirs, stands, water layer is separated into barrelling, then toluene layer is transferred to water washing tank, it will
Water layer is transferred in retort, and 75kg toluene is added into retort, is stirred, and stands, water layer is separated, and toluene layer merging is transferred to
In water washing tank, the brine for being added that 100kg mass fractions are 25% is given in water washing tank, is stirred 15 minutes, stands 30 minutes, divides and removes water
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, the 2- chlorobenzaldehydes of 27kg are added, maintains interior 25 DEG C of temperature, 1.5kg hexahydropyridines is added, stir 30 minutes, in 65 DEG C of conditions
Lower reduced-pressure backflow divides water 12 hours or more, and pressure when reduced-pressure backflow is -0.07Mpa, is cooled to 25 DEG C, 120kg water is added, stirs
It mixes, stands, layering, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethoxies
Base] ethyl acetoacetate toluene solution；
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 56kg n-hexanes are added, and stirring is cooled to 25 DEG C, stands, and extraction is just
Hexane rinse adds 56kg n-hexanes, is stirred under the conditions of 25 DEG C, stands, then extract n-hexane washing lotion out, under the conditions of 25 DEG C
Vacuum distillation removes remaining n-hexane, and 240kg glacial acetic acid is added, and stirring makes material dissolution, the 3- amino crotons of 64kg are added
Sour methyl esters maintains interior 25 DEG C of temperature, is stirred to react 65 hours or more, centrifugal filtration, filter residue is washed with 50kg glacial acetic acid, dries,
It is dried to loss on drying≤5% under the conditions of 60 DEG C, is cooled to room temperature, discharged, obtain phthalyl Amlodipine crude product；
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；
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；
Step 7, the preparation of amlodipine maleate crude product：
10g Amlodipines, 100ml water are added in 250ml eggplant-shape bottles, is stirred at room temperature, 3.9g maleic acids is dissolved in 40ml water,
30 DEG C of constant temperature is added dropwise in the Amlodipine solution in eggplant-shape bottle with dropping funel, is finished, and continues stirring 4 hours, is filtered, and is used
It washes filter cake 2 times, is dried in vacuo 8 hours or more under the conditions of 65 DEG C, obtains the amlodipine maleate crude product of white chunks, receive
Rate 91%, purity 99.2%；
Step 8, amlodipine maleate refine：
10g amlodipine maleate crude products are taken, are added in 250ml eggplant-shape bottles, then 80ml methanol is added into eggplant-shape bottle, are heated to
60 DEG C, stirring makes material be completely dissolved, and is cooled to 50 DEG C, and 1g activated carbons are added, and stirring is warming up to 65 DEG C, stirs 30min, hot mistake
Filter removes activated carbon, and 20ml methanol is added to clean eggplant-shape bottle, and vacuum distillation steams to volume of material 40ml, 120ml acetic acid is added
Ethyl ester carries out azeotropic distillation, steams volume 50ml, be cooled to room temperature, then be down to 0 DEG C, stirs 2h, filters, is dried under reduced pressure, obtains
Amlodipine maleate, yield 91.5%, purity 99.5%；
The synthesis technology is carried out by following reaction formula：
Embodiment 2：A kind of synthesis technology of amlodipine maleate, 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 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 is cooled to room temperature, discharges, obtain N- (the 2- hydroxyl second of 51kg in 70 DEG C, vacuum degree to be dried under conditions of -0.1MPa
Base)-phthalimide；The yield 91.6% of amlodipine maleate, purity 99.4%.
Embodiment 3：A kind of synthesis technology of amlodipine maleate, 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 divides water, when phegma moisture content≤0.2%, changes back stream as distillation, distill out 45kg toluene (as
The retarder thinner of 4- chloroacetyl acetacetic esters), it stirs lower cooling and gives retort nitrogen charging when temperature in tank is down to 45 DEG C, continue
It is cooled to 0 DEG C, N- (2- ethoxys)-phthalimide of 40kg is added with stirring, is subsequently added into 20kg sodium hydrides, adds
Finish, cover tightly cover, stirred under the conditions of 0 DEG C, the 4- chloroacetyl acetacetic esters of 38.4kg, 45kg toluene are pumped into simultaneously in measuring tank
It is uniformly mixed, the toluene solution of 4- chloroacetyl acetacetic esters is added dropwise into retort under the conditions of 0 DEG C, time for adding is controlled 4
Hour, it finishes, continues to be stirred to react, slowly heat up, so that reacting liquid temperature is slowly increased to 35 DEG C in 5 hours, the reaction time 12
Hour or more, it is warming up to 48 DEG C and continues to keep the temperature, until the reaction is complete, cooling controls interior 30 DEG C of temperature, adds 61kg glacial acetic acid, finish,
Continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds 180kg water, finish at 30 DEG C, continues stirring 30 minutes,
Stop nitrogen charging, stop 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, stirs, stands, water layer is separated into barrelling, then toluene layer is transferred to water washing tank, water layer is turned
Enter in retort, 75kg toluene is added into retort, stir, stand, water layer is separated, toluene layer merging is transferred to water washing tank
In, to the brine that 100kg mass fractions are 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；The yield of amlodipine maleate
91.5%, purity 99.5%.
Embodiment 4：A kind of synthesis technology of amlodipine maleate, 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 divides water, when phegma moisture content≤0.2%, changes back stream as distillation, distill out 45kg toluene (as
The retarder thinner of 4- chloroacetyl acetacetic esters), it stirs lower cooling and gives retort nitrogen charging when temperature in tank is down to 45 DEG C, continue
5 DEG C are cooled to, N- (2- ethoxys)-phthalimide of 40kg is added with stirring, is subsequently added into 20kg sodium hydrides, adds
Finish, cover tightly cover, stirred under the conditions of 5 DEG C, the 4- chloroacetyl acetacetic esters of 38.4kg, 45kg toluene are pumped into simultaneously in measuring tank
It is uniformly mixed, the toluene solution of 4- chloroacetyl acetacetic esters is added dropwise into retort under the conditions of 0 DEG C, time for adding is controlled 4
Hour, it finishes, continues to be stirred to react, slowly heat up, so that reacting liquid temperature is slowly increased to 38 DEG C in 5 hours, the reaction time 12
Hour or more, it is warming up to 51 DEG C and continues to keep the temperature, until the reaction is complete, cooling controls interior 35 DEG C of temperature, adds 61kg glacial acetic acid, finish,
Continuing stirring keeps material stirring in reaction solution uniform, and interior temperature control system adds 180kg water, finish at 35 DEG C, continues stirring 30 minutes,
Stop nitrogen charging, stop 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, stirs, stands, water layer is separated into barrelling, then toluene layer is transferred to water washing tank, water layer is turned
Enter in retort, 75kg toluene is added into retort, stir, stand, water layer is separated, toluene layer merging is transferred to water washing tank
In, to the brine that 100kg mass fractions are 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；The yield of amlodipine maleate
91.7%, purity 99.5%.
Embodiment 5：A kind of synthesis technology of amlodipine maleate, 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, the 2- chlorobenzaldehydes of 27kg are added, maintains interior 30 DEG C of temperature, 1.5kg hexahydropyridines is added, stir 30 minutes, in 65 DEG C of conditions
Lower reduced-pressure backflow divides water 12 hours or more, and pressure when reduced-pressure backflow is -0.08Mpa, is cooled to 30 DEG C, 120kg water is added, stirs
It mixes, stands, layering, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethoxies
Base] ethyl acetoacetate toluene solution；The yield 91.5% of amlodipine maleate, purity 99.4%.
Embodiment 6：A kind of synthesis technology of amlodipine maleate, 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, the 2- chlorobenzaldehydes of 27kg are added, maintains interior 35 DEG C of temperature, 1.5kg hexahydropyridines is added, stir 30 minutes, in 65 DEG C of conditions
Lower reduced-pressure backflow divides water 12 hours or more, and pressure when reduced-pressure backflow is -0.09Mpa, is cooled to 35 DEG C, 120kg water is added, stirs
It mixes, stands, layering, lower aqueous layer recovery processing, upper layer is 2- (support of 2- chlorine Bians) -4- [(2- phthalimides) ethoxies
Base] ethyl acetoacetate toluene solution；The yield 91.7% of amlodipine maleate, purity 99.4%.
Embodiment 7：A kind of synthesis technology of amlodipine maleate, 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, and 56kg n-hexanes are added, and stirring is cooled to 30 DEG C, stands, extraction just oneself
Alkane washing lotion adds 56kg n-hexanes, is stirred under the conditions of 30 DEG C, stands, then extract n-hexane washing lotion out, subtracts under the conditions of 30 DEG C
Remaining n-hexane is distilled off in pressure, and 240kg glacial acetic acid is added, and stirring makes material dissolution, the 3- amino crotonic acids of 64kg are added
Methyl esters maintains interior 30 DEG C of temperature, is stirred to react 65 hours or more, centrifugal filtration, filter residue is washed with 50kg glacial acetic acid, dries, 65
It is dried to loss on drying≤5% under the conditions of DEG C, is cooled to room temperature, discharged, obtain phthalyl Amlodipine crude product；Maleic acid ammonia
The yield 91.5% of Flordipine, purity 99.3%.
Embodiment 8：A kind of synthesis technology of amlodipine maleate, 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, and 56kg n-hexanes are added, and stirring is cooled to 35 DEG C, stands, extraction just oneself
Alkane washing lotion adds 56kg n-hexanes, is stirred under the conditions of 35 DEG C, stands, then extract n-hexane washing lotion out, subtracts under the conditions of 35 DEG C
Remaining n-hexane is distilled off in pressure, and 240kg glacial acetic acid is added, and stirring makes material dissolution, the 3- amino crotonic acids of 64kg are added
Methyl esters maintains interior 35 DEG C of temperature, is stirred to react 65 hours or more, centrifugal filtration, filter residue is washed with 50kg glacial acetic acid, dries, 70
It is dried to loss on drying≤5% under the conditions of DEG C, is cooled to room temperature, discharged, obtain phthalyl Amlodipine crude product；Maleic acid ammonia
The yield 91.5% of Flordipine, purity 99.4%.
Embodiment 9：A kind of synthesis technology of amlodipine maleate, 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；The yield 91.4% of amlodipine maleate,
Purity 99.6%.
Embodiment 10：A kind of synthesis technology of amlodipine maleate, 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；The yield 91.6% of amlodipine maleate,
Purity 99.6%.
Embodiment 11：A kind of synthesis technology of amlodipine maleate, 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 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；Horse
Come the yield 91.4% of sour Amlodipine, purity 99.6%.
Embodiment 12：A kind of synthesis technology of amlodipine maleate, 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 40
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；Horse
Come the yield 91.5% of sour Amlodipine, purity 99.4%.
Embodiment 13：A kind of synthesis technology of amlodipine maleate, difference from example 1 is that, step 7
For：10g Amlodipines, 100ml water are added in 250ml eggplant-shape bottles, is stirred at room temperature, 3.9g maleic acids is dissolved in 40ml water,
30 DEG C of constant temperature is added dropwise in the Amlodipine solution in eggplant-shape bottle with dropping funel, is finished, and continues stirring 4 hours, is filtered, and is used
It washes filter cake 2 times, is dried in vacuo under the conditions of 65 DEG C 8 hours or more, take out primary drying case per 2h in the drying process to remove
The steam volatilized obtains the amlodipine maleate crude product of white chunks, yield 91.5%, purity 99.6%；Maleic acid ammonia
The yield 91.7% of Flordipine, 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 maleate, 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 finishes, continues stirring 30 minutes, stop nitrogen charging, stop stirring, stand, water layer is separated into barrelling, toluene layer is transferred to water washing tank,
Water layer is transferred in retort, toluene is added into retort, is stirred, stands, water layer is separated into barrelling, then toluene layer is transferred to
Water layer is transferred in retort by water washing tank, and toluene is added into retort, is stirred, and stands, water layer is separated, and toluene is laminated
And be transferred in water washing tank, the brine for being added that mass fraction is 25% is given in water washing tank, is stirred 15 minutes, stands 30 minutes, divides and goes
Water 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 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 dries, dry, is cooled to room temperature, discharges, obtains phthalyl Amlodipine 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 maleate crude product：
Amlodipine, water are added in eggplant-shape bottle, are stirred at room temperature, maleic acid is soluble in water, and 30 DEG C of constant temperature is dripped with dropping funel
It adds in the Amlodipine solution in eggplant-shape bottle, finishes, continue stirring 4 hours, filter, filter cake is washed with water 2-3 times, in 65 DEG C of items
It is dried in vacuo 8 hours or more under part, obtains the amlodipine maleate crude product of white chunks, yield 91%, purity 99.2%；
Step 8, amlodipine maleate refine：
Amlodipine maleate crude product is taken, is added in eggplant-shape bottle, then methanol is added into eggplant-shape bottle, is heated to 60 DEG C, stirring makes
Material is completely dissolved, and is cooled to 50 DEG C, and activated carbon is added, and stirring is warming up to 65 DEG C, stirs 30min, and heat filtering removes deactivation
Charcoal, and methanol is added to clean eggplant-shape bottle, vacuum distillation steams to the half of volume of material, ethyl acetate is added, carries out azeotropic distillation,
Volume 50ml is steamed, room temperature is cooled to, then is down to 0 DEG C, is stirred, is filtered, is dried under reduced pressure, obtains amlodipine maleate, yield
91.5%, purity 99.5%；
The synthesis technology is carried out by following reaction formula：
2. the synthesis technology of amlodipine maleate 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.
3. the synthesis technology of amlodipine maleate 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 maleate 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, dries, dry, is cooled to often
Temperature, discharging, obtains phthalyl Amlodipine crude product.
5. the synthesis technology of amlodipine maleate according to claim 1, which is characterized in that dry in the step 4
Method is：It is dried to loss on drying≤5% under the conditions of 65 ± 5 DEG C.
6. the synthesis technology of amlodipine maleate according to claim 1, which is characterized in that in the step 7,
Primary drying case is taken out to remove the steam volatilized per 2h in drying process.
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| CN115583909A (en) * | 2022-10-25 | 2023-01-10 | 福州大学 | Method for producing N- (2-hydroxyethyl) -phthalimide by using ethanolamine to aminolyze phthalic anhydride residues |
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