CN105153170B - The dichloro-4,4 of persantine intermediate 2,6, the process for purification of 8 two piperidinopy rimidines simultaneously [5,4 D] pyrimidine - Google Patents
The dichloro-4,4 of persantine intermediate 2,6, the process for purification of 8 two piperidinopy rimidines simultaneously [5,4 D] pyrimidine Download PDFInfo
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- CN105153170B CN105153170B CN201510735750.8A CN201510735750A CN105153170B CN 105153170 B CN105153170 B CN 105153170B CN 201510735750 A CN201510735750 A CN 201510735750A CN 105153170 B CN105153170 B CN 105153170B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
It is related to a kind of dichloro-4,4 of persantine intermediate 2,6 the invention provides one kind, the process for purification of 8 two piperidinopy rimidines simultaneously [5,4 D] pyrimidine belongs to chemical industry synthesis field.The method carries out second-stage reaction including feeding intake, stirring, adjusting pH, and suction filtration reclaims acetone, the step such as washing and pickling filter cake.By the precise control to reaction conditions such as material proportion and temperature, the pH in course of reaction so that side reaction is few, the product yield for synthesizing is high and side reaction is few, impurity is easy to purifying less, and the solution of product is clarified or in opalescent, and compared to traditional synthesis, outward appearance is more preferably.
Description
Technical field
The present invention relates to chemical industry synthesis field, in particular to a kind of persantine intermediate 2, the chloro- piperazines of 4,8- bis- of 6- bis-
The process for purification of pyridine subbase pyrimido [5,4-D] pyrimidine.
Background technology
Persantine, alias DPD, Dipyridamole, Dipyridamole Curantyl is that non-nitrate esters coronary artery expands
Agent is opened, with expansion coronary vasodilator, promotes Doppler flow mapping to be formed and slight anticoagulation, with antiviral effect.Dichloride
Thing, Chinese：The piperidines of 2,6- bis- chloro- 4,8- bis- (5,4d) and pyrimidine, English name：DICHLORO-DIPIPERIDINE
HOMOPURINE, abbreviation DDH, are the medicine intermediates for manufacturing persantine.
Current DDH synthesis techniques are extensive due to technique, and side reaction is more, and impurity content is big in synthetic product, and product
Appearance luster it is poor, it is impossible to meet the requirement of follow-up fine pharmacy.
In view of this, it is special to propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of persantine intermediate 2, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,
4-D] pyrimidine process for purification, it has the advantages that, and impurity is few, product appearance color and luster is good.
In order to realize above-mentioned purpose of the invention, spy uses following technical scheme：
Persantine intermediate 2, the process for purification of the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine, including with
Lower step：
(1) acetone is added in container, 2,4,6,8- tetrachloro-pyrimidines simultaneously [5,4-D] pyrimidine is added while stirring, dripped
Continue to stir 5~10min into rear, obtain the first solution；
(2) mixed liquor of configuration piperidines and acetone, it is described to being added dropwise in first solution under the conditions of 25 DEG C~35 DEG C
Mixed liquor, reacts 15min~25min after being added dropwise to complete；
(3) add alkali regulation pH to 7~8, continue to stir after the completion of regulation；
(4) acetone is added, at least 5min is stirred after adding, suction filtration reclaims acetone, obtains filter cake, and water and quality is used alternatingly
Fraction is 25%~35% acid solution washing filter cake, and simultaneously [5,4-D] are phonetic for dry the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis-
Pyridine.
Existing synthesis technique is not fine enough for the control such as temperature reacted, while after the completion of reaction directly by subtracting
Pressure suction filtration reclaims acetone.This synthesis mode is not fine enough due to the control to reaction condition, and yield is relatively low.Produce simultaneously
Product colour is deeper, illustrates that the side reaction in course of reaction is more, and the corresponding impurity for producing is more.
In the technical program, the reaction of first stage is completed in step (1) and step (2), and in step (3) plus after alkali,
Many side reactions are eliminated, and impurity is converted into product, are the second stage reactions of whole reaction.
To filter cake alternately pickling and washing, the outward appearance of product, color and luster can be improved, make product be in the shallow colour of loess
Color is to tan crystals shape.The technical program is finely controlled for the order of addition of the whole temperature reacted, time, reactant
System so that the side reaction of reaction is significantly reduced.
Further, also including to the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- obtained by drying, simultaneously [5,4-D] pyrimidine enters
The step of row recrystallization, the mode of the recrystallization is specially：By the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- simultaneously [5,4-D]
Pyrimidine Stir forms recrystallization liquid in being dissolved in toluene, is heated with stirring to 90 DEG C~100 DEG C, press filtration crystallization.
When being produced in enormous quantities, because reacting dose is big, situations such as appearance luster difference generally can all occur in product, pass through
Filter cake is recrystallized, product can be made purer.Recrystallization can effectively reduce the impurity content in product.
Toluene is quickly to dissolve the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- simultaneously [5,4-D] pyrimidine, is suitable for use as weight
Recrystallisation solvent.It should be noted that can also be recrystallized using other solvents similar to toluene physical property, toluene exists
It is also recyclable after the completion of recrystallization.
Further, the press filtration crystallization is carried out in the following manner：First with water cooling recrystallization liquid, stirred crystallization,
After water temperature reaches 48 DEG C~52 DEG C, it is 10 DEG C~15 that recrystallization liquid is cooled to recrystallization liquid using 0 DEG C~8 DEG C of salt solution
DEG C, centrifugation；
The crystal ethanol water of acquisition is rinsed to grey decoloration, is dried.
By controlling the amplitude of cooling, progressively being lowered the temperature can make the more regular unification of crystal formation of recrystallization.
Material proportion between reactant is most important for the carrying out reacted and the positive movement of promotion chemical balance.Instead
The chemical equation answered is as follows：
Further, the piperidines and described 2,4,6,8- tetrachloro-pyrimidines mol ratio simultaneously between [5,4-D] pyrimidine is 2
~3：1.When piperidines and 2, when 4,6,8- tetrachloro-pyrimidines material proportion simultaneously between [5,4-D] pyrimidine is between 2 and 3, equal energy
Obtain yield higher.
Further, through the multiple practice summary of inventor, the piperidines and described 2,4,6,8- tetrachloro-pyrimidines are simultaneously [5,4-D]
Mol ratio between pyrimidine is 2.55：1, and the proportioning is the optimum response proportioning of this reaction.
Under the conditions of the material proportion, the yield highest of this reaction, and amount of by-products is less, is easy to the purifying of product to receive
Collection.
Further, the mass ratio between the piperidines and added alkali is 1~1.5：1.
As it was previously stated, in reaction solution plus during alkali, accelerating piperidines and 2,4,6,8- tetrachloro-pyrimidines simultaneously [5,4-D] pyrimidine
Reaction, promote reaction to be moved to positive reaction direction, corresponding side reaction is reduced, and impurity tails off.But I haven't seen you for ages draws for alkali number many
The pH value of the system that reacts changes, and can also influence the reaction rate of reaction.
The experiment proved that, the mass ratio between piperidines and the alkali is controlled 1~1.5：When 1, reaction system is entered through HPLC
Row detection, the impurity peaks in system seldom, illustrate that the growing amount of impurity in reaction system is little, that is to say, that in the reaction condition
Under, side reaction is less, beneficial to acquisition yield higher.
Still it is noted that if base excess is more, generation washing is difficult to remove with pickling in causing reaction system
Polymer, is unfavorable for the purifying of product.
It is highly preferred that the mass ratio between the piperidines and added alkali is 4：3.
When the mass ratio of piperidines and alkali is 4:When 3, the pH value of reaction system can be adjusted to appropriate level and will not
Polymer is generated in reaction system.
Further, the mass fraction of the ethanol solution is 90%~98%.
Be added dropwise piperidines when, piperidines is mixed with acetone first as solvent from acetone, then be added into containing
2,4,6,8- tetrachloro-pyrimidines simultaneously in the acetone soln of [5,4-D] pyrimidine, are easy to piperidines and 2, and 4,6,8- tetrachloro-pyrimidines are simultaneously [5,4-D]
Pyrimidine is fully contacted reaction.But the content of acetone crosses conference and causes the concentration of reactant to decline simultaneously, causes chemical balance to move to left,
Influence product yield.
Further, in step (2), in the mixed liquor, piperidines is 1 with the mass ratio of acetone：0.5~1.2.Match somebody with somebody at this
Than under the conditions of, reaction system can reach larger yield.
Also, through inventor's experimental verification, it is highly preferred that when the mass ratio of piperidines and acetone is 0.5~1, yield is more
It is high.
Compared with prior art, beneficial effects of the present invention are：
(1) the persantine intermediate 2 that the present invention is provided, 6- bis- chloro- piperidinopy rimidines of 4,8- bis- simultaneously [5,4-D] pyrimidine
The product yield that process for purification synthesizes is high and side reaction is few, and impurity is easy to purifying less.
(2) product obtained through this method is clarified or in micro emulsion in Qian Tu Yellow colors to tan crystals, and the solution of product
White, compared to traditional synthesis, outward appearance is more preferably.
Specific embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below will be in the embodiment of the present invention
Technical scheme be clearly and completely described, it is clear that described embodiment is a part of embodiment of the invention, rather than
Whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art are not making creative work premise
Lower obtained every other embodiment, belongs to the scope of protection of the invention.
Test example 1：
(1) acetone (reclaiming acetone+industrial acetone) 110g of dosage is put into, then starts stirring, tetrachloros are added at 20~30 DEG C
Compound 20g (0.074mol), stirs 15 minutes.
(2) under ice bath or water-bath, be added dropwise every time at 20-30 DEG C piperidines (12.9g 13.5g 14.2g 14.8g
15.4g 16g) and comparable quality acetone mixed liquor.20-30 DEG C is kept after adding to react 30 minutes.
(3) alkali is added dropwise at 20~30 DEG C again, and general control pH=8~9 are stirred 30 minutes at 30 DEG C.
(4) begin to warm up, acetone is recovered under reduced pressure, temperature control is recovered to reaction solution at 31~35 DEG C in stiff liquid.
(5) now stop heating, add water to full, stirring 30 minutes, filtering, washing is dried, and obtains dichloride (DDH).
Experimental result is shown in Table 1：
The tables of data of 1 test example of table 1
Wherein the 4th group the failure of an experiment does not obtain result, and dichloro is the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- simultaneously [5,4-
D] pyrimidine, tetrachloro is 2,4,6,8- tetrachloro-pyrimidines simultaneously [5,4-D] pyrimidine.Dichloro content represents the content in products therefrom, contains
Amount is bigger, illustrates that product is purer.
In above-mentioned experiment, no matter simultaneously whether [5,4-D] pyrimidine is with a batch of product, not to 2,4,6,8- tetrachloro-pyrimidines
Under same material proportion, as a result there is the fluctuation of yield.And under the experimental condition obtain dichloro product colour compared with
It is deep, illustrate that side reaction is more under the reaction conditions, generate more impurity.
Test example 2
Verify under conditions of alkali is not added with, the yield of reaction system.
Acetone and tetrachloro are sequentially added in reaction bulb, the acetone soln of piperidines, reaction is added under stirring in 0~5 DEG C
40min. is added water 50ml, and filtering, filter cake is washed with water, dry yellow solid, test data such as table 2.
The tables of data of 2 test example of table 2
Wherein the 1st group the failure of an experiment does not obtain result.
Data would know that, in the case where alkali is not added with, dichloro yield is extremely low from experiment 2, illustrates plus alkali regulation pH value can
To greatly improve the yield and yield of reaction.Determined by HPLC, plus reaction system starts the reaction of second section after alkali, is
The release process of piperidines.Most of impurity peaks can be eliminated.
Test example 3
Influence of the tetrachloro water content to yield and content when checking feeds intake.
110g acetone and tetrachloro 23.75g are sequentially added in reaction bulb, moisture are wherein contained in tetrachloro, under stirring in 0~
5 DEG C of mixed solutions of addition 6g containing piperidinyl-1 and acetone 16g, plus alkali 20g, reaction 40min. adds water 50ml, filters, filter cake water
Washing, dry yellow solid 23.5g, it is 92.71% to calculate two chlorinities, and yield is 80.1%, as shown in table 3：
The tables of data of 3 test example of table 3
Illustrate to influence little to reaction result containing moisture in reactant.
Test example 4
Reaction condition is optimized, the yield of confirmatory reaction system.
(1) acetone (reclaiming acetone+industrial acetone) 110g of input dosage, starts stirring, adds tetrachloride 20g, stirring
5~10 minutes.
(2) mixed liquor of piperidines is added dropwise at 25-35 DEG C.Adding rear natural temperature makes its reaction 20 minutes (survey material in acid
Property, illustrate that first segment reaction terminates).
(3) alkali, general control PH=7~8 are added dropwise again.Add, stirred 15 minutes under natural temperature.
(4) two experimental groups are chosen in addition 200g acetone in stiff liquid reaction solution.Stirring 5 minutes, suction filtration.Mother liquor
Acetone is reclaimed, filter cake is washed with water.
(5) dry, obtain dichloride.Experimental data is shown in Table 4
The tables of data of 4 test example of table 4
5th group and the 6th group of experiment wash experimental group for addition acetone, other experimental groups in filter wash cake, using pickling and water
Wash mode alternately.It is that would know that from upper table data, by the dichloro obtained under this reaction temperature and pH environment reactions, content
More than 93.5%, hence it is evident that improve.
While it is relatively low using the experimental group yield that acetone is washed, illustrate that pickling and water-washing method can alternately improve product
Yield.
Experimental group 7 is tested in the form of anti-throwing material, and the influence of its yield is little, illustrates in the reaction system,
The release sequence of material is little on yield influence.
Test example 5
Continuation is optimized to reaction condition, solvent when checking tetrachloro product quality is to the influence reacted and dropwise addition piperidines
How many pairs of experimental results influence.
With test example 4, test data is shown in Table 5 to experimental condition
The tables of data of 5 test example of table 5
Wherein, when the experiment of experimental group 1 and 5 is added dropwise piperidines, the less (mass ratio of piperidines and acetone of amounts of acetone of piperidines is dissolved
≤ 1), the more (mass ratio of piperidines and acetone of amounts of acetone of the dissolving piperidines of experimental group 3 and 4>1), experimental group 6,7 uses thick tetrachloro
(the more smart tetrachloro of purity is low) is tested, and experimental group 8 is tested using smart tetrachloro, and experimental group 2 is entered using aqueous thick tetrachloro
Row experiment.
As seen from the experiment, when piperidines is added dropwise, the ratio between piperidines and solvent is no more than 1, and quantity of solvent is excessive
Product yield can be influenceed.Contrast experiment's group 6,7 and 8 can show that alkali number is excessive also to reduce product yield simultaneously.When piperidines and alkali
Between mass ratio be 4:When 3, yield highest.In addition as seen from the above table, compared to thick tetrachloro is used, also can be corresponding using smart tetrachloro
Raising product yield.
Embodiment 1
(1) acetone (reclaiming acetone+industrial acetone) 110g of input dosage, starts stirring, adds tetrachloride 30g, stirring
5~10 minutes.
(2) mixed liquor of piperidines 24.0g is added dropwise under the conditions of 25-35 DEG C.Piperidines is 1 with the mass ratio of acetone:1, add
Natural temperature makes its reaction 20 minutes (surveying material in acidity, illustrate that first segment reaction terminates) afterwards.
(3) the mixed liquor of 18g alkali is added dropwise again, PH=7~8 are controlled.Add, stirred 15 minutes under natural temperature.
(4), in 180g acetone is added in stiff liquid reaction solution, stir 5 minutes, suction filtration.Disposing mother liquor acetone, filter cake is used
Washing.
(5) gained filter cake water sour with the 30% of mass fraction and enough again carries out replacing washing, refilters, and washes, and obtains
30.6 dichloride.The content for calculating dichloro is 99.83%, and yield is 75.0%.
Embodiment 2
(1) acetone (reclaiming acetone+industrial acetone) 110g of input dosage, starts stirring, adds tetrachloride 30g, stirring
5~10 minutes.
(2) mixed liquor of piperidines 24.0g is added dropwise under the conditions of 25-35 DEG C.Piperidines is 1 with the mass ratio of acetone:1, add
Natural temperature makes its reaction 20 minutes (surveying material in acidity, illustrate that first segment reaction terminates) afterwards.
(3) the mixed liquor of 18g alkali is added dropwise again, PH=7~8 are controlled.Add, stirred 15 minutes under natural temperature.
(4), in 180g acetone is added in stiff liquid reaction solution, stir 5 minutes, suction filtration.Disposing mother liquor acetone, filter cake is used
Washing.
(5) gained filter cake water sour with the 30% of mass fraction and enough again carries out replacing washing, refilters, and washes, and obtains
31.5 dichloride.The content for calculating dichloro is 95.92%, and yield is 77.2%.
Embodiment 3
The production environment under the big condition of production is simulated, inventory is increased, step is as follows：
(1) acetone (reclaiming acetone+industrial acetone) 110g of input dosage, starts stirring, adds tetrachloride 50g, stirring
5~10 minutes.
(2) mixed liquor of piperidines 40.0g is added dropwise under the conditions of 25-35 DEG C.Piperidines is 1 with the mass ratio of acetone:1, add
Natural temperature makes its reaction 20 minutes (surveying material in acidity, illustrate that first segment reaction terminates) afterwards.
(3) the mixed liquor of 30g alkali is added dropwise again, PH=7~8 are controlled.Add, stirred 15 minutes under natural temperature.
(4), in 180g acetone is added in stiff liquid reaction solution, stir 5 minutes, suction filtration.Disposing mother liquor acetone, filter cake is used
Washing.
(5) gained filter cake water sour with the 30% of mass fraction and enough again carries out replacing washing, refilters, and washes, and obtains
57.9 dichloride.The content for calculating dichloro is 99.6%, and yield is 84.86%.
(6) by dichloride input crystallization kettle, 10 times of toluene of dichloride quality are put into crystallization kettle, is stirred
Mix, fully dissolved between being heated to 90~100 DEG C, can press filtration after 20 minutes.
Crystallization kettle is first lowered the temperature with ordinary water, stirred crystallization.After ordinary water cools to 50 DEG C, (0~8 DEG C) cooling of salt solution is used instead, make
Temperature of charge can carry out centrifuge from dry at 10~15 DEG C.
Dichloro crystallized stock is disappeared with 95% ethanol rinse to grey-phenomenon.Receive material to be dried in the shade at shady and cool ventilation, detect
After pack.Disposing mother liquor toluene is applied mechanically, and the average yield of product is 80%.
In the product that above-described embodiment is obtained, the content of dichloro is very high, illustrates that product is more pure, to above-mentioned implementation
The product that example is obtained carries out outward appearance and defects inspecting, the results are shown in Table 6
The Product checking result of table 6 illustrates table
Testing result shows that the product that above-described embodiment is obtained is significantly reduced compared with the product that prior art is obtained, impurity,
Product is purer and outward appearance high-quality, crystal formation unification, is satisfied by the requirement of follow-up finishing.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (8)
1. persantine intermediate 2, the process for purification of the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine, its feature exists
In comprising the following steps：
(1) acetone is added in container, 2,4,6,8- tetrachloro-pyrimidines simultaneously [5,4-D] pyrimidine is added while stirring, after being added dropwise to complete
Continue to stir 5~10min, obtain the first solution；
(2) mixed liquor of configuration piperidines and acetone, to the mixing is added dropwise in first solution under the conditions of 25 DEG C~35 DEG C
Liquid, reacts 15min~25min after being added dropwise to complete；
(3) add alkali regulation pH to 7~8, continue to stir after the completion of regulation, wherein, the quality between the piperidines and added alkali
Than being 1~1.5：1；
(4) acetone is added, at least 5min is stirred after adding, suction filtration reclaims acetone, obtains filter cake, and water and mass fraction is used alternatingly
It is 25%~35% acid solution washing filter cake, dry the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- simultaneously [5,4-D] pyrimidine.
2. persantine intermediate 2 according to claim 1, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine
Process for purification, it is characterised in that also including to the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- obtained by drying simultaneously [5,4-D]
The step of pyrimidine is recrystallized, the mode of the recrystallization is specially：By the chloro- piperidinopy rimidines of 4,8- bis- of 2,6- bis- simultaneously
[5,4-D] pyrimidine Stir forms recrystallization liquid in being dissolved in toluene, is heated with stirring to 90 DEG C~100 DEG C, press filtration crystallization.
3. persantine intermediate 2 according to claim 2, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine
Process for purification, it is characterised in that press filtration crystallization is carried out in the following manner：First with water cooling recrystallization liquid, stirring
Crystallization, after water temperature reaches 48 DEG C~52 DEG C, recrystallization liquid is cooled to recrystallization liquid for 10 DEG C using 0 DEG C~8 DEG C of salt solution
~15 DEG C, centrifugation；
The crystal ethanol water of acquisition is rinsed to grey decoloration, is dried.
4. persantine intermediate 2 according to claim 1 and 2, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- are simultaneously [5,4-D]
The process for purification of pyrimidine, it is characterised in that the piperidines and described 2,4,6,8- tetrachloro-pyrimidines simultaneously rubbing between [5,4-D] pyrimidine
Your proportioning is 2~3：1.
5. persantine intermediate 2 according to claim 4, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine
Process for purification, it is characterised in that the piperidines and described 2,4,6,8- tetrachloro-pyrimidines simultaneously mole matching somebody with somebody between [5,4-D] pyrimidine
Than being 2.55：1.
6. persantine intermediate 2 according to claim 1, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine
Process for purification, it is characterised in that mass ratio between the piperidines and added alkali is 4：3.
7. persantine intermediate 2 according to claim 3, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- simultaneously [5,4-D] pyrimidine
Process for purification, it is characterised in that the mass fraction of the ethanol water be 90%~98%.
8. persantine intermediate 2 according to claim 1 and 2, the chloro- piperidinopy rimidines of 4,8- bis- of 6- bis- are simultaneously [5,4-D]
The process for purification of pyrimidine, it is characterised in that in step (2), in the mixed liquor, piperidines is 1 with the mass ratio of acetone：0.5~
1.2。
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| CN108383844B (en) * | 2018-03-26 | 2020-03-20 | 常州大学 | Synthesis method of 2, 6-dichloro-4, 8-dipiperidinopyrimido [5,4-D ] pyrimidine |
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