CN114380830A - Synthesis process of doxofylline - Google Patents
Synthesis process of doxofylline Download PDFInfo
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- CN114380830A CN114380830A CN202111625435.1A CN202111625435A CN114380830A CN 114380830 A CN114380830 A CN 114380830A CN 202111625435 A CN202111625435 A CN 202111625435A CN 114380830 A CN114380830 A CN 114380830A
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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Abstract
The invention discloses a synthesis process of doxofylline, which comprises the following steps: adding theophylline, halogenated acetaldehyde ethylene glycol, an acid-binding agent and a catalyst into an organic solvent; under the action of an acid-binding agent and a catalyst, theophylline and halogenated acetaldehyde ethylene acetal undergo a substitution reaction in an organic solvent to generate a crude doxofylline product, and the crude doxofylline product is refined to obtain doxofylline; wherein the weight ratio of the theophylline to the organic solvent, the acid-binding agent and the catalyst is 1: (3-4): (0.3-0.6): (0.006-0.007), the weight ratio of the theophylline to the haloacetaldehyde ethylene acetal is 1: (1-1.05).
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a synthesis process of doxofylline.
Background
Doxofylline (Doxofylline) is a new benzene base drug, is a derivative of xanthine, and has the chemical name of 2- (7-theophylline methyl) -1, 3-dioxolane. Doxofylline is a new generation methylpurine derivative which replaces theophylline drugs, is clinically used for treating diseases such as bronchial asthma, chronic obstructive pulmonary disease and dyspnea caused by other bronchospasm, and has lower toxicity and no addiction compared with similar products.
At present, the synthesis routes of doxofylline are more, and the main synthesis method is to prepare an intermediate theophylline firstly, and then the intermediate and ethylene glycol generate a crude product of doxofylline in an N, N-dimethylformamide solvent. However, the synthesis method introduces more solvents, so that the impurity content is high, and impurity removal and purification at the later stage are difficult.
Disclosure of Invention
Aiming at the problems, the invention designs a synthesis process of doxofylline, which comprises the following steps:
adding theophylline, halogenated acetaldehyde ethylene glycol, an acid-binding agent and a catalyst into an organic solvent;
under the action of an acid-binding agent and a catalyst, theophylline and halogenated acetaldehyde ethylene acetal undergo a substitution reaction in an organic solvent to generate a crude doxofylline product, and the crude doxofylline product is refined to obtain doxofylline;
wherein the weight ratio of the theophylline to the organic solvent, the acid-binding agent and the catalyst is 1: (3-4): (0.3-0.6): (0.006-0.007), the weight ratio of the theophylline to the haloacetaldehyde ethylene acetal is 1: (1-1.05).
Compared with the prior art, the invention has the beneficial effects that: the method adopts a one-step synthesis mode, under the action of an acid-binding agent and a catalyst, theophylline and haloacetaldehyde ethylene acetal are subjected to substitution reaction to directly generate a crude product of doxofylline, reaction steps are reduced, excessive solvent is avoided, side reaction is reduced, the impurity content is reduced, the product yield is improved, and the yield of doxofylline is 80-95%.
Preferably, the acid scavenger is an organic strong base.
The beneficial effect of this preferred scheme does: the organic strong base causes less side reaction in the reaction process, can reduce the impurity content and improve the reaction yield.
Preferably, the organic solvent is N, N-dimethylformamide,
and/or the acid-binding agent is sodium/potassium alkoxide,
and/or the catalyst is sodium iodide.
The beneficial effect of this preferred scheme does: the invention uses sodium alkoxide/potassium alkoxide as acid-binding agent, has better stability and less side reaction, can reduce the impurity content in crude doxofylline, and improves the purity and reaction efficiency of doxofylline; the sodium iodide can accelerate the reaction speed and efficiency and improve the product yield under the condition of lower cost, and is also used for controlling the reaction direction of the theophylline and the chloroacetaldehyde ethylene glycol and preventing the reverse reaction.
Preferably, the halogen atom in the haloacetaldehyde acetal can be fluorine, chlorine, bromine or iodine, and the haloacetaldehyde acetal is added at least twice.
The beneficial effect of this preferred scheme does: if the haloacetaldehyde ethylene acetal is added at one time, all reactants are wrapped, the reaction is blocked, and a large amount of reactants volatilize out at the same time, so that the reaction is completely influenced.
Preferably, the refining process comprises the steps of:
adding methanol into a reaction tank, adding a crude doxofylline product under stirring, heating, adding activated carbon after the crude doxofylline product is completely dissolved, stirring for 0.5-1h, filtering while hot to obtain a filter cake I, and washing the filter cake I with a methanol washing solution to obtain a first solution;
crystallizing the first solution, and performing centrifugal separation on a crystal to obtain a centrifugal substance;
drying the centrifugate to obtain doxofylline.
The beneficial effect of this preferred scheme does: the technological condition for refining doxofylline is simple and easy to operate, and the reaction yield can be improved to 80-95%; the obtained doxofylline has less impurities and the purity of 98.5-102.0%.
Preferably, the crude doxofylline: activated carbon: methanol: the weight ratio of the methanol washing liquid is 1: (0.03-0.07): (5-7): 1. preferably, the crystallization temperature is 0-5 ℃ and the time is 1-2 h; the drying temperature is 60-70 ℃ and the drying time is 2-6 h.
Preferably, the preparation of the crude doxofylline comprises the following steps:
adding an organic solvent into a reaction tank, adding the acid-binding agent and a catalyst under stirring, heating to 45-55 ℃, adding theophylline, heating to 115-plus 125 ℃, preserving heat for 2-3h, adding 1/2 haloacetaldehyde ethylene glycol, heating to 125-plus 135 ℃, preserving heat for 4-6h, adding 1/2 haloacetaldehyde ethylene glycol, continuing preserving heat for 25-35h at 125-plus 135 ℃, and completing the reaction when the TLC detects that the residual theophylline is similar to the configured 0.1% theophylline effect to obtain a crude doxofylline mixed solution;
filtering the crude doxofylline mixed solution while the solution is hot to obtain a filter cake II, and washing the filter cake II with an organic solvent washing solution to obtain a second solution;
crystallizing the second solution, and then performing centrifugal separation on a crystal to obtain a mother solution and a filter cake III;
washing the filter cake III by using methanol, and then carrying out centrifugal separation to obtain a centrifugal liquid and a centrifugate;
drying the centrifugate to obtain crude doxofylline.
The beneficial effect of this preferred scheme does: firstly, adding an acid-binding agent and a catalyst, changing the acid-binding agent into a molten state at the temperature of 45-55 ℃, increasing the contact area with theophylline, and further wrapping the theophylline; adding the halogenated acetaldehyde ethylene acetal twice to completely replace the halogenated acetaldehyde ethylene acetal with theophylline, so that the raw material waste caused by the large-scale volatilization of the halogenated acetaldehyde ethylene acetal is avoided;
under the action of an acid-binding agent and a catalyst, the crude doxofylline is synthesized by theophylline and haloacetaldehyde ethylene acetal at one time, so that the reaction steps are reduced, the efficiency is improved, the side reaction is reduced, the impurity content is effectively reduced, and the yield of the crude doxofylline is 65-80%.
Preferably, the adding proportion of the theophylline, the organic solvent washing liquid and the methanol is 1: (0.5-1): (1.9-2). Preferably, the crystallization temperature is-5-0 ℃, and the time is 1-2 h; the drying temperature is 60-70 ℃ and the drying time is 2-6 h.
The beneficial effect of this preferred scheme does: methanol can remove other soluble impurities in the filter cake III, and the original organic solvent is removed, so that the subsequent drying treatment is convenient, and the cost is low.
Preferably, the mother liquor is added into a reaction tank and heated, centrifugal liquid is added for dispersion, the mixture is stirred and cooled to 0-5 ℃, the temperature is kept for 1-2 hours, and a mother liquor extract is obtained after filtration, separation and drying;
adding methanol into a reaction tank, adding the mother liquor extract under stirring, sealing the tank, heating, adding activated carbon after the mother liquor extract is dissolved, stirring for 0.5-1h, filtering while hot to obtain a filter cake IV, and washing the filter cake IV by using a methanol washing solution to obtain a third solution; and cooling the third solution to 0-5 ℃ for crystallization, preserving heat for 1-2h, and then separating and drying to obtain a mother solution crude product (namely the crude product of doxofylline).
The beneficial effect of this preferred scheme does: the crude doxofylline product remained in the mother liquor is further extracted, so that the cost is reduced, and the reaction yield is improved.
Drawings
FIG. 1 is a chemical reaction equation for the production of doxofylline;
FIG. 2 is a synthetic route of crude doxofylline mixed liquor;
FIG. 3 is a synthetic route for crude doxofylline and crude mother liquor;
FIG. 4 shows the synthesis route of doxofylline.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
The embodiment provides a synthetic process of doxofylline, which comprises the steps of adding theophylline, halogenated acetaldehyde ethylene glycol, an acid-binding agent and a catalyst into an organic solvent, and carrying out substitution reaction on the theophylline and the halogenated acetaldehyde ethylene glycol in the organic solvent under the action of the acid-binding agent and the catalyst to generate a crude product of doxofylline. Alternatively, the acid scavenger is an organic strong base. In this embodiment, preferably, the organic solvent is N, N-Dimethylformamide (DMF), the acid-binding agent is sodium/potassium alkoxide, and the catalyst is sodium iodide. Further preferably, the acid-binding agent is sodium methoxide. Alternatively, the halogen atom in the haloacetaldehyde ethylene acetal may be fluorine, chlorine, bromine or iodine, and the haloacetaldehyde ethylene acetal is added at least twice. Preferably, in this embodiment, to reduce product toxicity and reduce environmental pollution, the haloacetaldehyde ethylene acetal is chloroacetaldehyde ethylene acetal, and the chloroacetaldehyde ethylene acetal is added in two steps. (the organic solvent, acid-binding agent, haloacetaldehyde ethylene acetal and other raw materials are selected as in the following examples, and are not described again.) the chemical reaction equation of this example is as follows:
the method specifically comprises the following steps:
(1) preparation of crude mixture of doxofylline
The synthetic route is shown in figure 2, adding N, N-dimethylformamide into a reaction tank under vacuum, adding sodium iodide and sodium methoxide while stirring, heating to 45 ℃, then slowly adding theophylline, uniformly stirring, heating to 115 ℃ and reacting for 3 hours. Alternatively, the weight ratio of the theophylline to the N, N-dimethylformamide, the sodium methoxide and the sodium iodide is 1: (3-4): (0.3-0.6): (0.006-0.007). In this embodiment, the weight ratio of the theophylline to the N, N-dimethylformamide, sodium methoxide and sodium iodide is 1: 3: 0.3: 0.006.
then chloroacetaldehyde ethylene glycol is added in two times, preferably in this embodiment, the weight ratio of the theophylline to the chloroacetaldehyde ethylene glycol is 1: 1. adding 1/2 chloroacetaldehyde ethylene glycol into a reaction tank, heating to 125 ℃, keeping the temperature for 4h, adding the rest 1/2 chloroacetaldehyde ethylene glycol, keeping the temperature at 125 ℃ for 25h, and detecting the effect of the residual theophylline similar to the effect of 0.1% of the prepared theophylline by TLC to finish the reaction (a developing agent: ethyl acetate) to obtain a crude doxofylline mixed solution;
(2) preparation of crude doxofylline
The synthetic route is shown in figure 3, and cold saline water is introduced into a jacket, so that the mixed solution of crude doxofylline is cooled to 90 ℃, and filtered while the mixed solution is hot to obtain a filter cake II; flushing the filter cake II with N, N-dimethylformamide with the weight of 0.75 times that of theophylline to obtain a second solution, carrying out crystallization treatment on the second solution at 0 ℃, preserving heat for 1h, and then carrying out centrifugal separation on a crystal to obtain a mother solution and a filter cake III; washing the filter cake III by using methanol with the weight 1.95 times that of theophylline, and then carrying out centrifugal separation to obtain a centrifugal liquid and a centrifugal substance; drying the centrifugate at 60 deg.C for 2h to obtain crude doxofylline.
Preferably, in this embodiment, the further extraction of the mother liquor includes the following steps: adding the mother liquor into a reaction tank, heating to form a porridge-like substance, adding the centrifugate, dispersing, stirring, cooling to 0 deg.C, keeping the temperature for 1h, filtering, separating, and drying to obtain a mother liquor extract; vacuumizing methanol into a reaction tank, adding a mother liquor extract under stirring, heating, adding activated carbon wetted by methanol after the mother liquor extract is completely dissolved, stirring for 0.5h, filtering while hot to obtain a filter cake IV, and then washing the filter cake IV by using a methanol washing solution to obtain a third solution; alternatively, the weight ratio of the mother liquor extract to methanol, activated carbon and methanol washing liquor is 1: (5-7): (0.03-0.07): 1. in this embodiment, the weight ratio of the mother liquor extract to the methanol, the activated carbon and the methanol washing solution is preferably 1:5:0.03: 1. And crystallizing the third solution at 0 ℃, preserving the heat for 1h, and then performing centrifugal separation and drying on the crystal to obtain a mother liquor crude product.
(3) Doxofylline refining
The synthetic route is shown in figure 4, methanol is added into a reaction tank in vacuum, crude doxofylline and crude mother liquor are added under stirring, the tank is sealed and heated to reflux, after the crude product is completely dissolved, activated carbon wetted by methanol is added, stirring is carried out for 0.5h, and hot filtration is carried out to obtain a filter cake I; washing the filter cake I by using a methanol washing liquid to obtain a first solution; in this embodiment, the weight ratio of (crude doxofylline + crude mother liquor), activated carbon, methanol and methanol washing solution is preferably 1: 0.03: 5: 1. introducing cold saline water to crystallize the first solution at 0 ℃, preserving heat for 1h, and then performing centrifugal separation on the crystal to obtain a centrifugal substance; drying the centrifugate at 60 deg.C for 2h to obtain doxofylline.
Preferably, in this embodiment, the reaction tank is a glass lining reaction tank, the centrifugal device is an LS-1200 type flat centrifuge, the filtering device is a stainless steel filter press, and the devices used in the following embodiments are the same as those in this embodiment, and therefore, the description thereof is omitted.
Example 2
The embodiment provides a synthesis process of doxofylline, which comprises the following steps:
(1) preparation of crude mixture of doxofylline
The synthetic route is shown in figure 2, adding N, N-dimethylformamide into a reaction tank under vacuum, adding sodium iodide and sodium methoxide while stirring, heating to 50 ℃, then slowly adding theophylline, uniformly stirring, heating to 120 ℃ and reacting for 2.5 h. In this embodiment, the ratio of theophylline to N, N-dimethylformamide, sodium methoxide and sodium iodide is 1: 3.42: 0.45: 0.0067.
then, chloroacetaldehyde ethylene glycol is added in two times, preferably in this embodiment, the adding ratio of the theophylline to the chloroacetaldehyde ethylene glycol is 1: 1.02. adding 1/2 chloroacetaldehyde ethylene glycol into a reaction tank, heating to 130 ℃, keeping the temperature for 5h, adding the rest 1/2 chloroacetaldehyde ethylene glycol, keeping the temperature at 130 ℃ for 30h, and detecting the effect of the residual theophylline similar to the effect of 0.1% of the prepared theophylline by TLC to finish the reaction (a developing agent: ethyl acetate) to obtain a crude doxofylline mixed solution;
(2) preparation of crude doxofylline
The synthetic route is shown in figure 3, and cold saline water is introduced into a jacket, so that the mixed solution of crude doxofylline is cooled to 95 ℃, and filtered while the mixed solution is hot to obtain a filter cake II; flushing the filter cake II with N, N-dimethylformamide with the weight of 0.78 times that of theophylline to obtain a second solution, cooling the second solution to-3 ℃ for crystallization, preserving heat for 1.5h, and then separating to obtain a mother solution and a filter cake III; washing the filter cake III by using methanol with the weight 1.97 times that of theophylline, and then carrying out centrifugal separation to obtain a centrifugal liquid and a centrifugal substance; drying the centrifugate at 65 deg.C for 4h to obtain crude doxofylline.
Preferably, in this embodiment, the further extraction of the mother liquor includes the following steps: adding the mother liquor into a reaction tank, heating to form a porridge-like substance, adding the centrifugate, dispersing, stirring, cooling to 3 deg.C, keeping the temperature for 1.5h, filtering, separating, and drying to obtain a mother liquor extract; adding methanol into a reaction tank in vacuum, adding a mother liquor extract under stirring, sealing the tank, heating to reflux, adding activated carbon wetted by methanol after the mother liquor extract is completely dissolved, stirring for 0.7h, filtering while hot to obtain a filter cake IV, and washing the filter cake IV by using a methanol washing solution to obtain a third solution; in this embodiment, the weight ratio of the mother liquor extract to the methanol, the activated carbon and the methanol washing solution is preferably 1:6:0.05: 1. And crystallizing the third solution at 3 ℃, preserving the heat for 1.5h, and then performing centrifugal separation and drying on the crystal to obtain a mother liquor crude product.
(3) Doxofylline refining
The synthetic route is shown in figure 4, methanol is added into a reaction tank in vacuum, crude doxofylline and crude mother liquor are added under stirring, the tank is sealed and heated to reflux, after the crude product is completely dissolved, activated carbon wetted by methanol is added, stirring is carried out for 0.7h, and hot filtration is carried out to obtain a filter cake I; washing the filter cake I by using a methanol washing liquid to obtain a first solution; in this embodiment, the weight ratio of (crude doxofylline + crude mother liquor), activated carbon, methanol and methanol washing solution is preferably 1: 0.05: 6: 1. introducing cold saline water to cool the first solution to 3 ℃ for crystallization, preserving heat for 1.5h, and then carrying out centrifugal separation on the crystal to obtain a centrifugal substance; drying the centrifugate at 65 deg.C for 4h to obtain doxofylline.
Example 3
The embodiment provides a synthesis process of doxofylline, which comprises the following steps:
(1) preparation of crude mixture of doxofylline
The synthetic route is shown in figure 2, adding N, N-dimethylformamide into a reaction tank under vacuum, adding sodium iodide and sodium methoxide while stirring, heating to 55 ℃, then slowly adding theophylline, uniformly stirring, heating to 125 ℃ and reacting for 2 hours. In this embodiment, the ratio of theophylline to N, N-dimethylformamide, sodium methoxide and sodium iodide is 1: 4: 0.6: 0.007.
then, chloroacetaldehyde ethylene glycol is added in two times, preferably in this embodiment, the adding ratio of the theophylline to the chloroacetaldehyde ethylene glycol is 1: 1.05. adding 1/2 chloroacetaldehyde ethylene glycol into a reaction tank, heating to 135 ℃, keeping the temperature for 6h, adding the rest 1/2 chloroacetaldehyde ethylene glycol, keeping the temperature at 135 ℃ for 35h, and detecting the effect of the residual theophylline similar to the effect of 0.1% of the prepared theophylline by TLC to finish the reaction (a developing agent: ethyl acetate) to obtain a crude doxofylline mixed solution;
(2) preparation of crude doxofylline
The synthetic route is shown in figure 3, and cold saline water is introduced into a jacket, so that the mixed solution of crude doxofylline is cooled to 100 ℃, and filtered while the mixed solution is hot to obtain a filter cake II; washing the filter cake II with N, N-dimethylformamide with the weight of 0.8 time that of theophylline to obtain a second solution, cooling the second solution to-5 ℃ for crystallization, preserving the temperature for 2 hours, and then carrying out centrifugal separation on the crystal to obtain a mother solution and a filter cake III; washing the filter cake III by using methanol with 2 times of theophylline weight, and then carrying out centrifugal separation to obtain a centrifugal liquid and a centrifugal substance; drying the centrifugate at 70 deg.C for 6h to obtain crude doxofylline.
Preferably, in this embodiment, the further extraction of the mother liquor includes the following steps: adding the mother liquor into a reaction tank, heating to form a porridge-like substance, adding the centrifugate, dispersing, stirring, cooling to 5 deg.C, keeping the temperature for 2h, filtering, separating, and drying to obtain a mother liquor extract; vacuumizing methanol, putting the methanol into a reaction tank, adding a mother liquor extract under stirring, sealing the tank, heating to reflux, adding activated carbon wetted by the methanol after the mother liquor extract is completely dissolved, stirring for 1h, filtering while hot to obtain a filter cake IV, and washing the filter cake IV by using a methanol washing solution to obtain a third solution; in this embodiment, the weight ratio of the mother liquor extract to the methanol, the activated carbon and the methanol washing solution is preferably 1:7:0.07: 1. And cooling the third solution to 5 ℃ for crystallization, preserving the heat for 2 hours, and then separating and drying to obtain a mother liquor crude product.
(3) Doxofylline refining
The synthetic route is shown in figure 4, methanol is added into a reaction tank in vacuum, crude doxofylline and crude mother liquor are added under stirring, the tank is sealed and heated to reflux, after the crude product is completely dissolved, activated carbon wetted by methanol is added, stirring is carried out for 1h, and hot filtration is carried out to obtain a filter cake I; washing the filter cake I by using a methanol washing liquid to obtain a first solution; in this embodiment, the weight ratio of (crude doxofylline + crude mother liquor), activated carbon, methanol and methanol washing solution is preferably 1: 0.07: 7: 1. introducing cold saline water to cool the first solution to 5 ℃ for crystallization, preserving heat for 2 hours, and then separating to obtain a centrifugal substance; drying the centrifugate at 70 deg.C for 6h to obtain doxofylline.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; all other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A synthesis process of doxofylline is characterized by comprising the following steps:
adding theophylline, halogenated acetaldehyde ethylene glycol, an acid-binding agent and a catalyst into an organic solvent;
under the action of an acid-binding agent and a catalyst, theophylline and halogenated acetaldehyde ethylene acetal undergo a substitution reaction in an organic solvent to generate a crude doxofylline product, and the crude doxofylline product is refined to obtain doxofylline;
wherein the weight ratio of the theophylline to the organic solvent, the acid-binding agent and the catalyst is 1: (3-4): (0.3-0.6): (0.006-0.007), the weight ratio of the theophylline to the haloacetaldehyde ethylene acetal is 1: (1-1.05).
2. The process of claim 1, wherein the acid scavenger is an organic strong base.
3. The process for synthesizing doxofylline according to claim 1, wherein the organic solvent is N, N-dimethylformamide,
and/or the acid-binding agent is sodium/potassium alkoxide,
and/or the catalyst is sodium iodide.
4. The process of claim 1, wherein the halogen atom in the haloacetaldehyde acetal is fluorine, chlorine, bromine, iodine, and the haloacetaldehyde acetal is added in at least two steps.
5. The process for synthesizing doxofylline according to claim 1, wherein said refining step comprises the following steps:
adding methanol into a reaction tank, adding a crude doxofylline product under stirring, heating, adding activated carbon after the crude doxofylline product is completely dissolved, stirring for 0.5-1h, filtering while hot to obtain a filter cake I, and washing the filter cake I with a methanol washing solution to obtain a first solution;
crystallizing the first solution, and performing centrifugal separation on a crystal to obtain a centrifugal substance;
drying the centrifugate to obtain doxofylline.
6. The process for synthesizing doxofylline according to claim 5, wherein the weight ratio of the crude doxofylline to the activated carbon, methanol and methanol washing solution is 1: (0.03-0.07): (5-7): 1.
7. the process for synthesizing doxofylline according to claim 5, wherein the crystallization temperature is 0-5 ℃ and the time is 1-2 h; the drying temperature is 60-70 ℃ and the drying time is 2-6 h.
8. The process for synthesizing doxofylline according to claim 1, wherein the preparation of crude doxofylline comprises the following steps:
adding an organic solvent into a reaction tank, adding the acid-binding agent and a catalyst under stirring, heating to 45-55 ℃, adding theophylline, heating to 115-plus 125 ℃, preserving heat for 2-3h, adding 1/2 haloacetaldehyde ethylene glycol, heating to 125-plus 135 ℃, preserving heat for 4-6h, adding 1/2 haloacetaldehyde ethylene glycol, continuing preserving heat for 25-35h at 125-plus 135 ℃, and completing the reaction when the TLC detects that the residual theophylline is similar to the configured 0.1% theophylline effect to obtain a crude doxofylline mixed solution;
filtering the crude doxofylline mixed solution while the solution is hot to obtain a filter cake II, and washing the filter cake II with an organic solvent washing solution to obtain a second solution;
crystallizing the second solution, and then performing centrifugal separation on a crystal to obtain a mother solution and a filter cake III;
washing the filter cake III by using methanol, and then carrying out centrifugal separation to obtain a centrifugal liquid and a centrifugate;
drying the centrifugate to obtain crude doxofylline.
9. The process for synthesizing doxofylline according to claim 8, wherein the weight ratio of theophylline to organic solvent wash to methanol is 1: (0.5-1): (1.9-2).
10. The process for synthesizing doxofylline according to claim 8, wherein the crystallization temperature is-5 to 0 ℃ and the time is 1 to 2 hours; the drying temperature is 60-70 ℃ and the drying time is 2-6 h.
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