CN110642858A - Preparation method of doxofylline - Google Patents
Preparation method of doxofylline Download PDFInfo
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- CN110642858A CN110642858A CN201911077867.6A CN201911077867A CN110642858A CN 110642858 A CN110642858 A CN 110642858A CN 201911077867 A CN201911077867 A CN 201911077867A CN 110642858 A CN110642858 A CN 110642858A
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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 method for preparing doxofylline, which comprises the following steps: in a reaction solvent, theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction under the action of an acid-binding agent to generate 7- (2, 2-dimethoxyethyl) theophylline; in a reaction solvent, 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol are subjected to acetal cyclization reaction under the action of a catalyst to generate a crude product of doxofylline; and heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain the doxofylline. The method has the advantages of easily controlled reaction conditions, high product purity of over 99.9 percent, simple and convenient product separation and purification, and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of doxofylline.
Background
Doxofylline (Doxofylline) is chemically 1, 3-dimethyl-7- (1, 3-dioxolan-2-yl) methyl-3, 7-dihydro-1H-purine-2, 6-dione. Doxofylline has a strong antiasthmatic effect, is a new drug for bronchiectasis, has a commercial name of Anismar, and is marketed in italy in 1988. The safety of doxofylline is obviously higher than that of theophylline and aminophylline, and the doxofylline is a new generation of methylpurine derivatives for replacing theophylline medicines. Doxofylline is clinically used for bronchial asthma and chronic obstructive pulmonary diseaseAnd other diseases such as dyspnea caused by bronchospasm, and the action mechanism is to control the development of the chronic inflammation of the respiratory tract by inhibiting the release of various inflammatory mediators and cytokines; inhibiting phosphodiesterase in airway smooth muscle cells activates proteases A and G, thereby reducing intracellular Ca2+Concentration of (d) and airway tension. In addition, the effect of doxofylline on relaxing bronchial smooth muscle is 10-15 times that of aminophylline, the effect is fast, only 30min is needed, and the duration of the drug effect is 12 h.
The synthetic routes of doxofylline are more, and different production routes, storage conditions and preparation processes are different for doxofylline. The existing preparation method of doxofylline has the defects of low yield, high cost, complex product separation and purification, serious three-waste pollution and the like. Therefore, the method has the advantages of improving the reaction yield, reducing the cost and simplifying the product separation and purification process, and is an urgent problem to be solved in the existing process for preparing doxofylline.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of doxofylline, which has the advantages of easily controlled reaction conditions, high yield, simple and convenient product separation and purification, and suitability for industrial production.
The invention is realized by the following technical scheme:
a preparation method of doxofylline comprises the following steps:
1) in a reaction solvent, theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction under the action of an acid-binding agent to generate 7- (2, 2-dimethoxyethyl) theophylline;
2) in a reaction solvent, carrying out acetal cyclization reaction on 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol under the action of a catalyst to generate a crude product of doxofylline;
3) heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain doxofylline;
wherein the reaction solvent is N, N-dimethylformamide or toluene, and the acid-binding agent is K2CO3Or triethylamine, and the catalyst is NaHSO4Or KHSO4。
Further, the preparation of the 7- (2, 2-dimethoxyethyl) theophylline comprises the following steps:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, and sequentially adding theophylline and a catalyst K2CO3Or triethylamine and bromoacetaldehyde dimethyl acetal are heated, and the reaction kettle is kept at the temperature of between 50 and 150 ℃ for reaction for 4 to 10 hours; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when the theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) adding purified water into the wet filter cake, stirring and pulping for 0.5-2 h, and then centrifuging to obtain a centrifugal substance;
6) drying the centrifugate to obtain 7- (2, 2-dimethoxyethyl) theophylline.
Further, the reaction material ratio in the step 1) is as follows: the mol ratio of the theophylline to the bromoacetaldehyde dimethyl acetal to the acid-binding agent is 1: 1-2: 1-2, wherein the mass ratio of the theophylline to the reaction solvent is 1: 1-3.
Further, the crystallization temperature in the step 3) is-30 ℃ to 10 ℃, and the crystallization time is 4 to 10 hours; the temperature of the ethanol and the purified water is 1-20 ℃; the drying treatment in the step 6) is carried out in a hot air circulating box, the drying temperature is 40-80 ℃, and the drying time is 3-10 h.
Further, the preparation of the crude doxofylline comprises the following steps:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, sequentially adding a catalyst, 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol, heating, and carrying out heat preservation reaction for 5-12 h when the temperature of the reaction kettle is between 80 and 150 ℃; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when 7- (2, 2-dimethoxyethyl) theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) and drying the wet filter cake to obtain a crude product of the doxofylline.
Further, the reaction material ratio in the step 1) is as follows: the mol ratio of 7- (2, 2-dimethoxyethyl) theophylline to ethylene glycol to the catalyst is 1: 1-2: the mass ratio of the 1-2, 7- (2, 2-dimethoxyethyl) theophylline to the reaction solvent is 1: 1-3.
Further, the crystallization temperature in the step 3) is-30 ℃ to 10 ℃, and the crystallization time is 3 to 10 hours; the temperature of the ethanol in the step 4) is 1-10 ℃; the drying treatment in the step 5) is carried out in a hot air circulation oven, the drying temperature is 40-80 ℃, and the drying time is 3-10 h.
Further, the preparation of doxofylline comprises the following steps:
1) adding a crude doxofylline product, dichloromethane and 70-95% ethanol into a dissolving tank, and heating and dissolving to obtain a mixed solution;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and filtering the crystallized liquid to obtain a filter cake;
4) and carrying out reduced pressure drying treatment on the filter cake to obtain the doxofylline.
Further, the reduced pressure drying treatment in the step 4) is carried out in a rotary vacuum drying oven, the drying temperature is controlled to be 40-80 ℃, and the drying time is 3-10 hours.
Further, in the step 2), filtering is carried out by adopting a 0.45um titanium rod; the crystallization temperature in the step 3) is-30-10 ℃, and the crystallization time is 3-10 h.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses a preparation method of doxofylline, which comprises the steps of firstly, taking theophylline as a reaction solvent in N, N-dimethylformamide or tolueneStarting material, and bromoacetaldehyde dimethyl acetal in acid-binding agent K2CO3Or the substitution reaction is carried out under the action of triethylamine to generate an intermediate 7- (2, 2-dimethoxyethyl) theophylline; then in a reaction solvent of N, N-dimethylformamide or toluene, the intermediate 7- (2, 2-dimethoxyethyl) theophylline and glycol are reacted in a catalyst of NaHSO4Or KHSO4Generating acetal cyclization reaction under the action of the raw material to generate a crude product of doxofylline; and finally, heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain the doxofylline. The method has the advantages of easily obtained reaction raw materials, low cost, easily controlled reaction conditions, high product purity of 99.9 percent, simple and convenient product separation and purification, economy, environmental protection and suitability for industrial production.
Drawings
FIG. 1 is a detection spectrum of a doxofylline standard sample of the present invention;
FIG. 2 is a detection spectrum of doxofylline related substances prepared by the method.
Detailed Description
The present invention will now be described in further detail, with the understanding that the present invention is to be considered as illustrative and not restrictive.
A preparation method of doxofylline comprises the following steps:
1) in a reaction solvent, theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction under the action of an acid-binding agent to generate 7- (2, 2-dimethoxyethyl) theophylline;
2) in a reaction solvent, carrying out acetal cyclization reaction on 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol under the action of a catalyst to generate a crude product of doxofylline;
3) heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain doxofylline;
wherein the reaction solvent is N, N-dimethylformamide or toluene, and the acid-binding agent is K2CO3Or triethylamine, and the catalyst is NaHSO4Or KHSO4。
The first step of reaction: theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction to prepare an intermediate 7- (2, 2-dimethoxyethyl) theophylline.
The second step of reaction: 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol are subjected to acetal cyclization reaction to prepare a crude product of doxofylline.
The third step: recrystallizing the crude doxofylline product to obtain the doxofylline.
The doxofylline is prepared by the following synthetic route:
further, the preparation of the 7- (2, 2-dimethoxyethyl) theophylline comprises the following steps:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, and sequentially adding theophylline and a catalyst K2CO3Or triethylamine and bromoacetaldehyde dimethyl acetal are heated, and the reaction kettle is kept at the temperature of between 50 and 150 ℃ for reaction for 4 to 10 hours; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when the theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) adding purified water into the wet filter cake, stirring and pulping for 0.5-2 h, and then centrifuging to obtain a centrifugal substance;
6) drying the centrifugate to obtain 7- (2, 2-dimethoxyethyl) theophylline.
Further, the reaction material ratio in the step 1) is as follows: the mol ratio of the theophylline to the bromoacetaldehyde dimethyl acetal to the acid-binding agent is 1: 1-2, and the mass ratio of the theophylline to the reaction solvent is 1: 1-3.
Further, the crystallization temperature in the step 3) is-30 ℃ to 10 ℃, and the crystallization time is 4 to 10 hours; the temperature of the ethanol and the purified water is 1-20 ℃; the drying treatment in the step 6) is carried out in a hot air circulating box, the drying temperature is controlled to be 40-80 ℃, and the drying time is 3-10 hours.
The first step of reaction: the intermediate 7- (2, 2-dimethoxyethyl) theophylline is prepared. Specifically, the reaction is carried out by adopting a one-pot feeding mode, a reaction solvent DMF (N, N-dimethylformamide) or methylbenzene is firstly added into a glass lining reaction kettle, a mechanical stirring device is started, and a reaction solid starting material theophylline and a catalyst K are sequentially added2CO3Or triethylamine and starting material bromoacetaldehyde dimethyl acetal, starting heat conducting oil heating and refluxing device, gradually heating up, controlling the reaction temperature between 50 ℃ and 150 ℃, and adding triethylamine or K as acid-binding agent2CO3Under the action, starting material theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction in a polar solvent, the reaction is carried out for 4-10 hours under the condition of heat preservation, an intermediate 7- (2, 2-dimethoxyethyl) theophylline is generated, the reaction process is detected by adopting Thin Layer Chromatography (TLC) (the solvent is dichloromethane and methanol with the volume ratio of 1: 1-3, and the developing agent is ethyl acetate), and the reaction is finished when the starting material theophylline spots are invisible. And filtering the reaction solution while the reaction solution is hot after the reaction is finished to obtain filtrate, and cooling, stirring and crystallizing. Controlling the crystallization temperature to be-30-10 ℃, controlling the crystallization time to be 4-10 hours, after crystallization is finished, carrying out centrifugal operation, leaching filter cakes by using 70-95% ethanol at the temperature of 1-20 ℃ until no liquid is spilled out to obtain wet filter cakes, stirring and pulping for 0.5-2 hours by using purified water with the dosage of 3 times of theophylline and the temperature of 1-20 ℃, centrifuging to obtain a centrifugal substance, carrying out normal-pressure drying in a hot air circulating box, controlling the drying temperature to be 40-80 ℃, and drying for 3-10 hours to obtain an intermediate 7- (2, 2-dimethoxyethyl) theophylline.
Further, the preparation of the crude doxofylline comprises the following steps:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, and sequentially adding a catalyst NaHSO4Or KHSO4Heating 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol, and carrying out heat preservation reaction for 5-12 h when the temperature of the reaction kettle is between 80 and 150 ℃; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when 7- (2, 2-dimethoxyethyl) theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) and drying the wet filter cake to obtain a crude product of the doxofylline.
Further, the reaction material ratio in the step 1) is as follows: the mol ratio of the 7- (2, 2-dimethoxyethyl) theophylline to the ethylene glycol to the catalyst is 1: 1-2, and the mass ratio of the 7- (2, 2-dimethoxyethyl) theophylline to the reaction solvent is 1: 1-3.
Further, the crystallization temperature in the step 3) is-30 ℃ to 10 ℃, and the crystallization time is 3 to 10 hours; the temperature of the ethanol in the step 4) is 1-10 ℃; the drying treatment in the step 5) is carried out in a hot air circulation oven, the drying temperature is controlled to be 40-80 ℃, and the drying time is 3-10 hours.
The second step of reaction: and preparing crude doxofylline. The method comprises the steps of carrying out reaction by adopting a one-pot feeding mode, firstly adding a reaction solvent toluene or N, N-dimethylformamide into a glass lining reaction kettle, starting a mechanical stirring device, sequentially adding a reaction solid material intermediate finished product and a catalyst potassium bisulfate or sodium bisulfate, then adding a reaction material ethylene glycol, starting a heat conduction oil heating reflux device, gradually heating up, controlling the reaction temperature to be 80-150 ℃, carrying out an acetal cyclization reaction on an intermediate 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol under the action of the catalyst, carrying out a heat preservation reaction for 5-12 hours, and reacting to generate a crude product of doxofylline; heating and refluxing to the water separator, discharging the lower layer liquid, and discharging the upper layer reflux to the reaction kettle; in the reaction process, Thin Layer Chromatography (TLC) is adopted to detect the reaction process (the solvent is dichloromethane and methanol with the mass ratio of 1: 1-3, the developing agent is ethyl acetate), and the reaction is completed when the intermediate 7- (2, 2-dimethoxyethyl) theophylline spot is invisible. And filtering the reaction solution while the reaction solution is hot after the reaction is finished to obtain filtrate, and cooling, stirring and crystallizing. And controlling the crystallization temperature to be-30-10 ℃, centrifuging after 3-10 hours of crystallization to obtain centrifugate and filter cakes, leaching the filter cakes by using 70-95% ethanol at the temperature of 1-10 ℃ until no liquid spills out to obtain wet filter cakes, drying the wet filter cakes in a hot air circulation oven, controlling the temperature to be 40-80 ℃ and the drying time to be 3-10 hours to obtain the crude doxofylline.
Further, the preparation of doxofylline comprises the following steps:
1) adding the crude doxofylline, dichloromethane and ethanol into a dissolving tank, and heating and dissolving to obtain a mixed solution;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and filtering the crystallized liquid to obtain a filter cake;
4) and carrying out reduced pressure drying treatment on the filter cake to obtain the doxofylline.
Further, the reduced pressure drying treatment of the step 4) is carried out in a rotary vacuum drying oven, and the pressure is-0.08 to-0.07 Mpa; the drying temperature is controlled to be 40-80 ℃, and the drying time is 3-10 h.
Further, in the step 2), filtering is carried out by adopting a 0.45um titanium rod; the crystallization temperature of the step 3) is-30 ℃ to-10 ℃, and the crystallization time is 3-10 hours.
The third step: recrystallizing the crude doxofylline product to prepare doxofylline, which comprises the following steps: and sequentially adding 70-95% of ethanol and dichloromethane into the dissolving tank, starting mechanical stirring, and then adding the crude product of doxofylline. Wherein the mass ratio of the crude doxofylline, dichloromethane and ethanol is 1:1: 1-4. And starting a heating reflux device, filtering to obtain filtrate after the crude doxofylline is completely dissolved, gradually cooling and crystallizing, controlling the crystallization temperature to be-30-10 ℃, crystallizing for 3-10 hours, filtering the crystallized liquid, performing suction filtration until no liquid drips out, drying the filter cake in a rotary vacuum drying oven, controlling the temperature drying to be 40-80 ℃, and drying for 3-10 hours to obtain the doxofylline.
And (3) analyzing a detection result:
the obtained doxofylline was detected by high performance liquid chromatography (chinese pharmacopoeia 2015 edition four parts general rules 0512), and the detection results were as follows:
1) related substances
The related substances are determined by high performance liquid chromatography (general rule 0512). The experimental process is carried out in dark and is prepared for new application.
The test solution is prepared by taking a proper amount of the product, precisely weighing, dissolving with a solvent, and quantitatively diluting to obtain a solution containing about 1mg per 1 ml. The solvent is acetonitrile and water with the volume ratio of 15: 85.
Taking theophylline reference substance about 10mg as a reference solution, precisely weighing, placing in a 10ml measuring flask, adding a solvent to dissolve and dilute to scale, shaking up, precisely weighing 1ml of the theophylline reference substance and 1ml of the test solution respectively, placing in the same 100ml measuring flask, diluting with the solvent to scale, shaking up, precisely weighing 5ml, placing in a 50ml measuring flask, diluting with the solvent to scale, and shaking up.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; acetonitrile-phosphate buffer solution (pH5.8) (volume ratio is 15: 85) is used as mobile phase; the detection wavelength is 273 nm; the injection volume was 10. mu.l.
The applicability of the system requires that the separation degree between a theophylline peak and a doxofylline peak in a chromatogram of a control solution is more than 10. The number of theoretical plates is not less than 2000 calculated according to doxofylline peak.
The measurement method precisely measures the test solution and the control solution, respectively injects into a liquid chromatograph, and records the chromatogram until the retention time of the main component peak is 3 times.
If a chromatographic peak consistent with theophylline retention time exists in the chromatogram of the limit test solution, the peak area is calculated according to an external standard method, and the peak area is not more than 0.1%; the peak area of other single impurities is not larger than the peak area (0.1%) of doxofylline in the control solution; the sum of the peak areas of the other impurities must not be greater than 4 times (0.4%) the area of the doxofylline peak in the control solution.
If a chromatographic peak with the same peak retention time as that in the contrast solution exists in a chromatogram of the test solution, the impurity content is 0.0 percent by calculating the peak area according to an external standard method;
2) loss on drying
1.0g of the product is taken and dried at 105 ℃ to constant weight, and the weight loss is reduced to 0.1 percent.
3) Determination of content
The measurement was carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition four parts general rules 0512).
Chromatographic conditions are as follows: using octadecylsilane chemically bonded silica as filler (Ximatec 18, 4.6mm × 150mm, 3 μm or chromatographic column with equivalent efficiency), using phosphate buffer (4.00 g potassium dihydrogen phosphate, 1000ml water is added for dissolution, using phosphoric acid to adjust pH value to 2.60) -acetonitrile (95:5) as mobile phase A, using phosphate buffer (pH value 2.60) -acetonitrile (75:25) as mobile phase B, and performing detection in gradient elution mode, wherein the gradient elution procedure is shown in Table 1; the detection wavelength is 273 nm; the flow rate was 1.0ml/min, the column temperature was 25 ℃. The separation degree of the impurity 5 and the main peak is not less than 1.5, and the theoretical plate number is not less than 2000 calculated according to the doxofylline peak.
The system applicability is as follows: precisely measuring impurity 5 reference substance and appropriate amount of doxofylline reference substance, diluting with solvent to obtain solution containing doxofylline 0.05mg and impurity 5 reference substance 1 μ g per 1ml, and using as system applicability solution. And (5) taking 10 mu l of the system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
The determination method comprises the following steps: precisely weighing appropriate amount of the product, dissolving with solvent, and quantitatively diluting to obtain solution containing 0.05mg per 1ml as test solution; precisely weighing appropriate amount of doxofylline reference substance, dissolving with solvent, and quantitatively diluting to obtain solution containing 0.05mg per 1ml as reference substance solution; and (3) respectively injecting 10 mu l of the reference solution and the test solution into a liquid chromatograph, recording chromatograms, calculating peak areas according to an external standard method as shown in figure 1 and figure 2, wherein the peaks of the standard sample and the finished product to be detected are shown in tables 2 and 3, and the content of doxofylline in the finished product to be detected is 99.9% according to the dry product.
TABLE 1 gradient elution procedure
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 6 | 100 | 0 |
| 42 | 0 | 100 |
| 45 | 100 | 0 |
| 50 | 100 | 0 |
Solvent: 10% acetonitrile.
TABLE 2 Peak Table of Standard samples
TABLE 3 inspection peak table
According to the technical scheme, the invention provides a preparation method of doxofylline, which comprises the steps of firstly taking theophylline as an initial raw material and bromoacetaldehyde dimethyl acetal in a reaction solvent N, N-dimethylformamide or toluene in the presence of triethylamine or K serving as an acid-binding agent2CO3The substitution reaction is carried out under the action of the catalyst to generate an intermediate 7- (2, 2-dimethyl)Oxyethyl) theophylline; then in a reaction solvent of N, N-dimethylformamide or toluene, the intermediate 7- (2, 2-dimethoxyethyl) theophylline and glycol are reacted in a catalyst of NaHSO4Or KHSO4Generating acetal cyclization reaction under the action of the raw material to generate a crude product of doxofylline; and finally, heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain the doxofylline. The method has the advantages of easily obtained reaction raw materials, low cost, easily controlled reaction conditions, high product purity of 99.9 percent, simple and convenient product separation and purification, economy, environmental protection and suitability for industrial production.
The embodiments given above are preferable examples for implementing the present invention, and the present invention is not limited to the above-described embodiments. Any non-essential addition and replacement made by the technical characteristics of the technical scheme of the invention by a person skilled in the art belong to the protection scope of the invention.
Claims (10)
1. A preparation method of doxofylline is characterized by comprising the following steps:
1) in a reaction solvent, theophylline and bromoacetaldehyde dimethyl acetal are subjected to substitution reaction under the action of an acid-binding agent to generate 7- (2, 2-dimethoxyethyl) theophylline;
2) in a reaction solvent, carrying out acetal cyclization reaction on 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol under the action of a catalyst to generate a crude product of doxofylline;
3) heating and dissolving the crude doxofylline, crystallizing, filtering, and drying under reduced pressure to obtain doxofylline;
wherein the reaction solvent is N, N-dimethylformamide or toluene, and the acid-binding agent is K2CO3Or triethylamine, and the catalyst is NaHSO4Or KHSO4。
2. The process for the preparation of doxofylline according to claim 1, characterized in that the preparation of 7- (2, 2-dimethoxyethyl) theophylline comprises the following steps:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, and sequentially adding theophylline and a catalyst K2CO3Or triethylamine, bromineHeating acetaldehyde dimethyl acetal, and carrying out heat preservation reaction for 4-10 h when the temperature of the reaction kettle is between 50 ℃ and 150 ℃; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when the theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) adding purified water into the wet filter cake, stirring and pulping for 0.5-2 h, and then centrifuging to obtain a centrifugal substance;
6) drying the centrifugate to obtain 7- (2, 2-dimethoxyethyl) theophylline.
3. The method for preparing doxofylline according to claim 2, characterized in that the reaction mass ratio in step 1) is: the mol ratio of the theophylline to the bromoacetaldehyde dimethyl acetal to the acid-binding agent is 1: 1-2: 1-2, wherein the mass ratio of the theophylline to the reaction solvent is 1: 1-3.
4. The preparation method of doxofylline according to claim 2, wherein the crystallization temperature in step 3) is-30 ℃ to 10 ℃, and the crystallization time is 4 to 10 hours; the temperature of the ethanol and the purified water is 1-20 ℃; the drying treatment in the step 6) is carried out in a hot air circulating box, the drying temperature is 40-80 ℃, and the drying time is 3-10 h.
5. The process for the preparation of doxofylline according to claim 1, wherein said crude doxofylline is prepared by the steps of:
1) adding a reaction solvent N, N-dimethylformamide or toluene into a reaction kettle, starting a stirring device, sequentially adding a catalyst, 7- (2, 2-dimethoxyethyl) theophylline and ethylene glycol, heating, and carrying out heat preservation reaction for 5-12 h when the temperature of the reaction kettle is between 80 and 150 ℃; monitoring the reaction process by adopting thin layer chromatography, finishing the reaction when 7- (2, 2-dimethoxyethyl) theophylline spots are invisible, and obtaining a mixed solution after the reaction is finished;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and centrifuging to obtain centrifugate and filter cake;
4) leaching the filter cake with 70-95% ethanol until no liquid is spilled out to obtain a wet filter cake;
5) and drying the wet filter cake to obtain a crude product of the doxofylline.
6. The method for preparing doxofylline according to claim 5, wherein the reaction material ratio in step 1) is: the mol ratio of 7- (2, 2-dimethoxyethyl) theophylline to ethylene glycol to the catalyst is 1: 1-2: the mass ratio of the 1-2, 7- (2, 2-dimethoxyethyl) theophylline to the reaction solvent is 1: 1-3.
7. The preparation method of doxofylline according to claim 5, wherein the crystallization temperature in step 3) is-30 ℃ to 10 ℃, and the crystallization time is 3 to 10 hours; the temperature of the ethanol in the step 4) is 1-10 ℃; the drying treatment in the step 5) is carried out in a hot air circulation oven, the drying temperature is 40-80 ℃, and the drying time is 3-10 h.
8. The process for the preparation of doxofylline according to claim 1, wherein said preparation of doxofylline comprises the steps of:
1) adding a crude doxofylline product, dichloromethane and 70-95% ethanol into a dissolving tank, and heating and dissolving to obtain a mixed solution;
2) filtering the hot mixed solution to obtain filtrate;
3) stirring the filtrate, cooling, crystallizing, and filtering the crystallized liquid to obtain a filter cake;
4) and carrying out reduced pressure drying treatment on the filter cake to obtain the doxofylline.
9. The preparation method of doxofylline according to claim 8, wherein the reduced pressure drying treatment in step 4) is performed in a rotary vacuum drying oven, the drying temperature is controlled to be 40-80 ℃, and the drying time is 3-10 h.
10. The process for preparing doxofylline according to claim 8, wherein the filtration in step 2) is performed using 0.45um titanium rod; the crystallization temperature in the step 3) is-30-10 ℃, and the crystallization time is 3-10 h.
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| CN111995625A (en) * | 2020-08-28 | 2020-11-27 | 开封康诺药业有限公司 | Preparation method of doxofylline |
| CN113234076A (en) * | 2021-05-26 | 2021-08-10 | 湖北午时药业股份有限公司 | Preparation method of doxofylline |
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| CN102936248A (en) * | 2012-10-30 | 2013-02-20 | 开封明仁药业有限公司 | Method for preparing doxofylline |
| CN105237538A (en) * | 2015-10-10 | 2016-01-13 | 斯卫东 | Preparation methods of doxofylline |
| CN108840872A (en) * | 2018-08-22 | 2018-11-20 | 湖北泓肽生物科技有限公司 | The synthetic method of doxofylline |
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| CN113234076A (en) * | 2021-05-26 | 2021-08-10 | 湖北午时药业股份有限公司 | Preparation method of doxofylline |
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