CN111592548B - Preparation method of theophylline sodium salt - Google Patents
Preparation method of theophylline sodium salt Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical chemicals, and particularly discloses a preparation method of theophylline sodium salt. The preparation method of the theophylline sodium salt comprises the following process steps: mixing cyanoacetic acid and acetic anhydride to react to obtain mixed anhydride, and carrying out condensation reaction on the mixed anhydride and 1, 3-dimethyl urea to obtain 1, 3-dimethyl cyanoacetylurea; the 1, 3-dimethyl cyanoacetylurea is subjected to cyclization, nitrosation, hydrogenation and acylation sequentially to obtain 1, 3-dimethyl-4-amino-5-formamido urea oxazine, and the 1, 3-dimethyl-4-amino-5-formamido urea oxazine is subjected to ring closure to obtain the theophylline sodium salt. The preparation method of the theophylline sodium salt has the advantages of mild and easily controlled reaction conditions, high product yield, few byproducts, no strong ammonia odor, low cost and less generated pollution wastes.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of theophylline sodium salt.
Background
The theophylline sodium salt is an important intermediate structure of xanthine drugs, and can be used for synthesizing caffeine, theobromine, theophylline, doxofylline, aminophylline, 8-chlorophylline and other series products.
The existing synthesis method of the theophylline sodium salt is that after the aqueous solution of cyanoacetic acid is dehydrated, acetic anhydride and 1, 3-dimethyl urea are added for condensation reaction to obtain 1, 3-dimethyl cyanoacetylurea; 1, 3-dimethyl cyanoacetylurea is cyclized under alkalinity to obtain 1, 3-dimethyl-4-iminouracil, and 1, 3-dimethyl-4-iminouracil and sodium nitrate are subjected to nitrosation reaction under acidity to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine; repeatedly pulping and washing the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine until the pH value is nearly neutral, and then carrying out hydrogenation reduction reaction to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine; carrying out acylation reaction on 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine and formic acid to obtain 1, 3-dimethyl-4-amino-5-formamide urea oxazine; adding alkali into 1, 3-dimethyl-4-amino-5-formamide carbamidazine to perform a ring-closure reaction to obtain theophylline sodium salt, and cooling, crystallizing and filtering to obtain a theophylline sodium salt product.
In the condensation reaction process in the existing synthesis method of the theophylline sodium salt, the phenomena of violent feeding reaction, bumping and difficult temperature control can occur, the side reaction of acetic anhydride and 1, 3-dimethyl urea is accelerated, and simultaneously, part of unreacted acetic anhydride can be evaporated out of the system, so that the yield of the 1, 3-dimethyl cyanoacetylurea is reduced, and the side reaction product is mixed in the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine in the subsequent reaction, so that the material is white and sticky, the washing and the suction filtration are difficult, a series of influences are caused on the subsequent reaction, and the yield and the quality of the theophylline sodium salt are finally influenced.
Disclosure of Invention
The invention provides a preparation method of theophylline sodium salt, aiming at the problems of difficult control of reaction process, low product yield, high byproduct content, strong ammonia smell of the product and generation of a large amount of waste gas pollutants in the existing synthesis method of theophylline sodium salt.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a preparation method of theophylline sodium salt comprises the following process steps:
a. the preparation method comprises the following steps of (1) mixing cyanoacetic acid and acetic anhydride to react to obtain mixed anhydride, carrying out condensation reaction on the mixed anhydride and 1, 3-dimethyl urea cyanide to obtain 1, 3-dimethyl urea cyanide, and carrying out cyclization and nitrosation reaction on the 1, 3-dimethyl urea cyanide to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine;
b. and (2) carrying out hydrogenation, formylation and ring closure reaction on the 1, 3-dimethyl-4-imino-5-isonitrophenylurazine to obtain theophylline sodium salt.
The condensation reaction in the traditional preparation method of the theophylline sodium salt is carried out by mixing cyanoacetic acid, 1, 3-dimethyl urea and acetic anhydride, then reacting simultaneously, and distilling off the generated acetic acid under reduced pressure. The inventor confirms through research that the cyanoacetic acid is not actually involved in the condensation reaction, but is a mixed acid anhydride generated by the reaction of the cyanoacetic acid and acetic anhydride. The acetic anhydride and the 1, 3-dimethyl urea can generate a condensation reaction to generate a byproduct, the cyanoacetic acid, the 1, 3-dimethyl urea and the acetic anhydride are simultaneously added, the reaction is violent, the bumping phenomenon exists, the temperature is not easy to control, the side reaction of the acetic anhydride and the 1, 3-dimethyl urea can be accelerated by the temperature rise, and simultaneously, a large amount of unreacted acetic anhydride can be evaporated out of the system, so that the yield of the 1, 3-dimethyl cyanoacetylurea is reduced. And the side reaction product is mixed in the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine in the subsequent reaction, so that the material is white and sticky and is difficult to wash and filter by water. A series of influences are caused to the subsequent reaction, thereby finally influencing the yield and the quality of the theophylline sodium salt.
The preparation method relates to the following chemical reaction formula:
compared with the prior art, in the preparation method of the theophylline sodium salt, the condensation reaction process adopts a sectional reaction mode, firstly, cyanoacetic acid and acetic anhydride are mixed, and then the mixed anhydride is reacted with the 1, 3-dimethyl urea, so that the side reaction is avoided, the conversion rate of raw materials is obviously improved, the reaction process is mild, the phenomena of high temperature, bumping and out-of-control reaction process in the reaction process are avoided, the utilization rate of the acetic anhydride is increased, and the yield and the purity of the product are improved.
Preferably, in step a, the mass ratio of the cyanoacetic acid, the acetic anhydride and the 1, 3-dimethylurea is 1:1.3-1.5: 1-1.2.
Preferably, in step a, the cyanoacetic acid is obtained by distilling an aqueous cyanoacetic acid solution under vacuum to remove water.
Preferably, in the step a, the temperature for the reaction of the cyanoacetic acid and the acetic anhydride is 40-100 ℃, and the reaction time is 20-60 min.
Further, in the step a, the reaction temperature of the cyanoacetic acid and the acetic anhydride is 60-80 ℃, and the reaction time is 30-40 min.
The optimized temperature and time for the reaction of the cyanoacetic acid and the acetic anhydride can further improve the yield of the mixed anhydride and reduce the loss of the acetic anhydride.
Preferably, in the step a, the temperature for reacting the mixed anhydride and the 1, 3-dimethyl urea is 40-100 ℃, and the reaction time is 30-120 min.
Further, in the step a, the temperature of the reaction of the mixed acid anhydride and the 1, 3-dimethyl urea is 60-80 ℃, and the reaction time is 60-90 min.
Preferably, in step a, primary separation of acetic acid is performed after the reaction of cyanoacetic acid with acetic anhydride and before the reaction of the mixed anhydride with 1, 3-dimethylurea, respectively, and the primary separation method of acetic acid is as follows: controlling the temperature of the reaction feed liquid between 70 and 90 ℃ and the vacuum degree between 0.095 and 0.2MPa, and distilling until no fraction is extracted.
Preferably, in step a, the 1, 3-dimethylcyanoacetylurea is subjected to cyclization and nitrosation reaction to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and the method comprises the following steps: removing acetic acid generated in the reaction feed liquid before cyclization reaction, adjusting the pH of the reaction feed liquid to be alkaline, and performing cyclization reaction; after the cyclization reaction is finished, adjusting the pH value of the reaction material liquid to acidity, and dropwise adding a sodium nitrite aqueous solution to perform nitrosation reaction on the 1, 3-dimethyl-4-imino uracil and sodium nitrite to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine. The method comprises the steps of dropwise adding a sodium nitrite aqueous solution into 1, 3-dimethyl-4-iminouracil to enable the 1, 3-dimethyl-4-iminouracil to react with sodium nitrite, so that the sodium nitrite can be directionally reacted, a large amount of yellow smoke generated by reaction liquid caused by a traditional one-time feeding mode is avoided, the load of a tail gas absorption system and the alkali consumption are reduced to the maximum extent, and compared with the traditional feeding mode, the alkali consumption is reduced to be less than 5% of a one-time feeding process. Meanwhile, the sodium nitrite aqueous solution is added in a dropwise manner, the crystal form of the product is moderate in size, the subsequent filter pressing separation of the 1, 3-dimethyl-4-imino-5-isonitrophenylurazine is facilitated, and a filter membrane cannot be blocked in the separation process.
Preferably, the method for removing acetic acid in the reaction feed liquid comprises the following steps: adding water with the mass of 5-20% of the feed of cyanoacetic acid into the reaction feed liquid, and carrying out reduced pressure distillation at 30-80 ℃ to take out acetic acid generated by the reaction.
After the condensation reaction is finished, acetic acid is removed in a water-in-acid mode, so that the residue of the acetic acid in the reaction liquid can be effectively reduced, and the alkali dosage in the cyclization reaction process is reduced.
Further, the method for removing acetic acid in the reaction feed liquid comprises the following steps: adding water with the mass of 10-15% of the mass of the cyanoacetic acid feed into the reaction feed liquid, and carrying out reduced pressure distillation at 40-60 ℃ to take out acetic acid generated by the reaction.
Preferably, the cyclization reaction temperature is 90-95 ℃, and the reaction time is 20-40 min.
Preferably, step a further comprises adding a quenching agent to the reaction solution after the nitrosation reaction is finished until the reaction solution is non-oxidizing. After quenching, the 1, 3-dimethyl-4-imino-5-isonitro urea oxazine can be separated.
The method of adding the quenching agent for quenching replaces the traditional method of removing the oxidizing property by repeated washing, greatly reduces the amount of wastewater, simplifies the process, avoids the loss caused by washing the materials, does not generate ammonia gas in the whole reaction process, avoids the pollution to the operating environment and the theophylline sodium salt product, and improves the quality stability of the theophylline sodium salt product. Meanwhile, the method of repeated washing is not adopted, so that the residual salt in the material can play a role of salting out during crystallization, and the use of liquid alkali in the ring-closing process is reduced.
Preferably, the alkalinity is between pH9 and 10.
Preferably, the acidity is ph 3.5-4.5.
Preferably, the mass concentration of the sodium nitrite aqueous solution is 35-40%, the pH value of the reaction material liquid is controlled to be 3.5-4.5 in the process of dropwise adding the sodium nitrite aqueous solution, and yellow smoke appears when the sodium nitrite aqueous solution is dropwise added into the reaction material liquid; the temperature of the nitrosation reaction is 30-40 ℃, and the reaction is continued for 20-30min after the dropwise addition of the sodium nitrite aqueous solution is finished. Wherein, the acid adopted for adjusting the pH value of the reaction liquid is acetic acid separated from the reaction liquid, and the pH value is controlled by the acetic acid of a condensation byproduct in the nitrosation reaction process, so that the reasonable utilization of resources is realized, the salt content in the nitrosation wastewater is single, and the environment-friendly recovery treatment is convenient. The pH value of the reaction material liquid is controlled to be 3.5-4.5 in the process of dropwise adding the sodium nitrite aqueous solution, so that the nitrosation reaction can be further promoted, the sufficient reaction of the sodium nitrite can be ensured, the generation of yellow smoke in the reaction process due to the local occurrence of the excessive condition of the sodium nitrite can be avoided, and the purity and the yield of the product can be ensured.
Preferably, the quenching agent is at least one of urea, dimethyl urea and sulfanilic acid.
Preferably, in step b, the hydrogenation method of the 1, 3-dimethyl-4-imino-5-isonitro urea oxazine comprises the following steps: adding 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine into water, pulping uniformly, adjusting the pH value to 7-8 to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine feed liquid, adding raney nickel into the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine feed liquid, and performing catalytic hydrogenation at the pressure of 0.3-0.4MPa and the temperature of 45-50 ℃ to obtain 1, 3-dimethyl-4, 5-diaminourea oxazine; the addition amount of the Raney nickel is 5-8% of the mass of the cyanoacetic acid.
Preferably, in the step b, formic acid and a phase transfer catalyst are added into the reaction liquid in the formylation reaction process, wherein the phase transfer catalyst is at least one of benzyltriethylammonium chloride, 18-crown-6, tetrabutylammonium chloride and tetrabutylammonium bromide, and the addition amount of the phase transfer catalyst is 0.4-0.6% of the mass of cyanoacetic acid; the addition amount of the formic acid is 0.35 to 0.45 percent of the mass of the cyanoacetic acid; the acylation reaction temperature is 50-90 ℃, and the reaction time is 20-60 min; the 1, 3-dimethyl-4, 5-diamino urea oxazine is subjected to formylation reaction to obtain the 1, 3-dimethyl-4-amino-5-formamide urea oxazine.
The phase transfer catalyst is added in the acylation reaction process, so that the dispersion contact effect of the 1, 3-dimethyl-4, 5-diaminocarbamidazine and formic acid can be obviously improved, the temperature of the formylation reaction is reduced, the decomposition of the 1, 3-dimethyl-4, 5-diaminocarbamidazine and the evaporation loss of formic acid are avoided, the yield and the quality of the theophylline sodium salt product are further improved, and the operation environment is improved.
Further, the acylation reaction temperature is 60-80 ℃, and the reaction time is 30-40 min.
Preferably, in the step b, the ring-closure reaction is carried out under the condition that the pH value is 8-10, the ring-closure reaction temperature is 85-90 ℃, and the reaction time is 20-40 min.
Preferably, the method further comprises crystallizing the sodium theophylline salt obtained in step b by the following method: cooling to 15-25 deg.C to precipitate theophylline sodium salt crystal, and vacuum filtering to obtain theophylline sodium salt solid.
The traditional alkali crystallization mode is replaced by the cooling crystallization and vacuum filtration mode to separate the theophylline sodium salt, so that the purity and yield of the theophylline sodium salt are further improved, the influence of high pH value on materials is avoided, and the processing burden of the mother liquor of subsequent separation is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle at the temperature of 70 ℃ and the vacuum degree of 0.095MPa, adding 800mL of acetic acid when reducing pressure and steaming water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual moisture with the acetic acid at the temperature of 90 ℃ and the vacuum degree of 0.095MPa, and distilling until no fraction is extracted. The temperature is reduced to 40 ℃, 1365g of acetic anhydride is added into the cyanoacetic acid with water removed, and the reaction is stirred for 20 min. Vacuum is started, acetic acid generated by the reaction is evaporated under reduced pressure, the temperature is controlled to be 70-90 ℃, the vacuum degree is controlled to be 0.095-0.2MPa, and no fraction is extracted. 1050g of 1, 3-dimethylurea is added, the temperature is controlled to be 40 ℃, and the mixture is stirred and reacted for 30 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted.
Adding 75mL of water into the reaction solution, carrying acid with water, controlling the temperature at 30 ℃ and the vacuum degree to be more than 0.095MPa, and extracting no fraction. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 9.0, heating to 90 ℃, and reacting for 20min under a heat preservation condition to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
Cooling the reaction liquid to 30 ℃, adjusting the pH value to 3.5 by using acetic acid separated in the step b, then beginning to dropwise add sodium nitrite aqueous solution (35 wt%), controlling the pH value to be 3.5-4.5 by using acetic acid, controlling the dropwise adding speed to be 0.05ml/s, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 20min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding urea into the reaction liquid, stirring to enable the reaction liquid to be detected to be non-oxidizing by using starch potassium iodide, and carrying out vacuum filtration to separate out the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 7.0 by using 30 wt% of sodium hydroxide solution, and adding water to fix the volume to 12000 mL. And adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 75g of Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.3MPa and the temperature to be 45 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 6g of benzyltriethylammonium chloride, heating to 50 ℃, dropwise adding 620g of 85 wt% formic acid, and reacting for 20min under the condition of heat preservation to obtain the 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium hydroxide solution into the reaction solution until the pH value of the reaction solution is 8, heating to 85 ℃, and keeping the temperature for 20min to allow 1, 3-dimethyl-4-amino-5-formamide carbamidazine to generate theophylline sodium salt through ring closure.
Cooling the reaction liquid to 15 ℃, and performing suction filtration and drying to obtain 2204.47g of theophylline sodium salt, wherein the content is 92.52%, the molar yield is 81.75%, and the calculation method of the molar yield is as follows: molar yield
The preparation method relates to the following chemical reaction formula:
example 2
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle, wherein the temperature is 50 ℃, the vacuum degree is 0.1MPa, adding 800mL of acetic acid when reducing pressure and evaporating water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual water with the acetic acid, and distilling until no fraction is extracted, wherein the temperature is 80 ℃, the vacuum degree is 0.1 MPa. To the dehydrated cyanoacetic acid was added 1575g of acetic anhydride at 100 ℃ and the reaction was stirred for 60 min. Vacuum is started, acetic acid generated by the reaction is evaporated under reduced pressure, the temperature is controlled to be 70-90 ℃, the vacuum degree is controlled to be 0.095-0.2MPa, and no fraction is extracted. 1260g of 1, 3-dimethylurea is added, the temperature is controlled to be 100 ℃, and the mixture is stirred and reacted for 120 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted.
Adding 300mL of water into the reaction solution, carrying acid with water, controlling the temperature to be 80 ℃ and the vacuum degree to be more than 0.095MPa, and extracting no fraction. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 10, heating to 95 ℃, and reacting for 40min under heat preservation to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
And (c) cooling the reaction liquid to 40 ℃, adjusting the pH value to 4.5 by using acetic acid separated in the step b, then beginning to dropwise add a sodium nitrite aqueous solution (40 wt%), controlling the pH value to be 3.5-4.5 by using acetic acid, keeping the dropwise adding speed at 0.1ml/s, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 30min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding dimethyl urea into the reaction liquid, stirring to ensure that the reaction liquid has no oxidability detected by using starch potassium iodide, and carrying out vacuum filtration to separate out the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 8 by using 30 wt% of sodium carbonate solution, and adding water to fix the volume to 12000 mL. Adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 120g Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.4MPa and the temperature to be 50 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 18-crown ether-69 g, heating to 90 ℃, dropwise adding 790g of 85 wt% formic acid, and reacting for 60min under the condition of heat preservation to obtain the 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium carbonate solution into the reaction solution until the pH value of the reaction solution is 10, heating to 90 ℃, and keeping the temperature for 40min to allow 1, 3-dimethyl-4-amino-5-formamido urea oxazine to generate theophylline sodium salt through ring closure.
The reaction solution is cooled to 25 ℃, filtered and dried to obtain 2195.38g of theophylline sodium salt with the content of 91.70 percent and the molar yield of 80.70 percent. The molar yield was calculated as in example 1.
Example 3
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle, wherein the temperature is 60 ℃, the vacuum degree is 0.15MPa, adding 800mL of acetic acid when reducing pressure and evaporating water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual water with the acetic acid, and distilling until no fraction is extracted, wherein the temperature is 90 ℃, the vacuum degree is 0.1 MPa. The temperature is reduced to 70 ℃, 1500g of acetic anhydride is added into the cyanoacetic acid with water removed, and the mixture is stirred and reacted for 35 min. Vacuum is started, acetic acid generated by the reaction is evaporated under reduced pressure, the temperature is controlled to be 70-90 ℃, the vacuum degree is controlled to be 0.095-0.2MPa, and no fraction is extracted. 1150g of 1, 3-dimethylurea is added, the temperature is controlled at 70 ℃, and the reaction is stirred for 70 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted.
Adding 180mL of water into the reaction solution, carrying acid with water, controlling the temperature at 50 ℃ and the vacuum degree to be more than 0.095MPa, and extracting no fraction. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 9.5, heating to 92 ℃, and reacting for 30min under heat preservation to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
And (c) cooling the reaction liquid to 35 ℃, adjusting the pH value to 4 by using acetic acid separated in the step b, then beginning to dropwise add a sodium nitrite aqueous solution (37.5 wt%), controlling the pH value to be between 3.5 and 4.5 by using acetic acid, controlling the dropwise adding speed to be 0.05ml/min, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 25min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding sulfanilic acid into the reaction liquid, stirring to enable the reaction liquid to be free of oxidability detected by potassium iodide starch, and performing vacuum filtration to separate out 1, 3-dimethyl-4-imino-5-isonitrophenyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 7 by using 30 wt% of sodium bicarbonate solution, and adding water to fix the volume to 12000 mL. Adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 90g of Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.35MPa and the temperature to be 48 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 7.5g of tetrabutylammonium chloride, heating to 70 ℃, dropwise adding 700g of 85 wt% formic acid, and reacting for 35min under the condition of heat preservation to obtain the 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium bicarbonate solution into the reaction solution until the pH value of the reaction solution is 9, heating to 88 ℃, and keeping the temperature for 300min to allow 1, 3-dimethyl-4-amino-5-formamide carbamidazine to ring-close to generate theophylline sodium salt.
The reaction solution is cooled to 20 ℃, filtered and dried to obtain 2238.33g of theophylline sodium salt with the content of 95.62 percent and the molar yield of 85.79 percent. The molar yield was calculated as in example 1.
Example 4
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle, wherein the temperature is 60 ℃, the vacuum degree is 0.15MPa, adding 800mL of acetic acid when reducing pressure and evaporating water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual water with the acetic acid, and distilling until no fraction is extracted, wherein the temperature is 90 ℃, the vacuum degree is 0.1 MPa. The temperature is reduced to 60 ℃, 1500g of acetic anhydride is added into the cyanoacetic acid with water removed, and the mixture is stirred and reacted for 30 min. Vacuum is started, acetic acid generated by the reaction is evaporated under reduced pressure, the temperature is controlled to be 70-90 ℃, the vacuum degree is controlled to be 0.095-0.2MPa, and no fraction is extracted. 1150g of 1, 3-dimethylurea is added, the temperature is controlled at 60 ℃, and the mixture is stirred and reacted for 60 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted.
Adding 150mL of water into the reaction solution, carrying acid with water, controlling the temperature at 40 ℃ and the vacuum degree to be more than 0.095MPa, and extracting no fraction. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 9.5, heating to 92 ℃, and reacting for 30min under heat preservation to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
And (c) cooling the reaction liquid to 35 ℃, adjusting the pH value to 4 by using acetic acid separated in the step b, then beginning to dropwise add a sodium nitrite aqueous solution (37.5 wt%), controlling the pH value to be between 3.5 and 4.5 by using acetic acid, controlling the dropwise adding speed to be 0.05ml/min, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 25min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding sulfanilic acid into the reaction liquid, stirring to enable the reaction liquid to be free of oxidability detected by potassium iodide starch, and performing vacuum filtration to separate out 1, 3-dimethyl-4-imino-5-isonitrophenyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 7 by using 30 wt% of sodium bicarbonate solution, and adding water to fix the volume to 12000 mL. Adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 90g of Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.35MPa and the temperature to be 48 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 7.5g of tetrabutylammonium chloride, heating to 60 ℃, dropwise adding 700g of 85 wt% formic acid, and reacting for 30min under the condition of heat preservation to obtain the 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium bicarbonate solution into the reaction solution until the pH value of the reaction solution is 9, heating to 88 ℃, and keeping the temperature for 300min to allow 1, 3-dimethyl-4-amino-5-formamide carbamidazine to ring-close to generate theophylline sodium salt.
The reaction solution is cooled to 20 ℃, filtered and dried to obtain 2193.28g of theophylline sodium salt with the content of 93.98 percent and the molar yield of 82.62 percent. The molar yield was calculated as in example 1.
Example 5
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle, wherein the temperature is 60 ℃, the vacuum degree is 0.15MPa, adding 800mL of acetic acid when reducing pressure and evaporating water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual water with the acetic acid, and distilling until no fraction is extracted, wherein the temperature is 90 ℃, the vacuum degree is 0.1 MPa. The temperature is reduced to 80 ℃, 1500g of acetic anhydride is added into the cyanoacetic acid with water removed, and the mixture is stirred and reacted for 40 min. Vacuum is started, acetic acid generated by the reaction is evaporated under reduced pressure, the temperature is controlled to be 70-90 ℃, the vacuum degree is controlled to be 0.095-0.2MPa, and no fraction is extracted. 1150g of 1, 3-dimethylurea is added, the temperature is controlled to be 80 ℃, and the reaction is stirred for 90 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted.
225mL of water is added into the reaction liquid, water is used for carrying acid, the temperature is controlled to be 60 ℃, the vacuum degree is more than 0.095MPa, and no fraction is extracted. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 9.5, heating to 92 ℃, and reacting for 30min under heat preservation to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
And (c) cooling the reaction liquid to 35 ℃, adjusting the pH value to 4 by using acetic acid separated in the step b, then beginning to dropwise add a sodium nitrite aqueous solution (37.5 wt%), controlling the pH value to be between 3.5 and 4.5 by using acetic acid, controlling the dropwise adding speed to be 0.05ml/min, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 25min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding sulfanilic acid into the reaction liquid, stirring to enable the reaction liquid to be free of oxidability detected by potassium iodide starch, and performing vacuum filtration to separate out 1, 3-dimethyl-4-imino-5-isonitrophenyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 7 by using 30 wt% of sodium bicarbonate solution, and adding water to fix the volume to 12000 mL. Adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 90g of Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.35MPa and the temperature to be 48 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 7.5g of tetrabutylammonium chloride, heating to 80 ℃, dropwise adding 700g of 85 wt% formic acid, and reacting for 40min under heat preservation to obtain 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium bicarbonate solution into the reaction solution until the pH value of the reaction solution is 9, heating to 88 ℃, and keeping the temperature for 300min to allow 1, 3-dimethyl-4-amino-5-formamide carbamidazine to ring-close to generate theophylline sodium salt.
The reaction solution is cooled to 20 ℃, filtered and dried to obtain 2201.87g of theophylline sodium salt with the content of 93.65 percent and the molar yield of 82.66 percent. The molar yield was calculated as in example 1.
Comparative example 1
Adding 1500g of 70 wt% cyanoacetic acid into a 20L glass reaction kettle, wherein the temperature is 60 ℃, the vacuum degree is 0.15MPa, adding 800mL of acetic acid when reducing pressure and evaporating water until no fraction is extracted, continuing reduced pressure distillation, carrying out residual water with the acetic acid, and distilling until no fraction is extracted, wherein the temperature is 90 ℃, the vacuum degree is 0.1 MPa. Cooling to 70 ℃, adding 1500g of acetic anhydride and 1150g of 1, 3-dimethyl urea into the dewatered cyanoacetic acid, controlling the temperature to 70 ℃, and stirring for reaction for 70 min. The acetic acid generated by the reaction is evaporated out under reduced pressure, the temperature is controlled between 70 ℃ and 90 ℃, the vacuum degree is controlled between 0.095MPa and 0.2MPa, and no fraction is extracted. (cyanoacetic acid, acetic anhydride and 1, 3-dimethylurea are reacted simultaneously).
Adding 180mL of water into the reaction solution, carrying acid with water, controlling the temperature at 50 ℃ and the vacuum degree to be more than 0.095MPa, and extracting no fraction. After the acetic acid is evaporated, adding water to a constant volume of 7000mL, heating to 85 ℃, dropwise adding liquid alkali until the pH value is 9.5, heating to 92 ℃, and reacting for 30min under heat preservation to cyclize 1, 3-dimethyl-4-iminouracil in the reaction liquid.
And (c) cooling the reaction liquid to 35 ℃, adjusting the pH value to 4 by using acetic acid separated in the step b, then beginning to dropwise add a sodium nitrite aqueous solution (37.5 wt%), controlling the pH value to be between 3.5 and 4.5 by using acetic acid, controlling the dropwise adding speed to be 0.05ml/min, stopping dropwise adding until yellow smoke is generated visually, detecting by using a starch potassium iodide test paper to turn blue, continuing to perform heat preservation reaction for 25min to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine, and repeatedly detecting the oxidability.
Adding sulfanilic acid into the reaction liquid, stirring to enable the reaction liquid to be free of oxidability detected by potassium iodide starch, and performing vacuum filtration to separate out 1, 3-dimethyl-4-imino-5-isonitrophenyl urea oxazine. Adding 10000mL of water into the 1, 3-dimethyl-4-imino-5-isonitroyl urazine filter cake, pulping uniformly, adjusting the pH value to 7 by using 30 wt% of sodium bicarbonate solution, and adding water to fix the volume to 12000 mL. Adding the feed liquid with constant volume into a 20L high-pressure hydrogenation kettle, adding 90g of Raney nickel catalyst, performing nitrogen replacement for three times and hydrogen replacement for three times, controlling the pressure to be 0.35MPa and the temperature to be 48 ℃ to perform hydrogenation reaction to obtain the 1, 3-dimethyl-4, 5-diaminourazine. After the reaction is finished, the catalyst is filtered out by suction when the catalyst is hot and is reserved for use.
Adding the filtrate into a 20L glass reaction kettle, adding 7.5g of tetrabutylammonium chloride, heating to 70 ℃, dropwise adding 700g of 85 wt% formic acid, and reacting for 35min under the condition of heat preservation to obtain the 1, 3-dimethyl-4-amino-5-formamide carbamidazine. Adding 30 wt% sodium bicarbonate solution into the reaction solution until the pH value of the reaction solution is 9, heating to 88 ℃, and keeping the temperature for 300min to allow 1, 3-dimethyl-4-amino-5-formamide carbamidazine to ring-close to generate theophylline sodium salt.
The reaction solution was cooled to 20 ℃, filtered and dried to obtain 1918.91g of theophylline sodium salt with a content of 88.63% and a molar yield of 68.17%. The molar yield was calculated as in example 1.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A preparation method of theophylline sodium salt is characterized in that: the method comprises the following process steps:
a. the preparation method comprises the following steps of (1) mixing cyanoacetic acid and acetic anhydride to react to obtain mixed anhydride, carrying out condensation reaction on the mixed anhydride and 1, 3-dimethyl urea cyanide to obtain 1, 3-dimethyl urea cyanide, and carrying out cyclization and nitrosation reaction on the 1, 3-dimethyl urea cyanide to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine;
the reaction temperature of the cyanoacetic acid and the acetic anhydride is 40-100 ℃, and the reaction time is 20-60 min;
the reaction temperature of the mixed anhydride and the 1, 3-dimethyl urea is 40-100 ℃, and the reaction time is 30-120 min;
adding a quenching agent into the reaction liquid after the nitrosation reaction is finished until the reaction liquid is non-oxidizing;
b. carrying out hydrogenation, formylation and ring-closure reaction on the 1, 3-dimethyl-4-imino-5-isonitrophenylurazine to obtain theophylline sodium salt; the hydrogenation method of the 1, 3-dimethyl-4-imino-5-isonitro-urea oxazine comprises the following steps: adding 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine into water, pulping uniformly, adjusting the pH value to 7-8 to obtain 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine feed liquid, adding raney nickel into the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine feed liquid, and performing catalytic hydrogenation at the pressure of 0.3-0.4MPa and the temperature of 45-50 ℃ to obtain 1, 3-dimethyl-4, 5-diaminourea oxazine.
2. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: in the step a, the mass ratio of the cyanoacetic acid to the acetic anhydride to the 1, 3-dimethyl urea is 1:1.3-1.5: 1-1.2; and/or
In step a, the cyanoacetic acid is obtained by distilling aqueous cyanoacetic acid solution under vacuum to remove water.
3. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: in the step a, the reaction temperature of the cyanoacetic acid and the acetic anhydride is 60-80 ℃, and the reaction time is 30-40 min; and/or
In the step a, the reaction temperature of the mixed anhydride and the 1, 3-dimethylurea is 60-80 ℃, and the reaction time is 60-90 min.
4. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: in the step a, the method for obtaining the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine by the cyclization and nitrosation reaction of the 1, 3-dimethyl cyanoacetylurea comprises the following steps: removing acetic acid generated in the reaction feed liquid before cyclization reaction, adjusting the pH of the reaction feed liquid to be alkaline, and performing cyclization reaction; after the cyclization reaction is finished, adjusting the pH value of the reaction material liquid to acidity, and dropwise adding a sodium nitrite aqueous solution to perform nitrosation reaction on the 1, 3-dimethyl-4-imino uracil and sodium nitrite to obtain the 1, 3-dimethyl-4-imino-5-isonitroyl urea oxazine.
5. The process for the preparation of theophylline sodium salt as claimed in claim 4, wherein: the method for removing acetic acid in the reaction feed liquid comprises the following steps: adding water with the mass of 5-20% of the mass of the cyanoacetic acid feed into the reaction feed liquid, and carrying out reduced pressure distillation at the temperature of 30-80 ℃ to take out acetic acid generated by the reaction; and/or
The cyclization reaction temperature is 90-95 ℃, and the reaction time is 20-40 min; and/or
The alkalinity is pH 9-10; and/or
The acidity is pH3.5-4.5; and/or the mass concentration of the sodium nitrite aqueous solution is 35-40%, the pH value of the reaction material liquid is controlled to be 3.5-4.5 in the process of dropwise adding the sodium nitrite aqueous solution, and yellow smoke appears when the sodium nitrite aqueous solution is dropwise added into the reaction material liquid; the temperature of the nitrosation reaction is 30-40 ℃, and the reaction is continued for 20-30min after the dropwise addition of the sodium nitrite aqueous solution is finished.
6. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: the quenching agent is at least one of urea, dimethyl urea and sulfanilic acid.
7. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: in the step b, the addition amount of the Raney nickel is 5-8% of the mass of the cyanoacetic acid.
8. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: in the step b, formic acid and a phase transfer catalyst are added into a reaction liquid in the formylation reaction process, wherein the phase transfer catalyst is at least one of benzyltriethylammonium chloride, 18-crown ether-6, tetrabutylammonium chloride and tetrabutylammonium bromide, and the addition amount of the phase transfer catalyst is 0.4-0.6% of the mass of cyanoacetic acid; the addition amount of the formic acid is 0.35 to 0.45 percent of the mass of the cyanoacetic acid; the formylation reaction temperature is 50-90 ℃, and the reaction time is 20-60 min; and/or
In the step b, ring-closure reaction is carried out under the condition that the pH value is 8-10, the ring-closure reaction temperature is 85-90 ℃, and the reaction time is 20-40 min.
9. The process for the preparation of theophylline sodium salt as claimed in claim 1, wherein: further comprising crystallizing the theophylline sodium salt obtained in the step b, wherein the crystallization method comprises the following steps: cooling to 15-25 deg.C to precipitate theophylline sodium salt crystal, and vacuum filtering to obtain theophylline sodium salt solid.
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