CN115611815A - A kind of cytosine synthetic method - Google Patents

Abstract

The invention provides a method for synthesizing cytosine, comprising the steps of: preparing an alkoxy acrylonitrile compound; putting an alcohol solution of urea and sodium methoxide into a xylene solution, raising the temperature to 88°C-95°C, and adding the alkoxy Base acrylonitrile compound, the time of dropping is 5.5-6 hours, and the solution temperature in the ring-closure kettle is 95°C-105°C during the dropwise addition; Incubate at 25°C-35°C for 2.5-3 hours; after the end of the heat preservation, add water to dissolve, transfer to a crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain cytosine. The method for synthesizing cytosine provided by the invention improves the recovery rate of cytosine.

Description

A kind of cytosine synthetic method

technical field

The invention relates to the field of organic chemical synthesis, in particular to a method for synthesizing cytosine.

Background technique

Cytosine is 4-amino-2-hydroxypyrimidine, which is one of the pyrimidine bases in nucleic acid, and is also an important intermediate in fine chemicals, pesticides and medicine; especially in the field of medicine, it is mainly used to synthesize anti-AIDS drugs and anti-hepatitis B drugs Mivudine, anticancer drugs gemcitabine, enoxitabine, and 5-fluorocytosine, etc. The existing synthesis methods of cytosine mainly include functional group conversion method and Pinner synthesis method.

Pinner synthesis method such as: 1.3peeters, etc. use 3-ethoxyacrylonitrile and 3,3-diethoxyacrylonitrile mixture and urea in the tert-butanol solution of potassium tert-butoxide to directly close the ring to obtain cytosine. rate does not exceed 62%. There are other Pinner synthesis methods, but the recovery rate of cytosine is not high.

Contents of the invention

In view of this, the purpose of the present invention is to provide a method for synthesizing cytosine to improve the recovery rate of cytosine.

A method for synthesizing cytosine, comprising the steps of: preparing a crude alkoxyacrylonitrile; putting an alcohol solution of urea and sodium methoxide into a xylene solution, raising the temperature to 88°C-95°C, and adding the alkoxyacrylonitrile dropwise For the crude product, the dropwise addition time is 5.5-6 hours, and the solution temperature in the ring-closure kettle is 75°C-85°C during the dropwise addition; after the dropwise addition, the temperature is lowered to 25°C-35°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve , transferred to a crystallization kettle for crystallization, adjusted the pH to be acidic, filtered and dried to obtain cytosine.

Optionally, the preparation of the crude alkoxyacrylonitrile product includes high-pressure reaction and acidification reaction, and the high-pressure reaction is: adding toluene and sodium methoxide sequentially in the autoclave, then transferring to acetonitrile and ethanol, and feeding CO Gas, the jacket is fed with steam to raise the temperature to 100°C-120°C, and react for 7-8 hours to obtain the nitrile acetaldehyde sodium salt condensate;

The acidification reaction is: transfer the nitrile acetaldehyde sodium salt condensate into an acidification kettle, add hydrochloric acid alcohol solution, react at 40°C-50°C for 3-4 hours, and then add liquid caustic soda to adjust Ph to be alkaline , to obtain the crude alkoxyacrylonitrile.

Optionally, the crude alkoxyacrylonitrile is: 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

Optionally, the alcohol solution of sodium methoxide is methanol solution or ethanol solution.

The method for synthesizing cytosine provided by the present invention uses unqualified acetonitrile produced by our company. For example, acetone in acetonitrile exceeds the standard and cannot leave the factory, so it can be used as a raw material for synthesizing cytosine. It does not affect the synthesis of cytosine; it can effectively use company resources, reduce costs and increase efficiency; in the preparation process of alkoxyacrylonitrile: the CO used is a by-product of the head office. If it is not used, CO needs to be burned. After use, it not only effectively reduces carbon emissions, but also creates economic benefits; the hydrochloric acid alcohol solution used in the preparation of alkoxyacrylonitrile is self-produced by the company; hydrochloric acid is a by-product of the head office, and the cost is very low or even no cost Alcohols, as catalysts for the production of cytosine, can be reused, so the cost of the overall hydrochloric acid ethanol solution is low, and can be produced according to production needs, without additional storage, reducing storage costs. Compared with the prior art, the present invention uses waste gas or waste products from other production lines of the company, changes the catalyst and temperature, and finally synthesizes cytosine to increase the yield to more than 90%.

detailed description

In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Apparently, the described embodiments are some, not all, embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention belong to the protection scope of the present invention.

The synthetic method of cytosine of the present invention, preferred synthetic 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude product, then 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile The crude methoxyacrylonitrile was used as starting material for the preparation of cytosine. Acetonitrile, CO gas, hydrochloric acid and other substances used in the synthesis of 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude products are by-products produced by other manufacturers or unqualified Products, the inventors of the present invention found in the process of producing cytosine that these by-products or unqualified products do not affect the quality and recovery rate of cytosine; production cost. Embodiments of the present invention are as follows:

Embodiment one

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in sequence, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then 240KG of CO gas is introduced into the autoclave, and the jacket is fed with steam to raise the temperature to 110°C, and react for 6 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 45°C, and then add 1200KG of liquid caustic soda to adjust the Ph to be alkaline to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, first put 3000KG of xylene solution, then put into methanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 90°C, and add the crude alkoxyacrylonitrile dropwise. The time of dropping is 5.5-6 hours. The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 600KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the methanol solution in the ring-closing kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, the theoretical calculation should obtain cytosine 655KG, and the actual cytosine 600KG, cytosine The yield of pyrimidine reached 91.6%.

Embodiment two

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in sequence, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then feed 240KG of CO gas into the autoclave successively, and steam into the jacket to raise the temperature to 100°C, and react for 8 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 40°C, and then add 1200KG of liquid caustic soda to adjust Ph to alkalinity to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, first put 3000KG of xylene solution, then put into methanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 95°C, and add the crude alkoxyacrylonitrile dropwise, the time of adding is 5.5-6 hours, drop The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 597KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the methanol solution in the ring-closing kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, theoretical calculation should obtain cytosine 655KG, and actually obtain cytosine 597KG, cytosine The yield of pyrimidine reached 91.1%.

Embodiment three

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in sequence, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then feed 240KG of CO gas into the autoclave successively, and steam into the jacket to raise the temperature to 120°C, and react for 7 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 50°C, and then add 1200KG of liquid caustic soda to adjust Ph to alkalinity to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, first put 3000KG of xylene solution, then put into methanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 88°C, and add the crude alkoxyacrylonitrile dropwise, the time of adding is 5.5-6 hours, drop The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 602KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the methanol solution in the ring-closing kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, theoretical calculation should obtain cytosine 655KG, and actually obtain cytosine 602KG, cytosine The yield of pyrimidine reached 91.9%.

Embodiment Four

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in sequence, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then feed 240KG of CO gas into the autoclave successively, and steam into the jacket to raise the temperature to 120°C, and react for 7 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 50°C, and then add 1200KG of liquid caustic soda to adjust Ph to alkalinity to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, put 3000KG of xylene solution first, then put into ethanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 95°C, and drop the crude alkoxyacrylonitrile for 5.5-6 hours. The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 595KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the ethanol solution in the ring-closing kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, theoretical calculation should obtain cytosine 655KG, and actually obtain cytosine 597KG, cytosine The yield of pyrimidine reached 90.8%.

Embodiment five

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in sequence, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then feed 240KG of CO gas into the autoclave successively, and steam into the jacket to raise the temperature to 110°C, and react for 7 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 45°C, and then add 1200KG of liquid caustic soda to adjust the Ph to be alkaline to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, first put 3000KG of xylene solution, then put into ethanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 88°C, and add the crude alkoxyacrylonitrile dropwise. The time of dropping is 5.5-6 hours. The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 602KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the ethanol solution in the ring-closing kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, theoretical calculation should obtain cytosine 655KG, and actually obtain cytosine 602KG, cytosine The yield of pyrimidine reached 91.3%.

Embodiment six

High-pressure reaction: Put 3000KG of toluene and 350KG of sodium methoxide into the autoclave in turn, then transfer to 242KG of acetonitrile and 240KG of ethanol, and then 240KG of CO gas is introduced into the autoclave, and the jacket is fed with steam to raise the temperature to 115°C, and react for 7 hours to obtain nitrile Acetaldehyde sodium salt condensate;

Acidification reaction: transfer the nitrile acetaldehyde sodium salt condensate into the acidification kettle, add 1100KG of hydrochloric acid alcohol solution, react for 3-4 hours at 50°C, and then add 1200KG of liquid caustic soda to adjust Ph to alkalinity to obtain alkoxypropylene Crude nitriles, namely 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile crude.

In the ring-closing kettle, put 3000KG of xylene solution first, then put into ethanol solution containing 900KG of urea and 500KG of sodium methoxide, raise the temperature to 90°C, add the crude product of alkoxyacrylonitrile dropwise, the time of dropping is 5.5-6 hours, drop The temperature of the solution in the ring-closing kettle is 80°C during the addition; after the dropwise addition, the temperature is lowered to 30°C and kept for 5-6 hours; after the heat preservation is completed, add water to dissolve, transfer to the crystallization kettle to crystallize, adjust the pH value to be acidic, filter and dry to obtain Cytosine 605KG.

Among them, toluene and xylene are solvents and do not participate in the reaction; the ethanol solution in the cyclization kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the above-mentioned substances, theoretical calculation should obtain cytosine 655KG, and actually obtain cytosine 605KG, cytosine The yield of pyrimidine reached 92.4%.

Comparative example one

Comparative Example 1 is compared with Example 1. The xylene solution is replaced with tert-butanol in the cyclization kettle, and the other steps are the same. The final cytosine obtained is 401KG, and the cytosine yield is 61.2%.

Comparative example two

Comparative Example 2 is compared with Example 1. In the cyclization kettle, the xylene solution is replaced with tert-butanol, and the crude product of alkoxyacrylonitrile is added dropwise. The duration of the addition is 5.5-6 hours. The temperature is 50°C; after the dropwise addition, the temperature is lowered to 50°C for 5-6 hours; the other steps are the same, the final cytosine obtained is 296KG, and the yield of cytosine is 45.2%.

Comparative example three

Comparative Example 3 is compared with Example 1. In the cyclization kettle, the xylene solution is replaced with tert-butanol, and the methanol solution is replaced with methyl formate. The other steps are the same. The cytosine finally obtained is 388KG, and the cytosine yield is 59.2%. .

Comparative example four

Comparative Example 4 is compared with Example 1. In the cyclization kettle, the xylene solution is replaced with tert-butanol, and the methanol solution is replaced with ethyl formate. The other steps are the same. The cytosine finally obtained is 393KG, and the cytosine yield is 60.2%. .

Comparative example five

Comparative Example 5 is compared with Example 1. In the cyclization kettle, the xylene solution is replaced by tert-butanol, the methanol solution is replaced by methyl formate, and the crude product of alkoxyacrylonitrile is added dropwise. The time for adding is 5.5-6 hours. The temperature of the solution in the ring-closing kettle was 50°C during the dropwise addition; after the dropwise addition, the temperature was lowered to 50°C for 5-6 hours; the other steps were the same; the final cytosine was 272KG, and the yield of cytosine was 41.5%.

Comparative example six

Comparative Example 6 is compared with Example 1. In the cyclization kettle, the xylene solution is replaced with tert-butanol, the methanol solution is replaced with ethyl formate, and the crude product of alkoxyacrylonitrile is added dropwise for 5.5-6 hours. The temperature of the solution in the ring-closing kettle was 50°C during the dropwise addition; after the dropwise addition, the temperature was lowered to 50°C for 5-6 hours; the other steps were the same; the final cytosine obtained was 303KG, and the yield of cytosine was 46.2%.

Comparative example seven

Comparative Example 7 is compared with Example 6. The xylene solution is replaced with tert-butanol in the cyclization kettle. The other steps and reaction temperature and time are the same. The final cytosine obtained is 428KG, and the cytosine yield is 65.3%.

Comparative example eight

Comparative Example 8 is compared with Example 6. In the cyclization kettle, the xylene solution is replaced with tert-butanol, and the crude product of alkoxyacrylonitrile is added dropwise. The time for adding is 5.5-6 hours. The temperature is 50°C; after the dropwise addition, the temperature is lowered to 50°C for 5-6 hours; the other steps are the same, the final cytosine obtained is 316KG, and the yield of cytosine is 48.2%.

Comparative example nine

Comparative Example 9 is compared with Example 6, the crude product of alkoxyacrylonitrile is added dropwise, and the time for adding is 5.5-6 hours. -6 hours; other steps are the same, the cytosine finally obtained is 539KG, and the yield of cytosine is 82.3%.

Comparative example ten

Comparative Example 9 is compared with Example 1, and the crude product of alkoxyacrylonitrile is added dropwise, and the dropping time is 5.5-6 hours. -6 hours; other steps are the same, the cytosine finally obtained is 539KG, and the yield of cytosine is 80.2%.

Comparative Example Eleven

Comparative Example 11 is compared with Example 1, the reaction is carried out in the cyclization kettle, the methanol solution is replaced with ethyl formate, and the crude product of alkoxyacrylonitrile is added dropwise for 5.5-6 hours. The temperature is 50°C; after the dropwise addition, the temperature is lowered to 50°C for 5-6 hours; the other steps are the same; the cytosine finally obtained is 505KG, and the yield of cytosine is 77.1%.

Comparative Example 12

Comparative Example 12 is compared with Example 6, the reaction in the cyclization kettle, the ethanol solution is replaced by ethyl formate, and the crude product of alkoxyacrylonitrile is added dropwise. The time for adding is 5.5-6 hours. The temperature is 80°C; after the dropwise addition, the temperature is lowered to 30°C for 5-6 hours; the other steps are the same; the cytosine finally obtained is 572KG, and the yield of cytosine is 87.4%.

Comparative Example Thirteen

Comparative Example 13 is compared with Example 6, reaction in the cyclization kettle, the ethanol solution is replaced with methyl formate, and the crude product of alkoxyacrylonitrile is added dropwise, and the duration of the addition is 5.5-6 hours. The temperature is 80°C; after the dropwise addition, the temperature is lowered to 30°C for 5-6 hours; the other steps are the same; the cytosine finally obtained is 559KG, and the yield of cytosine is 85.4%.

Comparative Example Fourteen

Comparative Example 14 was compared with Example 6, reacted in the cyclization kettle, the ethanol solution was replaced with ethyl formate, and the crude product of alkoxyacrylonitrile was added dropwise, and the duration of the addition was 5.5-6 hours. The temperature is 50°C; after the dropwise addition, the temperature is lowered to 50°C for 5-6 hours; the other steps are the same; the cytosine finally obtained is 518KG, and the yield of cytosine is 79.1%.

By the test of comparative example 1 to comparative example 14, the catalyzer that reacts in the cyclization still uses methyl formate or formic acid of the prior art, and the reaction solvent in the cyclization still uses the tert-butanol of the prior art, alkoxypropylene The dripping temperature and the holding temperature of qing used the constant temperature of 50° C. in the prior art; the above-mentioned parameters of Examples 1 to 6 are shown in Table 1, and the above-mentioned parameters of Comparative Examples 1 to 14 are shown in Table 2.

Table I

Table II

From Table 1 and Table 2, it can be compared that the present invention, in the cyclization still reaction, the reaction solvent is changed from the tert-butanol of the prior art to xylene solution, and the catalyzer is changed from the methyl formate/ethyl formate of the prior art. For methanol/ethanol, the reaction temperature of alkoxyacrylonitrile is changed from the constant temperature of 50°C in the prior art to 80°C and 30°C for heat preservation, and the yield of cytosine is above 90%, which is 50% compared with the prior art Below the yield, the present invention significantly improves the yield of cytosine. And, in the comparative example of the present invention, the reaction solvent, catalyst and reaction temperature are combined and compared respectively, and it is determined that in the ring-closure reaction of the present invention, the reaction solvent xylene, the catalyst ethanol/methanol, and the reaction temperature of alkoxyacrylonitrile are added dropwise at 80°C, 30 ℃ heat preservation, combined together can achieve the best effect.

The above description is a preferred embodiment of the present invention, it should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.

Claims (4)

1. A synthetic method for cytosine, characterized in that it comprises the steps of: preparing alkoxyacrylonitrile crude product; dropping into an alcoholic solution of urea and sodium methylate in xylene solution, warming up to 88°C-95°C, adding dropwise The alkoxyacrylonitrile crude product is added for 5.5-6 hours, and the temperature of the solution in the ring-closure kettle is 75°C-85°C during the dropwise addition; after the dropwise addition, the temperature is lowered to 25°C-35°C and kept for 5-6 hours; After the heat preservation is completed, add water to dissolve, transfer to a crystallization kettle for crystallization, adjust the pH value to be acidic, filter and dry to obtain cytosine. 2. the synthetic method of cytosine according to claim 1 is characterized in that, described preparation alkoxyacrylonitrile crude product comprises high-pressure reaction and acidification reaction, and described high-pressure reaction is: add toluene, methyl alcohol successively in autoclave Sodium, then transferred to acetonitrile and ethanol, CO gas was passed into the kettle, steam was passed into the jacket to raise the temperature to 100°C-120°C, and the reaction was carried out for 7-8 hours to obtain the cyanoacetaldehyde sodium salt condensate; The acidification reaction is: transfer the nitrile acetaldehyde sodium salt condensate into an acidification kettle, add hydrochloric acid alcohol solution, react at 40°C-50°C for 3-4 hours, and then add liquid caustic soda to adjust Ph to be alkaline , to obtain the crude alkoxyacrylonitrile. 3. the synthetic method of cytosine according to claim 2, is characterized in that, described alkoxyacrylonitrile crude product is: 3,3-diethoxyacrylonitrile and 3,3-dimethoxyacrylonitrile Crude. 4. the synthetic method of cytosine according to claim 1 is characterized in that, the alcohol solution of described sodium methylate is methanol solution or ethanol solution.