CN115611815A - Synthesis method of cytosine - Google Patents
Synthesis method of cytosine Download PDFInfo
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- CN115611815A CN115611815A CN202211236546.8A CN202211236546A CN115611815A CN 115611815 A CN115611815 A CN 115611815A CN 202211236546 A CN202211236546 A CN 202211236546A CN 115611815 A CN115611815 A CN 115611815A
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- cytosine
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- acrylonitrile
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 title claims abstract description 160
- 229940104302 cytosine Drugs 0.000 title claims abstract description 79
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 48
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 38
- -1 alkoxy acrylonitrile compound Chemical class 0.000 claims abstract description 38
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000001816 cooling Methods 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 18
- 230000008025 crystallization Effects 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004321 preservation Methods 0.000 claims abstract description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000004202 carbamide Substances 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- 230000002378 acidificating effect Effects 0.000 claims abstract description 9
- 230000001476 alcoholic effect Effects 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004090 dissolution Methods 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 239000012043 crude product Substances 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 230000020477 pH reduction Effects 0.000 claims description 18
- IUQNBIZTUXOMKO-UHFFFAOYSA-N [Na].O=CCC#N Chemical compound [Na].O=CCC#N IUQNBIZTUXOMKO-UHFFFAOYSA-N 0.000 claims description 16
- RKNAKGBQFBUEPY-UHFFFAOYSA-N 3,3-diethoxyprop-2-enenitrile Chemical compound CCOC(OCC)=CC#N RKNAKGBQFBUEPY-UHFFFAOYSA-N 0.000 claims description 12
- AGNINIWJJIXFSX-UHFFFAOYSA-N 3,3-dimethoxyprop-2-enenitrile Chemical compound COC(OC)=CC#N AGNINIWJJIXFSX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000011084 recovery Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 28
- 239000008096 xylene Substances 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 12
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 10
- 239000007789 gas Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000003482 Pinner synthesis reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HUPVIAINOSTNBJ-HWKANZROSA-N (e)-3-ethoxyprop-2-enenitrile Chemical compound CCO\C=C\C#N HUPVIAINOSTNBJ-HWKANZROSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229940087458 alcaine Drugs 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for synthesizing cytosine, which comprises the following steps: preparing an alkoxyacrylonitrile compound; adding an alcoholic solution of urea and sodium methoxide into a dimethylbenzene solution, heating to 88-95 ℃, dropwise adding the alkoxy acrylonitrile compound, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in a cyclization kettle is 95-105 ℃ during dropwise adding; after the dropwise addition is finished, preserving heat for 2.5-3 hours at the temperature of 80-90 ℃, and then cooling to the temperature of 25-35 ℃ and preserving heat for 2.5-3 hours; and after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine. The cytosine synthesis method provided by the invention can improve the recovery rate of cytosine.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a cytosine synthesis method.
Background
Cytosine is 4-amino-2-hydroxypyrimidine, is one of pyrimidine bases in nucleic acid, and is also an important intermediate of fine chemical engineering, pesticides and medicines; especially in the medical field, the method is mainly used for synthesizing anti-AIDS drugs and anti-hepatitis B drugs lamivudine, and anti-cancer drugs gemcitabine, enocitabine, 5-fluorocytosine and the like. The existing cytosine synthesis method mainly comprises a functional group conversion method and a Pinner synthesis method.
The Pinner synthesis method comprises the following steps: 1.3peeters et al prepared cytosine directly by cyclization of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxyacrylonitrile with urea in a solution of potassium tert-butoxide in tert-butanol at a yield of not more than 62%. In addition to other Pinner syntheses, the yield of cytosine was not high.
Disclosure of Invention
In view of this, the present invention aims to provide a method for synthesizing cytosine, which can improve the recovery rate of cytosine.
A method for synthesizing cytosine, comprising the steps of: preparing a crude product of alkoxy acrylonitrile; adding an alcoholic solution of urea and sodium methoxide into a dimethylbenzene solution, heating to 88-95 ℃, dropwise adding the alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in a cyclization kettle is 75-85 ℃ during dropwise adding; after the dripping is finished, cooling to 25-35 ℃ and preserving the heat for 5-6 hours; and after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine.
Optionally, the preparation of the crude alkoxyacrylonitrile product comprises a high pressure reaction and an acidification reaction, wherein the high pressure reaction comprises the following steps: sequentially adding toluene and sodium methoxide into an autoclave, then transferring acetonitrile and ethanol, introducing CO gas into the autoclave, introducing steam into a jacket, heating to 100-120 ℃, and reacting for 7-8 hours to obtain a cyanoacetaldehyde sodium salt condensate;
the acidification reaction is as follows: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding hydrochloric acid alcohol solution, reacting for 3-4 hours at 40-50 ℃, and then adding liquid alkali to adjust Ph to be alkaline, thus obtaining the alkoxy acrylonitrile crude product.
Alternatively, the crude alkoxyacrylonitrile is: 3, 3-diethoxyacrylonitrile and 3, 3-dimethoxyacrylonitrile crude products.
Optionally, the alcoholic solution of sodium methoxide is a methanol solution or an ethanol solution.
The cytosine synthesis method provided by the invention uses unqualified acetonitrile produced by the company, for example, acetone in the acetonitrile exceeds the standard and can not leave a factory, so that the acetonitrile can be used as a raw material for synthesizing cytosine; company resources can be effectively utilized, cost is reduced, and efficiency is improved; in the preparation of alkoxyacrylonitrile: the used CO is a byproduct of a general company, if the CO is not used, the CO needs to be burnt, so that the carbon emission is effectively reduced after the CO is used, and the economic benefit can be created; the alcaine solution used in the preparation process of alkoxy acrylonitrile is self-produced by the company; hydrochloric acid is a byproduct of a general company, the cost is very low or even the cost is not required, and the alcohol is used as a catalyst for producing cytosine and can be recycled, so that the total ethanol solution of hydrochloric acid has low cost, can be produced according to the production requirement, does not need additional storage, and reduces the storage cost. Compared with the prior art, the method utilizes waste gas or waste products of other production lines of the company to change the catalyst and the temperature, and finally synthesizes the cytosine, so that the yield is improved to over 90 percent.
Detailed Description
In order to make the objects, 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 with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the description of the embodiments of the invention given above, are within the scope of protection of the invention.
The synthesis method of cytosine firstly synthesizes 3, 3-diethoxyacrylonitrile and 3, 3-dimethoxyacrylonitrile crude products, and then 3, 3-diethoxyacrylonitrile and 3, 3-dimethoxyacrylonitrile crude products are used as raw materials to prepare cytosine. Acetonitrile, CO gas, hydrochloric acid and other substances used in the process of synthesizing the crude products of 3, 3-diethoxyacrylonitrile and 3, 3-dimethoxyacrylonitrile are byproducts or unqualified products produced by other manufacturers, and the inventor of the invention finds that the byproducts or the unqualified products do not influence the quality and the recovery rate of cytosine in the process of producing cytosine; the production cost is reduced because of the by-products and unqualified products produced by other manufacturers. The embodiment of the invention is concretely as follows:
example one
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 110 ℃, and reacting for 6 hours to obtain a cyanoacetaldehyde sodium salt condensate;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding 1100KG of hydrochloric acid alcoholic solution, reacting for 3-4 hours at 45 ℃, adding 1200KG of liquid alkali to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting methanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 90 ℃, dropwise adding crude alkoxy acrylonitrile for 5.5-6 hours, wherein the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine 600KG.
Wherein, the toluene and the xylene are solvents and do not participate in the reaction; the methanol solution in the cyclization kettle is a catalyst, and the adding amount is 100-200KG; according to the weight of the substances, the cytosine 655KG and the cytosine 600KG are obtained by theoretical calculation, and the cytosine yield reaches 91.6 percent.
Example two
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 100 ℃, and reacting for 8 hours to obtain a cyanoacetaldehyde sodium salt condensation compound;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding 1100KG of hydrochloric acid alcoholic solution, reacting for 3-4 hours at 40 ℃, adding 1200KG of liquid alkali to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting methanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 95 ℃, dropwise adding an alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dropwise addition is finished, cooling to 30 ℃ and preserving the temperature for 5-6 hours; after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the 597KG cytosine.
Wherein, the toluene and the xylene are solvents and do not participate in the reaction; the methanol solution in the cyclization kettle is a catalyst, and the adding amount is 100-200KG; according to the weight of the substances, the cytosine 655KG is theoretically obtained, the cytosine 597KG is actually obtained, and the yield of the cytosine reaches 91.1 percent.
EXAMPLE III
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 120 ℃, and reacting for 7 hours to obtain a cyanoacetaldehyde sodium salt condensate;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding alcohol solution of hydrochloric acid 1100KG, reacting for 3-4 hours at 50 ℃, adding liquid alkali 1200KG to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting methanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 88 ℃, dropwise adding alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain cytosine 602KG.
Wherein, the toluene and the xylene are solvents and do not participate in the reaction; the methanol solution in the cyclization kettle is a catalyst, and the addition amount is 100-200KG; according to the weight of the substances, the cytosine 655KG is obtained by theoretical calculation, the cytosine 602KG is actually obtained, and the yield of the cytosine reaches 91.9 percent.
Example four
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 120 ℃, and reacting for 7 hours to obtain a cyanoacetaldehyde sodium salt condensate;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding 1100KG of hydrochloric acid alcoholic solution, reacting for 3-4 hours at 50 ℃, adding 1200KG of liquid alkali to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting ethanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 95 ℃, dropwise adding crude alkoxy acrylonitrile for 5.5-6 hours, wherein the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; after the heat preservation is finished, adding water for dissolving, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine 595KG.
Wherein, the toluene and the xylene are solvents and do not participate in the reaction; the ethanol solution in the cyclization kettle is a catalyst, and the adding amount is 100-200KG; according to the weight of the substances, the cytosine 655KG and the cytosine 597KG are obtained by theoretical calculation, and the cytosine yield reaches 90.8 percent.
EXAMPLE five
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 110 ℃, and reacting for 7 hours to obtain a cyanoacetaldehyde sodium salt condensate;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding alcohol solution of hydrochloric acid 1100KG, reacting for 3-4 hours at 45 ℃, adding liquid alkali 1200KG to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting ethanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 88 ℃, dropwise adding alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain cytosine 602KG.
Wherein, the toluene and the xylene are solvents and do not participate in the reaction; the ethanol solution in the cyclization kettle is a catalyst, and the adding amount is 100-200KG; according to the weight of the substances, the cytosine 655KG is obtained by theoretical calculation, the cytosine 602KG is actually obtained, and the yield of the cytosine reaches 91.3 percent.
EXAMPLE six
High-pressure reaction: putting 3000KG of toluene and 350KG of sodium methoxide in turn into an autoclave, then transferring 242KG of acetonitrile and 240KG of ethanol, continuously introducing 240KG of CO gas into the autoclave, introducing steam into a jacket, heating to 115 ℃, and reacting for 7 hours to obtain a cyanoacetaldehyde sodium salt condensate;
and (3) acidification reaction: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding 1100KG of hydrochloric acid alcoholic solution, reacting for 3-4 hours at 50 ℃, adding 1200KG of liquid alkali to adjust Ph to be alkaline, and preparing alkoxy acrylonitrile crude products, namely 3, 3-diethoxy acrylonitrile and 3, 3-dimethoxy acrylonitrile crude products.
Putting 3000KG of xylene solution into a cyclization kettle, putting ethanol solution containing 900KG of urea and 500KG of sodium methoxide, heating to 90 ℃, dropwise adding an alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in the cyclization kettle is 80 ℃ during dropwise adding; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine 605KG.
Wherein, the toluene and the 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 substances, the cytosine 655KG and the cytosine 605KG are obtained by theoretical calculation, and the cytosine yield reaches 92.4 percent.
Comparison example 1
Comparison example one and example one, the xylene solution was changed to tert-butanol in the cyclization kettle, the other steps were the same, the final cytosine obtained was 401KG, and the yield of cytosine was 61.2%.
Comparative example II
Comparing the second comparative example with the second comparative example, namely replacing a dimethylbenzene solution with tert-butyl alcohol in a cyclization kettle, dropwise adding the crude alkoxy acrylonitrile for 5.5-6 hours, wherein the temperature of the solution in the cyclization kettle is 50 ℃ during dropwise adding; after the dropwise addition is finished, cooling to 50 ℃, and preserving the heat for 5-6 hours; the cytosine yield obtained in the end is 296KG with the same other steps as above, 45.2%.
Comparative example III
In comparison with the third comparative example, the xylene solution was replaced by t-butanol and the methanol solution by methyl formate in the cyclization kettle, and the cytosine yield was found to be 388KG in the same manner as in the other steps.
Comparative example four
Comparative example four in comparison with the example, the xylene solution was changed to tert-butanol and the methanol solution to ethyl formate in the cyclization kettle, and the same procedure was followed, whereby the final cytosine was 393KG with a cytosine yield of 60.2%.
Comparative example five
Comparison example five and example contrast, in the cyclization kettle the xylene solution is changed into tert-butyl alcohol, the methanol solution is changed into methyl formate, crude alkoxy acrylonitrile is dripped, the dripping time is 5.5-6 hours, the temperature of the solution in the cyclization kettle is 50 ℃; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same; the final cytosine yield was 272KG, 41.5%.
Comparative example six
Comparing the sixth control example with the sixth control example, the xylene solution is changed into tert-butyl alcohol in the cyclization kettle, the methanol solution is changed into ethyl formate, the crude alkoxy acrylonitrile is dripped for 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ when the crude alkoxy acrylonitrile is dripped; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same; the final cytosine obtained was 303KG with a cytosine yield of 46.2%.
Comparative example seven
The seven comparative examples and the six comparative examples were carried out by replacing the xylene solution with tert-butanol in the cyclization kettle, and the other steps and reaction temperature and reaction time were the same, so that the cytosine was 428KG and the yield of cytosine was 65.3%.
Eight comparative examples
Comparing the eighth control example with the sixth control example, the xylene solution is changed into tert-butyl alcohol in the cyclization kettle, the crude alkoxy acrylonitrile is dripped for 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ when the crude alkoxy acrylonitrile is dripped; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same, and the final cytosine obtained is 316KG, and the yield of the cytosine is 48.2%.
Nine comparative examples
The ninth comparative example is compared with the sixth example, crude alkoxy acrylonitrile is dripped, the dripping time is 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ during dripping; after the dropwise addition is finished, cooling to 50 ℃, and preserving the heat for 5-6 hours; the other steps are the same, and the final cytosine obtained is 539KG, and the yield of the cytosine is 82.3%.
Comparative example ten
The comparative example nine is compared with the example, the crude alkoxy acrylonitrile is dripped, the dripping time is 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ when the crude alkoxy acrylonitrile is dripped; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same, and the final cytosine obtained is 539KG, and the yield of the cytosine is 80.2%.
Comparative example eleven
Comparative example eleven is compared with the example, the reaction is carried out in the cyclization kettle, the methanol solution is changed into ethyl formate, the crude alkoxy acrylonitrile is dripped for 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ during dripping; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same; the final cytosine obtained was 505KG with a cytosine yield of 77.1%.
Comparative example twelve
The twelfth comparative example is compared with the sixth comparative example, the reaction is carried out in a cyclization kettle, the ethanol solution is changed into ethyl formate, the crude alkoxy acrylonitrile product is dripped for 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 80 ℃ during dripping; after the dropwise addition is finished, cooling to 30 ℃ and preserving the temperature for 5-6 hours; the other steps are the same; the final cytosine obtained was 572KG, yield of cytosine 87.4%.
Thirteen comparative example
Thirteen comparison examples and six comparison examples, the reaction in the cyclization kettle, the ethanol solution is changed into methyl formate, crude alkoxy acrylonitrile is dripped, the dripping time is 5.5 to 6 hours, the temperature of the solution in the cyclization kettle is 80 ℃ when dripping; after the dripping is finished, cooling to 30 ℃, and preserving heat for 5-6 hours; the other steps are the same; the final cytosine obtained was 559KG, yield 85.4% cytosine.
Fourteen comparative examples
Fourteen comparison examples and six comparison examples, the reaction is carried out in a cyclization kettle, the ethanol solution is changed into ethyl formate, crude alkoxy acrylonitrile is dripped for 5.5 to 6 hours, and the temperature of the solution in the cyclization kettle is 50 ℃ when the crude alkoxy acrylonitrile is dripped; after the dropwise addition is finished, cooling to 50 ℃, and preserving heat for 5-6 hours; the other steps are the same; the final cytosine obtained was 518KG, yield of cytosine was 79.1%.
According to the tests of the first comparative example to the fourteenth comparative example, methyl formate or formic acid in the prior art is used as a catalyst for reaction in the cyclization kettle, tert-butyl alcohol in the prior art is used as a reaction solvent in the cyclization kettle, and the constant temperature of 50 ℃ is used as the dropping temperature and the heat preservation temperature of alkoxy acrylonitrile in the prior art; the parameters of the first to sixth embodiments are shown in table one, and the parameters of the first to fourteenth comparative examples are shown in table two.
Watch 1
Watch 2
Compared with the table I and the table II, in the cyclization kettle reaction, a reaction solvent is changed from tert-butyl alcohol in the prior art into a xylene solution, a catalyst is changed from methyl formate/ethyl formate in the prior art into methanol/ethanol, the reaction temperature of alkoxy acrylonitrile is changed from 50 ℃ constant temperature in the prior art into dropwise adding 80 ℃ and 30 ℃ heat preservation, the yield of cytosine is over 90 percent, and compared with the yield below 50 percent in the prior art, the yield of cytosine is obviously improved. In the comparative example, the reaction solvent, the catalyst and the reaction temperature are respectively combined and compared, and the optimal effect can be achieved by combining the reaction solvent xylene, the catalyst ethanol/methanol and the alkoxy acrylonitrile in the cyclization kettle reaction at 80 ℃ and 30 ℃.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (4)
1. A method for synthesizing cytosine, comprising the steps of: preparing a crude alkoxy acrylonitrile product; adding an alcoholic solution of urea and sodium methoxide into a dimethylbenzene solution, heating to 88-95 ℃, dropwise adding the alkoxy acrylonitrile crude product, wherein the dropwise adding time is 5.5-6 hours, and the temperature of the solution in a cyclization kettle is 75-85 ℃ during dropwise adding; after the dripping is finished, cooling to 25-35 ℃ and preserving the heat for 5-6 hours; and after the heat preservation is finished, adding water for dissolution, transferring the solution into a crystallization kettle for crystallization, adjusting the pH value to be acidic, filtering and drying to obtain the cytosine.
2. The method for synthesizing cytosine as claimed in claim 1, wherein the preparation of the crude alkoxy acrylonitrile includes a high pressure reaction and an acidification reaction, the high pressure reaction is: sequentially adding toluene and sodium methoxide into an autoclave, then transferring acetonitrile and ethanol, introducing CO gas into the autoclave, introducing steam into a jacket, heating to 100-120 ℃, and reacting for 7-8 hours to obtain a cyanoacetaldehyde sodium salt condensate;
the acidification reaction is as follows: transferring the cyanoacetaldehyde sodium salt condensate into an acidification kettle, adding hydrochloric acid alcohol solution, reacting for 3-4 hours at 40-50 ℃, and then adding liquid alkali to adjust Ph to be alkaline, thus obtaining the alkoxy acrylonitrile crude product.
3. The method for synthesizing cytosine according to claim 2, wherein the crude alkoxyacrylonitrile is: 3, 3-diethoxyacrylonitrile and 3, 3-dimethoxyacrylonitrile crude products.
4. The method for synthesizing cytosine of claim 1, wherein the alcoholic solution of sodium methoxide is a methanol solution or an ethanol solution.
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