CN114349754B - Synthesis method of 2, 6-dichloropurine - Google Patents
Synthesis method of 2, 6-dichloropurine Download PDFInfo
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- CN114349754B CN114349754B CN202111631430.XA CN202111631430A CN114349754B CN 114349754 B CN114349754 B CN 114349754B CN 202111631430 A CN202111631430 A CN 202111631430A CN 114349754 B CN114349754 B CN 114349754B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0284—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aromatic ring, e.g. pyridinium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention discloses a method for synthesizing 2, 6-dichloropurine, which comprises the steps of firstly adding ionic liquid into a reaction kettle, stirring, then adding concentrated hydrochloric acid, and continuously adding 2-amino-6-chloropurine under stirring; continuously stirring, and adding sodium nitrite to react; after the reaction is finished, extracting with ethyl acetate to obtain crude product, recrystallizing with methanol to obtain 2, 6-dichloropurine white crystal, wherein the optimized chloride ionic liquid has good activation performance on 2-amino-6-chloropurine molecules, can selectively catalyze 2-amino-6-chloropurine to prepare 2, 6-dichloropurine, and can obviously inhibit side reactions such as azo, hydrolysis, ring opening and the like, thereby improving the reaction selectivity and yield. The yield of the 2, 6-dichloropurine calculated by the 2-amino-6-chloropurine is more than 98 percent, and the content is more than 99 percent.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a method for synthesizing 2, 6-dichloropurine.
Background
2, 6-dichloropurine is an antiviral agent, and is also an important pharmaceutical intermediate, and nucleoside products such as 2, 6-dichloropurine nucleoside, fludarabine, 2-chloro-6-aminopurine and the like can be synthesized. The molecular structure is as follows:
CAS number for 2, 6-dichloropurine 5451-40-1.
The 2, 6-dichloropurine mainly comprises the following synthesis methods: (1) the 2, 6-dichloropurine is directly obtained by chlorinating hypoxanthine 1-N-oxide with phosphorus oxychloride, but hypoxanthine 1-N-oxide is a raw material which is difficult to obtain. (2) 2, 6-dichloro-4, 5-diamino pyrimidine reacts with triethyl orthoformate to obtain 2, 6-dichloropurine, which has the disadvantages that chlorine atoms are easy to hydrolyze under high temperature and acidic conditions, and the yield is not high. (3) The 2-amino-6-chloropurine takes concentrated hydrochloric acid as a solvent, and is subjected to diazotization reaction under the catalysis of cuprous chloride to generate 2, 6-dichloropurine, and the process has the disadvantages of higher yield, easy exceeding of heavy metals in the product and difficult removal. (4) Concentrated hydrochloric acid-methanol is used as a solvent, 2, 6-dimercaptopurine reacts with chlorine, and the 2, 6-dichloropurine is obtained by neutralizing with liquid ammonia at extremely low temperature (dry ice-acetone bath). The method has the advantages of long preparation steps, serious pollution, troublesome chlorination by using chlorine and lack of industrial production value of the raw material 2, 6-dimercapto purine. Thus, there is a need for a simple and industrially valuable process for preparing 2, 6-dichloropurine.
Currently, the market demand of 2, 6-dichloropurine is gradually increasing, but the production amount of 2, 6-dichloropurine can not meet the market demand far enough due to the bottleneck problem of the process technology, and the production amount is expensive. The technology is urgent to find a technology which can reduce the production cost, has strong operability and can realize industrial production.
Disclosure of Invention
The invention provides a method for synthesizing 2, 6-dichloropurine aiming at various defects in the prior art.
The invention achieves the above object by the following technical scheme:
the invention discloses a synthesis method of 2, 6-dichloropurine, which comprises the following steps:
1) Firstly, adding an ionic liquid into a reaction kettle, stirring, then adding concentrated hydrochloric acid, and continuously adding 2-amino-6-chloropurine under stirring;
2) Continuously stirring, controlling the temperature to be 0-20 ℃, slowly adding sodium nitrite for reaction for 0.5-4 hours;
3) After the reaction is finished, extracting with ethyl acetate to obtain a crude product, and recrystallizing with methanol to obtain white crystals of the 2, 6-dichloropurine.
As a further improvement, the mass ratio of the raw materials 2-amino-6-chloropurine to the concentrated hydrochloric acid to the ionic liquid to the sodium nitrite is 100:100-200:500-1000:50-60.
As a further improvement, in the step 1) of the invention, the ionic liquid is 1-butyl-3-methylimidazole chloride salt [ BMIm ] Cl or 1-ethyl-3-methylimidazole chloride salt [ EMIm ] Cl or 1, 3-dimethylimidazole chloride salt [ DMIm ] Cl.
As a further improvement, in the step 3) of the invention, the mother liquor after extraction of ethyl acetate is cooled at the temperature of minus 10 ℃ for 24 hours, and the filtrate obtained after filtration and impurity removal is directly sleeved for the next batch reaction.
As a further improvement, the yield of the 2, 6-dichloropurine calculated by the 2-amino-6-chloropurine is more than 98 percent, and the content is more than 99 percent.
The beneficial effects of the invention are as follows:
1. the invention adopts chloride ionic liquid as a reaction solvent and a special catalyst for reaction. Through the optimized chloride ionic liquid, each reaction raw material can be well dissolved, and the reaction can be effectively catalyzed by utilizing the property of the chloride ionic liquid aqueous solution. The preferred molecular structure of the chloride ionic liquid of the invention is as follows:
the main body of the molecular structure is an imidazole heterocycle nitrogen-containing structure, which has a similar point to the purine molecular structure of the main body in 2-amino-6-chloropurine in the reaction. In the reaction system, diazotization reaction occurs under the action of 2-amino-6-chloropurine and sodium nitrite, and the reaction system has the problems of poor selectivity and low yield. The inventor has found in practice that the optimal chloride ionic liquid has good activation performance on 2-amino-6-chloropurine molecules, can selectively catalyze 2-amino-6-chloropurine to prepare 2, 6-dichloropurine, and can obviously inhibit side reactions such as azo, hydrolysis, ring opening and the like, thereby improving reaction selectivity and yield.
2. The invention adopts a reasonable post-treatment process, can realize green synthesis of products, greatly reduces three-waste discharge and reduces cost. The mother liquor after extraction of ethyl acetate in the process contains impurities generated by side reaction, salt generated by reaction and other impurities. The invention discovers that the extraction mother liquor can be subjected to impurity removal treatment, impurities and excessive salt can be removed by filtering and impurity removal through cooling at-10 ℃ for 24 hours, and the obtained filtrate can be directly used for the next batch of reaction, thereby greatly reducing three wastes and lowering the cost.
3. In the reaction, the comprehensive utilization of the process ensures that the yield of the 2, 6-dichloropurine calculated by the 2-amino-6-chloropurine is more than 98 percent and the content is more than 99 percent.
Detailed Description
The technical scheme of the present invention will be further described in detail with reference to specific examples, but the scope of the present invention is not limited to the examples.
Example 1
1) In a 1L reactor, 500g of 1-butyl-3-methylimidazole chloride [ BMIm ] Cl serving as an ionic liquid was added and stirred. Then, 100g of concentrated hydrochloric acid was added. 100g of 2-amino-6-chloropurine were added with stirring.
2) Stirring is continued, the temperature is controlled at 0 ℃, and 50g of sodium nitrite is slowly added for reaction. The reaction time was 4 hours.
3) After the reaction, the crude product was extracted with ethyl acetate (500 ml x 4), concentrated and recrystallized from methanol to yield 108g of 2, 6-dichloropurine white crystals. Melting point: 180-182 deg.c, 97.3% yield and 99.1% content.
4) The mother solution after extraction of ethyl acetate is fully cooled at the temperature of minus 10 ℃ for 24 hours for separating out materials, and the filtrate obtained after filtration and impurity removal is directly sleeved for the next batch reaction. After the concentrated hydrochloric acid is supplemented, the reaction can be stably carried out, and the yield of the final product is 97.0 percent and the content is 99.1 percent.
Example 2
1) In a 2L reactor, 1000g of ionic liquid 1-ethyl-3-methylimidazole chloride [ EMim ] Cl was added and stirred. Then 200g of concentrated hydrochloric acid was added. 100g of 2-amino-6-chloropurine were added with stirring.
2) Stirring is continued, the temperature is controlled at 20 ℃, and 60g of sodium nitrite is slowly added for reaction. The reaction time was 0.5 hours.
3) After the reaction, the crude product was extracted with ethyl acetate (500 ml x 4), concentrated and recrystallized from methanol to yield 109g of 2, 6-dichloropurine white crystals. Melting point: 180-182 deg.c, 98.2% yield and 99.3% content.
4) The mother solution after extraction of ethyl acetate is fully cooled at the temperature of minus 10 ℃ for 24 hours for separating out materials, and the filtrate obtained after filtration and impurity removal is directly sleeved for the next batch reaction. After the concentrated hydrochloric acid is supplemented, the reaction can be stably carried out, and the yield of the final product is 98.0 percent and the content is 99.1 percent.
Example 3
1) In a 2L reactor, 750g of 1, 3-dimethylimidazole chloride [ DMim ] Cl serving as an ionic liquid is firstly added and stirred. 150g of concentrated hydrochloric acid are then added. 100g of 2-amino-6-chloropurine were added with stirring.
2) Stirring is continued, the temperature is controlled at 10 ℃, and 55g of sodium nitrite is slowly added for reaction. The reaction time was 2 hours.
3) After the reaction, the crude product was extracted with ethyl acetate (500 ml x 4), concentrated and recrystallized from methanol to yield 110g of 2, 6-dichloropurine white crystals. Melting point: 180-182 deg.c, yield of 99.0% and content of 99.5%.
4) The mother solution after extraction of ethyl acetate is fully cooled at the temperature of minus 10 ℃ for 24 hours for separating out materials, and the filtrate obtained after filtration and impurity removal is directly sleeved for the next batch reaction. After the concentrated hydrochloric acid is supplemented, the reaction can be stably carried out, and the yield of the final product is 98.2 percent and the content is 99.2 percent.
Comparative example 1
1) In a 1L reactor, 500g of concentrated hydrochloric acid was first charged and stirred. After stirring for 30 minutes, 100g of 2-amino-6-chloropurine was added. After stirring thoroughly for 30 minutes, the mixture was cooled to 10℃or below, and 300g of zinc chloride was slowly added.
2) Continuously stirring and cooling to below 0 ℃, controlling the temperature to 0 ℃, and slowly adding 55g of sodium nitrite to react. The reaction time was 2 hours.
3) After the reaction, extraction with ethyl acetate (500 ml x 4) gives crude product, which after concentration is recrystallized from methanol to give 66.5g of 2, 6-dichloropurine white crystals. Melting point: 180-182 deg.c, yield of 60.0% and content of 99.0%.
As can be seen, in comparative example 1, no chloride ionic liquid was added, and only zinc chloride and concentrated hydrochloric acid were added, so that the product yield was greatly reduced to 60%.
Comparative example 2
1) In a 1L reactor, 500g of concentrated hydrochloric acid was first charged and stirred. After stirring for 30 minutes, 100g of 2-amino-6-chloropurine was added.
2) Continuously stirring and cooling to below 0 ℃, controlling the temperature to 0 ℃, and slowly adding 55g of sodium nitrite to react. The reaction time was 2 hours.
3) After the reaction, extraction with ethyl acetate (500 ml x 4) gives crude product, which after concentration is recrystallized from methanol to give 30g of 2, 6-dichloropurine white crystals. Melting point: 180-182 deg.c, yield of 27.0% and content of 99.0%.
It can be seen that in comparative example 2, as compared with comparative example 1, not only the chloride ionic liquid but also zinc chloride was not added, and the product yield was greatly reduced to 27%.
Finally, it should also be noted that the above list is merely a specific example of the invention. Obviously, the invention is not limited to the above embodiment examples, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
Claims (4)
1. The synthesis method of the 2, 6-dichloropurine is characterized by comprising the following steps of:
1) Firstly, adding an ionic liquid into a reaction kettle, stirring, then adding concentrated hydrochloric acid, and continuously adding 2-amino-6-chloropurine under stirring;
2) Continuously stirring, controlling the temperature to be 0-20 ℃, slowly adding sodium nitrite for reaction for 0.5-4 hours;
3) After the reaction is finished, extracting by using ethyl acetate to obtain a crude product, and recrystallizing by using methanol to obtain a white 2, 6-dichloropurine crystal;
the ionic liquid is 1-butyl-3-methylimidazole chloride [ BMIm ] Cl or 1-ethyl-3-methylimidazole chloride [ EMIm ] Cl or 1, 3-dimethylimidazole chloride [ DMIm ] Cl.
2. The method for synthesizing 2, 6-dichloropurine according to claim 1, wherein the mass ratio of the raw materials 2-amino-6-chloropurine to concentrated hydrochloric acid to ionic liquid to sodium nitrite is 100:100-200:500-1000:50-60.
3. The method for synthesizing 2, 6-dichloropurine according to claim 1 or 2, wherein in said step 3), the mother liquor after extraction of ethyl acetate is cooled at-10 ℃ for 24 hours, and the filtrate obtained after filtration and impurity removal is directly used in the next batch.
4. A method for synthesizing 2, 6-dichloropurine according to claim 3 wherein the yield of 2, 6-dichloropurine calculated as 2-amino-6-chloropurine is greater than 98% and the content is greater than 99%.
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Inventor after: Zhang Zhiguo Inventor after: Shen Bo Inventor after: Yan Jixiao Inventor after: Wang Jiahao Inventor after: Zhao Weibing Inventor after: Li Biao Inventor before: Zhang Zhiguo Inventor before: Shen Bo Inventor before: Yan Jixiao Inventor before: Wang Jiahao Inventor before: Zhao Weibing Inventor before: Li Biao |