CN116947948A - Synthesis method of crotonoside and analogues thereof - Google Patents

Abstract

The application discloses a synthesis method of crotonoside and analogues thereof, belonging to the technical field of pharmaceutical chemistry. The method is characterized in that 2-nitropurine derivatives are used as raw materials, and are heated and reacted in an organic solvent in the presence of acetyl hydroxamic acid and alkali metal/alkaline earth metal carbonate to obtain the crotonoside and analogues thereof. The method for preparing the crotonoside and the analogues thereof has the advantages of low cost, simplicity and convenience in operation, mild reaction conditions and good substrate adaptability, and provides a concise way for preparing the compounds.

Description

A kind of synthetic method of crotonin and its analogues

Technical field

The invention belongs to the technical field of medicinal chemistry, and specifically relates to a synthesis method of crotonin and its analogues.

Background technique

Crotonoside (also called isoguanosine, CAS1818-71-9) is a natural nucleoside compound, which was first isolated from the seeds of the traditional Chinese medicine Crotonoside. Croton seeds belong to the dried and mature fruits of Crotontig lium L., a plant of the Euphorbiaceae family, and are traditional Chinese medicinal materials. Crotonin is an important active component of Croton. Studies have shown that crotonin has a variety of physiological activities, such as increasing intestinal peristalsis, lowering blood pressure, stimulating the brain to enrich AMP (adenylate), and having a significant inhibitory effect on S180 ascites tumors and Ehrlich solid tumors in mice. , can show selective post-inhibitory effects in acute myeloid leukemia (AML) cells by inhibiting FLT3 and HDAC3/6, and can have anti-arrhythmic effects by regulating sodium and calcium channels in rabbit ventricular myocytes. In addition, crotonin is an isomer of guanosine, a structural fragment of RNA in organisms. It can be embedded into RNA fragments as a guanosine analog and perform gene expression, thus having important uses in biochemical research. Its 2-carbonylpurine derivative, which is similar to crotonin, also has good physiological activity.

At present, in addition to isolating crotonin from natural resources, there are mainly three chemical synthesis routes:

1) 2-substituted (I, Cl or NH ₂ ) adenosine can be obtained by light hydrolysis or diazotization reaction, but the selectivity is poor and the yield is very low, or 2-hydroxy-6-thio-substituted purine nucleoside can be obtained by aminolysis , but it is difficult to synthesize raw materials;

2) After silicon ether protection, isoguanine is condensed with group-protected ribose under the catalysis of TMSOTf or SnCl ₄ , and then the protecting group is removed. The disadvantage is that there are many steps, low yield, and the synthesis of isoguanine is also very difficult. ;

3) Aminoimidazole carboxamide nucleoside is biomimically synthesized through cyclization of isoguanosine, but the yield is very low and has no synthetic value.

The above three reaction routes limit the expansion of the synthesis scale of crotonin. Synthesizing crotonin from cheap and easily available raw materials can avoid the tedious steps of separation and extraction from natural products, and can also solve the problems of low yield in existing chemical synthesis methods. It can expand the source of crotonin, thereby expanding its The scope of application is of great significance.

Contents of the invention

In order to solve the deficiencies of the prior art, the present invention provides a heating reaction in an organic solvent using 2-nitropurine derivatives as raw materials in the presence of acetohydroxamic acid and alkali metal or alkaline earth metal carbonate M ₂ CO ₃ , to obtain crotonin and its analogues. 2-nitropurine derivatives can be synthesized from cheap purine nucleosides through the tetrabutylammonium nitrate/trifluoromethanesulfonic anhydride system. There are many reports, and the method is mature and convenient. By using this method to obtain crotonin and its analogues, the cost is low, the operation is simple, the reaction conditions are mild, and the substrate adaptability is good, which demonstrates the superiority and simplicity of the synthesis method.

The technical solution of the present invention is: a synthesis method of crotonin and its analogues, which is synthesized through the following reaction equation:

Wherein: M is selected from alkali metal or alkaline earth metal; R ¹ is selected from hydrogen, alkyl, allyl, benzyl, 2-chlorobenzyl, P is selected from hydrogen, acetyl or benzoyl; R ² is selected from hydrogen, chlorine, fluorine, methoxy or amino.

The method includes the following steps: using 2-nitropurine derivative A as a raw material, heating and reacting in an organic solvent in the presence of acetohydroxamic acid and M ₂ CO ₃ to obtain crotonin and its analogue B;

Further, in the above technical solution, M ₂ CO ₃ is selected from Na ₂ CO ₃ , K ₂ CO ₃ or Cs ₂ CO ₃ .

Further, in the above technical solution, the molar ratio of 2-nitropurine derivative A, acetohydroxamic acid and M ₂ CO ₃ is 1:1.5~4.5:2~6.

Further, in the above technical solution, the organic solvent is selected from one or more of water, ethanol, methanol, acetonitrile, and dimethyl sulfoxide.

Further, in the above technical solution, the reaction temperature is 50-100°C, and the reaction time is 2-24 hours.

Further, in the above technical solution, the product For the convenience of structural description, structure B is used in this application.

By using this method to obtain crotonin and its analogues, the cost is low, the operation is simple, the reaction conditions are mild, and the substrate adaptability is good, which demonstrates the superiority and simplicity of the synthesis method.

According to the basic principles of chemical reactions, the method for converting 2-nitro group into 2-hydroxyl group is hydrolysis reaction. In order to increase the nucleophilicity of hydroxyl group, strong bases such as high concentration sodium hydroxide and tetrabutylammonium hydroxide are required. Acetohydroxamic acid can react with weak bases such as potassium carbonate. The oxygen atom has good nucleophilicity and can react with the 2-nitro group to obtain intermediate III. However, III is unstable and randomly rearranges to obtain the target product II. The equation is expressed as follows:

During the reaction process, acetylamino increases the nucleophilicity of oxygen atoms, making up for the shortcomings of strong bases such as high-concentration sodium hydroxide and tetrabutylammonium hydroxide.

Detailed ways

The present invention will be described in detail below with reference to examples.

Example 1:

In the reaction bottle, add (0.312g, 1mmol), acetohydroxamic acid (0.15g, 2mmol) and potassium carbonate (0.345g, 2.5mmol) were added to acetonitrile (10mL), heated to 80°C in an oil bath and reacted for 4h. TLC showed that the raw materials When the reaction is complete, the reaction solution is concentrated under reduced pressure and recrystallized from water to obtain /> 0.251g, yield 89%. White solid, mp238-240℃. ¹ HNMR (DMSO-d ₆ ,400MHz) δ10.88(s,1H),8.37(s,1H),7.83(brs,2H),5.81(d,J＝6.0Hz, 1H),5.47(d,J＝6.0Hz,1H),5.19(d,J＝4.8Hz,1H),5.05(t,J＝4.8Hz,1H),4.52-4.48(m,1H),4.12- 4.09(m,1H),3.93(d,J＝3.6Hz,1H),3.67-3.52(m,2H); ¹³ CNMR(DMSO-d ₆ ,100MHz)δ160.2,156.0,151.6,137.1,112.4,84.1, 83.3,75.6,61.1.

Example 2: With 1 mmol As raw materials, changing other reaction conditions, the reaction results are as follows:

Example 3:

In the reaction bottle, add (0.255g, 1mmol), acetohydroxamic acid (0.187g, 2.5mmol) and sodium carbonate (0.318g, 3mmol) were added to acetonitrile (10mL), heated to 80°C in an oil bath and reacted for 6 hours. TLC showed that the raw materials When the reaction is complete, the reaction solution is concentrated under reduced pressure and recrystallized from ethanol to obtain /> 0.21g, yield 93%. White solid, mp168-170℃. ¹ HNMR (DMSO-d ₆ ,400MHz) δ10.42(s,1H),9.25(s,1H),8.21(s,H),7.37-7.31(m,5H), 3.81(s,2H),; ¹³ CNMR(100MHz,DMSO-d ₆ )δ152.2,151.4,150.8,142.6,134.2,131.1,129.1,128.9,127.4,47.8.

Example 4:

In the reaction bottle, add (0.312g, 1mmol), acetohydroxamic acid (0.337g, 4.5mmol) and potassium carbonate (0.828g, 6mmol) were added to H ₂ O (20mL), heated to 80°C in an oil bath and reacted for 6h, TLC It shows that the reaction of the raw materials is complete, the reaction solution is concentrated under reduced pressure, and the water is recrystallized to obtain /> 0.212g, yield 75%.

Example 5:

In the reaction bottle, add (0.209g, 1mmol), acetohydroxamic acid (0.187g, 2.5mmol) and sodium carbonate (0.318g, 3mmol) were added to ethanol (10mL), heated to 80°C in an oil bath and reacted for 6h. TLC showed that the raw materials When the reaction is complete, the reaction solution is concentrated under reduced pressure and subjected to column chromatography to obtain/> 0.162g, yield 90%. White solid, mp182-184℃. ¹ HNMR (DMSO-d ₆ ,400MHz) δ10.49(s,1H),8.18(s,H),4.16(s,3H),3.76(s,3H); ¹³ CNMR (100MHz, DMSO-d ₆ )δ158.6,152.4,149.8,142.0,114.2,54.3,31.7.

The basic principles and main features of the present invention and the advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have other aspects. Various changes and modifications are possible, which fall within the scope of the claimed invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims (5)

1. A method for synthesizing crotonin and its analogs, which is characterized in that it includes the following steps: using 2-nitropurine derivative A as raw material, in the presence of acetohydroxamic acid and M ₂ CO ₃ , in an organic solvent Heating reaction produces crotonin and its analogue B; the reaction equation is expressed as follows: Wherein: M is selected from alkali metal or alkaline earth metal; R ¹ is selected from hydrogen, alkyl, allyl, benzyl, 2-chlorobenzyl, P is selected from hydrogen, acetyl or benzoyl; R ² is selected from hydrogen, chlorine, fluorine, methoxy or amino. 2. The method for synthesizing crotonin and its analogues according to claim 1, characterized in that: M ₂ CO ₃ is selected from Na ₂ CO ₃ , K ₂ CO ₃ or Cs ₂ CO ₃ . 3. The synthesis method of crotonin and its analogs according to claim 1, characterized in that: the molar ratio of 2-nitropurine derivative A, acetohydroxamic acid and M ₂ CO ₃ is 1:1.5-4.5:2 -6. 4. The method for synthesizing crotonin and its analogues according to claim 1, characterized in that the organic solvent is selected from one or more of water, ethanol, methanol, acetonitrile, and dimethyl sulfoxide. 5. The synthesis method of crotonin and its analogs according to claim 1, characterized in that: the reaction temperature is 50-100°C, and the reaction time is 2-24h.