A method for synthesizing crotonin and its analogs

Abstract

The present invention discloses a method for synthesizing crotonin and its analogs, belonging to the field of pharmaceutical chemistry. Crotonin and its analogs are obtained by heating a 2-nitropurine derivative as a raw material in the presence of acetohydroxamic acid and an alkali metal / alkaline earth metal carbonate in an organic solvent. The method for obtaining crotonin and its analogs has the advantages of low cost, simple operation, mild reaction conditions, and good substrate adaptability, providing a concise route for the preparation of such compounds.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for synthesizing crotonin and its analogs. Background Art

[0002] Crotonoside (also known as isoguanosine, CAS 1818-71-9) is a natural nucleoside compound first isolated from the seeds of the traditional Chinese medicine Croton tiglium. Croton tiglium seeds are the dried, mature fruits of the plant Croton tiglium L., a member of the Euphorbiaceae family, and are a traditional Chinese medicinal material. Crotonoside is a key active ingredient in Croton tiglium. Research has shown that crotonoside exhibits a variety of physiological activities, including enhancing intestinal motility, lowering blood pressure, and stimulating AMP (adenosine monophosphate) accumulation in the brain. It has significant inhibitory effects on S180 ascites tumors and Ehrlich solid tumors in mice, exhibits selective post-inhibitory effects in acute myeloid leukemia (AML) cells by inhibiting FLT3 and HDAC3 / 6, and exhibits antiarrhythmic effects by regulating sodium-calcium channels in rabbit ventricular myocytes. Furthermore, crotonoside is an isomer of guanosine, a structural fragment of RNA in vivo. It can be incorporated into RNA fragments as a guanosine analog and promote gene expression, making it an important biochemical research target. Its 2-carbonyl purine derivative, similar to crotonin, also has good physiological activity.

[0003] At present, in addition to isolating crotonin from natural resources, there are three main chemical synthesis routes:

[0004] 1) 2-substituted (I, Cl, or NH2) adenosine can be obtained through photohydrolysis or diazotization, but the selectivity is poor and the yield is very low. Alternatively, 2-hydroxy-6-thio substituted purine nucleosides can be obtained through aminolysis, but the raw material synthesis is difficult.

[0005] 2) Isoguanine is protected by silyl ether and condensed with group-protected ribose under TMSOTf or SnCl4 catalysis, and then the protecting group is removed to obtain it. The disadvantages are that there are many steps, low yield, and the synthesis of isoguanine is also very difficult;

[0006] 3) Aminoimidazolecarboxamide nucleoside is used to synthesize isoguanosine through cyclization biomimetic synthesis, but the yield is very low and it has no synthetic value.

[0007] The above three reaction routes limit the scale-up of crotonin synthesis. Synthesizing crotonin from inexpensive and readily available raw materials can avoid the tedious steps of separation and extraction from natural products and address the low yields associated with existing chemical synthesis methods. This is of great significance for expanding the source of crotonin and, therefore, its application range. Summary of the Invention

[0008] To address the deficiencies of the prior art, the present invention provides a method for obtaining crotonin and its analogs using 2-nitropurine derivatives as raw materials, in the presence of acetohydroxamic acid and an alkali metal or alkaline earth metal carbonate, M2CO3, and a heating reaction in an organic solvent. 2-Nitropurine derivatives can be synthesized from inexpensive purine nucleosides using a tetrabutylammonium nitrate / trifluoromethanesulfonic anhydride system, a method that has been widely reported and is mature and convenient. This method provides crotonin and its analogs with low cost, ease of operation, mild reaction conditions, and good substrate adaptability, demonstrating the superiority and simplicity of this synthetic method.

[0009] The technical solution of the present invention is: a method for synthesizing crotonin and its analogs, which is synthesized by the following reaction equation:

[0010]

[0011] Wherein: M is selected from alkali metals or alkaline earth metals; R 1 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.

[0012] The method comprises the following steps: using 2-nitropurine derivative A as a raw material, heating in an organic solvent in the presence of acetohydroxamic acid and M2CO3 to react, thereby obtaining crotonin and its analogue B;

[0013] Furthermore, in the above technical solution, M2CO3 is selected from Na2CO3, K2CO3 or Cs2CO3.

[0014] Furthermore, in the above technical solution, the molar ratio of 2-nitropurine derivative A, acetohydroxamic acid and M2CO3 is 1:1.5~4.5:2~6.

[0015] Furthermore, in the above technical solution, the organic solvent is selected from one or more of water, ethanol, methanol, acetonitrile, and dimethyl sulfoxide.

[0016] Furthermore, in the above technical solution, the reaction temperature is 50-100° C., and the reaction time is 2 to 24 hours.

[0017] Furthermore, in the above technical solution, the product For the convenience of structural description, structure B is used in this application.

[0018] Crotonoside and its analogs are obtained by adopting this method, which has low cost, simple operation, mild reaction conditions and good substrate adaptability, indicating the superiority and simplicity of this synthetic method.

[0019] According to the basic principles of chemical reactions, the conversion of a 2-nitro group to a 2-hydroxyl group is a hydrolysis reaction. To increase the nucleophilicity of the hydroxyl group, a high concentration of a strong base such as sodium hydroxide or tetrabutylammonium hydroxide is required. Acetohydroxamic acid reacts with weak bases such as potassium carbonate. The oxygen atom has good nucleophilicity and reacts with the 2-nitro group to produce intermediate III. However, III is unstable and randomly rearranges to yield the target product II. This is represented by the following equation:

[0020]

[0021] During the reaction, the acetylamino group increases the nucleophilicity of the oxygen atom, compensating for the deficiency of strong bases such as high concentrations of sodium hydroxide and tetrabutylammonium hydroxide. DETAILED DESCRIPTION

[0022] The present invention is described in detail below with reference to the embodiments.

[0023] Example 1:

[0024] In the reaction flask, add (0.312 g, 1 mmol), acetohydroxamic acid (0.15 g, 2 mmol) and potassium carbonate (0.345 g, 2.5 mmol) were added to acetonitrile (10 mL) and heated to 80 ° C in an oil bath for 4 h. TLC showed that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure and recrystallized from water to obtain 0.251 g, yield 89%. White solid, mp 238-240°C. 1 HNMR(DMSO-d6,400MHz)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-d6,100MHz)δ160.2,156.0,151.6,137.1,112.4,84.1,83.3,75.6,61.1.

[0025] Example 2: 1 mmol As raw materials, changing other reaction conditions, the reaction results are as follows:

[0026]

[0027] Example 3:

[0028] In the reaction flask, add (0.255 g, 1 mmol), acetohydroxamic acid (0.187 g, 2.5 mmol) and sodium carbonate (0.318 g, 3 mmol) were added to acetonitrile (10 mL) and heated to 80 ° C in an oil bath for 6 h. TLC showed that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure and recrystallized from ethanol to obtain 0.21 g, yield 93%. White solid, mp 168-170°C. 1 HNMR(DMSO-d6,400MHz)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-d6)δ152.2,151.4,150.8,142.6,134.2,131.1,129.1,128.9,127.4,47.8.

[0029] Example 4:

[0030] In the reaction flask, add (0.312 g, 1 mmol), acetohydroxamic acid (0.337 g, 4.5 mmol) and potassium carbonate (0.828 g, 6 mmol) were added to H2O (20 mL) and heated to 80°C in an oil bath for 6 h. TLC showed that the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure and recrystallized from water to obtain 0.212 g, yield 75%.

[0031] Example 5:

[0032] In the reaction flask, add (0.209 g, 1 mmol), acetohydroxamic acid (0.187 g, 2.5 mmol) and sodium carbonate (0.318 g, 3 mmol) were added to ethanol (10 mL) and heated to 80 ° C in an oil bath for 6 h. TLC showed that the raw materials were completely reacted. The reaction solution was concentrated under reduced pressure and column chromatography was obtained. 0.162 g, yield 90%. White solid, mp 182-184°C. 1 HNMR(DMSO-d6,400MHz)δ10.49(s,1H),8.18(s,H),4.16(s,3H),3.76(s,3H); 13 CNMR(100MHz,DMSO-d6)δ158.6,152.4,149.8,142.0,114.2,54.3,31.7.

[0033] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing crotonin and its analogs, characterized in that: The following steps are involved: Using 2-nitropurine derivative A as raw material, in the presence of acetohydroxamic acid and M2CO3, heating reaction in an organic solvent to obtain crotonin and its analog B; the reaction equation is as follows: Wherein: M2CO3 is selected from Na2CO3, K2CO3 or Cs2CO3; R 1 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 crotonoside and its analogs according to claim 1, characterized in that: The molar ratio of 2-nitropurine derivative A, acetohydroxamic acid and M2CO3 is 1:1.5-4.5:2-6.

3. The method for synthesizing crotonoside and its analogs according to claim 1, characterized in that: The organic solvent is selected from one or more of water, ethanol, methanol, acetonitrile and dimethyl sulfoxide.

4. The method for synthesizing crotonoside and its analogs according to claim 1, characterized in that: The reaction temperature is 50-100°C and the reaction time is 2-24h.

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