阅读说明：本技术 一种硝酸催化次黄嘌呤衍生物的合成方法 (Synthetic method of nitric acid catalyzed hypoxanthine derivative ) 是由 夏然 陈磊山 李峰 杨政楠 谢思琪 孙爱丽 于 2021-07-20 设计创作，主要内容包括：本发明公开了一种硝酸催化次黄嘌呤衍生物的合成方法,属于药物化学技术领域。6-氯嘌呤衍生物与溶剂混合,加入催化量硝酸加热反应,中和反应中产生的酸,减压除去溶剂,得到次黄嘌呤衍生物。采用该方法得到次黄嘌呤衍生物,成本低,纯度高,底物适应性好,去除了传统方法中多种杂质,分离提纯方便,表明了次黄嘌呤衍生物品质的可靠性。(The invention discloses a method for synthesizing hypoxanthine derivative under catalysis of nitric acid, and belongs to the technical field of pharmaceutical chemistry. Mixing the 6-chloropurine derivative with a solvent, adding a catalytic amount of nitric acid, heating for reaction, neutralizing acid generated in the reaction, and removing the solvent under reduced pressure to obtain the hypoxanthine derivative. The hypoxanthine derivative obtained by the method has the advantages of low cost, high purity, good substrate adaptability, removal of various impurities in the traditional method, convenient separation and purification, and capability of indicating the reliability of the quality of the hypoxanthine derivative.)

1. A method for synthesizing hypoxanthine derivative catalyzed by nitric acid is characterized in that the hypoxanthine derivative is synthesized by the following reaction equation:

the synthesis method comprises the following steps:

mixing the 6-chloropurine derivative (I) with a solvent, adding a catalytic amount of nitric acid, heating for reaction, neutralizing acid generated in the reaction, and removing the solvent under reduced pressure to obtain a hypoxanthine derivative (II);

wherein: r¹Selected from hydrogen, allyl, benzyl, 2-A chlorobenzyl group, P is selected from hydrogen, acetyl or benzoyl; r²Selected from hydrogen, chlorine or amino.

2. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the molar ratio of the nitric acid to the 6-chloropurine derivative is 0.01-0.02: 1.

3. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the mass concentration of the nitric acid is 1-68%.

4. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the solvent is a mixed solvent formed by mixing one or more of acetonitrile, chloroform, toluene and dichloromethane with water.

5. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the reaction time is 2-6 h.

6. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the reaction temperature is 80-120 ℃.

7. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 5, wherein: the volume ratio of the water to other solvents is 1: 1-10.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthetic method of a hypoxanthine derivative catalyzed by nitric acid.

Background

Hypoxanthine derivatives have a wide range of applications in chemotherapy, biochemistry and chemical synthesis. Such as hypoxanthine nucleoside injection, is clinically used for leucopenia or thrombocytopenia, various acute and chronic liver diseases, pulmonary heart disease and the like. Didanosine, also known as didanosine and didanosine, is an antiviral drug and is clinically used in combination with other antiviral drugs to treat type i HIV infection. In addition, the hypoxanthine derivative is used to connect the substituent group to purine 6 position via carbonyl conversion reaction to obtain medicine with high physiological activity and high curative effect, and is important way of developing antiviral and antitumor medicine. At present, hypoxanthine derivatives are synthesized using three types of systems:

under the action of alkali, hypoxanthine and a reagent with a leaving group undergo nucleophilic substitution reaction. The system has the defects of many hypoxanthine reaction sites, lack of selectivity of reaction, complex by-products and no application value.

Under the action of strong alkali, hydroxyl of the di-6-chloropurine derivative attacks the 6 th site, chloride ions leave, and the hypoxanthine derivative is obtained. The reaction system has the defects of strong alkali system, corrosion on equipment and large amount of acid for neutralization in post-treatment, and generates byproduct salt.

The tri-and 6-chloropurine derivatives are hydrolyzed in an acid solvent or in a strong acid environment, such as acetic acid, hydrochloric acid and the like, and have the defects of harsh reaction conditions, poor substrate adaptability and the like.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a synthetic method of a hypoxanthine derivative catalyzed by nitric acid. Mixing the 6-chloropurine derivative with a solvent, adding a catalytic amount of nitric acid, heating for reaction, neutralizing acid generated in the reaction, and removing the solvent under reduced pressure to obtain the hypoxanthine derivative. The hypoxanthine derivative obtained by the method has the advantages of low cost, high purity, good substrate adaptability, removal of various impurities in the traditional method, convenient separation and purification, and capability of indicating the reliability of the quality of the hypoxanthine derivative.

The technical scheme of the invention is as follows: a synthetic method of nitric acid catalyzed hypoxanthine derivative comprises the following steps:

mixing the 6-chloropurine derivative (I) with a solvent, adding a catalytic amount of nitric acid, heating for reaction, neutralizing acid generated in the reaction, and removing the solvent under reduced pressure to obtain a hypoxanthine derivative (II).

The following equation is used:

wherein:

R¹selected from hydrogen, allyl, benzyl, 2-chlorobenzyl, P is selected from hydrogen, acetyl or benzoyl;

R²selected from hydrogen, chlorine or amino.

Further, in the technical scheme, the molar ratio of the nitric acid to the 6-chloropurine derivative substance is 0.01-0.02: 1.

Further, in the technical scheme, the mass concentration of the nitric acid is 1-68%.

Further, in the above technical solution, the solvent is a mixed solvent formed by mixing one or more of acetonitrile, chloroform, toluene, and dichloromethane with water. Preferably, the volume ratio of the water to other solvents is 1: 1-10.

Further, in the technical scheme, the reaction time is 2-6 h.

Further, in the technical scheme, the reaction temperature is 80-120 ℃.

The 6-chloropurine derivative obtained by the method has low cost, high purity and good substrate adaptability, removes a plurality of impurities in the traditional method, is convenient to separate and purify, and proves the reliability of the quality of the hypoxanthine derivative.

The presumed reaction mechanism is:

catalytic amount of H⁺Binding with purine N7 to form a salt, activating the C-Cl bond, H₂O as a nucleophile to attack the 6-position, Cl^-Leaving, and finally neutralizing to form H⁺Obtaining the hypoxanthine derivative. The reaction by-product is H⁺With the progress of the reaction, H⁺The amount is increased stepwise so that less nitric acid ensures that the reaction is stabilized at a higher rate and thus the reaction is faster.

After the above reaction formulas are combined, H is consumed by the reaction₂O, with H as a by-product⁺. Namely:

the actual acting agent is H⁺However, comparative experiments have shown that other acids, such as HCl or H₂SO₄The reaction can also take place, but not as well as with HNO₃The yield is high.

Detailed Description

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

Example 1:

in a reaction flask, 6-chloropurine (0.154g, 1mmol) was added to acetonitrile (4mL) and H₂O (1mL), 68% nitric acid (0.13. mu.L, 0.02mmol) was added, heated to 80 ℃ for 2h, and saturated NaHCO was added₃The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.125g of hypoxanthine with a yield of 92%.

Example 2:

in a reaction flask, 6-chloropurine (0.154g, 1mmol) was added to toluene (4mL) and H₂To O (1mL), 68% nitric acid (0.13. mu.L, 0.02mmol) was added, and the mixture was heated to 80 ℃ to reactFor 2h, add saturated NaHCO₃The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.116g of hypoxanthine with a yield of 85%.

Example 3:

in a reaction flask, 6-chloropurine (0.154g, 1mmol) was added to chloroform (4mL) and H₂O (1mL), 68% nitric acid (0.13. mu.L, 0.02mmol) is added, the reaction flask is sealed, the mixture is heated to 80 ℃ for reaction for 4h, and saturated NaHCO is added₃The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.103g of hypoxanthine with a yield of 76%.

Example 4:

in a reaction flask, 6-chloropurine (0.154g, 1mmol) was added to acetonitrile (4mL) and H₂O (1mL), 10% nitric acid (11.9. mu.L, 0.02mmol) was added, heated to 80 ℃ for reaction for 2h, and saturated NaHCO was added₃The solution was neutralized, and the reaction mixture was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.124g of hypoxanthine with a yield of 91%.

Example 5:

in a reaction flask, 6-chloropurine (0.154g, 1mmol) was added to acetonitrile (4mL) and H₂O (1mL), 37% hydrochloric acid (1.67. mu.L, 0.02mmol) was added, the mixture was heated to 80 ℃ to react for 2h, and saturated NaHCO was added₃The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.076g of hypoxanthine with a yield of 56%.

Example 6

In a reaction flask, N9-benzyl-6-chloropurine (0.244g, 1mmol) was added to acetonitrile (4mL) and H₂O (1mL), 68% nitric acid (0.13. mu.L, 0.02mmol) was added, heated to 80 ℃ for reaction for 2h, and saturated NaHCO was added₃The solution was neutralized, and the reaction mixture was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.210g of N9-benzyl-hypoxanthine in a yield of 93%. A white solid. m.p.254-256 ℃.¹H NMR(400MHz,CDCl₃):9.13(brs,1H),9.00(s,1H),8.07(s,1H),7.34-7.27(m,5H),5.43(s,2H)；¹³C NMR(100MHz,CDCl₃) 152.8,151.5,148.6,145.2,134.9,133.9,129.2,128.7,127.9, 47.2; HRMS press C₁₂H₁₁N₄O[M+H]⁺Calculated value 227.0933, actualValue 227.0935.

Example 7

In a reaction flask, N9-benzyl-6-chloro-2-aminopurine (0.259g, 1mmol) was added to acetonitrile (4mL) and H₂O (1mL), 68% nitric acid (0.13. mu.L, 0.02mmol) was added, heated to 80 ℃ for reaction for 6h, and saturated NaHCO was added₃The solution was neutralized, and the reaction mixture was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.214g of N9-benzyl-guanine in 89% yield. A white solid. m.p.302-304 ℃.¹H NMR(CDCl₃,400MHz):8.71(brs,1H),7.71(s,1H),7.25-7.71(m,5H),5.26(s,2H),5.13(s,2H)；¹³C NMR(CDCl₃100MHz) 46.5,127.7,128.4,129.0,135.4,142.3,149.9,160.0; HRMS press C₁₂H₁₁N₅NaO[M+Na]⁺Calculated 264.0861, actual 264.0863.

The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.