CN113480539B - Synthetic method of nitric acid catalyzed hypoxanthine derivative - Google Patents
Synthetic method of nitric acid catalyzed hypoxanthine derivative Download PDFInfo
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- CN113480539B CN113480539B CN202110835083.6A CN202110835083A CN113480539B CN 113480539 B CN113480539 B CN 113480539B CN 202110835083 A CN202110835083 A CN 202110835083A CN 113480539 B CN113480539 B CN 113480539B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
- C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- 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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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
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Abstract
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.
Description
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. For example, the 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:
1. and (3) performing nucleophilic substitution reaction on hypoxanthine and a reagent with a leaving group under the action of alkali. The system has the defects of many hypoxanthine reaction sites, lack of selectivity of the reaction, complex by-products and no application value.
2. Under the action of strong alkali, hydroxyl of the 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.
3. The 6-chloropurine derivative is hydrolyzed in an acid solvent or in a strong acid environment, such as acetic acid, hydrochloric acid and the like used as reaction solvents, and the defects of harsh reaction conditions, poor substrate adaptability and the like exist.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a synthetic method of a nitric acid catalyzed hypoxanthine derivative. 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 reaction equation is used to represent the following:
wherein:
R 1 selected from hydrogen, allyl, benzyl, 2-chlorobenzyl,
P is selected from hydrogen, acetyl or benzoyl;
R 2 selected from hydrogen, chlorine or amino.
Further, in the above technical means, the molar ratio of the amount of nitric acid to the 6-chloropurine derivative substance is 0.01 to 0.02.
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.
Further, in the technical scheme, the reaction time is 2-6 h.
Further, in the above 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 shows that the quality of the hypoxanthine derivative is reliable.
The presumed reaction mechanism is:
catalytic amount of H + Binding with purine N7 to form a salt, activating the C-Cl bond, H 2 O as a nucleophile attacks 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 reaction 2 O, the by-product produced is H + . Namely:
the actual acting reagent is H + However, comparative experiments have shown that other acids, such as HCl or H 2 SO 4 The reaction can also take place, but not as well as with HNO 3 The 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 (4 mL) and H 2 O (1 mL), 68% nitric acid (0.13. Mu.L, 0.02 mmol) was added, heated to 80 ℃ for 2h, and saturated NaHCO was added 3 The 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:
6-chloropurine (0.154g, 1mmol) was added to toluene (4 mL) and H in a reaction flask 2 O (1 mL), 68% nitric acid (0.13. Mu.L, 0.02 mmol) was added, heated to 80 ℃ for 2h, and saturated NaHCO was added 3 The 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 (4 mL) and H 2 O (1 mL), 68% nitric acid (0.13. Mu.L, 0.02 mmol) is added, the reaction flask is sealed, the mixture is heated to 80 ℃ for reaction for 4h, and saturated NaHCO is added 3 The 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 (4 mL) and H 2 O (1 mL), 10% nitric acid (11.9. Mu.L, 0.02 mmol) was added, heated to 80 ℃ for 2h, saturated NaHCO was added 3 The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.124g of hypoxanthine in a yield of 91%.
Example 5:
6-chloropurine (0.154g, 1) was charged into a reaction flaskmmol) was added to acetonitrile (4 mL) and H 2 O (1 mL), 37% hydrochloric acid (1.67. Mu.L, 0.02 mmol) was added, the mixture was heated to 80 ℃ to react for 2h, and saturated NaHCO was added 3 The 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 (4 mL) and H 2 O (1 mL), 68% nitric acid (0.13. Mu.L, 0.02 mmol) was added, heated to 80 ℃ for reaction for 2h, and saturated NaHCO was added 3 The solution was neutralized, and the reaction solution 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 ℃. 1 H NMR(400MHz,CDCl 3 ):9.13(brs,1H),9.00(s,1H),8.07(s,1H),7.34-7.27(m,5H),5.43(s,2H)； 13 C NMR(100MHz,CDCl 3 ) 152.8,151.5,148.6,145.2,134.9,133.9,129.2,128.7,127.9,47.2; HRMS press C 12 H 11 N 4 O[M+H] + Calculated value 227.0933 and actual value 227.0935.
Example 7
In a reaction flask, N9-benzyl-6-chloro-2-aminopurine (0.259g, 1mmol) was added to acetonitrile (4 mL) and H 2 O (1 mL), 68% nitric acid (0.13. Mu.L, 0.02 mmol) was added, heated to 80 ℃ for 6h, saturated NaHCO was added 3 The solution was neutralized, and the reaction solution was transferred to a concentration apparatus and concentrated under reduced pressure to obtain 0.214g of N9-benzyl-guanine with a yield of 89%. White solid. m.p.302-304 ℃. 1 H NMR(CDCl 3 ,400MHz):8.71(brs,1H),7.71(s,1H),7.25-7.71(m,5H),5.26(s,2H),5.13(s,2H)； 13 C NMR(CDCl 3 100 MHz) 46.5,127.7,128.4,129.0,135.4,142.3,149.9,160.0; HRMS press C 12 H 11 N 5 NaO[M+Na] + Calculated 264.0861 and actual 264.0863.
The foregoing shows and describes the general principles and features of the present invention, together with the 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.
Claims (5)
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); the molar ratio of the nitric acid to the 6-chloropurine derivative is 0.01-0.02; the solvent is a mixed solvent formed by mixing acetonitrile and water.
2. 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%.
3. The method for synthesizing hypoxanthine derivatives catalyzed by nitric acid according to claim 1, wherein: the reaction time is 2-6 h.
4. The method of synthesizing a nitric acid catalyzed hypoxanthine derivative according to claim 1, wherein: the reaction temperature is 80-120 ℃.
5. The method for synthesizing hypoxanthine derivatives catalyzed by nitric acid according to claim 1, wherein: the volume ratio of water to acetonitrile is 1-10.
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