CN114835711B - Method for cracking nucleoside compound - Google Patents
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- CN114835711B CN114835711B CN202210447674.0A CN202210447674A CN114835711B CN 114835711 B CN114835711 B CN 114835711B CN 202210447674 A CN202210447674 A CN 202210447674A CN 114835711 B CN114835711 B CN 114835711B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- 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
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
- B01J27/053—Sulfates
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- 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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- C07H1/06—Separation; Purification
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
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Abstract
The invention discloses a method for cracking nucleoside compounds, which uses acid calcium sulfate as solvent to crack nucleoside compounds to prepare base compounds and D-ribose, and the method for preparing base compounds (adenine, guanine, hypoxanthine) and D-ribose by using acid calcium sulfate to catalyze and crack nucleoside compounds provided by the invention can achieve the yield of adenine, guanine and hypoxanthine of more than 95% and the purity of 99.0%, and can directly obtain D-ribose. The yield of D-ribose can reach 80 percent. The method for preparing adenine, guanine, hypoxanthine and D-ribose in one step has the advantages of simple and convenient operation, low cost and availability of catalyst, low reaction temperature, good product color, good product quality, high yield, low impurity content, low production cost and the like, and has obvious implementation value, social benefit and economic benefit.
Description
Field of the art
The invention relates to a method for cracking nucleoside compounds, in particular to a method for cracking nucleoside compounds by using acid calcium sulfate.
(II) background art
D-ribose is a functional five-carbon monosaccharide. D-ribose is an important component of the genetic material ribonucleic acid (RNA) in organisms and plays a critical role in the metabolic processes of organisms. The D-ribose has certain sweet taste, and can be added into food to increase food flavor. The D-ribose and the derivatives thereof can be used as synthesis intermediates of various nucleoside drugs, such as zalcitabine, stavudine, lamivudine, cytidine and the like.
Adenine is an important intermediate for preparing adefovir and tenofovir, guanine is an important intermediate for synthesizing acyclovir, ganciclovir and other medicaments, and hypoxanthine can be used for preparing 6-chloropurine and other products. They all can be cleaved catalytically from adenosine, guanosine, inosine in acetic anhydride (CN 101701026a, CN101701027 a) to give the corresponding base and tetraacetylribose. Lv Xiuyang et al invented a method for preparing adenine and D-ribose by supercritical water cleavage of adenosine at 170 ℃ (CN 101125854A). The adenine yield was 87% and the purity was 90.2%. The method has the advantages that the reaction temperature is too high, and the product D-ribose is easy to deteriorate at high temperature and cannot be utilized. A method for preparing adenine and D-ribose (CN 111410669A) by cleaving adenosine with a mineral acid as a catalyst has been reported in Smart et al: reacting concentrated sulfuric acid for 48 hours at the temperature of 40 ℃, wherein the adenine yield is 92% and the purity is 98%; hydrochloric acid was reacted at 60℃for 20 hours with an adenine yield of 63.9% and a purity of 91%. The nucleoside cleavage process route has the defects of long reaction time, ribose acetylation product or incapability of directly obtaining D-ribose and the like. The strong acid is directly used as a catalyst, so that the corrosion is strong, and the equipment requirement is increased; and because of its strong acidity, the reactants and products are partially carbonized during the cracking process, so that the purity of the obtained products is reduced and the post-treatment process is increased.
The biological enzyme method for splitting nucleoside has also been reported, but the application is limited due to the problems of high price, high cost, complex subsequent separation process and the like of the enzyme.
Acidic calcium sulfate (Acidic Calcium Sulflate, ACS for short) is an acidic or low pH solution of a novel slightly soluble group iia complex (AGIIS) developed by the company of milrnike, usa (US 25348299, CN 100490684C), and is mainly used for: food production, disinfection, biological decontamination, agricultural applications, medical applications, detoxification of substances, and the like.
Therefore, the development of a novel method for cleavage of nucleosides, which is concise, efficient and mild, has important significance. The invention aims to provide an application of ACS in catalytic cracking of nucleoside compounds.
(III) summary of the invention
Aiming at the defects of the prior art, the invention provides a method for cracking nucleoside compounds, which is simple and convenient to operate, good in product color, excellent in quality, low in impurity content, low in production cost and high in reaction yield.
The technical scheme adopted by the invention is as follows:
the invention provides a method for cracking a nucleoside compound, which is characterized in that a nucleoside compound shown in a formula (I) is cracked in acid calcium sulfate to prepare a base compound shown in a formula (II) and D-ribose shown in a formula (III), and the acid calcium sulfate (Acidic Calcium Sulflate) is called ACS for short.
When the compound of formula (I) is adenosine, R 1 ＝NH 2 ，R 2 =h; when the compound is guanosine, R 1 ＝NH 2 ，R 2 =oh; when the compound is inosine, R 1 ＝OH，R 2 =h; r in formula (II) 1 、R 2 R in the same formula (I) 1 、R 2 。
The Acidic Calcium Sulfate (ACS) is prepared as follows: dripping 98% concentrated sulfuric acid into deionized water, stirring, cooling to 8-12 ℃ in an ice bath, and adding calcium sulfate; then adding the mixture of the calcium compound and deionized water in batches at the temperature of 8-12 ℃, continuously preserving heat and stirring for 3-6 hours (preferably 4 hours), and filtering to obtain filtrate, namely the acid calcium sulfate (ACS for short). The compound of calcium is calcium hydroxide, calcium oxide, calcium carbonate or calcium bicarbonate, more preferably calcium hydroxide; the volume consumption of the concentrated sulfuric acid is 87mL/g based on the mass of the calcium sulfate; the mass ratio of the calcium compound to the concentrated sulfuric acid is 0.175:1; the mass ratio of the total deionized water to the calcium sulfate is 99:1.
Preferably, the method for cracking the nucleoside compound comprises the following steps: (1) Stirring and mixing a nucleoside compound shown in a formula (I) with acid calcium sulfate, heating the mixture to 50-60 ℃ and reacting for 3-6 hours (preferably 55 ℃ and 5 hours), stopping heating, cooling the reaction liquid to room temperature, and filtering to obtain filtrate (brown yellow aqueous solution containing D-ribose) and a filter cake; the mass ratio of the nucleoside compound to the acidic calcium sulfate is 1:1-3 (preferably 1:2);
(2) Adding the filter cake obtained in the step (1) into distilled water, regulating the pH value of the solution to be neutral (preferably pH 7) by using a 10% sodium hydroxide aqueous solution, heating until boiling is completely dissolved, stopping heating, cooling to room temperature, standing to precipitate a solid, carrying out suction filtration, and drying the filter cake to obtain a base compound shown in a formula (II); the volume consumption of distilled water is 15mL/g based on the mass of the nucleoside compound in the step (1);
(3) And (3) regulating the pH value of the filtrate in the step (1) to 2-4 (preferably 3) by using a 10% sodium hydroxide aqueous solution, adding active carbon, decoloring for 30 minutes at 50 ℃, filtering, performing ion exchange purification on the filtrate until the pH value of the effluent is neutral, removing part of water by rotary evaporation under reduced pressure, adding absolute ethyl alcohol, cooling to room temperature, crystallizing, filtering, and vacuum drying a filter cake at 60 ℃ to obtain the D-ribose shown in the formula (III). The addition amount of the active carbon is 1-5% by mass of the filtrate, preferably 3%; the effect of the absolute ethanol is crystallization, preferably in an amount of 5-10 times the volume of the concentrate.
The method for ion exchange purification of the filtrate in the step (3) comprises the following steps: the filtrate is purified by 001X 7H strong acid styrene cation exchange resin (natural flow through), the effluent is purified by D301R macroporous weak base anion exchange resin (natural flow through), and the effluent is collected.
Compared with the prior art, the invention has the beneficial effects that:
the method for preparing the base compound (adenine, guanine, hypoxanthine) and the D-ribose by using the Acid Calcium Sulfate (ACS) to catalytically crack the nucleoside compound can achieve the yield of the adenine, guanine and hypoxanthine of more than 95 percent and the purity of 99.0 percent, and can directly obtain the D-ribose. The yield of D-ribose can reach 80 percent.
The method for preparing adenine, guanine, hypoxanthine and D-ribose in one step has the advantages of simple and convenient operation, low cost and availability of catalyst, low reaction temperature, good product color, good product quality, high yield, low impurity content, low production cost and the like, and has obvious implementation value, social benefit and economic benefit.
(IV) description of the drawings
FIG. 1 is an HPLC chart of the product obtained in example 1.
(fifth) detailed description of the invention
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
EXAMPLE 1 preparation of Acidic Calcium Sulfate (ACS)
435mL of 98% strength concentrated sulfuric acid was added dropwise to a 2 liter flask containing 285mL of deionized water, stirred, cooled to 8℃in an ice bath, 5g of calcium sulfate was added, and the temperature was controlled between 8 and 12 ℃. 140g of calcium hydroxide powder (food grade, purity over 98%) was mixed with 210g of deionized water, stirred, added in portions to the flask, and the addition was complete. The temperature and stirring were continued for 4 hours. Filtering to obtain filtrate, namely Acid Calcium Sulfate (ACS).
EXAMPLE 2ACS cleavage of adenosine
(1) 10g of adenosine and 20g of the acidic calcium sulfate prepared in example 1 were sequentially added into a 100mL three-necked flask, and after stirring and heating the mixture to 55℃and reacting for 5 hours, the sample was taken and the adenosine conversion was 99.5% as measured by high performance liquid chromatography. Stopping heating after the reaction is completed, cooling to room temperature, and filtering to obtain filtrate (brown yellow aqueous solution containing D-ribose) and a filter cake;
(2) Adding the filter cake obtained in the step (1) into a 250mL round-bottom flask, adding 150mL distilled water, regulating the pH value of the solution to be neutral (pH is 7) by using a 10% sodium hydroxide aqueous solution, heating to be boiling, stopping heating after the filter cake is completely dissolved in water, cooling to room temperature, standing, precipitating white solid, carrying out suction filtration, drying the filter cake to obtain the white solid, namely 4.75g of adenine, wherein the yield is 93.9% (calculated by adenosine), and the detected purity is 99.02% (high performance liquid chromatography area normalization method, HPLC for short, see figure 1 and table 1, and peak 1 in table 1 is adenine).
Adenine chromatographic detection conditions: chromatographic column: xbridge TM C18 (250X 4.6mm,5 μm); mobile phase composition ratio: CH (CH) 3 CN:H 2 O＝5:95 (V/V); flow rate: 1.0mL/min; detection wavelength: 254nm; column temperature: 25 ℃.
TABLE 1 high performance liquid chromatography for adenine
(3) And (3) regulating the pH value of the filtrate in the step (1) to 3 by using a 10% sodium hydroxide aqueous solution, adding active carbon (the added amount of the active carbon is 3% by mass of the filtrate), decoloring for 30 minutes at 50 ℃, and filtering to obtain a colorless and transparent D-ribose solution. Naturally and slowly flowing the D-ribose solution through 001X 7H type strong acid styrene cation exchange resin, then naturally and slowly flowing the discharged solution through D301R macroporous weak base anion exchange resin, detecting the discharged solution to be neutral (pH is 7) by using pH test paper, removing part of water by decompression rotary evaporation, adding absolute ethyl alcohol, cooling, crystallizing, filtering, and vacuum drying a filter cake at 60 ℃ to obtain 3.8g of solid which is consistent with the D-ribose standard sample, and has a melting point: 79-81 ℃.
EXAMPLE 3ACS cleavage of guanosine
The adenosine in example 2 was changed to guanosine, and the other reaction conditions were unchanged. 5.07g of guanine was obtained in a yield of 94.9% (calculated as guanosine) and a purity of 99.1% under the same chromatographic conditions as adenine. 3.2g of D-ribose solid was obtained. Melting point: 79-81 ℃.
EXAMPLE 4ACS cleavage of inosine
The adenosine in example 2 was changed to inosine, and the other reaction conditions were unchanged. 4.79g of hypoxanthine is obtained, the yield is 94.5% (calculated as guanosine), the purity is 99.2%, and the chromatographic detection conditions are the same as adenine. 3.3g of D-ribose solid was obtained. Melting point: 79-81 ℃.
Claims (6)
1. A method for cracking a nucleoside compound is characterized in that the method is to crack the nucleoside compound shown in a formula (I) in acid calcium sulfate to prepare a base compound shown in a formula (II) and D-ribose shown in a formula (III);
when the compound of formula (I) is adenosine, R 1 ＝NH 2 ，R 2 =h; when the compound is guanosine, R 1 ＝NH 2 ，R 2 =oh; when the compound is inosine, R 1 ＝OH，R 2 =h; r in formula (II) 1 、R 2 R in the same formula (I) 1 、R 2 ；
The method for cracking the nucleoside compound comprises the following steps: (1) Stirring and mixing a nucleoside compound shown in a formula (I) with acid calcium sulfate, heating the mixture to 50-65 ℃ and reacting for 3-6 hours, stopping heating, cooling the reaction liquid to room temperature, and filtering to obtain filtrate and a filter cake;
(2) Adding the filter cake obtained in the step (1) into distilled water, regulating the pH value of the solution to be neutral by using a sodium hydroxide aqueous solution with the mass concentration of 10%, heating until boiling and dissolving are complete, stopping heating, cooling to room temperature, standing to precipitate solid, carrying out suction filtration, and drying the filter cake to obtain a base compound shown in a formula (II);
(3) Regulating the pH value of the filtrate in the step (1) to 2-4 by using a 10% sodium hydroxide aqueous solution, adding active carbon, decoloring for 30 minutes at 50 ℃, filtering, performing ion exchange purification on the filtrate until the pH value of the effluent is neutral, removing part of water by rotary evaporation under reduced pressure, adding absolute ethyl alcohol, cooling to room temperature, crystallizing, filtering, and vacuum drying a filter cake at 60 ℃ to obtain the D-ribose shown in the formula (III).
2. The method of claim 1, wherein the mass ratio of nucleoside compound to acidic calcium sulfate in step (1) is 1:1-3.
3. The method of claim 1, wherein step (2) adjusts the pH of the solution to 7.
4. The method of claim 1, wherein the activated carbon added in step (3) is 1-5% by mass of the filtrate.
5. The method of claim 1, wherein step (3) adjusts the pH to 3.
6. The method of claim 1, wherein the filtrate of step (3) is subjected to an ion exchange purification process comprising: the filtrate is purified by 001X 7H strong acid styrene cation exchange resin, the effluent is purified by D301R macroporous weak base anion exchange resin, and the effluent is collected.
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| CN106719809A (en) * | 2017-01-17 | 2017-05-31 | 荆门市磊鑫石膏制品有限公司 | A kind of preparation method of acid calcium sulfate |
| CN109575028B (en) * | 2018-12-21 | 2021-06-29 | 新乡医学院 | Method for hydrolyzing adenosine by cation exchange resin catalysis-separation coupling technology |
| CN111961056A (en) * | 2020-08-26 | 2020-11-20 | 通辽德胜生物科技有限公司 | Method for simultaneously synthesizing hypoxanthine and tetraacetyl ribose by utilizing inosine |
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