CN115109104B - Synthesis method of 3' -deoxyadenosine - Google Patents

Synthesis method of 3' -deoxyadenosine Download PDF

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CN115109104B
CN115109104B CN202210978752.XA CN202210978752A CN115109104B CN 115109104 B CN115109104 B CN 115109104B CN 202210978752 A CN202210978752 A CN 202210978752A CN 115109104 B CN115109104 B CN 115109104B
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梁兴勇
刘安林
王磊
邱中豪
许致宁
丁新刚
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Sichuan University of Science and Engineering
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a method for synthesizing 3' -deoxyadenosine, which is based on the characteristic that benzoyl can directionally migrate in an acidic environment, has mild reaction conditions in the whole process and simple treatment, and the required medicines are cheap and easy to obtain, the intermediate products are synthesized by a one-pot method, few intermediate products are separated and purified by a silica gel column chromatography, the operation time of subsequent experimental treatment and separation and purification is saved, and the time of the whole reaction process is greatly shortened. And the final yield is ensured as multiple purifications are not needed, the total yield can reach 30%, and the product can reach the level of ten grams at one time.

Description

Synthesis method of 3' -deoxyadenosine
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 3' -deoxyadenosine.
Background
The following method is generally used in the prior art to synthesize cordycepin (3-deoxyadenosine, compound 13):
the method has the following defects:
a) After each step of experimental reaction is finished, the separation and purification are carried out by utilizing silica gel column chromatography, so that a great amount of time is wasted, the waste of experimental products is caused, and the total yield is never high;
b) The preparation reaction of the compound 4 involves selective removal of 1,2:5, 6-di-O-isopropylidene and 1,2:3, 5-di-O-isopropylidene of the compound 7, the dosage of experimental medicines and the reaction need to be precisely mastered, the reaction is still immature, and the separation and purification of the compound 4 can be complicated and further influence the experimental yield; the periodic acid and sodium borohydride belong to easy-to-poison and easy-to-explosion articles, and are troublesome in the process of purchasing medicines;
c) In the preparation process of the compound 8, primary alcohol needs to be selectively protected, side reaction products are generated in the process, and a great amount of time is occupied in separation and purification due to the small polarity difference between the byproducts and the main products.
In summary, in the existing process of preparing 3-deoxyribose, there are problems of selective protection and selective removal of the protecting functional group, difficulty in purchasing experimental medicines, and the need of silica gel column chromatography separation and purification of all intermediate products, which results in longer time of the whole production process and lower total experimental yield.
Disclosure of Invention
Aiming at the prior art, the invention provides a synthesis method of 3' -deoxyadenosine, which aims to solve the problems of long time consumption and low yield of the existing cordycepin synthesis method.
In order to achieve the above purpose, the technical scheme adopted by the invention is that the synthesis method of the 3' -deoxyadenosine is provided, and comprises the following steps:
s1: methylation modification is carried out on D-xylose to obtain a compound shown as a formula (I);
s2: carrying out dehydroxylation treatment on the compound shown in the formula (I) to obtain a compound shown in the formula (II);
s3: dissolving a compound shown as a formula (II) in organic acid, adding acetic anhydride and concentrated sulfuric acid, reacting for 0.5-2 h in ice bath, and separating and purifying a product;
s4: dissolving N6-benzoyl adenine in acetonitrile, then adding N, O-bis (trimethylsilyl) acetamide in an inert gas atmosphere, and stirring until the reaction system is clear; then adding the product after separation and purification in S3, then dripping the trifluoromethane sulfonate, stirring and reacting for 10-20 min at room temperature after dripping, then heating the system to 75-85 ℃, preserving heat and reacting for 1-2 h, then separating and purifying, then mixing the purified substance with methanol, introducing ammonia gas, and reacting for 2-4 h at 50-60 ℃ to obtain the final product.
On the basis of the technical scheme, the invention can be improved as follows.
Further, methylation modification of D-xylose includes the steps of:
s11: dissolving D-xylose in an organic solvent, adding acetyl chloride under ice bath, reacting for 35-45 min at room temperature, concentrating, and purifying to obtain a product I;
s12: dissolving the first product in an organic solvent, adding triethylene diamine, reacting for 10-20 min at room temperature, adding triphenylchloromethane, and continuously stirring for reacting for 1.5-2.5 h; then adding pyridine into the reaction system under ice bath condition, stirring and reacting for 0.5h, adding benzoyl chloride, heating to 40 ℃, continuously stirring and reacting for 2h, extracting, concentrating to obtain a product II;
s13: dissolving the product II in a mixed solvent of dichloromethane and methanol, adding p-toluenesulfonic acid monohydrate, stirring at room temperature for reaction for 8-12 h, and then extracting, concentrating and purifying to finish methylation modification of D-xylose.
Further, the mol ratio of the product I to the triethylene diamine, the triphenylchloromethane, the pyridine and the benzoyl chloride is 0.2-0.25:0.45-0.5:0.45-0.5:2.9-2.95:0.95-1.
Further, the dehydroxylation treatment of the compound of formula (I) comprises the steps of:
s21: dissolving a compound shown in a formula (I) and carbon disulfide in an organic solvent, adding sodium hydride, stirring and reacting for 45-55 min, then adding methyl iodide, continuously stirring and reacting for 1h, and then concentrating and purifying to obtain a product III;
s22: co-dissolving azodiisobutyronitrile and tributyltin hydride in an organic solvent to obtain a mixed solution; dissolving the product III in an organic solvent, refluxing for 0.5h at 100-120 ℃, then dripping the mixed solution into a reaction system, continuously stirring for reaction for 1-3 h, concentrating and purifying to finish the dehydroxylation treatment of the compound shown in the formula (I).
Further, the molar ratio of the compound shown in the formula (I) to the carbon disulfide, the sodium hydride and the methyl iodide is 0.05-0.1:0.35-0.45:0.1-0.2:0.1-0.2.
Further, the mol ratio of the product tri to the azodiisobutyronitrile and the tributyltin hydride is 0.05-0.1:0.01-0.05:0.05-0.1.
Further, the molar ratio of the compound shown in the formula (II) to acetyl bromide and N6-benzoyl adenine is 0.005-0.01:0.001-0.005:0.01-0.015.
The beneficial effects of the invention are as follows: the 3' -deoxyadenosine (cordycepin) synthesis method is carried out based on the characteristic that benzoyl can directionally migrate in an acidic environment, the reaction condition of the whole process is mild, the treatment is simple, the required medicines are cheap and easy to obtain, the intermediate products are mostly synthesized by adopting a one-pot method, few intermediate products are separated and purified by a silica gel column chromatography, the operation time of subsequent experimental treatment and separation and purification is saved, and the time of the whole reaction process is greatly shortened. And the final yield is ensured as multiple purifications are not needed, the total yield can reach 30%, and the product can reach the level of ten grams at one time.
Detailed Description
The following describes the present invention in detail with reference to examples.
Example 1
A preparation method of 3' -deoxyadenosine (cordycepin), comprising the following steps:
(1) Synthesis of methyl-2, 3-di-O-benzoyl-5-triphenylmethyl- α/β -D-ribofuranose (Compound 1)
The reaction equation is as follows:
a) D-xylose (60.00 g,0.40 mol) was weighed into a dry round bottom flask, methanol (500 mL) was added, acetyl chloride (32 mL) was slowly added dropwise under ice bath conditions, and the ice bath conditions were removed for reaction at room temperature for 40min. TLC [ V (MeOH): V (EA) =1:5 ] the reaction was complete. Excess organic acid in the system was neutralized by adding dry sodium bicarbonate powder, filtered to remove most of the salt, concentrated under vacuum, and mixed solution of 2500mL [ V (MeOH): V (EA) =1:4 ] was dissolved, and then filtered twice (desalting) with a filter funnel with celite (3 cm) and concentrated under vacuum to give colorless syrup.
b) After the product (40.00 g,0.24 mol) obtained in the step a) was dissolved in acetonitrile (1330 mL), triethylenediamine (54.70 g,0.49 mol) was added thereto and stirred at room temperature for 15 minutes, and then triphenylchloromethane (135.90 g,0.49 mol) was added thereto and stirred at room temperature for 2 hours.
c) Then, the reaction system was transferred to ice bath conditions and pyridine (235 mL,2.92 mol) was added thereto and stirred for 0.5 hours, and then benzoyl chloride (113 mL,0.98 mol) was slowly added dropwise thereto, and the mixture was stirred at 40℃for 2 hours. And (3) treatment: after concentrating the system in vacuo, methylene chloride (1000 mL) and water (1000 mL) were added and mixed and stirred, and the mixture was added to a separatory funnel and divided into three layers, from top to bottom, respectively, a water layer, a white benzoic acid layer, and a methylene chloride layer after dissolution of the product. After the lower organic phase was taken, the aqueous layer was washed twice with dichloromethane (2 x 500 ml), and the organic phases were combined, dried over saturated brine and anhydrous sodium sulfate, and concentrated in vacuo to give compound 1 (140.80 g, 91%).
(2) Synthesis of methyl-2, 5-di-O-benzoyl-alpha/beta-D-ribofuranose (Compound 2)
The reaction equation is as follows:
compound 1 (120.00 g,0.195 mol) was dissolved in methylene chloride (975 mL) and methanol (1.95 mL) and stirred for 10min, after which p-toluenesulfonic acid monohydrate (74.10 g,0.39 mol) was added and stirred at room temperature for 10h. And (3) treatment: the anhydrous sodium carbonate powder after grinding is added to neutralize the redundant organic acid of the system, and a large amount of bubbles can appear in the system and change from yellow liquid to colorless liquid in the process. When the pH value of the reaction system is regulated to be close to neutral, purified water is added for extraction, an organic phase is sequentially washed by saturated sodium carbonate solution and saturated sodium chloride solution, then vacuum-concentrated and collected, and then separated and purified by a silica gel chromatographic column, and the polarity of eluent is as follows: [ V (PE): V (EA) =6:1 ], to give colorless syrup-like compound 2 (34.80 g, 48%).
The data of the detection spectrum of the compound 2 are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.02-7.88(m,6H),7.47(q,J＝8.4,8.0Hz,3H),7.38-7.29(m,6H),7.18(d,J＝6.4Hz,1H),5.22(s,1H),5.17(s,1H),5.02(s,1H),4.72-4.56(m,3H),4.46(ddd,J＝23.6,11.6,6.4Hz,2H),4.34(d,J＝4.4Hz,1H),3.37(s,3H),3.32(s,1H).13C NMR(100MHz,CDCl3)δ166.74,166.65,166.5,165.5,133.6,133.4,133.2,133.1,129.96,129.90,129.8,129.7,129.0,128.5,128.43,128.37,127.95,127.86,127.2,106.7,100.9,81.76,81.2,81.1,75.9,74.5,73.9,64.2,63.3,60.4,55.7,55.5,53.4.
(3) Synthesis of methyl-2, 5-di-O-benzoyl-3-deoxy- α/β -D-ribofuranose Synthesis (Compound 3)
The reaction equation is as follows:
a) Compound 2 (28.72 g,0.08 mmol) and carbon disulphide (24 mL,0.40 mol) were dissolved in anhydrous tetrahydrofuran (195 mL) and sodium hydride (3.70 g,0.15 mol) was slowly added, and methyl iodide (10 mL,0.15 mol) was added dropwise after stirring for 50min and stirring was completed for 1h. And (3) treatment: dropwise adding glacial acetic acid to neutralize the pH value of the reaction system, concentrating in vacuum, collecting, removing salt and insoluble impurities by using a silica gel short chromatographic column, and eluting with the polarity of the eluent: [ V (PE): V (EA) =10:1 ], a yellow syrup-like compound was obtained.
b) The product (34.90 g,0.08 mol) obtained in the step a) is dissolved by anhydrous toluene (400 mL), and then the mixture is placed at 110 ℃ for condensation reflux for 0.5h, and the anhydrous toluene (50 mL) is used for dissolving azodiisobutyronitrile (3.10 g,0.02 mmol) and tributyltin hydride (24 mL,0.09 mol) and then the mixture is dripped into a reaction system for reaction for 2h. And (3) treatment: vacuum concentrating the reaction system, collecting, removing salt and insoluble impurities by using a silica gel short chromatographic column, and eluting the polarity of the eluent: [ V (PE): V (EA) =100:1→V (PE): V (EA) =10:1 ]. Colorless syrup compound 3 (25.8 g, 94%) was obtained.
The data of the detection spectrum of the compound 3 are as follows: 1 H NMR(600MHz,CDCl 3 )δ8.12-8.02(m,5H),7.60-7.56(m,2H),7.48-7.43(m,5H),5.41(d,J＝4.2Hz,1H),5.08(s,1H),4.78(m,1H),4.51(dd,J＝11.4,4.2Hz,1H),4.36(dd,J＝11.4,6.0Hz,1H),3.39(s,3H),2.37-2.27(m,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.4,165.7,133.3,133.1,129.9,129.73,129.71,128.44,128.39,107.0,78.2,77.5,67.2,54.7,32.0.
(4) Synthesis of 3-deoxy-N6-benzoyl-9- (2 ',5' -di-O-benzoyl-3 ' -deoxy-beta-D-ribose) adenosine (Compound 4)
The reaction equation is as follows:
a) Compound 3 (23.0 g,0.06 mmol) was dissolved in a round bottom flask at room temperature using glacial acetic acid (190 mL), stirred for 10min, then acetic anhydride (26 mL,0.28 mol) was added and transferred to an ice bath environment, concentrated sulfuric acid (13 mL,0.25 mol) was slowly added dropwise, and stirring was stopped for 1h. After the completion of the reaction, a 500mL beaker was prepared, 100mL of a saturated sodium carbonate ice water solution was added, and an ethyl acetate solution having a volume of 1/3 of the saturated sodium carbonate ice water solution was added to the upper layer, the reaction system was diluted with 100mL of ethyl acetate, then slowly dropped into the beaker, stirred to neutralize the pH, then the organic layer was separated and taken out, the aqueous layer was washed twice with ethyl acetate, then dried with anhydrous sodium sulfate, and concentrated under reduced pressure. A yellow syrup-like product was obtained.
b) N6-benzoyladenine (11.5 g,0.05 mol) was dissolved in freshly distilled anhydrous acetonitrile (200 mL), followed by the introduction of inert gas (nitrogen) for 10min, and then N, O-bis (trimethylsilyl) acetamide (BSA) (30.0 g,0.15 mol) was added, and stirred until the reaction system was completely clear, and the reaction was continued for 10min; then, the yellow syrup-like product (12.0 g, 0.04 mol) prepared in the above a) was added, and then, trimethylsilyl triflate (49 g,0.22 mol) was slowly added dropwise, and the reaction was stirred at room temperature for 15min after the addition, then, the system was warmed to 80 ℃ for 1h, tlc detection (VPE: vea=5:4) was completed, and then, the reaction was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent polarity: VPE: vea=10:1) to give product 4 (14.4 g, 82%).
The data of the detection spectrum of the compound 4 are as follows: 1 H NMR(600MHz,CDCl 3 )δ8.75(s,1H),8.20(s,1H),8.07(dd,J＝7.8,1.2Hz,2H),8.02(dd,J＝8.4,1.2Hz,2H),7.99(dd,J＝8.4,1.2Hz,2H),7.74-7.35(m,10H),6.28(d,J＝1.2Hz,1H),6.13(d,J＝6.0Hz,1H),4.90(m,1H),4.75(dd,J＝12.0,3.0Hz,1H),4.59(dd,J＝12.0,5.4Hz,1H),3.01(ddd,J＝14.4,10.2,6.0Hz,1H),2.53-2.48(m,1H)； 13 C NMR(150MHz,CDCl 3 )δ166.3,165.8,152.7,151.1,149.7,142.1,133.8,133.7,133.4,132.8,129.8,129.6,129.4,128.9,128.8,128.6,128.5,127.9,123.6,90.6,79.2,78.4,64.9,33.6.
(5) Synthetic cordycepin (Compound 5)
The reaction equation is as follows:
180mL of anhydrous methanol and compound 4 (3.19 g,0.01 mol) were sequentially added to a high-pressure reaction flask, and the mixture was dissolved by stirring; after introducing ammonia gas, the reaction was carried out at 55℃for 3 hours. Slowly cooling to room temperature, vacuum concentrating at a temperature less than 35 deg.C, adding 100mL of water and 100mL of dichloromethane, extracting, freezing the water phase, and lyophilizing to obtain light yellow solid cordycepin (compound 5,2.05g, 85.1%).
The detection spectrum data of cordycepin (compound 5) is: 1 H NMR(400MHz,DMSO-d6)δ:8.36(s,1H),8.15(s,1H),7.30(s,2H),5.87(d,J＝6.0Hz,1H),5.69(d,J＝5.6Hz,1H),5.19-5.17(m,1H),4.57(s,1H),4.34(s,1H),3.69-3.66(m,1H),3.51-3.46(m,1H),2.27-2.20(m,2H),1.93-1.90(m,2H)； 13 c NMR (100 MHz, DMSO-d 6) delta 156.1,152.2,149.0,139.1,119.1,90.8,80.8,74.7,62.7,34.4. Although the present invention is described in detail with reference to the examplesThe description is in detail but should not be construed as limiting the scope of protection of this patent. Various modifications and variations which may be made by those skilled in the art without the creative effort are within the scope of the patent described in the claims.

Claims (5)

1. The synthesis method of the 3' -deoxyadenosine is characterized by comprising the following steps of:
s1: methylation modification is carried out on D-xylose to obtain a compound shown as a formula (I);
；
methylation modification of D-xylose includes the following steps:
s11: dissolving D-xylose in an organic solvent, adding acetyl chloride under ice bath, reacting for 35-45 min at room temperature, concentrating, and purifying to obtain a product I;
s12: dissolving the first product in an organic solvent, adding triethylene diamine, reacting for 10-20 min at room temperature, adding triphenylchloromethane, and continuously stirring and reacting for 1.5-2.5 h; then adding pyridine into the reaction system under ice bath condition, stirring to react 0.5-h, adding benzoyl chloride, heating to 40 ℃, continuing stirring to react 2-h, extracting, concentrating to obtain a product II;
s13: dissolving a product II in a mixed solvent of dichloromethane and methanol, adding p-toluenesulfonic acid monohydrate, stirring at room temperature for reaction for 8-12 hours, and then extracting, concentrating and purifying to finish methylation modification of D-xylose;
s2: carrying out dehydroxylation treatment on the compound shown in the formula (I) to obtain a compound shown in the formula (II);
；
the dehydroxylation treatment of the compound of formula (I) comprises the steps of:
s21: dissolving a compound shown in a formula (I) and carbon disulfide in an organic solvent, adding sodium hydride, stirring and reacting for 45-55 min, then adding methyl iodide, continuously stirring and reacting for 1-h, and then concentrating and purifying to obtain a product III;
s22: co-dissolving azodiisobutyronitrile and tributyltin hydride in an organic solvent to obtain a mixed solution; dissolving the product III in an organic solvent, refluxing at 100-120 ℃ for 0.5-h, then dripping the mixed solution into a reaction system, continuously stirring for reacting for 1-3 hours, concentrating and purifying to finish the dehydroxylation treatment of the compound shown in the formula (I);
s3: dissolving a compound shown as a formula (II) in organic acid, adding acetic anhydride and concentrated sulfuric acid, reacting for 0.5-2 h in an ice bath, and then separating and purifying a product;
s4: dissolving N6-benzoyl adenine in acetonitrile, then adding N, O-bis (trimethylsilyl) acetamide in an inert gas atmosphere, and stirring until the reaction system is clear; and then adding the product after separation and purification in the step S3, dropwise adding trimethyl silicone triflate, stirring at room temperature after the dropwise adding, reacting for 10-20 min, heating the system to 75-85 ℃, reacting for 1-2 h at a constant temperature, separating and purifying, mixing the purified substance with methanol, introducing ammonia gas, and reacting for 2-4 h at 50-60 ℃ to obtain the product.
2. The method for synthesizing 3' -deoxyadenosine according to claim 1, wherein: the molar ratio of the product I to the triethylene diamine, the triphenylchloromethane, the pyridine and the benzoyl chloride is 0.2-0.25:0.45-0.5:0.45-0.5:2.9-2.95:0.95-1.
3. The method for synthesizing 3' -deoxyadenosine according to claim 1, wherein: the molar ratio of the compound shown in the formula (I) to the carbon disulfide, the sodium hydride and the methyl iodide is 0.05-0.1:0.35-0.45:0.1-0.2:0.1-0.2.
4. The method for synthesizing 3' -deoxyadenosine according to claim 1, wherein: the molar ratio of the product tri to the azodiisobutyronitrile to the tributyltin hydride is 0.05-0.1:0.01-0.05:0.05-0.1.
5. The method for synthesizing 3' -deoxyadenosine according to claim 1, wherein: the molar ratio of the compound shown in the formula (II) to acetyl bromide and N6-benzoyl adenine is 0.005-0.01:0.001-0.005:0.01-0.015.
CN202210978752.XA 2022-08-15 2022-08-15 Synthesis method of 3' -deoxyadenosine Active CN115109104B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588840A (en) * 2013-11-20 2014-02-19 武汉佰福泰制药有限公司 Method for synthetizing cordycepin
CN106478755A (en) * 2015-08-25 2017-03-08 苏州佰福泰生物技术有限公司 A kind of method that use wood sugar efficiently synthesizes cordycepin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588840A (en) * 2013-11-20 2014-02-19 武汉佰福泰制药有限公司 Method for synthetizing cordycepin
CN106478755A (en) * 2015-08-25 2017-03-08 苏州佰福泰生物技术有限公司 A kind of method that use wood sugar efficiently synthesizes cordycepin

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Title
Synthesis and Antifungal Activity of 3′-Deoxyribonucleosides;Anil Kumar ，等;《Nucleosides and Nucleotides》;第13卷(第5期);1049-1058 *
虫草素的全合成研究;李启欢，等;《有机化学》;第33卷;第1340-1344页 *
虫草素的合成研究进展;汪晶，等;《化学通报》;第84卷(第8期);第787-792页 *

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