CN115651047B - Process for preparing 2' -O-methyl nucleosides - Google Patents
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Abstract
The invention relates to a preparation method of 2' -O-methyl nucleoside, which takes alkoxide as a hydrogen-withdrawing reagent, and the nucleoside and a methylation reagent CH are reacted under the action of the hydrogen-withdrawing reagent 3 I, reacting to generate 2' -O-methyl nucleoside. The alkoxide is used as a hydrogen extraction reagent, so that the use and storage processes are safer, the reaction selectivity and the reaction depth are ensured, the reaction danger is reduced, and the safety of personnel environment is facilitated.
Description
Technical Field
The invention relates to the field of nucleoside chemical synthesis, in particular to 2' -O-methyl adenosine synthesis.
Background
Nucleic acid drugs are artificially synthesized DNA or RNA fragments with disease treatment functions, including antisense nucleic acids, ribozymes, small interfering RNAs, aptamers and the like, which are widely applied to treatment of gene-defective diseases and cancers. Because of the specific combination with DNA or RNA, the polypeptide has wider application prospect. However, the nucleic acid drug as a foreign oligonucleotide is easily and rapidly decomposed by host nuclease and is not easily absorbed by target organs or cells. Thus, there is a need for nuclease-resistant modified oligonucleotides to improve delivery and stability of nucleic acid drugs. The 2' -O-methyl nucleoside has good hybridization property, higher thermal stability and ribozyme resistance, and is beneficial to the transmission and combination of the artificial oligonucleotide in vivo. Since 2 '-O-methyl-guanosine can be used for synthesizing an antiretroviral cap analogue with excellent translation properties, 2-amino-2' -O-methyladenosine also has high research value as an important raw material thereof.
The yield is lower in the nucleoside methylation method, taking 2-amino-2 ' -O-methyl nucleoside as an example, the most commonly used method for synthesizing 2-amino-2 ' -O-methyl nucleoside in production is to take sodium hydride as a reaction hydrogen extraction reagent to promote the combination of methyl in the methylation reagent and 2' -OH of the 2-amino-nucleoside, the selectivity of the reaction promoted by the sodium hydride is superior to other hydrogen extraction reagents, and the yield of about 50 percent can be obtained, but the activity of the sodium hydride is particularly strong, the storage environment needs to be kept dry, the tightness is good, and spontaneous combustion can occur in humid air; and the reaction system needs to be anhydrous, sodium hydride is very easy to react with water, and can react violently to generate hydrogen when meeting water, so that the sodium hydride is difficult to store and easy to deteriorate. The sodium hydride catalyzes the reaction of the raw material 2-amino-2' -O-methyladenosine and the methylating agent to generate hydrogen, which is easy to cause combustion and explosion, so that the sodium hydride brings great danger in the using and storing process.
Other synthesis methods of 2-amino-2' -O-methyl nucleoside also include a reaction system which takes diazomethane as a methylation reagent and stannous chloride as a hydrogen pulling reagent, but the selectivity of the method is lower than that of sodium hydride, and the toxicity of stannous chloride and azomethane is higher and the environmental pollution is higher.
Disclosure of Invention
In view of the safety problem, toxicity and environmental pollution of the 2 '-O-methyl nucleoside synthesis method in the prior art, the invention aims to provide a preparation method of 2' -O-methyl nucleoside, which takes alkoxide as a hydrogen extraction reagent, and the nucleoside shown in formula I and a methylation reagent CH react under the action of the hydrogen extraction reagent 3 I to produce the 2' -O-methyl nucleoside of formula II, wherein the reaction formula is as follows:
wherein B is 2-amino-adenine, adenine or uracil.
Further, the alkoxide is selected from one or more of potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
Further, the molar ratio of the hydrogen abstraction reagent to the 2-amino-nucleoside is (0.5-1.5): 1; preferably (0.8-1.2) 1, more preferably 1.1:1.
further, the temperature of the reaction is-15 to 60 ℃, more preferably 10 to 30 ℃.
Further, the reaction time of the reaction is 60-180min.
Further, the reaction is carried out in a solvent, which is N, N-dimethylformamide.
Further, the volume mass ratio of the N, N-dimethylformamide to the nucleoside shown in the formula I is (10-20): 1.
further, said nucleoside of formula I with CH 3 The molar ratio of I is 1: (0.5-2), preferably 1: (1-1.2).
Further, the method also comprises a post-treatment process: the post-treatment is crystallization; preferably, the crystallization solvent is selected from one or more of ethyl acetate, ethanol and methanol.
The invention provides a method for methylation of nucleoside, which comprises the following steps:
s1: reacting the nucleoside of formula I with a hydrogen abstraction reagent alkoxide, wherein 2' -OH of 2-amino-adenosine loses H to form an oxyanion;
s2: the oxygen anion is further reacted with a methylating agent CH 3 I, to produce the 2' -O-methyl nucleoside shown in the formula II.
The invention achieves the following positive effects: the invention provides a process route for promoting methylation of 2' -O-methyl nucleoside by using alkoxide as a hydrogen-withdrawing reagent. Alkoxides are safer to use and store than sodium hydride. The reaction selectivity and the reaction depth are ensured, and meanwhile, the reaction danger is reduced, so that the safety of personnel and environment is facilitated; the generated impurities are few in variety, and the post-treatment process is simpler.
Drawings
FIG. 1 is an HPLC chromatogram of the reaction solution in example 1.
FIG. 2 is an HPLC chromatogram of the purified 2-amino-2' -O-methyl gland of example 1.
Detailed Description
The present invention will be described in detail with reference to the following embodiments, but it should be understood that the scope of the present invention is not limited by these embodiments and the principle of the present invention, but is defined by the claims.
In the present invention, anything or things which are not mentioned are directly applicable to those known in the art without any change except what is explicitly stated. Moreover, any embodiment described herein may be freely combined with one or more other embodiments described herein, and the technical solutions or ideas thus formed are considered part of the original disclosure or original description of the present invention, and should not be considered as new matters not disclosed or contemplated herein, unless a person skilled in the art would consider such combination to be clearly unreasonable.
All features disclosed in this invention may be combined in any combination and such combinations are understood to be disclosed or described herein unless a person skilled in the art would consider such combinations to be clearly unreasonable.
The numerical points disclosed in the present specification include not only the numerical points specifically disclosed in the examples but also the endpoints of each numerical range in the specification, and ranges in which any combination of the numerical points is disclosed or recited should be considered as ranges of the present invention.
Technical and scientific terms used herein are to be defined only in accordance with their definitions, and are to be understood as having ordinary meanings in the art without any definitions.
The invention provides a preparation method of 2' -O-methyl nucleoside, which takes alkoxide as a hydrogen-withdrawing reagent, and nucleoside shown in formula I and a methylation reagent C are reacted under the action of the hydrogen-withdrawing reagentH 3 I to produce the 2' -O-methyl nucleoside of formula II, wherein the reaction formula is as follows:
wherein B is 2-amino-adenine, adenine or uracil.
In the reaction process, the reaction is carried out in two steps:
s1: reacting nucleoside with alkoxide, losing H from 2' -OH to form oxygen anion;
s2: the oxygen anion is further reacted with a methylating agent CH 3 I, reacting to generate 2' -O-methyl nucleoside.
In the invention, alkoxide is used as a hydrogen extraction reagent, the selectivity of synthesizing 2' -O-methyl nucleoside is about 60 percent, and the reaction efficiency is equivalent to that of sodium hydride; but also avoids the dangerous factors in the reaction process. In the development process, inorganic base such as KOH or NaOH is used as a hydrogen extraction reagent, the conversion rate of KOH is lower than that of sodium hydride, the analysis should be that the alkalinity of KOH is lower than that of sodium hydride in DMF, and the impurity species produced in the reaction process are more than those in the reaction with the sodium hydride, so that the final yield is influenced. Therefore, the alkoxide as a hydrogen-withdrawing agent for the methylation reaction also makes the industrial production safer without affecting the reaction yield.
The alkoxide as hydrogen extracting reagent in the present invention refers to a compound in which hydrogen in hydroxyl group in alcohol molecule is replaced by metal, such as sodium alkoxide, potassium alkoxide, lithium alkoxide, which can significantly improve product selectivity and yield. In order to improve the reaction selectivity and yield of the 2' -O-methyl nucleoside; the hydrogen-withdrawing reagent is selected from one or more of potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the hydrogen-withdrawing effect of the hydrogen-withdrawing reagents is equivalent when the hydrogen-withdrawing reagents are used, and the use safety is high.
In order to further improve the reaction efficiency of the hydrogen extraction reagent, the molar ratio of the hydrogen extraction reagent to the raw materials is (0.5-1.5): 1 in the range of allowing the starting materials to react completely and improving the selectivity of the reaction product, preferably (0.8-1.2): 1, more preferably 1.1:1.
in order to improve the reaction efficiency and the product yield, the reaction temperature is-15-60 ℃, and the reaction time is 60-180min. The selectivity is reduced and the product yield is low due to the overhigh reaction temperature; too low a reaction temperature is not favorable for the reaction to proceed sufficiently.
In order to be more beneficial to the methylation reaction, in the step S1, the reaction temperature is 10-30 ℃, and the reaction time is 10-60min. In the step S2, the reaction temperature is 10-30 ℃, and the reaction time is 60-180min.
In order to obtain better technical effects, the reaction is carried out in a solvent, and a good solvent with high polarity is preferably selected during the reaction because the polarity of the reaction raw materials in the invention is high; preferably, the solvent is N, N-Dimethylformamide (DMF). In order to fully dissolve the raw materials and ensure that a reaction system is more stable, the volume-to-mass ratio (ml/g) of the N, N-dimethylformamide to the raw materials is (10-20): 1, the temperature of the raw material dissolved in DMF is 90-100 ℃.
To increase the yield of the reaction, the nucleoside is reacted with CH 3 The molar ratio of I is 1: (0.5-2); the molar ratio of the two reactants in the range can not only ensure that the reaction is fully carried out, but also can not cause the waste of resources; in a specific example the molar ratio can be 1.5,1, 1, 1.2, 1.
In order to make the reaction system more stable, the methylating agent CH 3 I is diluted with the reaction solvent, in the specific example, CH, before addition 3 The volume ratio of I to the reaction solvent (DMF) is 1: (10-20), the reaction system is more stable.
In order to further improve the selectivity of the reaction and enable more target products with 2' -methylation to be generated in the reaction, when the methylating agent is added, the target products are generated most favorably by controlling the dropping speed to be 1-5mL/min in a dropping mode.
After the reaction is finished, a quenching agent is required to be added to stop the reaction, and the quenching agent is methanol.
The preparation method for preparing the 2' -O-methyl adenosine also comprises a post-treatment process: the post-treatment is crystallization, and the crystallization solvent is one or more selected from ethyl acetate, ethanol and methanol.
Example 1
10g of 2-amino-adenosine (35.46 mmol) and 150mL of DMF were put in a 500mL four-necked flask, and the temperature was raised to 90 to 100 ℃ and the mixture was stirred to dissolve the solid. After the solid was dissolved in DMF, the temperature was naturally decreased to 20 ℃ and 2.1g of sodium methoxide (38.89 mmol) was added and stirred for 15min. Then 2.2mL of methyl iodide (35.35 mmol) was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction was carried out for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) and the reaction starting material was completely reacted. HPLC (fig. 1) of the reaction solution showed: the content of 2-amino-2' -O-methyladenosine was 66.9%.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. Adding 100mL of ethyl acetate to dissolve the distilled materials, stirring and scattering for 1h, filtering out a white solid insoluble in ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 6.4g of solid was obtained with a yield of 61.0% and a purity of 99.3% by HPLC (FIG. 2).
Example 2
10g of 2-amino-adenosine and 150mL of DMF were put into a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. After the solid was dissolved in DMF, the temperature was naturally decreased to 20 ℃ and 1.9g (35.19 mmol) of sodium methoxide was added and stirred for 15min. Then 2.2mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction was carried out for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) was carried out until the reaction degree was unchanged.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. And adding 100mL of ethyl acetate to dissolve the distilled material, stirring and scattering for 1h, filtering out a white solid which is insoluble in the ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 6.0g of solid is obtained, the yield is 57.2 percent, and the purity is 98.8 percent.
Example 3
10g of 2-amino-adenosine and 150mL of DMF were put into a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. After the solid was dissolved in DMF and cooled to 20 ℃ naturally, 2.3g (42.59 mmol) of sodium methoxide was added and stirred for 15min. Then 2.2mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction was carried out for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) and the reaction starting material was completely reacted.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is finished until almost no solvent is distilled off, the distillation is stopped under the reduced pressure. And adding 100mL of ethyl acetate to dissolve the distilled material, stirring and scattering for 1h, filtering out a white solid which is insoluble in the ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 6.3g of solid is obtained, the yield is 60.0 percent, and the purity is 98.0 percent.
Example 4
10g of 2-amino-adenosine and 150mL of DMF were added to a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. After the solid was dissolved in DMF, the temperature was naturally decreased to 20 ℃ and 2.8g (51.85 mmol) of sodium methoxide was added and stirred for 15min. Then 2.2mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction was carried out for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) and the reaction starting material was completely reacted.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. Adding 100mL of ethyl acetate to dissolve the distilled materials, stirring and scattering for 1h, filtering out a white solid insoluble in ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 4.5g of solid is obtained, the yield is 42.8 percent, and the purity is 98.4 percent.
Example 5
10g of adenosine and 150mL of DMF were added to a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. After the solid is dissolved in DMF, the temperature is naturally reduced to 20 ℃, 2.2g (41.16 mmol) of potassium ethoxide is added, and the mixture is stirred for 15min. Then 5.3mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction was carried out for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) and the reaction starting material was completely reacted.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. Adding 100mL of ethyl acetate to dissolve the distilled materials, stirring and scattering for 1h, filtering out a white solid insoluble in ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF into the obtained filter cake, evaporating the solvent to dryness in a water bath at 60 ℃ under reduced pressure, adding 50mL of methanol, and crystallizing for 5 hours. After filtration and drying, 6.4g of solid is obtained, the yield is 60.8 percent, and the purity is 99.1 percent.
Comparative example 1
10g of 2-amino-adenosine and 150mL of DMF were put into a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. And (3) after the solid is dissolved clearly in DMF, naturally cooling to 30 ℃, and then maintaining the temperature for 20 to 30 ℃. 1.7g of sodium hydroxide was added thereto, and the mixture was stirred for 15min. Then 2.2mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction solution is naturally heated to-5 ℃ and reacts for 2h. TLC detection (developing solvent: 10% methanol/DCM) was carried out until the reaction degree was unchanged.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. Adding 100mL of ethyl acetate to dissolve the distilled materials, stirring and scattering for 1h, filtering out a white solid insoluble in ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 4.1g of solid is obtained, the yield is 39.0 percent, and the purity is 98.0 percent.
Comparative example 2
10g of 2-amino-adenosine and 150mL of DMF were put into a 500mL four-necked flask, and the mixture was heated to 90 to 100 ℃ and stirred to dissolve the solid. And after the solid is dissolved clearly in DMF, naturally cooling to 30 ℃, and then placing the four-mouth bottle in refrigerating fluid at the temperature of-15 ℃. When the temperature of the reaction solution is reduced to-10 ℃, 1.5g of sodium amide is added and stirred for 15min. Then 2.2mL of methyl iodide was diluted with 50mL of DMF and added to the four-necked flask at a dropping rate of 5 mL/min. After the dropwise addition, the reaction solution is naturally heated to-5 ℃ and reacts for 2 hours. TLC detection (developing solvent: 10% methanol/DCM) until no further change in the extent of reaction occurred.
The reaction solution was cooled to-10 ℃ and 10 mL of methanol was slowly added dropwise. After the dropwise addition, the mixture is distilled under reduced pressure in a water bath at 60 ℃, and after the distillation is carried out until the solvent is hardly distilled off, the distillation is stopped by releasing the pressure. Adding 100mL of ethyl acetate to dissolve the distilled materials, stirring and scattering for 1h, filtering out a white solid insoluble in ethyl acetate, dissolving the solid in 50mL of ethanol again, and stirring for 5h to precipitate a white solid. Filtering, washing the filter cake with 50mL of ethanol, adding 120mL of DMF solution into the obtained filter cake, evaporating the solvent to dryness under reduced pressure in a water bath at 60 ℃, adding 50mL of methanol solution, and crystallizing for 5 hours. After filtration and drying, 3.7g of solid is obtained, the yield is 35.4%, and the purity is 98.1%.
In conclusion, the invention provides a process route for promoting the methylation reaction of 2' -O-methyl nucleoside by using alkoxide as a hydrogen extraction reagent. Alkoxides are safer to use and store than sodium hydride. The reaction selectivity and the reaction depth are ensured, the reaction danger is reduced, and the safety of personnel environment is facilitated; the generated impurities are few in variety, and the post-treatment process is simpler.
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the scope of the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (9)
1. A method for preparing 2' -O-methyl nucleoside, which is characterized in that: taking alkoxide as a hydrogen extraction reagent, and reacting the nucleoside shown in the formula I with a methylation reagent CH under the action of the hydrogen extraction reagent 3 I to produce the 2' -O-methyl nucleoside of formula II, wherein the reaction formula is as follows:
The alkoxide is selected from one or more of potassium methoxide, sodium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
2. The method of claim 1, wherein the molar ratio of the hydrogen abstraction reagent to the nucleoside of formula I is (0.5-1.5): 1.
3. The method of claim 1, wherein the molar ratio of the hydrogen abstraction reagent to the nucleoside of formula I is (0.8-1.2): 1.
4. The method according to claim 1, wherein the reaction temperature is 10 to 30 ℃.
5. The method according to claim 1, wherein the reaction time is 60 to 180min.
6. The method according to claim 1, wherein the reaction is carried out in a solvent which is N, N-dimethylformamide.
7. The method according to claim 6, wherein the volume-to-mass ratio (ml/g) of the N, N-dimethylformamide to the nucleoside of formula I is (10 to 20): 1.
8. the method of claim 1, wherein said nucleoside of formula I is conjugated to CH 3 The molar ratio of I is 1: (0.5-2).
9. The method according to claim 1, further comprising a post-treatment process of: the post-treatment is crystallization; the crystallization solvent is selected from one or more of ethyl acetate, ethanol and methanol.
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| CN1498221A (en) * | 2001-01-22 | 2004-05-19 | Nucleoside derivatives as inhibitors of RNA-dependent PNA viral polymerase | |
| CN103319555A (en) * | 2013-07-01 | 2013-09-25 | 淮海工学院 | Preparation method of 2'-methoxy adenosine |
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| CN1498221A (en) * | 2001-01-22 | 2004-05-19 | Nucleoside derivatives as inhibitors of RNA-dependent PNA viral polymerase | |
| CN103319555A (en) * | 2013-07-01 | 2013-09-25 | 淮海工学院 | Preparation method of 2'-methoxy adenosine |
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