CN108409818B - Method for synthesizing cytosine nucleoside - Google Patents
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- CN108409818B CN108409818B CN201810470464.7A CN201810470464A CN108409818B CN 108409818 B CN108409818 B CN 108409818B CN 201810470464 A CN201810470464 A CN 201810470464A CN 108409818 B CN108409818 B CN 108409818B
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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
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The invention discloses a method for synthesizing cytosine nucleoside, belonging to the field of nucleoside synthesis in organic chemistry. The reaction steps are as follows: with N4Acyl cytosine as raw material, trimethyl silicon acetate and B (C)6F5)3The cytosine can be obtained by condensation of the catalyst and the tetraacetyl ribose and deprotection of acid or alkali, the whole process only needs two steps of reaction, and the N is prevented from being treated by using a large amount of silane4The-acetylcytosine is subjected to silicon etherification and then condensed with the tetraacetyl ribose, so that a tin tetrachloride condensing agent is eliminated, the raw material cost is reduced, and the total yield reaches 80%.
Description
Technical Field
The invention belongs to the field of organic chemistry, relates to synthesis of pyrimidine nucleoside, and particularly relates to a method for synthesizing cytosine nucleoside.
Background
Cytosine nucleoside, chemical name: 2-carbonyl-4-aminopyrimidine, CAS No.: 65-46-3, molecular formula C9H13N3O5The compound is a main basic group component in nucleic acid RNA, and can be used as a very important medical intermediate for preparing medicaments such as antiviral medicaments, antitumor cytarabine medicaments, citicoline medicaments and the like. The following methods are reported in the literature:
(1) nishimara et al proposed a new method for chemically synthesizing perantadine as early as 1964, namely reacting N4-acetylcytosine protected by silyl ether with 1-chlorotriphenyljia-premna (alpha and beta mixture) under the condition of heating and refluxing to generate cytidine with a mixed configuration (alpha configuration and beta configuration), and separating the two isomers by combining recrystallization and column chromatography to obtain alpha-cytidine and beta-configuration (natural cytidine). The method has the defects of complex flow, low yield, difficult obtainment of the raw material 1-chlorotritoyl ribose, mixture of alpha and beta configurations, products after the reaction of the mixture are also two isomers, and difficult post-treatment. The method can not realize large-scale production.
(2) Helmut et al use uridine as a raw material, undergo hexamethylsilylation to obtain 4,2 ', 5' -tetrasilylated uridine, and then undergo one-step high-pressure ammonolysis in a dry container to obtain cytidine. The starting material for this process is uridine, itself a natural nucleoside, an uncommon biochemical reagent. The method comprises the steps of carrying out silicon etherification by using expensive uridine as a raw material, then carrying out ammonolysis at the forced condition of 165 ℃ and under the pressure of 25 atmospheres to remove the 2 ', 3 ' and 5 ' silicon ether protecting groups, and reducing hydroxyl groups to ammonolyze the 4-silicon ether protecting groups into amino groups. The yield of the step is low, the reaction conditions are harsh, and the scheme is difficult to realize industrial production.
(3) Sugiura Y et al acylated cytosine as the starting material with isobutyric anhydride to give N4Isobutyryl cytosine, then condensed with 1-acetyl-2, 3, 5-tribenzoyl ribofuranose, and aminolyzed to prepare cytidine. The raw materials of isobutyric anhydride and 1-acetyl-2, 3, 5-tribenzoyl ribofuranose used in the method have higher price and low yield, and are not suitable for industrial production.
(4) Vorbruggen H et al prepare cytidine by condensation and deprotection of fully-silated cytosine and 1-acetyl-2, 3, 5-tribenzoyl ribose under the catalytic action of trimethylsilyl trifluoromethanesulfonate. In the method, the silyl etherified cytosine is easy to deliquesce, the raw material 1-acetyl-2, 3, 5-tribenzoyl ribose is not easy to obtain, and the method has low yield and cannot be industrially produced.
Disclosure of Invention
In order to overcome the defects, the invention uses N4Acyl cytosine and tetraacetyl ribose as precursorsThe acyl-protected cytidine is obtained by catalytic condensation reaction under the condition of a combined catalyst, when cytosine is not protected by silicon etherification, the nitrogen on the cytosine has weakened capability of attacking ribofuranose, the activity of C-N glycosidic bond is reduced, the selection of the catalyst is very critical to the reaction, and different catalysts can generate position isomers and double-substituted products.
A method for synthesizing a cytosine nucleoside, the reaction comprising: by using N4Acylcytosine 1 with tetraacetylribose 2 in trimethylsilylacetate and B (C)6F5)3Condensing under catalysis to obtain acyl protected cytidine 3, and then deprotecting the acyl protected cytidine 3 under acidic or alkaline conditions to obtain cytidine.
The reaction equation is as follows:
the method specifically comprises the following steps:
first, N is4Mixing-acylcytosine 1 and tetraacetylribose 2, adding trimethylsilylacetate and solvent, cooling to 0-10 deg.C, and slowly adding dropwise B (C)6F5)3Controlling the temperature of the solution at 0-20 ℃, after finishing dripping, heating to 45-55 ℃, continuing to perform heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw materials basically disappear, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting with a solvent, combining organic phases, drying and concentrating until acyl protected cytidine 3 oily matter is obtained, and directly putting the oily matter into the next reaction;
and secondly, dispersing the oily matter in the last step into methanol, reacting at 10-40 ℃ under an acidic condition or an alkaline condition, completely deprotecting by HPLC detection, evaporating reaction liquid, adding methanol, cooling to separate out cytidine, and refining by using 95% ethanol to obtain a cytidine refined product 4 with the purity of more than 99%.
Further, in the above technical solution, in the first step, N is added4-acylcytosine is selected from N4-acetylcytosine, N4-benzoylcytosine or N4-propionylcytosine. In the actual reaction, N is preferred from the viewpoint of the reaction yield4-benzoylcytosine; from the viewpoint of economy, N is preferred4-acetylcytosine followed by N4-propionylcytosine.
Further, in the above technical scheme, the acidic condition is that anhydrous hydrogen chloride or acetyl chloride is added into an alcoholic solution; the alkaline condition is ammonia methanol or ammonia ethanol solution. During the production process, the deprotection is preferably performed by using a hydrogen chloride methanol solution or an ammonia methanol solution.
Further, in the above technical solution, the condensation reaction solvent is selected from dichloroethane, chloroform, toluene or dioxane. Preferably, the solvent is dichloroethane.
Further, in the above technical scheme, the N4-cytosine, the trimethylsilyl acetate and the B (C)6F5)3The molar ratio is 1:0.05-0.3: 0.01-0.05.
Among the condensation catalysts, the use of SnCl4, TiCl4, BF3-Et2O catalysts as the above starting materials produces by-products which are N-3 substituted, or N1/N3-disubstituted as the main isomers. Addition of B (C)6F5)3Can reduce the consumption of trimethyl silicon acetate, and when the two catalysts can be mixed and used in low catalytic consumption, condensation can be smoothly generated, and when B (C) is used6F5)3When the amount of N4-cytosine used is 0.5 equivalent or more, the reaction yield tends to decrease.
The invention has the beneficial effects that:
1. the design route is novel, and the process does not need to pass through N4The step of silicon etherification for protecting cytosine simplifies the production operation and saves the production cost.
2. The method cancels tin tetrachloride, reduces the production of solid waste and liquid waste, and reduces the environmental protection cost.
3. Compared with the traditional process, the process has simple operation and stable yield amplification process, and avoids the silicon etherification process.
The specific embodiment is as follows:
example 1
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetyl cytosine (80g, 0.52mol), dichloroethane 300mL, trimethylsilyl chlorideAcetic ester (10.3g, 0.078mol), cooling the reaction solution to 0-10 ℃, and slowly dropwise adding B (C)6F5)3(8.0g, 0.0156mol) solution, controlling the temperature at 0-20 ℃, after finishing dripping, heating to 45-55 ℃, continuing to perform heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw materials basically disappear, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting by a solvent, combining organic phases, drying and concentrating to obtain acyl protected cytidine 3 oily matter, and directly feeding the oily matter into the next reaction.
Dispersing the oily matter in the last step into methanol, introducing ammonia gas (60g, 3.5mol), reacting at 10-40 ℃, detecting by HPLC to remove the protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by using 95% ethanol to obtain 102g of cytidine with the purity of more than 99%, and performing HPLC: 99.8% and a yield of 80%.
Example 2
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetyl cytosine (80g, 0.52mol), dichloroethane 300mL, trimethylsilylacetate (6.9g, 0.052mol) was added, the reaction solution was cooled to 0-10 deg.C, and B (C) was slowly added dropwise6F5)3(8.0g, 0.0156mol) solution, controlling the temperature at 0-20 ℃, after finishing dripping, heating to 45-55 ℃, continuing to perform heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw materials basically disappear, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting by a solvent, combining organic phases, drying and concentrating to obtain acyl protected cytidine 3 oily matter, and directly feeding the oily matter into the next reaction.
Dispersing the oily matter in the last step into 500mL of methanol, introducing ammonia gas (60g, 3.5mol), reacting at 30 ℃, detecting by HPLC to remove the protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by using 95% ethanol to obtain 90g of cytidine with the purity of more than 99%, and performing HPLC: 99.9% and a yield of 71%.
Example 3
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetylcytosine (80g, 0.52mol), chloroform (300 mL), trimethylsilylacetate (10.3g, 0.078mol) was added, the reaction mixture was cooled to 0-10 ℃, and B (C) was slowly added dropwise6F5)3(8.0g, 0.0156mol) solution, temperature controlled at 0And (3) after finishing dripping at the temperature of minus 20 ℃, heating to 45-55 ℃, continuing to perform heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw materials basically disappear, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting by using a solvent, combining organic phases, drying and concentrating to obtain an acyl protected cytidine 3 oily substance, and directly adding the oily substance into the next reaction.
Dispersing the oily matter in the last step into 500mL of methanol, introducing ammonia gas (60g, 3.5mol), reacting at 30 ℃, detecting by HPLC to remove the protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by using 95% ethanol to obtain 99g of cytidine with the purity of more than 99%, and performing HPLC: 99.6% and yield 78%.
Example 4
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetyl cytosine (80g, 0.52mol), dichloroethane 300mL, trimethylsilylacetate (10.3g, 0.078mol) was added, the reaction solution was cooled to 0-10 deg.C, and B (C) was slowly added dropwise6F5)3(8.0g, 0.0156mol) solution, controlling the temperature at 0-20 ℃, after finishing dripping, heating to 45-55 ℃, continuing to perform heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw materials basically disappear, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting by a solvent, combining organic phases, drying and concentrating to obtain acyl protected cytidine 3 oily matter, and directly feeding the oily matter into the next reaction.
Dispersing the oily matter in the last step into methanol, introducing hydrogen chloride (146g, 4mol), reacting at 20 ℃, detecting by HPLC to remove protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by 95% ethanol to obtain 102g of cytidine with purity of more than 99%, and performing HPLC: 99.4% and yield 80%.
Example 5
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetyl cytosine (80g, 0.52mol), dichloroethane 300mL, trimethylsilylacetate (10.3g, 0.078mol) was added, the reaction solution was cooled to 0-10 deg.C, and B (C) was slowly added dropwise6F5)3(5.3g, 0.0104mol) solution, controlling the temperature at 0-20 deg.C, dripping, heating to 45-55 deg.C, keeping the temperature for reaction, HPLC detecting until the raw material basically disappears, cooling, slowly adding saturated sodium bicarbonate for neutralization, and separatingAnd extracting the solution with a solvent, combining organic phases, drying and concentrating to obtain an acyl protected cytidine 3 oily substance, and directly putting the oily substance into the next reaction.
Dispersing the oily matter in the last step into methanol, introducing ammonia gas (60g, 3.5mol), reacting at 30 ℃, detecting by HPLC to remove protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by using 95% ethanol to obtain 90g of cytidine with purity of more than 99%, and performing HPLC: 99.4% and a yield of 71%.
Example 6
Into a 500mL three-necked flask equipped with a stirrer and a thermometer, N was added4Acetyl cytosine (80g, 0.52mol), dichloroethane 300mL, trimethylsilylacetate (10.3g, 0.078mol) was added, the reaction solution was cooled to 0-10 deg.C, and B (C) was slowly added dropwise6F5)3(13.3g, 0.026mol) solution, controlling the temperature at 0-20 ℃, after finishing dripping, heating to 45-55 ℃, continuing to carry out heat preservation reaction, detecting by HPLC (high performance liquid chromatography) until the raw material basically disappears, cooling, slowly adding saturated sodium bicarbonate for neutralization, separating liquid, extracting by a solvent, combining organic phases, drying and concentrating to obtain acyl protected cytidine 3 oily matter, and directly adding the oily matter into the next reaction;
dispersing the oily matter in the last step into methanol, introducing ammonia gas (60g, 3.5mol), reacting at 10-40 ℃, detecting by HPLC to remove the protection completely, evaporating the reaction solution to dryness, adding methanol, cooling to precipitate cytidine, refining by using 95% ethanol to obtain 102g of cytidine with the purity of more than 99%, and performing HPLC: 99.8% and a yield of 80%.
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.
Claims (4)
1. A method for synthesizing a cytosine nucleoside, comprisingThe following steps: by using N4Acylcytosine 1 with tetraacetylribose 2 in trimethylsilylacetate and B (C)6F5)3The acyl protected cytidine 3 is obtained by condensation under catalysis, and the reaction equation is as follows:said N is4-acylcytosine is selected from N4-acetylcytosine, N4-benzoylcytosine or N4-propionylcytosine; said N is4Acylcytosines, trimethylsilanoates and B (C)6F5)3The molar ratio is 1:0.05-0.3: 0.01-0.05.
2. The method of synthesizing a cytosine nucleoside of claim 1, further comprising: and carrying out deprotection on the acyl protected cytidine 3 under an acidic condition or a basic condition to obtain the cytidine.
3. The method of synthesizing a cytosine nucleoside of claim 2, wherein: the acidic condition is that anhydrous hydrogen chloride or acetyl chloride is added into alcoholic solution; the alkaline condition is ammonia methanol or ammonia ethanol solution.
4. The method of synthesizing a cytosine nucleoside of claim 1, wherein: the condensation reaction is carried out in a solvent selected from dichloroethane, chloroform, toluene or dioxane.
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