CN108409818A - A kind of method of synthesizing cytimidine nucleosides - Google Patents
A kind of method of synthesizing cytimidine nucleosides Download PDFInfo
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- CN108409818A CN108409818A CN201810470464.7A CN201810470464A CN108409818A CN 108409818 A CN108409818 A CN 108409818A CN 201810470464 A CN201810470464 A CN 201810470464A CN 108409818 A CN108409818 A CN 108409818A
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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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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention discloses a kind of method of synthesizing cytimidine nucleosides, belongs to nucleosides in organic chemistry and synthesize field.Its reaction step is as follows：With N4Acyl group cytimidine is raw material, with trimethyl silicane acetic acid esters and B (C6F5)3It is condensed for catalyst and 1,2,3,5-Tetra-O-Acetyl-D-Ribose, can be obtained cytimidine using acid or alkalinity deprotection, whole process only needs two-step reaction, avoids using a large amount of silicon amine alkane to N4Acetylcytosine carries out silicon etherificate and is condensed again with 1,2,3,5-Tetra-O-Acetyl-D-Ribose, eliminates butter of tin condensing agent, reduces cost of material, total recovery reaches 80%.
Description
Technical field
The invention belongs to organic chemistry fileds, are related to the synthesis of pyrimidine nucleoside, and in particular to a kind of synthesizing cytimidine nucleosides
Method.
Background technology
Cytidine, chemical name：2- carbonyl -4- aminopyrimidines, No. CAS：65-46-3, molecular formula C9H13N3O5, it is
Principal bases constituent in nucleic acid RNA can be used for preparing antiviral, anti-swollen as very important medicine intermediate
The drugs such as tumor cytarabine and citicoline.The method of document report has following several at present：
(1) Nishimara et al. just proposed a kind of new method of chemical synthesis Bo Agan early in 1964, that is, utilized silicon
The N4- acetyl group cytimidine of ether protection and 1- chloro triphenyl person's first chances ribose (α and β mixtures) are anti-under reflux condition
Mix-configuration cytidine (α configurations and beta comfiguration) should be generated, is then combined two kinds of isomer separations using recrystallization and column chromatography
Respectively obtain α-cytidine and beta configuration (natural cytidine).The disadvantages of this method is that flow is complicated, yield is low, its raw material 1- chloros three
Benzoyl ribose is difficult to obtain, and is α, and the mixture of two kinds of configurations of β, product is also two kinds of isomeries after participating in reaction
Body, post-processing are difficult.This method cannot achieve large-scale production.
(2) Helmut et al. is raw material using uridine, is etherified to obtain 4,2 ', 5 '-four silicon ethers by hexamethyl silicon amine alkane silicon
Change uridine, then a step high pressure ammonia solution obtains cytidine in the container of re-dry.The starting material of this method makes uridine, uridine itself
It is also a kind of natural nucleus glycoside, is rare biochemical reagents.And be etherified its silicon as raw material using expensive uridine, then by forcing
165 DEG C of condition, ammonolysis under 25 atmospheric pressure, makes the silicon ether protecting group of 2 ', 3 ', 5 ' positions be detached from, and restores hydroxyl, and 4 silicon ethers is made to protect
Shield base ammonolysis becomes amino.This step yield is low, and severe reaction conditions, the program are difficult to realize industrialized production.
(3) Sugiura Y. et al. are acylated to obtain N with isobutyric anhydride using cytimidine as raw material4Isobutyryl born of the same parents are phonetic
Pyridine, then with 1- acetyl -2,3,5- tri-benzoyl ribofuranoses are condensed, and ammonolysis prepares cytidine.The raw materials used isobutyl of the method
Acid anhydrides and 1- acetyl -2,3,5- tri-benzoyl ribofuranose higher prices, and yield is low, is not suitable for industrialized production.
(4) cytimidine and 1- acetyl -2,3,5- tri-benzoyl ribose that Vorbruggen H et al. are etherified with total silicon exist
Under Trimethylsilyl trifluoromethanesulfonate catalytic action cytidine is prepared by condensation, deprotection.In this method, the cytimidine of silicon etherificate
It easily deliquesces, raw material 1- acetyl -2,3,5- tri-benzoyl ribose is difficult to obtain, and this method yield is low, can not industrialized production.
Invention content
In order to overcome drawbacks described above, the present invention is with N4Acyl group cytimidine and 1,2,3,5-Tetra-O-Acetyl-D-Ribose are raw material, in combination catalyst
Under the conditions of catalyzing and condensing be obtained by the reaction acyl group protection cytidine, when cytimidine does not have silicon etherification protection, nitrogen attack furan on cytimidine
It mutters ribose reduced capability, C-N is reduced at glycosidic bond activity, and to reacting very crucial, different catalyst can produce for the selection of catalyst
Raw position isomer and disubstituted product.
A kind of method of synthesizing cytimidine nucleosides, operation include：Using N4Acyl group cytimidine 1 and four acetyl cores
Sugar 2 is in trimethyl silicane acetic acid esters and B (C6F5)3Acyl group protection cytidine 3 is condensed to yield under catalysis, then acyl group protection cytidine 3 passes through
Cytidine is obtained after acid condition or alkaline condition deprotection.
Reaction equation is as follows：
Specifically comprise the following steps：
The first step, by N4Acyl group cytimidine 1,1,2,3,5-Tetra-O-Acetyl-D-Ribose 2 mix, and add trimethyl silicane acetic acid esters and solvent, drop
B (C are slowly added dropwise to 0-10 DEG C in temperature6F5)3Solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, after continuation of insurance
Temperature reaction, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic
Mutually merge, it is dry to be concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step；
The grease of previous step is scattered in methanol by second step, in acid condition or under alkaline condition, 10-40 DEG C
Reaction, HPLC detect deprotection completely, are evaporated reaction solution, and cooling precipitation cytidine after methanol is added, essence is carried out with 95% ethyl alcohol
99% or more cytidine fine work 4 of purity is made.
Further, in the above-mentioned technical solutions, in the first step, by N4Acyl group cytimidine is selected from N4Acetyl born of the same parents are phonetic
Pyridine, N4Benzoyl cytosine or N4Propionyl cytimidine.In real reaction, from reaction yield angle, preferably N4Benzoyl born of the same parents
Pyrimidine；Consider from economy point, preferably N4Acetylcytosine, followed by N4Propionyl cytimidine.
Further, in the above-mentioned technical solutions, the acid condition is that alcoholic solution is added in anhydrous hydrogen chloride or chloroacetic chloride
In；Alkaline condition is ammonia methanol or cholamine solution.In process of production, preferably hydrogen chloride methanol solution or methanolic ammonia solution are de-
Protection.
Further, in the above-mentioned technical solutions, condensation reaction solvent is selected from dichloroethanes, chloroform, toluene or dioxanes.
Preferred solvent is dichloroethanes.
Further, in the above-mentioned technical solutions, the N4- cytimidines, trimethyl silicane acetic acid esters and B (C6F5)3Molar ratio
It is 1:0.05-0.3:0.01-0.05.
In condensation catalyst, for above-mentioned raw materials, using SnCl4, TiCl4, BF3-Et2O catalyst will produce
Main isomer is N-3 substitutions or the disubstituted by-products of N1/N3-.Add B (C6F5)3Trimethyl silicane acetic acid esters can be reduced
Dosage is smoothly condensed, when being used in mixed way when making two catalyst can be using low catalytic amount as B (C6F5)3Dosage
When to be more than 0.5 equivalent of raw material N4- cytimidines, reaction yield has reduction trend.
Advantageous effect of the invention：
1, design route is novel, and technique requires no N4The silicon etherification step of cytimidine is protected, production operation saving is simplified
Production cost.
2, butter of tin is eliminated, reduces the useless production of solid waste, liquid, reduces environmentally friendly cost.
3 and traditional handicraft ratio, technological operation is simple, stablizes in yield amplification process, avoids silicon etherification procedure.
Specific embodiment：
Embodiment 1
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), two
Trimethyl silicane acetic acid esters (10.3g, 0.078mol) is added in chloroethanes 300mL, and reaction solution is cooled to 0-10 DEG C, and B is slowly added dropwise
(C6F5)3(8.0g, 0.0156mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, and it is anti-to continue heat preservation
It answers, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic to be harmonious
And drying is concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step.
The grease of previous step is scattered in methanol, ammonia (60g, 3.5mol), 10-40 DEG C of reaction, HPLC are being passed through
Detection deprotection is complete, is evaporated reaction solution, cools down after addition methanol and cytidine is precipitated, carry out being refining to obtain purity with 95% ethyl alcohol
99% or more cytidine 102g, HPLC：99.8%, yield 80%.
Embodiment 2
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), two
Trimethyl silicane acetic acid esters (6.9g, 0.052mol) is added in chloroethanes 300mL, and reaction solution is cooled to 0-10 DEG C, and B is slowly added dropwise
(C6F5)3(8.0g, 0.0156mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, and it is anti-to continue heat preservation
It answers, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic to be harmonious
And drying is concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step.
The grease of previous step is scattered in 500mL methanol, ammonia (60g, 3.5mol) is being passed through, 30 DEG C are reacted,
HPLC detection deprotections are complete, are evaporated reaction solution, cool down after addition methanol and cytidine is precipitated, be refining to obtain with 95% ethyl alcohol
Purity 99% or more cytidine 90g, HPLC：99.9%, yield 71%.
Embodiment 3
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), chlorine
Imitative 300mL, is added trimethyl silicane acetic acid esters (10.3g, 0.078mol), reaction solution is cooled to 0-10 DEG C, and B (C are slowly added dropwise6F5)3
(8.0g, 0.0156mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, continue insulation reaction,
HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, solvent extraction, and organic phase merges,
It is dry to be concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step.
The grease of previous step is scattered in 500mL methanol, ammonia (60g, 3.5mol) is being passed through, 30 DEG C are reacted,
HPLC detection deprotections are complete, are evaporated reaction solution, cool down after addition methanol and cytidine is precipitated, be refining to obtain with 95% ethyl alcohol
Purity 99% or more cytidine 99g, HPLC：99.6%, yield 78%.
Embodiment 4
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), two
Trimethyl silicane acetic acid esters (10.3g, 0.078mol) is added in chloroethanes 300mL, and reaction solution is cooled to 0-10 DEG C, and B is slowly added dropwise
(C6F5)3(8.0g, 0.0156mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, and it is anti-to continue heat preservation
It answers, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic to be harmonious
And drying is concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step.
The grease of previous step is scattered in methanol, hydrogen chloride (146g, 4mol), 20 DEG C of reactions, HPLC inspections are being passed through
It is complete to survey deprotection, is evaporated reaction solution, cools down after addition methanol and cytidine is precipitated, carry out being refining to obtain purity with 95% ethyl alcohol
99% or more cytidine 102g, HPLC：99.4%, yield 80%.
Embodiment 5
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), two
Trimethyl silicane acetic acid esters (10.3g, 0.078mol) is added in chloroethanes 300mL, and reaction solution is cooled to 0-10 DEG C, and B is slowly added dropwise
(C6F5)3(5.3g, 0.0104mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, and it is anti-to continue heat preservation
It answers, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic to be harmonious
And drying is concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step.
The grease of previous step is scattered in methanol, ammonia (60g, 3.5mol), 30 DEG C of reactions, HPLC detections are being passed through
Deprotection is complete, is evaporated reaction solution, and cooling precipitation cytidine after methanol is added, carries out being refining to obtain purity 99% with 95% ethyl alcohol
Above cytidine 90g, HPLC：99.4%, yield 71%.
Embodiment 6
In with blender and thermometer 500mL there-necked flasks, N is added4Acetyl group cytimidine (80g, 0.52mol), two
Trimethyl silicane acetic acid esters (10.3g, 0.078mol) is added in chloroethanes 300mL, and reaction solution is cooled to 0-10 DEG C, and B is slowly added dropwise
(C6F5)3(13.3g, 0.026mol) solution, control temperature are added dropwise at 0-20 DEG C, are warming up to 45-55 DEG C, and it is anti-to continue heat preservation
It answers, HPLC is detected to raw material to disappear substantially, and cooling is slowly added to saturated sodium bicarbonate and neutralizes, liquid separation, and solvent extraction is organic to be harmonious
And drying is concentrated into obtain acyl group protection 3 grease of cytidine and direct plunge into react in next step；
The grease of previous step is scattered in methanol, ammonia (60g, 3.5mol), 10-40 DEG C of reaction, HPLC are being passed through
Detection deprotection is complete, is evaporated reaction solution, cools down after addition methanol and cytidine is precipitated, carry out being refining to obtain purity with 95% ethyl alcohol
99% or more cytidine 102g, HPLC：99.8%, yield 80%.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (6)
1. a kind of method of synthesizing cytimidine nucleosides, which is characterized in that include the following steps：Using N4Acyl group cytimidine 1 and four
Acetyl ribose 2 is in trimethyl silicane acetic acid esters and B (C6F5)3Acyl group protection cytidine 3 is condensed to yield under catalysis, reaction equation is such as
Under：
2. the method for synthesizing cytimidine nucleosides according to claim 1, which is characterized in that further include：Acyl group protects cytidine 3 to pass through
Cytidine is obtained after peracidity condition or alkaline condition deprotection.
3. the method for synthesizing cytimidine nucleosides according to claim 2, it is characterised in that：The acid condition is anhydrous chlorination
Hydrogen or chloroacetic chloride are added in alcoholic solution；Alkaline condition is ammonia methanol or cholamine solution.
4. according to the method for synthesizing cytimidine nucleosides described in claim 1, it is characterised in that：N4Acyl group cytimidine is selected from N4Acetyl
Cytimidine, N4Benzoyl cytosine or N4Propionyl cytimidine.
5. the method for synthesizing cytimidine nucleosides according to claim 1, it is characterised in that：Condensation reaction carries out in a solvent,
Solvent is selected from dichloroethanes, chloroform, toluene or dioxanes.
6. the method for synthesizing cytimidine nucleosides according to claim 1, it is characterised in that：N4- cytimidines, trimethyl silicane acetic acid
Ester is 1 with 3 molar ratios of B (C6F5):0.05-0.3:0.01-0.05.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113735926A (en) * | 2021-09-14 | 2021-12-03 | 江苏香地化学有限公司 | Synthesis process of uridine |
| CN114717280A (en) * | 2022-03-29 | 2022-07-08 | 浙江工业大学 | Synthesis method of monopilavir |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735926A (en) * | 2021-09-14 | 2021-12-03 | 江苏香地化学有限公司 | Synthesis process of uridine |
| CN114717280A (en) * | 2022-03-29 | 2022-07-08 | 浙江工业大学 | Synthesis method of monopilavir |
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