CN109336937A - A kind of preparation method of Ribavirin - Google Patents
A kind of preparation method of Ribavirin Download PDFInfo
- Publication number
- CN109336937A CN109336937A CN201811601108.0A CN201811601108A CN109336937A CN 109336937 A CN109336937 A CN 109336937A CN 201811601108 A CN201811601108 A CN 201811601108A CN 109336937 A CN109336937 A CN 109336937A
- Authority
- CN
- China
- Prior art keywords
- ribavirin
- preparation
- ribose
- reaction
- acetyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- 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
- C07H19/056—Triazole or tetrazole radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods of Ribavirin, belong to medical synthesis technical field.1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester are first carried out condensation reaction under elemental iodine catalysis by the present invention, obtain Ribavirin intermediate, Ribavirin intermediate is then carried out ammonolysis reaction, obtains Ribavirin.The Ribavirin intermediate yield and purity that method provided by the invention obtains are higher, and the yield of Ribavirin intermediate is 80%~82%, and purity is 98.5%~98.7%；And the total recovery and purity of the Ribavirin being finally prepared are higher, and total recovery is 77.6%~79.5%, purity 98.5%.
Description
Technical field
The present invention relates to medical synthesis technical field more particularly to a kind of preparation methods of Ribavirin.
Background technique
Ribavirin (English: Ribavirin) also known as virazole, ribavirin, Nice can wait, chemical name are as follows: 1-
β-D-RIBOSE base -1H-1,2,4,-triazole -3- carboxylic acid amides is the antiviral drugs of broad spectrum high-effect, belongs to synthetic nucleosides
Class medicine can inhibit inosinicacid -5- phosphate dehydrogenase, and inosinicacid is blocked to be converted into guanylic acid, to inhibit the RNA and DNA of virus
Synthesis has DNA virus and RNA virus and inhibits duplication effect.
It has been reported that the synthetic method of Ribavirin include three kinds, be chemical method, fermentation method and enzymatic method respectively, wherein
Fermentation method is at high cost there are the microculture time is long, is easy to produce miscellaneous bacteria, and conversion ratio is low, and product is not readily separated purification etc. and lacks
Point；The yield of enzymatic method target product is not high, and enzyme source is difficult to obtain, expensive, is not suitable for large-scale production.
The main production process of Ribavirin is chemical synthesis at present, and chemical synthesis can be divided into four kinds of methods again:
Halogeno-sugar method, double-(p-nitrophenyl)-phosphate catalytic condensation method, p-methyl benzenesulfonic acid/benzene sulfonic acid/methanesulfonic acid catalyzed condensation
Method, stannic chloride catalysis condensation method and iodine catalytic condensation.
Halogeno-sugar method is after carrying out Silanization reaction with 1,2,4- triazole carboxylate methyl ester and hexamethyldisilane, with tetrem
Acyl ribose bromide reacts in acetonitrile is made intermediate, and then target product is made in ammonolysis.The examination of silanization used in the method
Agent is expensive, must be post-processed after Silanization reaction, just can be carried out condensation reaction, the time of condensation reaction is long, and yield is low；And
And 1,2,3,5-Tetra-O-Acetyl-D-Ribose bromide needs are made by 1,2,3,5-Tetra-O-Acetyl-D-Ribose bromination, itself property is unstable, easy quilt when long-time heating
It decomposes and destroys, influence the yield and quality of product.Referring to document: Zheng Renhua, Sun Li, Pei Wen ribavirin study on the synthesis into
Open up [J] Zhejiang Polytechnical University journal, 2003, (31) 3:336-339.
Double-(p-nitrophenyl)-phosphate catalytic condensation method needs for 1,2,3,5-Tetra-O-Acetyl-D-Ribose to be heated to 165~170 DEG C, in height
The lower reaction of temperature melting, 1,2,3,5-Tetra-O-Acetyl-D-Ribose are easy to happen coking and decomposition.The catalyst price that this method uses is higher, and can produce
Raw by-product p-nitrophenol, is unfavorable for purifying products, so that production cost is higher.Referring to document: Witkowski.J.T.,
K.Roland.,Robins,R.Sidwell.W.,and Simon.L.N.Design,synthesis,and broad
spectrum antiviral activity of 1-P-D-Ribofuranosyl-1,2,4-triazole-3-
carboxamide and related nucleosides[J].J.Med.Chem.,1972,15(11):1150-1154.
Catalyst used in p-methyl benzenesulfonic acid/benzene sulfonic acid/methanesulfonic acid catalyzed condensation method belongs to highly acid organic catalyst,
It is easy to remove the acetyl group of 1,2,3,5-Tetra-O-Acetyl-D-Ribose and midbody product, influences the conversion ratio of reaction.By-product it is complex and
It is sticky, it is unfavorable for the purifying of product.Referring to document: Li Yongshu, Mei Liqin, Tan is at chivalrous solid super-strong acid SO4 2-/TiO2Catalysis is closed
[J] colleges and universities chemical engineering journal, 2010, (24) 2:286-289 are studied at ribavirin condensation compound.
Stannic chloride catalysis condensation method be easy to cause heavy metal ion to remain, and influences the quality of final products.Referring to document:
Banff A.Oro B D, Frigerio M.Process for preparation of L-ribavirin. [P] .CN:
1535278A.2004-10-06。
In short, there are at high cost, method is complicated, product yield and purity are low for the preparation method of Ribavirin in the prior art
The problems such as.
Summary of the invention
The present invention provides a kind of preparation method of Ribavirin, method provided by the invention is without using expensive examination
Agent, and method is simple, and Ribavirin yield and purity are higher.
The present invention provides a kind of preparation methods of Ribavirin, comprising the following steps:
(1) 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester are subjected to condensation reaction under elemental iodine catalysis, obtain Li Bawei
Woods intermediate；The temperature of the condensation reaction is 100~130 DEG C；
(2) the Ribavirin intermediate for obtaining the step (1) carries out ammonolysis reaction, obtains Ribavirin.
Preferably, the time of condensation reaction is 1~3h in the step (1).
Preferably, the mass ratio of the 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester is 1~3:1.
Preferably, the mass ratio of the 1,2,3,5-Tetra-O-Acetyl-D-Ribose and elemental iodine is 1:0.01~0.05.
Preferably, after the completion of step (1) condensation reaction, further include successively vacuumized and recrystallization processing, obtain
To Ribavirin intermediate.
Preferably, the time vacuumized is 1~2h.
Preferably, the recrystallization solvent includes one of methanol, ethyl alcohol, isopropanol, n-butanol, acetone and acetonitrile
Or it is a variety of.
Preferably, step (2) ammonolysis reaction carries out in enough nitrogen atmospheres, and the temperature of the ammonolysis reaction is
0~10 DEG C, the time of the ammonolysis reaction is 2~5h.
Preferably, step (2) ammonolysis reaction carries out in organic solvent, the organic solvent include methanol, ethyl alcohol,
One of isopropanol, n-butanol, acetone and acetonitrile are a variety of.
The present invention provides a kind of preparation methods of Ribavirin, first by 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester in iodine
Simple substance catalysis is lower to carry out condensation reaction, obtains Ribavirin intermediate, Ribavirin intermediate is then carried out ammonolysis reaction, is obtained
To Ribavirin.Temperature of the present invention in first step condensation reaction is 100~130 DEG C, and reaction temperature is moderate, 1,2,3,5-Tetra-O-Acetyl-D-Ribose
Coking and decomposition are less likely to occur, so that the reaction yield of Ribavirin intermediate improves a lot；In addition, the present invention is made with iodine
For the catalyst of condensation reaction, promote 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester that condensation reaction effectively occurs, since iodine has
Sublimation characteristics facilitate recycling to use, and using elemental iodine as catalyst, reduce manufacturing cost.Embodiment the result shows that, this hair
The Ribavirin intermediate yield and purity that the method for bright offer obtains are higher, and the yield of Ribavirin intermediate is 80%~
82%, purity is 98.5%~98.7%；And the total recovery and purity of the Ribavirin being finally prepared are higher, total recovery
It is 77.6%~79.5%, purity 98.5%.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic spectrogram for the Ribavirin that the embodiment of the present invention 1 is prepared；
Fig. 2 is the carbon nuclear magnetic spectrogram for the Ribavirin that the embodiment of the present invention 1 is prepared.
Specific embodiment
The present invention provides a kind of preparation methods of Ribavirin, comprising the following steps:
(1) 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester are subjected to condensation reaction under elemental iodine catalysis, obtain Li Bawei
Woods intermediate；
(2) the Ribavirin intermediate for obtaining the step (1) carries out ammonolysis reaction, obtains Ribavirin.
1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester are carried out condensation reaction under elemental iodine catalysis by the present invention, obtain Li Ba
Wei Lin intermediate.After 1,2,3,5-Tetra-O-Acetyl-D-Ribose is preferably heated to dissolution by the present invention, triazole carboxylate methyl ester and elemental iodine are added.?
In the present invention, the triazole carboxylate methyl ester is preferably 1,2,4- triazole -3- carboxylate methyl esters.In the present invention, the tetrem
The mass ratio of acyl ribose and triazole carboxylate methyl ester is preferably 1~3:1, further preferably 1.5~2.5:1, most preferably
2.5:1.In the present invention, the mass ratio of the 1,2,3,5-Tetra-O-Acetyl-D-Ribose and elemental iodine is preferably 1:0.01~0.05, further preferably
For 1:0.02~0.04.In the present invention, the temperature of the condensation reaction is preferably 100~130 DEG C, further preferably 110
~120 DEG C, the time is preferably 1~3h, further preferably 1.5~2.5h.
In the present invention, the condensation reaction principle is shown in formula I:
The present invention generates by-product acetic acid in condensation reaction, and the present invention preferably takes out condensation reaction products
It is vacuum-treated, to remove by-product acetic acid.In the present invention, the time of the vacuumize process is preferably 1~2h；Vacuum degree is excellent
It is selected as 0.08~0.09MPa.
After vacuumize process, the condensation reaction products after vacuumizing preferably are carried out recrystallization processing by the present invention, obtain benefit
Ba Weilin intermediate.In the present invention, the recrystallization processing with solvent preferably include methanol, ethyl alcohol, isopropanol, n-butanol,
One of acetone and acetonitrile are a variety of.In the present invention, the specific method of the recrystallization is preferred are as follows: by the contracting after vacuumizing
It closes reaction product and is cooled to 60~70 DEG C, recrystallization solvent is then added, continue cool to room temperature, solid is precipitated, solid is through washing
It washs and dries, obtain Ribavirin intermediate.
After obtaining Ribavirin intermediate, the Ribavirin intermediate is carried out ammonolysis reaction by the present invention, obtains Li Ba
Wei Lin.In the present invention, the ammonolysis reaction preferably carries out in organic solvent, and the organic solvent preferably includes methanol, second
One of alcohol, isopropanol, n-butanol, acetone and acetonitrile are a variety of.The present invention preferably by Ribavirin intermediate and described has
Solvent mixing, is then passed through enough ammonias at low temperature, carries out ammonolysis reaction.In the present invention, among the Ribavirin
The quality of body and the volume ratio of organic solvent are preferred: 1~1.25g:1mL.In the present invention, the temperature of the low temperature is preferably 0
~10 DEG C.In the present invention, the ammonolysis reaction preferably carries out in enough ammonia atmospheres, and the temperature of the ammonolysis reaction is excellent
It is selected as 0~10 DEG C, further preferably 2~8 DEG C, more preferably 4~6 DEG C, the time is preferably 2~5h, further preferably 3~
4h。
In the present invention, when the organic solvent is preferably methanol, the ammonolysis reaction principle is as shown in Formula II:
After the completion of ammonolysis reaction, the present invention preferably stops logical ammonia, and the ammonolysis reaction product is stood, and is precipitated solid
Then body collects solid, obtain product Ribavirin.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.
Embodiment 1
In the four-hole boiling flask of the 250mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl core of 100.0g is added
Sugar, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, 40.0g 1,2 is added,
4- triazole carboxylate methyl ester, two kinds of materials after mixing, are added 1.4g iodine, are continuously heating to 115 DEG C, keep the temperature 2 hours,
Then start to vacuumize, steam by-product acetic acid；After 1 hour, reaction stops, and is cooled to 70 DEG C hereinafter, take methanol 100mL, adds
Enter in flask, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, and is done
It is dry, obtain Ribavirin intermediate [1- (2,3,5- tri--O- acetyl group-β-D-RIBOSE base) -1H-1,2,4- triazole -3-
Carboxylate methyl ester], yield 82% is (in terms of 1,2,3,5-Tetra-O-Acetyl-D-Ribose, similarly hereinafter.) through detecting, the fusing point of intermediate product is 105-107 DEG C of (document
106-108 DEG C of value), it is 98.7% that HPLC, which measures purity,.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL methanol, stirring form uniform slurry, and low temperature (0 DEG C) is passed through ammonia, until slurry becomes transparent, continue
Enough ammonias are passed through, then react 2.5h at 0 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, is produced
'Libaweilin '.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 79.5%.Through detecting, product Ribavirin
Fusing point be 165-167 DEG C (166-168 DEG C of literature value), HPLC measure purity be 98.5%.
Nuclear-magnetism characterization is carried out to the Ribavirin that embodiment 1 obtains, as a result as depicted in figs. 1 and 2, wherein Fig. 1 is benefit bar
The hydrogen nuclear magnetic spectrogram of Wei Lin, Fig. 2 are the carbon nuclear magnetic spectrogram of Ribavirin.
1HNMR:3.44-3.49 (m), 1H, 3.56-3.59 (m), 1H, 3.90-3.93 (m), 1H, 4.07-4.09 (dd),
1H, 4.31-4.33 (t), 1H, 4.88-4.91 (t), 1H, 5.16-5.18 (d), 1H, 5.54 (s), 1H, 5.78 (s), 1H, 7.59
(s), 1H, 7.81 (s), 1H, 8.84 (s), 1H.
13CNMR:61.73,70.40,74.92,85.91,92.18,145.40,157.71,160.85.
Embodiment 2
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl core of 200.0g is added
Sugar, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, 80.0g 1,2 is added,
4- triazole carboxylate methyl ester, two kinds of materials after mixing, are added 2.8g iodine, are continuously heating to 120 DEG C, keep the temperature 2 hours,
Then start to vacuumize, steam by-product acetic acid.After 2 hours, reaction stops, and is cooled to 70 DEG C hereinafter, take methanol 150mL, adds
Enter in flask, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, and is done
It is dry, obtain Ribavirin intermediate [1- (2,3,5- tri--O- acetyl group-β-D-RIBOSE base) -1H-1,2,4- triazole -3-
Carboxylate methyl ester], yield 80.5%.Through detecting, the fusing point of intermediate product is 105-107 DEG C (106-108 DEG C of literature value), and HPLC is surveyed
Obtaining purity is 98.6%.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL ethyl alcohol, stirring form uniform slurry, and low temperature (10 DEG C) is passed through ammonia, until slurry becomes transparent, continue
Enough ammonias are passed through, then react 3h at 10 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, is produced
'Libaweilin '.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 78.1%.Through detecting, product Ribavirin
Fusing point be 165-167 DEG C (166-168 DEG C of literature value), HPLC measure purity be 98.5%.
Embodiment 3
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl core of 250.0g is added
Sugar, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, tri- nitrogen of 100.0g is added
Triazole carboxylic acid's methyl esters, two kinds of materials after mixing, are added 3.5g iodine, are continuously heating to 115 DEG C, keep the temperature 2 hours, then open
Beginning vacuumizes, and steams by-product acetic acid.After 1 hour, reaction stops, and is cooled to 70 DEG C hereinafter, take methanol 200mL, flask is added
In, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, dry, is obtained
To Ribavirin intermediate [1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylic acid
Methyl esters], yield 80%.Through detecting, the fusing point of intermediate product is 105-107 DEG C (106-108 DEG C of literature value), and HPLC measures purity
It is 98.5%.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL isopropanol, stirring form uniform slurry, and low temperature (5 DEG C) is passed through ammonia, until slurry becomes transparent, after
It is continuous to be passed through enough ammonias, 3h is then reacted at 5 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, is produced
'Libaweilin '.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 77.6%.Through detecting, product Ribavirin
Fusing point be 165-167 DEG C (166-168 DEG C of literature value), HPLC measure purity be 98.5%.
Embodiment 4
In the four-hole boiling flask of the 1000mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl of 500.0g is added
Ribose, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, 200.0g tri- is added
Nitrogen triazole carboxylic acid's methyl esters, two kinds of materials after mixing, are added 7.0g iodine, are continuously heating to 120 DEG C, keep the temperature 2 hours, then
Start to vacuumize, steams by-product acetic acid.After 2 hours, reaction stops, and is cooled to 70 DEG C hereinafter, taking methanol 400mL, addition is burnt
In bottle, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, dry,
Obtain Ribavirin intermediate [1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylic
Sour methyl esters], yield 82%.Through detecting, the fusing point of intermediate product is 105-107 DEG C (106-108 DEG C of literature value), and HPLC measures pure
Degree is 98.7%.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL n-butanol, stirring form uniform slurry, and low temperature (4 DEG C) is passed through ammonia, until slurry becomes transparent, after
It is continuous to be passed through enough ammonias, then 3.5h is reacted at 4 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, obtains
Product Ribavirin.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 79.5%.Through detecting, product Li Bawei
The fusing point of woods is 165-167 DEG C (166-168 DEG C of literature value), and it is 98.5% that HPLC, which measures purity,.
Embodiment 5
In the four-hole boiling flask of the 1000mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl of 500.0g is added
Ribose, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, 210.0g tri- is added
Nitrogen triazole carboxylic acid's methyl esters, two kinds of materials after mixing, are added 7.0g iodine, are continuously heating to 120 DEG C, keep the temperature 2 hours, then
Start to vacuumize, steams by-product acetic acid.After 2 hours, reaction stops, and is cooled to 70 DEG C hereinafter, taking methanol 400mL, addition is burnt
In bottle, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, dry,
Obtain Ribavirin intermediate [1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylic
Sour methyl esters], yield 81%.Through detecting, the fusing point of intermediate product is 105-107 DEG C (106-108 DEG C of literature value), and HPLC measures pure
Degree is 98.5%.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL methanol, stirring form uniform slurry, and low temperature (3 DEG C) is passed through ammonia, until slurry becomes transparent, continue
Enough ammonias are passed through, then react 4h at 3 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, obtains product
Ribavirin.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 78.6%.Through detecting, product Ribavirin
Fusing point is 165-167 DEG C (166-168 DEG C of literature value), and it is 98.5% that HPLC, which measures purity,.
Embodiment 6
In the four-hole boiling flask of the 1000mL equipped with mechanical stirring, thermometer and distilling apparatus, tetra- acetyl of 500.0g is added
Ribose, oil bath heating is to 100 DEG C, after being all fused into transparency liquid to 1,2,3,5-Tetra-O-Acetyl-D-Ribose, opens stirring, 210.0g tri- is added
Nitrogen triazole carboxylic acid's methyl esters, two kinds of materials after mixing, are added 8.0g iodine, are continuously heating to 115 DEG C, keep the temperature 2 hours, then
Start to vacuumize, steams by-product acetic acid.After 2 hours, reaction stops, and is cooled to 70 DEG C hereinafter, taking methanol 500mL, addition is burnt
In bottle, stirring keeps material dissolution uniform, pours out into beaker.Standing is cooled to room temperature, and solid is precipitated, and is filtered, and is washed, dry,
Obtain Ribavirin intermediate [1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylic
Sour methyl esters], yield 80%.Through detecting, the fusing point of intermediate product is 105-107 DEG C (106-108 DEG C of literature value), and HPLC measures pure
Degree is 98.5%.
In the four-hole boiling flask of the 500mL equipped with mechanical stirring, thermometer and distilling apparatus, by the intermediate of Ribavirin
[1- (tri--O- acetyl group-β of 2,3,5--D-RIBOSE base) -1H-1,2,4- triazole -3- carboxylate methyl ester] 100.0g with
The mixing of 100mL ethyl alcohol, stirring form uniform slurry, and low temperature (8 DEG C) is passed through ammonia, until slurry becomes transparent, continue
Enough ammonias are passed through, then react 4.5h at 8 DEG C.Stop logical ammonia, stand, solid is precipitated, filters out the solid, is produced
'Libaweilin '.The yield of ammonolysis reaction is 97%, and the total recovery of two-step reaction is 77.6%.Through detecting, product Ribavirin
Fusing point be 165-167 DEG C (166-168 DEG C of literature value), HPLC measure purity be 98.5%.
The carbon nuclear magnetic spectrogram and hydrogen nuclear magnetic spectrogram for the Ribavirin that embodiment 2~6 obtains are identical as Fig. 1 and Fig. 2, herein not
It repeats again.
To sum up, the preparation method of Ribavirin provided by the invention obtains Ribavirin intermediate yield and purity compared with
Height, the yield of Ribavirin intermediate are 80%~82%, and purity is 98.5%~98.7%；And the benefit being finally prepared
The total recovery and purity of Ba Weilin is higher, and total recovery is 77.6%~79.5%, purity 98.5%.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of preparation method of Ribavirin, comprising the following steps:
(1) 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester are subjected to condensation reaction under elemental iodine catalysis, obtained in Ribavirin
Mesosome；The temperature of the condensation reaction is 100~130 DEG C；
(2) the Ribavirin intermediate for obtaining the step (1) carries out ammonolysis reaction, obtains Ribavirin.
2. preparation method according to claim 1, which is characterized in that in the step (1) time of condensation reaction be 1~
3h。
3. preparation method according to claim 1, which is characterized in that the 1,2,3,5-Tetra-O-Acetyl-D-Ribose and triazole carboxylate methyl ester
Mass ratio is 1~3:1.
4. preparation method according to claim 1, which is characterized in that the mass ratio of the 1,2,3,5-Tetra-O-Acetyl-D-Ribose and elemental iodine is
1:0.01~0.05.
5. preparation method according to claim 1, which is characterized in that after the completion of step (1) condensation reaction, further include
It is successively vacuumized and recrystallization is handled, obtain Ribavirin intermediate.
6. preparation method according to claim 5, which is characterized in that the time vacuumized is 1~2h.
7. preparation method according to claim 5 or 6, which is characterized in that the recrystallization solvent includes methanol, second
One of alcohol, isopropanol, n-butanol, acetone and acetonitrile are a variety of.
8. preparation method according to claim 1, which is characterized in that step (2) ammonolysis reaction is in enough nitrogen
It is carried out in atmosphere, the temperature of the ammonolysis reaction is 0~10 DEG C, and the time of the ammonolysis reaction is 2~5h.
9. preparation method according to claim 1 or 8, which is characterized in that step (2) ammonolysis reaction is in organic solvent
Middle progress, the organic solvent include one of methanol, ethyl alcohol, isopropanol, n-butanol, acetone and acetonitrile or a variety of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811601108.0A CN109336937B (en) | 2018-12-26 | 2018-12-26 | Preparation method of ribavirin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811601108.0A CN109336937B (en) | 2018-12-26 | 2018-12-26 | Preparation method of ribavirin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109336937A true CN109336937A (en) | 2019-02-15 |
| CN109336937B CN109336937B (en) | 2020-08-25 |
Family
ID=65297241
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811601108.0A Active CN109336937B (en) | 2018-12-26 | 2018-12-26 | Preparation method of ribavirin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109336937B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111647033A (en) * | 2020-06-08 | 2020-09-11 | 济南明鑫制药股份有限公司 | Method for preparing ribavirin by one-pot method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286046A (en) * | 2011-08-11 | 2011-12-21 | 广东肇庆星湖生物科技股份有限公司 | Preparation method of ribavirin |
| CN104910215A (en) * | 2015-05-22 | 2015-09-16 | 浙江工业大学 | Method for using tetraacetylribose crystallization residual liquor after splitting decomposition of nucleoside |
-
2018
- 2018-12-26 CN CN201811601108.0A patent/CN109336937B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286046A (en) * | 2011-08-11 | 2011-12-21 | 广东肇庆星湖生物科技股份有限公司 | Preparation method of ribavirin |
| CN104910215A (en) * | 2015-05-22 | 2015-09-16 | 浙江工业大学 | Method for using tetraacetylribose crystallization residual liquor after splitting decomposition of nucleoside |
Non-Patent Citations (2)
| Title |
|---|
| ATEF M.AMER ET AL.: "Synthesis and Antimicrobial Activities of New N-Glycoside from Phenyl Pyrazole Derivatives", 《UNIVERSAL JOURNAL OF CHEMISTRY》 * |
| 姚其正: "《核苷化学合成》", 30 June 2005, 化学工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111647033A (en) * | 2020-06-08 | 2020-09-11 | 济南明鑫制药股份有限公司 | Method for preparing ribavirin by one-pot method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109336937B (en) | 2020-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Prisbe et al. | A Novel and efficient preparation of 21, 31-dideoxynucleosides1 | |
| JPH0662663B2 (en) | Desazapurine-nucleoside-derivative | |
| EP3760637A2 (en) | Stable solid forms of regadenoson | |
| CN109336937A (en) | A kind of preparation method of Ribavirin | |
| JPS637199B2 (en) | ||
| JPS6310787A (en) | Nucleotide analog, production thereof and antiviral agent | |
| Efange et al. | Synthesis and biological activities of 2-pyrimidinone nucleosides. 2. 5-Halo-2-pyrimidinone 2'-deoxyribosides | |
| JP4071738B2 (en) | 2'-deoxyuridine derivatives used as hydrogelators | |
| May Jr et al. | Synthesis of v-triazolo [4, 5-c] pyridine nucleosides and 4-(. beta.-D-ribofuranosyl) amino-1, 2, 3-thiadiazolo [5, 4-b] pyridine via a rearrangement | |
| CN110655506B (en) | Preparation method of tegafur | |
| US3948885A (en) | 5-Hydroxyl-1,2,3-triazole-4-carboxamide nucleoside | |
| Gonzalez et al. | New approach to the total synthesis of showdomycin: Stereochemistry study of the intermediate and related products | |
| Wu et al. | Design, synthesis, and characterization of photolabeling probes for the study of the mechanisms of the antiviral effects of ribavirin | |
| Vojtech et al. | One-pot synthesis of 2-C-glycosylated benzimidazoles from the corresponding methanal dimethyl acetals | |
| Allavudeen et al. | A method for obtaining equilibrium tautomeric mixtures of reducing sugars via glycosylamines using nonaqueous media | |
| TW199155B (en) | ||
| Carmona et al. | Branched-chain fluoro nitro d-and l-sugars from glucose | |
| CN109134565A (en) | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition | |
| CN111808157B (en) | Preparation method of adenosine bulk drug | |
| Fossey et al. | Synthesis of N-1β-D-Arabinofuranosyl and N-1-2′-Deoxy-β-D-erythro-pentofuranosyl Thieno [3, 2-d] Pyrimidine Nucleosides | |
| CN109134566A (en) | A kind of 1/20 water Ribavirin compound | |
| CN110229170B (en) | Preparation method of 5-aza Marangucycline B | |
| Baer et al. | Synthesis of 3-amino-3-deoxy-α-d-mannopyranosyl α-d-mannopyranoside by way of a regioselective Sn2 displacement in an unsymmetrical, disecondary ditriflate of a disaccharide | |
| EP0171171B1 (en) | A process for preparing 2-beta-d-ribofuranosylselenazole-4-carboxamide | |
| CN109503681B (en) | 2-Fluoro-L-ristosamine compound and synthetic method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |