CN101891786B - Ribavirin compound and new preparation method thereof - Google Patents
Ribavirin compound and new preparation method thereof Download PDFInfo
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- CN101891786B CN101891786B CN2010102439710A CN201010243971A CN101891786B CN 101891786 B CN101891786 B CN 101891786B CN 2010102439710 A CN2010102439710 A CN 2010102439710A CN 201010243971 A CN201010243971 A CN 201010243971A CN 101891786 B CN101891786 B CN 101891786B
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- triazole
- ribavirin
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- ribofuranosyl
- ethanoyl
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Abstract
The invention relates to a ribavirin compound and a new preparation method thereof. The method comprises the following steps: using tetraacetylribose and 1,2,4-triazole-3-methyl-carboxylate to perform a condensation reaction under microwave radiation, and performing ammonolysis to prepare ribavirin. By using the method of the invention, the reaction time is greatly shortened and the yield is greatly increased, and the method lays a foundation for the industrial production of chemical synthesis.
Description
Technical field
The present invention relates to a kind of ribavirin compound and new preparation method thereof, belong to medical technical field.
Background technology
Ribavirin, chemistry is by name: 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxylic acid amides, molecular formula: C
8H
12N
4O
5, molecular weight: 244.21, structural formula is:
Ribavirin is a broad-spectrum antiviral drug.Its mechanism of action mainly is to suppress the inosine desaturase, and blocking-up inosine-phosphoric acid is to the effects such as conversion of xanthosine--phosphoric acid, thereby it is synthetic to suppress nucleic acid, stops virus replication.Ribavirin is absorbed very soon, and Plasma Concentration peaks in 60～90 minutes.Get into and generate active metabolite-ribavirin list phosphoric acid in the body after the phosphorylation, can concentrate in red corpuscle, eliminate about 24 hours of transformation period, mainly contain kidney and discharge, only have on a small quantity and discharge by ight soil.Be applicable to viral upper respiratory tract infection, the skin bleb virus infection.
Ribavirin synthetic has three kinds of methods, i.e. chemical method, fermentation method and enzymatic method.The synthetic route of having reported at present:
(1) fermentation method is at D-glucose, and inosine in the substratum of 5-adenosine or D-ribose, adds 1,2,4-triazole-3-carboxylic acid amides (TCA) and biological inoculum, room temperature condition was cultivated 2-8 days down, get final product ribavirin.
This method exists microorganism culturing generally under 20-40 ℃, to carry out, and is easy to generate assorted bacterium; Shortcomings such as ribavirin decomposes easily, and the microorganism culturing time is long, and cost is high, and transformation efficiency is low.
(2) enzymatic method is with inosine, guanosine, xanthosine or D-ribose-1-SULPHOSUCCINIC ACID ESTER and 1,2, and 4-triazole-3-carboxylic acid amides (TCA) is a raw material, synthetic ribavirin under the effect of nucleoside phosphorylase esterase (PN Pase).
This method total recovery is lower, has only about 40%, is not suitable for large-scale production.
(3) chemical synthesis
(A) the inosine method is starting raw material with the inosine, makes tetrem acyl ribose through acylation reaction; With 1,2,4-triazole-3-carboxylate methyl ester (TCM) melt condensation is separated through ammonia-methanol solution ammonia again, obtains title product then.
(B) the nucleosides acid system is starting raw material with Nucleotide, makes nucleosides through hydrolysis earlier, makes tetrem acyl ribose through acetylization reaction again, then through condensation, the synthetic title product of ammonolysis reaction.
(C) the adenosine method is starting raw material with the adenosine, cuts off earlier with one step of acetylize and realizes, makes tetrem acyl ribose, separates through condensation, ammonia and makes title product.
(D) the halogeno-sugar method with tetrem acyl ribose bromide and the reaction of triazole carboxylate methyl ester (TCM) pyrocondensation, makes title product through ammonolysis reaction earlier again.
All there is long reaction time in the synthetic ribavirin of above-mentioned chemical synthesis, and yield is low, and setting-up point is high, and tetrem acyl ribose is prone to defectives such as decomposition.
Summary of the invention
The object of the present invention is to provide a kind of new preparation method of ribavirin compound, condensation reaction takes place under microwave condition, carry out ammonia again and separate, make ribavirin by tetrem acyl ribose and triazole methyl esters.The inventive method can make the reaction times shorten greatly, and yield improves a lot, for the suitability for industrialized production of chemical synthesis is laid a good foundation.
The present invention provides a kind of compound method of ribavirin compound, by tetrem acyl ribose and triazole methyl esters condensation reaction takes place under microwave condition and obtains 1-(2,3; 5-three-O-ethanoyl-β-D-ribofuranosyl)-and 1H-1,2,4-triazole-3-carboxylate methyl ester; Again to 1-(2,3,5-three-O-ethanoyl-β-D-ribofuranosyl)-1H-1; 2,4-triazole-3-carboxylate methyl ester carries out ammonia to be separated, and makes the final product ribavirin.
Microwave power 400W wherein, microwave heating is to 55-65 ℃.
Synthetic route is:
Wherein, (I) be starting raw material triazole methyl esters;
(II) be starting raw material tetrem acyl ribose;
(III) be the final product ribavirin.
As a preferred embodiment of the present invention, the compound method of ribavirin compound provided by the invention, concrete preparation process is:
(1) tetrem acyl ribose and triazole methyl esters, trifluoromethanesulfonic acid are reacted 30-60min under microwave condition, cool to room temperature adds solvent, heating for dissolving; White solid is separated out in cooling again, filters washing; Drying gets 1-(2,3; 5-three-O-ethanoyl-β-D-ribofuranosyl)-and 1H-1,2,4-triazole-3-carboxylate methyl ester;
(2) in autoclave, with 1-(2,3; 5-three-O-ethanoyl-β-D-ribofuranosyl)-and 1H-1,2,4-triazole-3-carboxylate methyl ester and solvent; At room temperature feed ammonia and make reaction kettle keep the pressure of 2-4kg, reaction 4-5h reclaims unnecessary ammonia then; Removal of solvent under reduced pressure, residuum is used ethyl alcohol recrystallization, gets the product ribavirin.
In the aforesaid method, solvent is selected from a kind of in ethanol, ether, methyl alcohol, Virahol, propyl carbinol, acetonitrile, phenylcarbinol, the acetone, is preferably methyl alcohol.
In the aforesaid method, step (1) microwave condition is: power 400W is heated to 55-65 ℃.
Embodiment
Embodiment 1
1-(2,3,5-three-O-ethanoyl-β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxylate methyl ester synthetic
In the there-necked flask that TM and churned mechanically 2000ml are housed, add 318g (1mol) tetrem acyl ribose, the triazole methyl esters of 127.10g (1mol), the 20g trifluoromethanesulfonic acid is put into microwave reactor; Power 400W is set, is heated to 55 ℃, insulation reaction 60min, cool to room temperature, the methyl alcohol of adding 1000ml; Heating for dissolving, inclining, and separates out a large amount of white solids after the cooling, filters washing; Drying gets 1-(2,3,5-three-O-ethanoyl-β-D-ribofuranosyl)-1H-1; 2,4-triazole-3-carboxylate methyl ester product 350g, yield: 91%, MP:106 ℃.
Embodiment 2
Synthesizing of ribavirin
1-(2,3,5-three-O-ethanoyl-β-D-the ribofuranosyl)-1H-1 that in autoclave, adds 191g (0.5mol), 2; The methyl alcohol of 4-triazole-3-carboxylate methyl ester and 2000ml at room temperature feeds ammonia and makes reaction kettle keep the pressure of 2kg, reacts 5h; Reclaim unnecessary ammonia then, removal of solvent under reduced pressure, residuum is used ethyl alcohol recrystallization; Get ribavirin Forest products 110g, yield: 90%, MP:168 ℃.
Embodiment 3
1-(2,3,5-three-O-ethanoyl-β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxylate methyl ester synthetic
In the there-necked flask that TM and churned mechanically 2000ml are housed, add 318g (1mol) tetrem acyl ribose, the triazole methyl esters of 127.10g (1mol), the 20g trifluoromethanesulfonic acid is put into microwave reactor; Power 400W is set, is heated to 65 ℃, insulation reaction 30min, cool to room temperature, the methyl alcohol of adding 1000ml; Heating for dissolving, inclining, and separates out a large amount of white solids after the cooling, filters washing; Drying gets 1-(2,3,5-three-O-ethanoyl-β-D-ribofuranosyl)-1H-1; 2,4-triazole-3-carboxylate methyl ester product 354.6g, yield: 92.2%, MP:106 ℃.
Embodiment 4
Synthesizing of ribavirin
1-(2,3,5-three-O-ethanoyl-β-D-the ribofuranosyl)-1H-1 that in autoclave, adds 191g (0.5mol), 2; The methyl alcohol of 4-triazole-3-carboxylate methyl ester and 2000ml at room temperature feeds ammonia and makes reaction kettle keep the pressure of 4kg, reacts 4h; Reclaim unnecessary ammonia then, removal of solvent under reduced pressure, residuum is used ethyl alcohol recrystallization; Get ribavirin Forest products 111.3g, yield: 91.1%, MP:168 ℃.
Structural identification
1HNMR(DMSO-d
6)δ：3.56-3.69(m，2H，5′-CH
2)，3.84-3.86(m，1H，3′-H)，3.96-3.98(m，1H，4′-H)，4.65(t，J＝4.8Hz，1H，2′-H)，5.24(brs，1H，3′-OH)，5.49(brs，1H，5′-OH)，5.56(brs，1H，2′-OH)，6.86(d，J＝2.5Hz，1H，1′-H)，8.13(s，1H，NCHN)，10.33(br?s，2H，NH
2)。
Claims (4)
1. the preparation method of a ribavirin compound as follows,
It is characterized in that concrete preparation process is:
(1) tetrem acyl ribose and triazole methyl esters, trifluoromethanesulfonic acid were reacted 30-60 minute under microwave condition, cool to room temperature adds solvent, heating for dissolving; White solid is separated out in cooling again, filters washing; Drying gets 1-(2,3; 5-three-O-ethanoyl-β-D-ribofuranosyl)-and 1H-1,2,4-triazole-3-carboxylate methyl ester;
(2) in autoclave, with 1-(2,3; 5-three-O-ethanoyl-β-D-ribofuranosyl)-and 1H-1,2,4-triazole-3-carboxylate methyl ester and solvent; At room temperature feed ammonia and make reaction kettle keep the pressure of 2-4kg, reacted 4-5 hour, reclaim unnecessary ammonia then; Removal of solvent under reduced pressure, residuum is used ethyl alcohol recrystallization, obtains the product ribavirin.
2. method according to claim 1 is characterized in that the solvent that uses in step (1) and the step (2) all is selected from a kind of in ethanol, ether, methyl alcohol, Virahol, propyl carbinol, acetonitrile, phenylcarbinol, the acetone.
3. method according to claim 1 is characterized in that the solvent that uses in step (1) and the step (2) is methyl alcohol.
4. method according to claim 1, it is characterized in that microwave condition is in the step (1): power 400W is heated to 55-65 ℃.
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| CN2010102439710A CN101891786B (en) | 2010-08-04 | 2010-08-04 | Ribavirin compound and new preparation method thereof |
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| CN101891786B true CN101891786B (en) | 2012-09-05 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102127134B (en) * | 2010-12-02 | 2012-11-14 | 海南美兰史克制药有限公司 | Ribavirin compound and novel preparation method thereof |
| CN102786572A (en) * | 2011-05-17 | 2012-11-21 | 中国医学科学院药物研究所 | Ribavirin crystal C characterization and preparation methods, and applications of Ribavirin crystal C in medicines and healthcare products |
| CN102786571B (en) * | 2011-05-17 | 2017-02-22 | 中国医学科学院药物研究所 | Ribavirin crystal D, its preparation method, and its applications in medicines and healthcare products |
| CN102952104A (en) * | 2011-08-17 | 2013-03-06 | 黑龙江省松花江药业有限公司 | Furan compound |
| CN104910215B (en) * | 2015-05-22 | 2018-02-13 | 浙江工业大学 | A kind of method that raffinate is crystallized using 1,2,3,5-Tetra-O-Acetyl-D-Ribose after nucleolytic |
| CN105693793B (en) * | 2016-03-22 | 2018-12-21 | 湖北美林药业有限公司 | A kind of Ribavirin compound and its pharmaceutical composition |
| CN109134565A (en) * | 2017-08-15 | 2019-01-04 | 李双喜 | 1/10 water Ribavirin compound of one kind and its pharmaceutical composition |
| CN109134566A (en) * | 2017-08-18 | 2019-01-04 | 樊艳芳 | A kind of 1/20 water Ribavirin compound |
| 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 |
|---|---|---|---|---|
| CN1535278A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
| CN101397316A (en) * | 2008-10-23 | 2009-04-01 | 浙江工业大学 | Chemical synthesis method of ribavirin condensation compound |
-
2010
- 2010-08-04 CN CN2010102439710A patent/CN101891786B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535278A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
| CN101397316A (en) * | 2008-10-23 | 2009-04-01 | 浙江工业大学 | Chemical synthesis method of ribavirin condensation compound |
Non-Patent Citations (2)
| Title |
|---|
| J. T. Witkowski, et al..Design, Synthesis, and Broad Spectrum Antiviral Activity of 1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide and Related Nucleosides.《Journal of Medicinal Chemsitry》.ACS,1972,第15卷(第11期),第1150-1154页. * |
| J.T.Witkowski et al..Design |
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Effective date of registration: 20130726 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Wang Ming |
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