CN108484691A - A kind of chemical synthesis process of ribavirin condensation compound - Google Patents
A kind of chemical synthesis process of ribavirin condensation compound Download PDFInfo
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- CN108484691A CN108484691A CN201810687926.0A CN201810687926A CN108484691A CN 108484691 A CN108484691 A CN 108484691A CN 201810687926 A CN201810687926 A CN 201810687926A CN 108484691 A CN108484691 A CN 108484691A
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- Prior art keywords
- ribavirin
- chemical synthesis
- synthesis process
- condensation compound
- dissolved
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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
Abstract
The invention discloses a kind of chemical synthesis process of ribavirin condensation compound of chemosynthesis technical field, this method is as follows：S1：11,2,4 triazoles of trimethylsilyl 1H, 3 formamide, hmds and ammonium sulfate are added in the three-necked bottle of 500ml；S2：Evaporated under reduced pressure obtains yellow oil；S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate using the detection of thin plate chromatography chromatography；S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol；S5：Then addition ethyl alcohol, is filtered after being sufficiently stirred；S6：Filter cake after merging is dissolved in ethyl alcohol in a heated condition, after bleaching agent bleaching, filter crystallisation by cooling, white crystalline powder is made, the improved raw materials technology of the present invention is easy to get, and reaction condition is mild, each intermediate is not necessarily to isolate and purify, easy to operate, total recovery can reach 65% or more, and the purity of Ribavirin obtained is 99% or more.
Description
Technical field
The invention discloses a kind of chemical synthesis process of ribavirin condensation compound, specially chemosynthesis technical field.
Background technology
Virazole also known as Ribavirin, ribavirin, Nice can wait, and be the antiviral drugs of broad spectrum high-effect, Li Bawei
Woods is a kind of antiviral agent, belongs to the synthesis of nucleoside medicine, has inhibiting effect, mechanism unclear many DNA and RNA virus.
It is now widely used for the prevention of viral disease.Common formulations have injection, tablet, oral solution, aerosol etc..But it is existing
Ribavirin synthetic method condensation when high temperature easily make raw material decomposes, yield relatively low；Reaction under high pressure is needed to be up to tens when ammonolysis
Hour；Need to be through overweight aminating reaction when preparing raw material, explosive, preparation process is easy to operate.For this purpose, we have proposed a kind of profits
The chemical synthesis process of Ba Weilin condensation products comes into operation, to solve the above problems.
Invention content
The purpose of the present invention is to provide a kind of chemical synthesis process of ribavirin condensation compound, to solve above-mentioned background skill
The problem of being proposed in art.
To achieve the above object, the present invention provides the following technical solutions：A kind of chemical synthesis side of ribavirin condensation compound
Method, this method are as follows：
S1：By 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides, hmds and ammonium sulfate are added to
In the three-necked bottle of 500ml, heating reflux reaction is cooled to room temperature to clarifying；
S2：Evaporated under reduced pressure obtains yellow oil, and is dissolved in the dichloromethane of 200~300ml, adds tetrem
Acyl ribose, is then added dropwise stannic chloride；
S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate, acutely stirred using the detection of thin plate chromatography chromatography
Rear stratification is mixed, organic phase is washed with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying, filtering, and filtrate decompression boils off
Solvent；
S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol, 5~7h is stirred at room temperature, is precipitated white
Color precipitates, and filtering, filter cake is dried under reduced pressure after being washed with methanol；
S5：Then addition ethyl alcohol, filters after being sufficiently stirred, after filter cake is washed with methanol, is dried under reduced pressure and merges filter cake；
S6：Filter cake after merging is dissolved in ethyl alcohol in a heated condition, after bleaching agent bleaching, filters crystallisation by cooling,
White crystalline powder is made.
Preferably, in the step S1, the additive amount of 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides are 11
The additive amount of~12g, hmds are 200~300ml, and the additive amount of ammonium sulfate is 0.5~1g.
Preferably, in the step S1, the temperature of heating is 95~100 DEG C, and heating time is 5~7h.
Preferably, in the step S2, the additive amount of 1,2,3,5-Tetra-O-Acetyl-D-Ribose is 30~40g, the dripping quantity of stannic chloride is 5~
7ml。
Preferably, it in the step S2, when adding 1,2,3,5-Tetra-O-Acetyl-D-Ribose, is carried out in ice bath, and the temperature control of ice bath
At 0~5 DEG C.
Preferably, in the step S3, sodium bicarbonate aqueous solution is 100~120ml, is washed 3~5 times.
Preferably, in the step S6, the temperature of heating is 40~60 DEG C, and is dissolved in the ethyl alcohol of 95%, 150~180ml
In solution.
Preferably, in the step S6, decolorising agent is one kind in activated carbon, carclazyte or absorption resin.
Compared with prior art, the beneficial effects of the invention are as follows：The improved raw materials technology of the present invention is easy to get, reaction condition
Mildly, each intermediate is not necessarily to isolate and purify, and easy to operate, total recovery can reach 65% or more, Ribavirin obtained
Purity is 99% or more.
Specific implementation mode
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
The every other embodiment that technical staff is obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment one
A kind of chemical synthesis process of ribavirin condensation compound, this method are as follows：
S1：By 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides 11g, hmds 200ml and sulfuric acid
Ammonium 0.5g is added in the three-necked bottle of 500ml, and for heating reflux reaction to clarifying, the temperature of heating is 95 DEG C, heating time 5h,
It is cooled to room temperature；
S2：Evaporated under reduced pressure obtains yellow oil, and is dissolved in the dichloromethane of 200ml, and four are added in ice bath
Acetyl ribose 30g, and the temperature of ice bath is controlled at 0 DEG C, and stannic chloride 5ml is then added dropwise；
S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate, acutely stirred using the detection of thin plate chromatography chromatography
Rear stratification is mixed, organic phase saturated sodium bicarbonate aqueous solution 100ml is washed 3 times, anhydrous sodium sulfate drying, filtering, filtrate
Decompression boils off solvent；
S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol, 5h is stirred at room temperature, it is heavy that white is precipitated
It forms sediment, filtering, filter cake is dried under reduced pressure after being washed with methanol；
S5：Then addition ethyl alcohol, filters after being sufficiently stirred, after filter cake is washed with methanol, is dried under reduced pressure and merges filter cake；
S6：Filter cake after merging is dissolved in a heated condition in the ethyl alcohol of 95%, 150ml, and the temperature of heating is 40 DEG C, warp
After crossing bleaching agent bleaching, crystallisation by cooling is filtered, white crystalline powder is made.
Embodiment two
A kind of chemical synthesis process of ribavirin condensation compound, this method are as follows：
S1：By 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides 12g, hmds 300ml and sulfuric acid
Ammonium 1g is added in the three-necked bottle of 500ml, and for heating reflux reaction to clarifying, the temperature of heating is 100 DEG C, heating time 7h,
It is cooled to room temperature；
S2：Evaporated under reduced pressure obtains yellow oil, and is dissolved in the dichloromethane of 300ml, and four are added in ice bath
Acetyl ribose 40g, and the temperature of ice bath is controlled at 5 DEG C, and stannic chloride 7ml is then added dropwise；
S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate, acutely stirred using the detection of thin plate chromatography chromatography
Rear stratification is mixed, organic phase saturated sodium bicarbonate aqueous solution 120ml is washed 5 times, anhydrous sodium sulfate drying, filtering, filtrate
Decompression boils off solvent；
S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol, 7h is stirred at room temperature, it is heavy that white is precipitated
It forms sediment, filtering, filter cake is dried under reduced pressure after being washed with methanol；
S5：Then addition ethyl alcohol, filters after being sufficiently stirred, after filter cake is washed with methanol, is dried under reduced pressure and merges filter cake；
S6：Filter cake after merging is dissolved in a heated condition in the ethyl alcohol of 95%, 180ml, and the temperature of heating is 60 DEG C, warp
After crossing bleaching agent bleaching, crystallisation by cooling is filtered, white crystalline powder is made.
Embodiment three
A kind of chemical synthesis process of ribavirin condensation compound, this method are as follows：
S1：By 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides 11.5g, hmds 260ml and sulphur
Sour ammonium 0.8g is added in the three-necked bottle of 500ml, and for heating reflux reaction to clarifying, the temperature of heating is 97 DEG C, and heating time is
6h is cooled to room temperature；
S2：Evaporated under reduced pressure obtains yellow oil, and is dissolved in the dichloromethane of 260ml, and four are added in ice bath
Acetyl ribose 35g, and the temperature of ice bath is controlled at 2 DEG C, and stannic chloride 6ml is then added dropwise；
S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate, acutely stirred using the detection of thin plate chromatography chromatography
Rear stratification is mixed, organic phase saturated sodium bicarbonate aqueous solution 110ml is washed 4 times, anhydrous sodium sulfate drying, filtering, filtrate
Decompression boils off solvent；
S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol, 6h is stirred at room temperature, it is heavy that white is precipitated
It forms sediment, filtering, filter cake is dried under reduced pressure after being washed with methanol；
S5：Then addition ethyl alcohol, filters after being sufficiently stirred, after filter cake is washed with methanol, is dried under reduced pressure and merges filter cake；
S6：Filter cake after merging is dissolved in a heated condition in the ethyl alcohol of 95%, 160ml, and the temperature of heating is 50 DEG C, warp
After crossing bleaching agent bleaching, crystallisation by cooling is filtered, white crystalline powder is made.
Acidity detects
This product 1.0g is taken, after adding water 50ml to dissolve, adds saturated potassium chloride solution 0.2ml, shakes up, is measured (2010 in accordance with the law
Two VI H of annex of version pharmacopeia), pH value is 4.0~6.5；
The clarity and color of solution
This product 0.5g is taken, after adding water 10ml to dissolve, solution answers clear, colorless；
Related substance
This product is taken, flowing phased soln is added and the solution in every 1ml containing about 0.4mg is made as test solution, precision amount
1ml is taken, is set in 100ml measuring bottles, scale is diluted to mobile phase, shakes up, as a contrast solution.According to the chromatography under assay item
Condition takes 20 μ l of contrast solution, injects liquid chromatograph, conditioning instrumentation sensitivity, it is about full scale to make the peak height at principal component peak
25%；It is accurate again to measure test solution and each 20 μ l of contrast solution, it is injected separately into liquid chromatograph, record chromatogram to master
At 2 times of swarming retention time, if any impurity peaks in the chromatogram of test solution, the peak area of single impurity is not greater than pair
According to 0.25 times (0.25%) of solution main peak area, main peak area that is each impurity peak area and being not greater than contrast solution
(1.0%)；
Loss on drying
This product is taken, is dried to constant weight at 105 DEG C, less loss weight must not cross 0.5% (two annex VIII of version pharmacopeia in 2010
L)；
Residue on ignition
This product 1.0g is taken, checks (two VIII N of annex of version pharmacopeia in 2010) in accordance with the law, remaining residue must not cross 0.1%；
Heavy metal
The residue left under residue on ignition item is taken, checks (two annex of version pharmacopeia in 2010, VIII the second methods of H) in accordance with the law, containing weight
Metal must not cross 10/1000000ths；
Assay
It is measured according to high performance liquid chromatography (two V D of annex of version pharmacopeia in 2010)；
Chromatographic condition and system suitability
Hydrogen type cation exchange resin with the crosslinked one divinyl copolymer of styrene of sulfonation is filler；With water
(adjusting pH value to 2.5 ± 0.1 with dilute sulfuric acid) is mobile phase；Detection wavelength is 207nm.Number of theoretical plate is calculated by Ribavirin peak
Not less than 2000；
Measuring method
Take this product, it is accurately weighed, add flowing phased soln and quantify dilution be made it is molten containing about 50 μ g of Ribavirin in every 1ml
Liquid, precision measure 20 μ l and inject liquid chromatograph, record chromatogram；It separately takes Ribavirin reference substance appropriate, is measured in the same method.By outer
Mark method with calculated by peak area to get；
Storage
Shading is sealed.
In summary, highly preferred embodiment of the present invention is embodiment three, the improved raw materials technology of the present invention is easy to get,
Reaction condition is mild, and each intermediate is not necessarily to isolate and purify, and easy to operate, total recovery can reach 65% or more, profit obtained
The purity of Ba Weilin is 99% or more.Although an embodiment of the present invention has been shown and described, for the common skill of this field
For art personnel, it is possible to understand that can be carried out without departing from the principles and spirit of the present invention to these embodiments a variety of
Change, modification, replacement and modification, the scope of the present invention is defined by the appended.
Claims (8)
1. a kind of chemical synthesis process of ribavirin condensation compound, it is characterised in that：This method is as follows：
S1：By 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides, hmds and ammonium sulfate are added to
In the three-necked bottle of 500ml, heating reflux reaction is cooled to room temperature to clarifying；
S2：Evaporated under reduced pressure obtains yellow oil, and is dissolved in the dichloromethane of 200~300ml, adds four acetyl cores
Stannic chloride is then added dropwise in sugar；
S3：After the reaction was complete, reaction solution is poured into the ice water of sodium bicarbonate, after being vigorously stirred using the detection of thin plate chromatography chromatography
Stratification, organic phase are washed with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying, filtering, and filtrate decompression boils off solvent；
S4：Product made from step S3 is dissolved in the ammonia saturated solution of methanol, 5~7h is stirred at room temperature, it is heavy that white is precipitated
It forms sediment, filtering, filter cake is dried under reduced pressure after being washed with methanol；
S5：Then addition ethyl alcohol, filters after being sufficiently stirred, after filter cake is washed with methanol, is dried under reduced pressure and merges filter cake；
S6：Filter cake after merging is dissolved in ethyl alcohol in a heated condition, after bleaching agent bleaching, is filtered crystallisation by cooling, is made
White crystalline powder.
2. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S1, the additive amount of 1- trimethylsilyls -1H-1,2,4- triazole -3- formamides are 11~12g, and hmds adds
Dosage is 200~300ml, and the additive amount of ammonium sulfate is 0.5~1g.
3. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S1, the temperature of heating is 95~100 DEG C, and heating time is 5~7h.
4. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S2, the additive amount of 1,2,3,5-Tetra-O-Acetyl-D-Ribose is 30~40g, and the dripping quantity of stannic chloride is 5~7ml.
5. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
It in S2, when adding 1,2,3,5-Tetra-O-Acetyl-D-Ribose, is carried out in ice bath, and the temperature of ice bath is controlled at 0~5 DEG C.
6. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S3, sodium bicarbonate aqueous solution is 100~120ml, is washed 3~5 times.
7. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S6, the temperature of heating is 40~60 DEG C, and is dissolved in the ethanol solution of 95%, 150~180ml.
8. a kind of chemical synthesis process of ribavirin condensation compound according to claim 1, it is characterised in that：The step
In S6, decolorising agent is one kind in activated carbon, carclazyte or absorption resin.
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| CN201810687926.0A CN108484691A (en) | 2018-06-28 | 2018-06-28 | A kind of chemical synthesis process of ribavirin condensation compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535277A (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 |
| WO2017155923A1 (en) * | 2016-03-07 | 2017-09-14 | Emory University | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
-
2018
- 2018-06-28 CN CN201810687926.0A patent/CN108484691A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535277A (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 |
| WO2017155923A1 (en) * | 2016-03-07 | 2017-09-14 | Emory University | Nucleotide and nucleoside therapeutic compositions and uses related thereto |
Non-Patent Citations (1)
| Title |
|---|
| 蔡玉瑛等: "利巴韦林的合成", 《中国医药工业杂志》 * |
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Application publication date: 20180904 |