CN108484691A - A kind of chemical synthesis process of ribavirin condensation compound - Google Patents

Abstract

The invention discloses a chemical synthesis method of a ribavirin condensate in the technical field of chemical synthesis. The specific steps of the method are as follows: S1: 1-trimethylsilyl-1H-1,2,4-triazole ‑3‑formamide, hexamethyldisilamine and ammonium sulfate were added to a 500ml three-necked flask; S2: evaporated to dryness under reduced pressure to obtain a yellow oil; S3: after the reaction was detected by thin-plate chromatography, the reaction Pour the solution into ice water of sodium bicarbonate; S4: dissolve the product obtained in step S3 in a saturated ammonia solution of methanol; S5: then add ethanol, stir and filter; S6: combine the filter cake under heating conditions Soluble in ethanol, after being decolorized by a decolorizing agent, filtered and cooled to crystallize to obtain a white crystal powder, the improved process raw materials of the present invention are easy to obtain, the reaction conditions are mild, each intermediate does not need to be separated and purified, the operation is simple, and the total yield can reach Reaching more than 65%, the purity of the prepared ribavirin is more than 99%.

Description

A kind of chemical synthesis method of ribavirin condensate

technical field

The invention discloses a chemical synthesis method of a ribavirin condensate, and specifically belongs to the technical field of chemical synthesis.

Background technique

Ribavirin, also known as Ribavirin, Ribavirin, Niscor, etc., is a broad-spectrum and potent antiviral drug. Ribavirin is an antiviral drug that belongs to synthetic nucleoside drugs. and RNA viruses have inhibitory effect, the mechanism is not clear. It is widely used in the prevention and treatment of viral diseases. Common dosage forms include injections, tablets, oral liquids, aerosols, etc. However, in the existing ribavirin synthesis method, the high temperature during condensation is easy to decompose the raw material, and the yield is low; the high pressure reaction is required for tens of hours during ammonolysis; The process is not easy to operate. For this reason, we put forward a kind of chemical synthesis method of ribavirin condensate and put it into use, to solve the above-mentioned problems.

Contents of the invention

The object of the present invention is to provide a chemical synthesis method of ribavirin condensate, to solve the problems raised in the above-mentioned background technology.

In order to achieve the above object, the present invention provides the following technical scheme: a chemical synthesis method of ribavirin condensate, the specific steps of the method are as follows:

S1: Add 1-trimethylsilyl-1H-1,2,4-triazole-3-carboxamide, hexamethyldisilazide and ammonium sulfate to a 500ml three-necked bottle, heat to reflux until clarification , cooled to room temperature;

S2: Evaporate to dryness under reduced pressure to obtain a yellow oil, and dissolve it in 200-300ml of dichloromethane, add tetraacetyl ribose, and then add tin chloride dropwise;

S3: After the completion of the reaction was detected by thin-plate chromatography, the reaction solution was poured into ice water with sodium bicarbonate, stirred vigorously and allowed to stand for stratification, the organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled off the solvent under reduced pressure;

S4: Dissolving the product obtained in step S3 in a methanol-saturated ammonia solution, stirring at room temperature for 5-7 hours, a white precipitate precipitates, filtering, washing the filter cake with methanol, and drying under reduced pressure;

S5: Add ethanol subsequently, filter after fully stirring, wash the filter cake with methanol, dry under reduced pressure and combine the filter cake;

S6: The combined filter cakes are dissolved in ethanol under heating conditions, decolorized by a decolorizing agent, filtered and cooled to crystallize to obtain a white crystal powder.

Preferably, in the step S1, the added amount of 1-trimethylsilyl-1H-1,2,4-triazole-3-carboxamide is 11-12 g, and the added amount of hexamethyldisilamine is 200-300ml, the amount of ammonium sulfate added is 0.5-1g.

Preferably, in the step S1, the heating temperature is 95-100° C., and the heating time is 5-7 hours.

Preferably, in the step S2, the amount of tetraacetyl ribose added is 30-40 g, and the amount of tin chloride added dropwise is 5-7 ml.

Preferably, in the step S2, when adding tetraacetyl ribose, it is carried out in an ice bath, and the temperature of the ice bath is controlled at 0-5°C.

Preferably, in the step S3, the sodium bicarbonate aqueous solution is 100-120 ml and washed 3-5 times.

Preferably, in the step S6, the heating temperature is 40-60°C, and the mixture is dissolved in 95%, 150-180ml ethanol solution.

Preferably, in the step S6, the decolorizing agent is one of activated carbon, clay or adsorption resin.

Compared with the prior art, the beneficial effects of the present invention are: the improved process raw materials of the present invention are easy to obtain, the reaction conditions are mild, each intermediate does not need to be separated and purified, the operation is simple, the total yield can reach more than 65%, and the obtained The purity of ribavirin is above 99%.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Embodiment one

A kind of chemical synthesis method of ribavirin condensate, the concrete steps of this method are as follows:

S1: Add 11g of 1-trimethylsilyl-1H-1,2,4-triazole-3-carboxamide, 200ml of hexamethyldisilamine and 0.5g of ammonium sulfate to a 500ml three-necked bottle, and heat Reflux reaction until clarification, the heating temperature is 95°C, the heating time is 5h, and cooled to room temperature;

S2: Evaporate to dryness under reduced pressure to obtain a yellow oil, and dissolve it in 200ml of dichloromethane, add 30g of tetraacetyl ribose in an ice bath, and control the temperature of the ice bath at 0°C, then add tin chloride dropwise 5ml;

S3: After the completion of the reaction is detected by thin-plate chromatography, the reaction solution is poured into ice water of sodium bicarbonate, stirred vigorously and left to stand for stratification, and the organic phase is washed 3 times with 100 ml of saturated aqueous sodium bicarbonate solution, and anhydrous sodium sulfate Dry, filter, and evaporate the filtrate to remove the solvent under reduced pressure;

S4: dissolving the product obtained in step S3 in a saturated ammonia solution of methanol, stirring at room temperature for 5 hours, a white precipitate precipitated, filtered, and the filter cake was washed with methanol and dried under reduced pressure;

S5: Add ethanol subsequently, filter after fully stirring, wash the filter cake with methanol, dry under reduced pressure and combine the filter cake;

S6: The combined filter cake is dissolved in 95%, 150ml of ethanol under heating conditions, the heating temperature is 40°C, after being decolorized by a decolorizing agent, it is filtered and cooled to crystallize to obtain a white crystal powder.

Embodiment two

A kind of chemical synthesis method of ribavirin condensate, the concrete steps of this method are as follows:

S1: Add 12g of 1-trimethylsilyl-1H-1,2,4-triazole-3-carboxamide, 300ml of hexamethyldisilamine and 1g of ammonium sulfate to a 500ml three-necked flask, heat to reflux React until clarification, the heating temperature is 100°C, the heating time is 7h, and cooled to room temperature;

S2: Evaporate to dryness under reduced pressure to obtain a yellow oil, and dissolve it in 300ml of dichloromethane, add 40g of tetraacetylribose in an ice bath, and control the temperature of the ice bath at 5°C, then add tin chloride dropwise 7ml;

S3: After the completion of the reaction is detected by thin-plate chromatography, the reaction solution is poured into ice water of sodium bicarbonate, stirred vigorously and left to stand for stratification, and the organic phase is washed 5 times with 120 ml of saturated aqueous sodium bicarbonate solution, anhydrous sodium sulfate Dry, filter, and evaporate the filtrate to remove the solvent under reduced pressure;

S4: dissolving the product obtained in step S3 in a saturated ammonia solution of methanol, stirring at room temperature for 7 hours, a white precipitate precipitated, filtered, and the filter cake was washed with methanol and dried under reduced pressure;

S5: Add ethanol subsequently, filter after fully stirring, wash the filter cake with methanol, dry under reduced pressure and combine the filter cake;

S6: The combined filter cake is dissolved in 95% and 180ml of ethanol under heating conditions, the heating temperature is 60°C, after being decolorized by a decolorizing agent, it is filtered and cooled to crystallize to obtain a white crystal powder.

Embodiment three

A kind of chemical synthesis method of ribavirin condensate, the concrete steps of this method are as follows:

S1: Add 11.5g of 1-trimethylsilyl-1H-1,2,4-triazole-3-carboxamide, 260ml of hexamethyldisilamine and 0.8g of ammonium sulfate into a 500ml three-necked bottle, Heating to reflux reaction until clarification, the heating temperature is 97°C, the heating time is 6h, and cooled to room temperature;

S2: Evaporate to dryness under reduced pressure to obtain a yellow oil, and dissolve it in 260ml of dichloromethane, add 35g of tetraacetyl ribose in an ice bath, and control the temperature of the ice bath at 2°C, then add tin chloride dropwise 6ml;

S3: After the completion of the reaction is detected by thin-plate chromatography, the reaction solution is poured into ice water of sodium bicarbonate, stirred vigorously and left to stand for stratification, and the organic phase is washed 4 times with 110ml of saturated aqueous sodium bicarbonate solution, anhydrous sodium sulfate Dry, filter, and evaporate the filtrate to remove the solvent under reduced pressure;

S4: dissolving the product obtained in step S3 in a saturated ammonia solution of methanol, stirring at room temperature for 6 hours, a white precipitate precipitated, filtered, and the filter cake was washed with methanol and dried under reduced pressure;

S5: Add ethanol subsequently, filter after fully stirring, wash the filter cake with methanol, dry under reduced pressure and combine the filter cake;

S6: The combined filter cake was dissolved in 95%, 160ml of ethanol under heating conditions, the heating temperature was 50°C, after being decolorized by a decolorizing agent, filtered and cooled to crystallize to obtain a white crystal powder.

acidity test

Take 1.0g of this product, add 50ml of water to dissolve, add 0.2ml of saturated potassium chloride solution, shake well, and measure according to the law (2010 edition of Pharmacopoeia II Appendix VIH), the pH value is 4.0-6.5;

Clarity and color of the solution

Take 0.5g of this product, add 10ml of water to dissolve, the solution should be clear and colorless;

relative substance

Take this product, add mobile phase to dissolve and make a solution containing about 0.4mg per 1ml as the test solution, accurately measure 1ml, put it in a 100ml measuring bottle, dilute to the mark with mobile phase, shake well, and use it as a control solution . According to the chromatographic conditions under the content determination item, get contrast solution 20 μ l, inject liquid chromatograph, adjust instrument sensitivity, make the peak height of main component peak be about 25% of full scale; Then accurately measure need testing solution and contrast solution Each 20 μl was injected into the liquid chromatograph, and the chromatogram was recorded to twice the retention time of the main component peak. If there is an impurity peak in the chromatogram of the test solution, the peak area of a single impurity should not be greater than 0.25 times the main peak area of the control solution. (0.25%), the sum of each impurity peak area must not be greater than the main peak area (1.0%) of the contrast solution;

Loss on drying

Take this product and dry it at 105°C to constant weight, and the weight loss should not exceed 0.5% (Appendix VIII L of Part Two of the Pharmacopoeia of the 2010 Edition);

Residue on ignition

Take 1.0g of this product, check according to law (Appendix VIII N of Part Two of the Pharmacopoeia, 2010 Edition), and the remaining residue shall not exceed 0.1%;

heavy metal

Take the residue left under the item of residue on ignition, and check it according to the law (2010 edition of Pharmacopoeia, Appendix ⅧH, second method), and the heavy metal content should not exceed 10 parts per million;

Assay

Measure according to high performance liquid chromatography (2010 edition pharmacopoeia two appendix ⅤD);

Chromatographic conditions and system suitability test

Use sulfonated cross-linked styrene-divinyl copolymer hydrogen type cation exchange resin as filler; use water (adjust pH value to 2.5±0.1 with dilute sulfuric acid) as mobile phase; detection wavelength is 207nm. The number of theoretical plates is not less than 2000 based on ribavirin peak calculation;

Assay

Take this product, accurately weigh it, add mobile phase to dissolve and quantitatively dilute to make a solution containing about 50 μg of ribavirin per 1 ml, accurately measure 20 μl and inject it into the liquid chromatograph, and record the chromatogram; take another ribavirin An appropriate amount of reference substance was determined in the same way. According to the external standard method to calculate the peak area, that is;

storage

Shade, sealed and stored.

Based on the above, the best embodiment of the present invention is Embodiment 3. The improved process raw materials of the present invention are easy to obtain, the reaction conditions are mild, the intermediates do not need to be separated and purified, the operation is simple, and the total yield can reach more than 65%. , the purity of the prepared ribavirin is more than 99%. Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

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.