CN111471027B - Synthesis process of ribavirin intermediate and intermediate - Google Patents

Synthesis process of ribavirin intermediate and intermediate Download PDF

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CN111471027B
CN111471027B CN202010435545.0A CN202010435545A CN111471027B CN 111471027 B CN111471027 B CN 111471027B CN 202010435545 A CN202010435545 A CN 202010435545A CN 111471027 B CN111471027 B CN 111471027B
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ribavirin
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triazole
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formamide
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CN111471027A (en
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谈平忠
谈平安
魏巍
黄明辉
田晨煦
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Guang'an Runkang Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/20—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/22—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups further bound to nitrogen atoms, e.g. hydrazidines

Abstract

The invention discloses a synthesis process of a ribavirin intermediate and the intermediate, wherein oxalic acid monohydrazide ester is used as a raw material, and the ribavirin intermediate 1,2, 4-triazole-3-formamide is obtained by condensation, ammonolysis and cyclization with ortho-formic acid triester in sequence. The process selects oxalic acid monohydrazide ester as a starting material, has the advantages of easily obtained raw materials, low price, short synthetic route, no use of expensive raw materials such as hypophosphorous acid and the like, no use of dangerous raw materials such as hydrogen peroxide and the like, no adoption of a dangerous process 'diazotization reaction', mild reaction conditions, almost no generation of waste water and waste solids in the whole synthetic process, environmental protection, simple operation and high yield.

Description

Synthesis process of ribavirin intermediate and intermediate
Technical Field
The invention relates to the technical field of synthesis of ribavirin intermediates, and particularly relates to a synthesis process of a ribavirin intermediate and an intermediate.
Background
With the development of economic globalization, global climate warming and massive antibiotic abuse by human, many germs have strong drug resistance and rapid gene mutation, such as SARS, avian influenza, HlNl A, 2019-nCoV and other viruses appearing in recent years seriously endanger human health, and the dosage of antiviral drugs is increased greatly. Ribavirin is a very important antiviral drug. Ribavirin (English: Ribavirin), also known as Ribavirin, nicergo, etc., was synthesized in 1970 by the ICN pharmaceutical company Joseph T.Witkowski. The antiviral drug is a broad-spectrum and strong-effect antiviral drug, belongs to a synthetic nucleoside drug, has an inhibiting effect on a plurality of DNA and RNA viruses, is used for treating hepatitis C and human respiratory tract fusion virus (RSV) by matching with long-acting interferon by the American Food and Drug Administration (FDA), and is widely applied to the prevention and treatment of viral diseases at present. The common dosage forms include injection, tablet, oral liquid, aerosol, etc.
Methyl 1,2, 4-triazole-3-carboxylate and 1,2, 4-triazole-3-formamide are important intermediates for synthesizing ribavirin. At present, about 700 tons of ribavirin are produced in China every year, 630 tons of 1,2, 4-triazole-3-carboxylic acid methyl ester are needed, the yield accounts for more than 60% of the world yield, and developed countries in the western world increasingly import the ribavirin from China, so that the market prospect of the 1,2, 4-triazole-3-carboxylic acid methyl ester is very wide. 1,2, 4-triazole-3-carboxylic acid methyl ester can also be prepared into a plurality of derivatives containing other active groups, such as 3-cyano-1, 2, 4-triazole-3-carboxylic acid methyl ester, 1,2, 4-triazole-3-formamide and other compounds, and according to the report of CN200410064933.3, the American Gilles de Pagii company has developed a new anti-cancer drug by using 3-cyano-1, 2, 4-triazole-3-carboxylic acid methyl ester, and once the drug enters the promotion and application stage, the market demand of 1,2, 4-triazole-3-carboxylic acid methyl ester is greatly increased.
1,2, 4-triazole-3-carboxylic acid methyl ester having the formula:
Figure GDA0003012256160000011
many documents report about the synthesis of 1,2, 4-triazole-3-carboxylic acid methyl ester, but the synthesis has different problems of complicated route, difficult operation, dangerous process, more 'three wastes' and high cost.
A chemical reagent 2006, 28(8), 503-504 reports that diethyl oxalate is used as a raw material, and the 1,2, 4-triazole-3-methyl formate is prepared by aminolysis, methyl ether acetate hydrazinolysis, cyclization and methyl esterification, and the route is as follows:
Figure GDA0003012256160000021
the method has low yield, more byproducts and too high cost of formamidine acetate, and is not suitable for industrial production.
EP118699 and Tetrahedron 56(2000)9495-9502 report that 5-amino-1, 2, 4-triaza-3-formic acid is used as raw material, and 1,2, 4-triaza-3-ethyl formate is prepared by diazotization and methyl esterification, and the route is as follows:
Figure GDA0003012256160000022
the method needs to use hypophosphorous acid, and is expensive; the danger coefficient of the diazotization reaction is higher; and the esterification yield is low; the raw material 5-amino-1, 2, 4-triazo-3-formic acid is not easy to obtain; the discharge amount of three wastes in industrial production is huge, the pollution is serious, and the prospect is great.
At present, lime nitrogen is generally used as a raw material in industrial production, aminoguanidine bicarbonate is prepared by hydrazinolysis of hydrazine hydrate, grass acylation is carried out, cyclization is carried out under an alkaline condition, methyl esterification is carried out, and finally diazotization deamination is carried out to obtain the product. The route is as follows:
Figure GDA0003012256160000023
the method has long circuit; and adopts a dangerous process of 'diazotization reaction'; meanwhile, the three wastes are high, and the environmental pollution is great; the operation is not easy; is not suitable for industrial production.
Chinese patent CN101830858.B reports that oxalic acid monomethyl ester hydrazide is prepared by reacting dimethyl oxalate with hydrazine hydrate, then 5-mercapto-1, 2, 4-triazole-3-methyl carboxylate is prepared by ring closure with ammonium thiocyanate, and finally the target product 1,2, 4-triazole-3-methyl carboxylate is obtained by oxidative desulfurization with 30% hydrogen peroxide. The route is as follows:
Figure GDA0003012256160000024
the method uses dangerous hydrogen peroxide, and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide a synthesis process of a ribavirin intermediate, which has the advantages of low and safe raw material cost, mild reaction conditions, short synthesis route and no pollution, and solves the problems of complicated synthesis technical route, difficult operation, high risk, high cost and pollution of the existing ribavirin intermediate.
The invention is realized by the following technical scheme:
a synthesis process of a ribavirin intermediate comprises the steps of taking oxalic acid monohydrazide as a raw material, and sequentially carrying out condensation, ammonolysis and cyclization with ortho-formic acid triester to obtain the ribavirin intermediate 1,2, 4-triazole-3-formamide.
The invention provides a novel synthesis process of ribavirin intermediate 1,2, 4-triazole-3-formamide, which adopts oxalic acid monohydrazide as a starting raw material, has the advantages of easily obtained and low price of the raw material, short synthesis route, no use of expensive raw materials such as hypophosphorous acid and dangerous raw materials such as hydrogen peroxide, no adoption of a dangerous process of diazotization reaction, mild reaction conditions, almost no generation of waste water and waste solids in the whole synthesis process, environmental protection, simple operation and high yield, and has remarkable social and economic benefits and commercial application values.
In conclusion, the synthesis process disclosed by the invention is low in raw material cost, safe, mild in reaction condition, short in synthesis route and free of pollution, and solves the problems of complex synthesis technical route, difficult operation, high risk, high cost and pollution of the existing ribavirin intermediate.
Further, the method comprises the following steps:
s1: in an alcohol solvent, oxalic acid monohydrazide ester and ortho-formic acid triester are subjected to condensation reaction to generate oxalyl hydrazine ether;
s2: reacting oxalyl hydrazine ether with ammonia gas to generate oxalyl hydrazine diamine;
s3: the oxalic hydrazine diamine is subjected to a cyclization reaction to generate ribavirin intermediate 1,2, 4-triazole-3-formamide.
The specific synthetic route is as follows:
Figure GDA0003012256160000031
further, the alcohol solvent is methanol or ethanol.
Further, the reaction temperature of the ring closing reaction is 0-100 ℃, and the time is 8-48 h.
Furthermore, the reaction temperature of the ring closing reaction is 50-80 ℃ and the time is 20-36 h.
Further, the weight ratio of the oxalic acid monohydrazide ester to the orthoformic acid triester is 1:1.6-2.0 or the molar ratio of the oxalic acid monohydrazide ester to the orthoformic acid triester is 1: 1-4.
Further, the molar ratio of the oxalyl hydrazine ether to the ammonia gas is 1: 3.5-4.5.
The invention further improves the yield by reasonably controlling the reaction parameters and the molar ratio of the materials in the synthesis process.
Among them, the raw material oxalic acid monohydrazide ester is well documented, and is synthesized according to the following documents:
Szmuszkovicz,J.；Greig,M.E.；Journal of Medicinal and Pharmaceutical Chemistry； vol.4；(1961)；p.259–296。
the structural formula of the oxalic acid monohydrazide ester is as follows:
Figure GDA0003012256160000041
wherein R is1Is CH3Or CH3CH2；
The orthoformate is CH (OR)2)3Wherein R is2Is CH3Or CH3CH2。
A synthesis process of a ribavirin intermediate comprises the following steps:
s1: in an alcohol solvent, oxalic acid monohydrazide ester and ortho-formic acid triester are subjected to condensation reaction to generate oxalyl hydrazine ether;
s2: reacting oxalyl hydrazine ether with ammonia gas to generate oxalyl hydrazine diamine;
s3: carrying out a cyclization reaction on the oxalic hydrazine diamine to generate a ribavirin intermediate 1,2, 4-triazole-3-formamide;
s4: 1,2, 4-triazole-3-formamide is used as a raw material and is subjected to esterification reaction with alcohol to generate a ribavirin intermediate 1,2, 4-triazole-3-methyl carboxylate.
The specific synthetic route is as follows:
Figure GDA0003012256160000042
wherein, the compound B and the compound C have new structures which are not reported.
Further, the weight ratio of the 1,2, 4-triazole-3-formamide to the alcohol is 1:5-6, the temperature of the esterification reaction is 80-90 ℃, and the time is 4-6 h.
An intermediate for synthesizing ribavirin intermediate 1,2, 4-triazole-3-formamide has the following structural formula:
R1OOC-CONHN＝CHOR2
wherein R is1Is CH3Or CH3CH2，R2Is CH3Or CH3CH2。
An intermediate for synthesizing ribavirin intermediate 1,2, 4-triazole-3-formamide, which has the following structural formula
H2NOC-CONHN＝CHNH2。
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the synthesis process has the advantages of short route, short production period and simple operation.
2. The synthesis process provided by the invention has the advantages of few three wastes, almost no solid waste and waste water, environmental friendliness and environmental friendliness.
3. The synthesis process has the advantages of simple and easily obtained raw materials and low production cost.
4. The synthesis process is safe and reliable, and does not involve dangerous processes such as oxidation, diazotization and the like.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is a drawing of Compound B of example 11A HNMR map;
FIG. 2 is a drawing of Compound C of example 11A HNMR map;
FIG. 3a is an LC-UV spectrum of Compound D in example 1;
FIG. 3b is an LC-MS spectrum of Compound D in example 1;
FIG. 3c is an LC-MS spectrum of compound D of example 1 with a retention time of 0.35 min;
FIG. 4 is a drawing of Compound E from example 51A HNMR map;
FIG. 5a is the LC-UV spectrum of Compound E in example 5;
FIG. 5b is an LC-MS spectrum of Compound E in example 5;
FIG. 5c is an MS spectrum of Compound E in example 5 with a retention time of 0.56 min in the LC-MS spectrum
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1:
a synthesis process of ribavirin intermediate 1,2, 4-triazole-3-formamide, and a synthesis route (in a structural formula of A, B, C, R)1＝R2＝-CH3)：
Figure GDA0003012256160000061
The synthesis operation steps are as follows:
s1: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; to this was added 200mL of anhydrous methanol, and while stirring, methyl monohydrazide oxalate (Compound A) (59g, 0.5mol) was added, and trimethyl orthoformate (106.1g, 1.0mol) was added in one portion and reacted at room temperature for 4 hours; after the reaction is finished, concentrating and recovering methanol and excess methanolTrimethyl orthoformate; the residue is oxalic acid monohydrazide methyl ether (oxalyl hydrazine methyl ether compound B, R)1＝R2Me)76g, theoretical yield: 95 percent.1H NMR(400MHz， DMSO-d6) The crude product is shown as a mixture of four geometric isomers, consistent with the structural features of two pairs of double bonds in the molecule. Wherein the content of the first and second substances,1H NMR(DMSO-d6) The spectrum (as shown in fig. 1) shows that the chemical shift value of the isomer with the highest content is as follows: delta.3.72 (s,3H, CH)3),3.80(s,3H，CH3) 8.38(s,1H, CH), 11.69(s,1H, NH). The crude product was used in the next reaction without further purification.
S2: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; to this was added oxalyl hydrazine ether (Compound B, R)1＝R2Me 76.0g, 0.475mol), 200mL of anhydrous alcohol was added, ammonia gas (32.3g, 1.9mol) was added, the temperature was controlled at 48-50 ℃, and the reaction was terminated until no starting material was analyzed by central control, and the reaction mixture was used in the next reaction without purification. In order to identify the product structure, a little reactant is taken, filtered, washed and dried to obtain crude product (compound C) of the oxalic hydrazine diamine;1H NMR (DMSO-d6) The map (as shown in figure 2) is consistent with the expected product structure.
S3: after the aminolysis reaction (ammonia reaction) in the step S2 is finished, the reaction solution of the oxalic hydrazine diamine is not processed, and the temperature is continuously increased to 75-80 ℃ for reaction for 20 hours. And cooling, crystallizing, filtering and drying the reaction liquid to obtain a ribavirin intermediate 1,2, 4-triazole-3-formamide (compound D), and reacting in the steps S2 and S3 to obtain the yield of 98%. LC-MS shows, MH+Calculated molecular ion peak mass to charge ratio: 113.04, found: 113.3 (as shown in figures 3a-3 c).
According to the method of example 5, the 1,2, 4-triazole-3-formamide obtained in the step can be converted into 1,2, 4-triazole-3-methyl carboxylate, and the chemical structure of the 1,2, 4-triazole-3-formamide is proved to be correct.
Example 2:
this example is based on example 1, and differs from example 1 in that:
step S1 Synthesis of oxalic acid monohydrazide ethyl ether B (R1＝R2Et), step S2 uses oxalic acid monohydrazide ethyl ether as starting material, and the specific process of oxalic acid monohydrazide ethyl ether synthesis is as follows:
500mL three-necked flask equipped with magnetic stirring and thermometer was added with 200mL of absolute ethanol, and ethyl oxalyl monohydrazide (0.5mol, R) was added under stirring1＝CH3CH2-, triethyl orthoformate (0.5mol), heating and refluxing for reaction for 2 h; after the reaction was completed, the reaction mixture was concentrated. The residue is oxalic acid monohydrazide ethyl ether B (R)1＝R2Et), yield 95%.
Example 3:
s1: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; to this was added 200mL of anhydrous methanol, and to this was added methyl monohydrazide oxalate (Compound A, R)1＝CH359g, 0.5mol), adding trimethyl orthoformate (159.2g, 1.5mol) once again, and reacting for 4 hours at room temperature; after the reaction is finished, concentrating and recovering methanol and excessive trimethyl orthoformate; the residue is oxalic acid monohydrazide methyl ether (oxalyl hydrazine methyl ether compound B, R)1＝R2＝CH3)76.8g, molar yield: 96 percent;
s2: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; to this was added oxalyl hydrazine ether (Compound B, R)1＝R2＝ CH30.475mol), adding 200mL of anhydrous alcohol, introducing ammonia (28.3g, 1.66mol), controlling the temperature to be 48-50 ℃, reacting until no raw material exists in the process of central control analysis, finishing the reaction, filtering and drying to obtain the hydrazinodiamine (compound C);
s3: after the aminolysis reaction (ammonia reaction) in the step S2 is finished, the reaction solution of the oxalic hydrazine diamine is not processed, and the temperature is continuously increased to 95-100 ℃ for reaction for 10 hours. And cooling, crystallizing, filtering and drying the reaction liquid to obtain the ribavirin intermediate 1,2, 4-triazole-3-formamide (compound D), wherein the yield of the two steps of S2 and S3 is 98%.
Example 4:
s1: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; to this was added 200mL of anhydrous methanol, and to this was added methyl monohydrazide oxalate (Compound A, R)1＝CH359g, 0.5mol), and thenTrimethyl orthoformate (212.2g, 2.0mol) is added in one time and reacted for 4 hours at room temperature; after the reaction is finished, concentrating and recovering methanol and excessive trimethyl orthoformate; the residue is oxalic acid monohydrazide methyl ether (oxalyl hydrazine methyl ether compound B)77g, and the molar yield is as follows: 96 percent;
s2: a 500mL three-mouth bottle equipped with a magnetic stirring thermometer; adding oxalyl hydrazine ether (compound B, 0.475mol), adding 200mL of anhydrous alcohol, introducing ammonia (36.3g, 2.1mol), controlling the temperature to be 48-50 ℃, reacting until no raw material exists in the process of central control analysis, finishing the reaction, filtering, and drying to obtain the oxalyl hydrazine diamine (compound C);
s3: after the aminolysis reaction (ammonia reaction) in the step S2 is finished, the reaction solution of the oxalic hydrazine diamine is not processed, and the temperature is continuously increased to 95-100 ℃ for reaction for 8 hours. And cooling, crystallizing, filtering and drying the reaction liquid to obtain the ribavirin intermediate 1,2, 4-triazole-3-formamide (compound D), wherein the yield of the two steps of S2 and S3 is 98%.
Example 5:
a synthesis process of ribavirin intermediate methyl 1,2, 4-triazole-3-carboxylate comprises the following steps:
a 500mL single-mouth bottle is magnetically stirred and is cooled by a condenser, 1,2, 4-triazole-3-formamide (52.1g and 0.465mol) is added into the reaction bottle, 282.9g of 24% HCl/MeOH solution is added once again, the temperature is raised to the bath temperature of 80 ℃ for reflux reaction, and after 4 hours, a sample is taken and is subjected to HPLC central control analysis; after the reaction is finished, cooling the reaction liquid to room temperature, and filtering to remove inorganic salt; concentrating the reaction solution until about 200g of reaction solution remains, stirring and crystallizing the concentrated mother solution at 5 ℃ for 1h, filtering, and washing a filter cake once by using methanol; then the crude product is dried to obtain a crude product of the dried crude product of the 1,2, 4-triazole-3-carboxylic acid methyl ester (compound E) (53.1g, molar yield: 90%); recrystallizing with methanol to obtain pure product.1H NMR (as shown in FIG. 4) and LC-MS (as shown in FIGS. 5a-5 c) are in accordance with the documents [ EP118699 and Tetrahedron 56(2000) 9495-.
This example prepared methyl 1,2, 4-triazole-3-carboxylate with a melting point, UV, 1H and 13C NMR consistent with literature reports and commercial products, and a HPLC retention time consistent with commercial products.
The process for the synthesis of 1,2, 4-triazole-3-carboxamide in this example was synthesized as described in example 1.
The specific synthetic route is as follows:
Figure GDA0003012256160000081
the above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. A synthesis process of a ribavirin intermediate is characterized in that oxalic acid monohydrazide ester is used as a raw material, and the raw material is subjected to condensation, ammonolysis and cyclization with ortho-formic acid triester to obtain the ribavirin intermediate 1,2, 4-triazole-3-formamide.
2. The synthesis process of the ribavirin intermediate as described in claim 1, which comprises the following steps:
s1: in an alcohol solvent, oxalic acid monohydrazide ester and ortho-formic acid triester are subjected to condensation reaction to generate oxalyl hydrazine ether;
s2: carrying out ammonolysis reaction on oxalyl hydrazine ether and ammonia gas to generate oxalyl hydrazine diamine;
s3: the oxalic hydrazine diamine is subjected to a cyclization reaction to generate ribavirin intermediate 1,2, 4-triazole-3-formamide.
3. The synthesis process of the ribavirin intermediate as claimed in claim 2, wherein the alcohol solvent is methanol or ethanol.
4. The synthesis process of the ribavirin intermediate as claimed in claim 2, wherein the reaction temperature of the ring closure reaction is 0-100 ℃ and the time is 8-48 h.
5. The synthesis process of the ribavirin intermediate as claimed in claim 4, wherein the reaction temperature of the ring closure reaction is 50-80 ℃ and the time is 20-36 h.
6. The synthesis process of the ribavirin intermediate as claimed in claim 2, wherein the molar ratio of the oxalic acid monohydrazide ester to the orthoformate triester is 1: 1-4.
7. The synthesis process of the ribavirin intermediate as claimed in claim 2, wherein the molar ratio of the oxalyl hydrazine ether to ammonia gas is 1: 3.5-4.5.
8. A synthesis process of a ribavirin intermediate is characterized by comprising the following steps:
s1: in an alcohol solvent, oxalic acid monohydrazide ester and ortho-formic acid triester are subjected to condensation reaction to generate oxalyl hydrazine ether;
s2: carrying out ammonolysis reaction on oxalyl hydrazine ether and ammonia gas to generate oxalyl hydrazine diamine;
s3: carrying out a cyclization reaction on the oxalic hydrazine diamine to generate a ribavirin intermediate 1,2, 4-triazole-3-formamide;
s4: 1,2, 4-triazole-3-formamide is used as a raw material and is subjected to esterification reaction with alcohol to generate a ribavirin intermediate 1,2, 4-triazole-3-methyl carboxylate.
9. An intermediate for synthesizing a ribavirin intermediate 1,2, 4-triazole-3-formamide is characterized in that the structural formula is as follows:
R1OOC-CONHN＝CHOR2
wherein R is1And R2Are simultaneously CH3Or R is1And R2Are simultaneously CH3CH2。
10. An intermediate for synthesizing a ribavirin intermediate 1,2, 4-triazole-3-formamide is characterized in that the structural formula is as follows:
H2NOC-CONHN＝CHNH2。
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