CN106432111A - Method for synthesizing ribavirin drug intermediate 1,2,4-triazole-3-carboxylic acid methyl ester - Google Patents
Method for synthesizing ribavirin drug intermediate 1,2,4-triazole-3-carboxylic acid methyl ester Download PDFInfo
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- CN106432111A CN106432111A CN201610824164.5A CN201610824164A CN106432111A CN 106432111 A CN106432111 A CN 106432111A CN 201610824164 A CN201610824164 A CN 201610824164A CN 106432111 A CN106432111 A CN 106432111A
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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
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Abstract
The invention discloses a method for synthesizing a ribavirin drug intermediate 1,2,4-triazole-3-carboxylic acid methyl ester. The method includes the following steps that 30 L of a water solution, 20 mL-30 mL of a concentrated phosphoric acid solution, 31 mol of 5-amino-1,2,4-triazole-3-carboxylic acid methyl ester sulfate and 11 mol-12 mol of ethylene glycolis ethylene ether are added into a reaction container, the temperature of the solution is reduced to be 6 DEG C to 10 DEG C, 800 ml-1,000 ml of a potassium bisulfite solution with the certain concentration is dropwise added, the temperature of the solution is controlled to be 12 DEG C to 16 DEG C, the stirring speed is controlled to be 100 rpm to 200 rpm after adding, the reaction time is controlled to be 3 h to 5 h, and a reaction endpoint is measured with potassium iodide; after centrifugation is carried out, the obtained solid is added into a cyclohexane solution in multiple times, the temperature of the solution is controlled to be 55 DEG C to 60 DEG C, a denitrification reaction is carried out, immediate filtration is carried out after the reaction is completed, the temperature of the filtered liquid is reduced to be 15 DEG C to 20 DEG C, yellow solid is separated out, centrifuged and recrystallized with a cyclohexane solution, and the 1,2,4-triazole-3-carboxylic acid methyl ester is obtained.
Description
Technical field
The present invention relates to a kind of synthetic method of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester.
Background technology
Ribavirin is the antiviral drugs of broad spectrum high-effect, is now widely used for the preventing and treating of viral disease.Conventional agent
Type has injection, tablet, oral liquid, aerosol etc..Ribavirin is that nucleoside transporting may absorb about 45% from digestive tract,
This is that appropriateness increases fat meal (about 75%).Once in blood plasma, ribavirin is also turned by nucleoside by the transport of cell membrane
Fortune.Ribavirin be distributed widely in a organized way, including cerebrospinal fluid and brain.The captured cell of the pharmacokineticss of ribavirin
Interior, particularly Red blood corpuscle (erythrocyte), lacks this enzyme, once it is added kinases, and the therefore medicine of acquisition high concentration,
Based on removal phosphate acid salts.The medicine transform of most kinase activity, the form of positive nucleotide, be by gland
Purine kinases.This enzyme is more enlivened in the cell that virus infects.1,2,4- triazole -3- carboxylate methyl ester is used as ribavirin
Pharmaceutical intermediate, its synthetic method is good and bad for pharmaceutical synthesis product quality is improved, and reduces by-products content and has Important Economic
Meaning.
Content of the invention
It is an object of the invention to provide a kind of conjunction of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester
Become method, comprise the steps：I () adds aqueous solution 30L in reaction vessel, 20 30mL, 5- amino -1 of concentrated phosphoric acid,
2,4- triazole -3- carboxylate methyl ester sulfate 31mol, 11 12mol of ethylene glycol ethyl ethers diether, reduce solution temperature to 6--10 DEG C,
The certain density bisulfite potassium solution 800-1000ml of Deca, control solution temperature is in 12--16 DEG C, and control after adding is stirred
Speed is mixed for 100 200rpm, the response time controls in 3 5h, reaction end is determined with potassium iodide starch paper, after centrifugation, will
The solid for obtaining is added in cyclohexane solution several times, and control solution temperature carries out denitrification reaction, reaction knot at 55--60 DEG C
Filtered while hot after bundle, filtrate temperature is reduced to 15--20 DEG C, is separated out yellow solid, centrifugation, then is tied with cyclohexane solution again
Crystalline substance, obtains 1,2,4- triazole -3- carboxylate methyl esters；Wherein, the concentrated phosphoric acid described in step (i) is 60 75% for mass fraction
Concentrated phosphoric acid, the bisulfite potassium solution described in step (i) for mass fraction 50 65% bisulfite potassium solution, step
Suddenly the cyclohexane solution described in (i) is the cyclohexane solution of mass fraction 90 95%, described in step (i) by the solid for obtaining
It is 59 times to be added to the number of times used by cyclohexane solution several times.
Whole course of reaction can use following reaction equation to represent：
The invention has the advantages that：The intermediate link of reaction is reduced, reaction temperature and response time is reduced, improve anti-
Answer yield.
Specific embodiment
With reference to example is embodied as, the invention will be further described：
A kind of synthetic method of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester
Example 1：
Aqueous solution 30L is added in reaction vessel, mass fraction is 60% concentrated phosphoric acid 20mL, 5- amino -1,2,
4- triazole -3- carboxylate methyl ester sulfate 31mol, ethylene glycol ethyl ethers diether 11mol, reduce solution temperature to 6 DEG C, and Deca quality is divided
The bisulfite potassium solution 800ml of number 50%, control solution temperature is in 12 DEG C, and after adding, control mixing speed is 100rpm,
Response time controls in 3h, determines reaction end with potassium iodide starch paper, after centrifugation, the solid for obtaining is divided 5 times and is added to matter
In the cyclohexane solution of amount fraction 90%, control solution temperature carries out denitrification reaction at 55 DEG C, and reaction terminates afterwards mistake while hot
Filter, filtrate temperature is reduced to 15 DEG C, separates out yellow solid, is centrifuged, then the cyclohexane solution recrystallization with mass fraction 90%,
Obtain 1,2,4- triazole -3- carboxylate methyl ester 2086.61g, yield 53%.
Example 2：
Aqueous solution 30L is added in reaction vessel, mass fraction is 65% concentrated phosphoric acid 25mL, 5- amino -1,2,
4- triazole -3- carboxylate methyl ester sulfate 31mol, ethylene glycol ethyl ethers diether 11.5mol, reduce solution temperature to 8 DEG C, Deca quality
The bisulfite potassium solution 900ml of fraction 60%, control solution temperature is in 14 DEG C, and after adding, control mixing speed is
150rpm, the response time controls in 4h, determines reaction end with potassium iodide starch paper, after centrifugation, the solid for obtaining is divided 7 times and is added
Enter in the cyclohexane solution of mass fraction 92%, control solution temperature carries out denitrification reaction at 57 DEG C, and reaction is taken advantage of after terminating
Heat filtering, filtrate temperature is reduced to 17 DEG C, separates out yellow solid, centrifugation, then the cyclohexane solution weight with mass fraction 92%
Crystallization, obtains 1,2,4- triazole -3- carboxylate methyl ester 2322.83g, yield 59%.
Example 3：
Aqueous solution 30L is added in reaction vessel, mass fraction is 75% concentrated phosphoric acid 30mL, 5- amino -1,2,
4- triazole -3- carboxylate methyl ester sulfate 31mol, ethylene glycol ethyl ethers diether 12mol, reduce solution temperature to 10 DEG C, Deca quality
The bisulfite potassium solution 1000ml of fraction 65%, control solution temperature is in 16 DEG C, and after adding, control mixing speed is
200rpm, the response time controls in 5h, determines reaction end with potassium iodide starch paper, after centrifugation, the solid for obtaining is divided 9 times and is added
Enter in the cyclohexane solution of mass fraction 95%, control solution temperature carries out denitrification reaction at 60 DEG C, and reaction is taken advantage of after terminating
Heat filtering, filtrate temperature is reduced to 20 DEG C, separates out yellow solid, centrifugation, then the cyclohexane solution weight with mass fraction 95%
Crystallization, obtains 1,2,4- triazole -3- carboxylate methyl ester 2519.68g, yield 64%.
Claims (4)
1. the synthetic method of 1,2,4- triazole -3- carboxylate methyl ester of a kind of ribavirin pharmaceutical intermediate, it is characterised in that include
Following steps：
I () adds aqueous solution 30L, 20 30mL, 5- amino-1,2,4-triazol -3- carboxylic of concentrated phosphoric acid in reaction vessel
Sour methosulfate 31mol, 11 12mol of ethylene glycol ethyl ethers diether, reduce solution temperature to 6--10 DEG C, and Deca is certain density
Bisulfite potassium solution 800-1000ml, control solution temperature is in 12--16 DEG C, and after adding, control mixing speed is 100
200rpm, the response time controls in 3 5h, determines reaction end with potassium iodide starch paper, after centrifugation, the solid for obtaining is divided many
Secondary be added in cyclohexane solution, control solution temperature carries out denitrification reaction at 55--60 DEG C, reaction terminate after mistake while hot
Filter, filtrate temperature is reduced to 15--20 DEG C, is separated out yellow solid, centrifugation, then is used cyclohexane solution recrystallization, obtains 1,2,4- tri-
Nitrogen azoles -3- carboxylate methyl ester；Wherein, the concentrated phosphoric acid described in step (i) is concentrated phosphoric acid that mass fraction is 60 75%.
2. a kind of synthesis side of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester according to claim 1
Method, it is characterised in that the bisulfite potassium solution described in step (i) is the bisulfite potassium solution of mass fraction 50 65%.
3. a kind of synthesis side of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester according to claim 1
Method, it is characterised in that the cyclohexane solution described in step (i) is the cyclohexane solution of mass fraction 90 95%.
4. a kind of synthesis side of ribavirin pharmaceutical intermediate 1,2,4- triazole -3- carboxylate methyl ester according to claim 1
Method, it is characterised in that the number of times used by cyclohexane solution that is added to the solid for obtaining several times described in step (i) is 59
Secondary.
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| Application Number | Priority Date | Filing Date | Title |
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| AU2016102211A AU2016102211A4 (en) | 2015-12-23 | 2016-12-23 | Ribavirin drug intermediates 1,2,4-triazole-3-carboxylic acid methyl ester synthesis method |
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| CN2015109817883 | 2015-12-23 | ||
| CN201510981788.3A CN105439968A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate |
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| CN201610824164.5A Pending CN106432111A (en) | 2015-12-23 | 2016-09-17 | Method for synthesizing ribavirin drug intermediate 1,2,4-triazole-3-carboxylic acid methyl ester |
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Application publication date: 20170222 |
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