CN105439968A - Synthesis method of ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate - Google Patents
Synthesis method of ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate Download PDFInfo
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- CN105439968A CN105439968A CN201510981788.3A CN201510981788A CN105439968A CN 105439968 A CN105439968 A CN 105439968A CN 201510981788 A CN201510981788 A CN 201510981788A CN 105439968 A CN105439968 A CN 105439968A
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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 relates to a synthesis method of a ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate, which comprises the following steps: adding 30L of water solution, 20-30mL of concentrated phosphoric acid solution, 31 mol of methyl 5-amino-1,2,4-triazolyl-3-carboxylate sulfate and 11-12 mol of ethylene glycol ethyl diether into a reaction vessel, lowering the temperature of the solution to 6-10 DEG C, dropwisely adding 800-1000ml of potassium bisulfite solution with a certain concentration, and controlling the temperature of the solution at 12-16 DEG C; after finishing addition, controlling the stirring rate at 100-200 rpm and the reaction time at 3-5 hours, and determining the reaction end point with potassium iodide test paper; centrifuging, adding the obtained solid into a cyclohexane solution by many times, and carrying out denitrification reaction while controlling the temperature of the solution at 55-60 DEG C; and after the reaction finishes, filtering while the solution is hot, lowering the temperature of the filtrate to 15-20 DEG C to precipitate a yellow solid, centrifuging, and recrystallizing with a cyclohexane solution to obtain the methyl 1,2,4-triazolyl-3-carboxylate.
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 of broad spectrum high-effect, is widely used in the control of virus disease at present.Common formulations has injection, tablet, oral liquid, aerosol etc.Ribavirin is that nucleoside transporting may absorb about 45% from digestive tube, and this is that appropriateness increases fat meal (about 75%).Once in blood plasma, ribavirin is also by nucleoside transporting by the transport of cytolemma.Ribavirin be distributed widely in a organized way, comprise cerebrospinal fluid and brain.In the cell that the pharmacokinetics of ribavirin is captured, particularly red blood cell (red corpuscle), lacks this enzyme, once it is added kinases, and therefore obtains the medicine of high density, to remove phosphate acid salts.The medicine transform of most kinase activity, the form of positive Nucleotide is by adenine kinase.This enzyme is comparatively active in the cell of virus infection.1,2,4-triazole-3-carboxylate methyl ester is as ribavirin pharmaceutical intermediate, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide a kind of ribavirin pharmaceutical intermediate 1, 2, the synthetic method of 4-triazole-3-carboxylate methyl ester, comprise the steps: that (i) adds aqueous solution 30L in reaction vessel, concentrated phosphoric acid 20-30mL, 5-amino-1, 2, 4-triazole-3-carboxylate methyl ester vitriol 31mol, ethylene glycol ethyl ethers diether 11-12mol, reduce solution temperature to 6--10 DEG C, drip certain density bisulfite potassium solution 800-1000ml, control solution temperature and be in 12--16 DEG C, adding rear control stirring velocity is 100-200rpm, reaction times controls at 3-5h, with potassium iodide starch paper assaying reaction terminal, after centrifugal, the solid obtained is joined in cyclohexane solution several times, control solution temperature at 55--60 DEG C, carry out denitrification reaction, filtered while hot after reaction terminates, filtrate temperature is reduced to 15--20 DEG C, separate out yellow solid, centrifugal, use cyclohexane solution recrystallization again, obtain 1, 2, 4-triazole-3-carboxylate methyl ester, wherein, concentrated phosphoric acid described in step (i) to be massfraction be 60-75% concentrated phosphoric acid, bisulfite potassium solution described in step (i) is the bisulfite potassium solution of massfraction 50-65%, cyclohexane solution described in step (i) is the cyclohexane solution of massfraction 90-95%, described in step (i) the solid obtained is joined cyclohexane solution number of times used is several times 5-9 times.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
Embodiment
Below in conjunction with concrete embodiment, 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, massfraction is the concentrated phosphoric acid 20mL of 60%, 5-amino-1, 2, 4-triazole-3-carboxylate methyl ester vitriol 31mol, ethylene glycol ethyl ethers diether 11mol, reduce solution temperature to 6 DEG C, drip the bisulfite potassium solution 800ml of massfraction 50%, control solution temperature and be in 12 DEG C, adding rear control stirring velocity is 100rpm, reaction times controls at 3h, with potassium iodide starch paper assaying reaction terminal, after centrifugal, the solid obtained is divided and joins for 5 times in the cyclohexane solution of massfraction 90%, control solution temperature at 55 DEG C, carry out denitrification reaction, filtered while hot after reaction terminates, filtrate temperature is reduced to 15 DEG C, separate out yellow solid, centrifugal, use the cyclohexane solution recrystallization of massfraction 90% again, obtain 1, 2, 4-triazole-3-carboxylate methyl ester 2086.61g, yield 53%.
Example 2:
Aqueous solution 30L is added in reaction vessel, massfraction is the concentrated phosphoric acid 25mL of 65%, 5-amino-1, 2, 4-triazole-3-carboxylate methyl ester vitriol 31mol, ethylene glycol ethyl ethers diether 11.5mol, reduce solution temperature to 8 DEG C, drip the bisulfite potassium solution 900ml of massfraction 60%, control solution temperature and be in 14 DEG C, adding rear control stirring velocity is 150rpm, reaction times controls at 4h, with potassium iodide starch paper assaying reaction terminal, after centrifugal, the solid obtained is divided and joins for 7 times in the cyclohexane solution of massfraction 92%, control solution temperature at 57 DEG C, carry out denitrification reaction, filtered while hot after reaction terminates, filtrate temperature is reduced to 17 DEG C, separate out yellow solid, centrifugal, use the cyclohexane solution recrystallization of massfraction 92% again, obtain 1, 2, 4-triazole-3-carboxylate methyl ester 2322.83g, yield 59%.
Example 3:
Aqueous solution 30L is added in reaction vessel, massfraction is the concentrated phosphoric acid 30mL of 75%, 5-amino-1, 2, 4-triazole-3-carboxylate methyl ester vitriol 31mol, ethylene glycol ethyl ethers diether 12mol, reduce solution temperature to 10 DEG C, drip the bisulfite potassium solution 1000ml of massfraction 65%, control solution temperature and be in 16 DEG C, adding rear control stirring velocity is 200rpm, reaction times controls at 5h, with potassium iodide starch paper assaying reaction terminal, after centrifugal, the solid obtained is divided and joins for 9 times in the cyclohexane solution of massfraction 95%, control solution temperature at 60 DEG C, carry out denitrification reaction, filtered while hot after reaction terminates, filtrate temperature is reduced to 20 DEG C, separate out yellow solid, centrifugal, use the cyclohexane solution recrystallization of massfraction 95% again, obtain 1, 2, 4-triazole-3-carboxylate methyl ester 2519.68g, yield 64%.
Claims (4)
1. the synthetic method of ribavirin pharmaceutical intermediate 1,2, a 4-triazole-3-carboxylate methyl ester, is characterized in that, comprise the steps:
I () adds aqueous solution 30L in reaction vessel, concentrated phosphoric acid 20-30mL, 5-amino-1, 2, 4-triazole-3-carboxylate methyl ester vitriol 31mol, ethylene glycol ethyl ethers diether 11-12mol, reduce solution temperature to 6--10 DEG C, drip certain density bisulfite potassium solution 800-1000ml, control solution temperature and be in 12--16 DEG C, adding rear control stirring velocity is 100-200rpm, reaction times controls at 3-5h, with potassium iodide starch paper assaying reaction terminal, after centrifugal, the solid obtained is joined in cyclohexane solution several times, control solution temperature at 55--60 DEG C, carry out denitrification reaction, filtered while hot after reaction terminates, filtrate temperature is reduced to 15--20 DEG C, separate out yellow solid, centrifugal, use cyclohexane solution recrystallization again, obtain 1, 2, 4-triazole-3-carboxylate methyl ester, wherein, the concentrated phosphoric acid described in step (i) is massfraction is the concentrated phosphoric acid of 60-75%.
2. the synthetic method of a kind of ribavirin pharmaceutical intermediate 1,2,4-triazole-3-carboxylate methyl ester according to claim 1, it is characterized in that, the bisulfite potassium solution described in step (i) is the bisulfite potassium solution of massfraction 50-65%.
3. the synthetic method of a kind of ribavirin pharmaceutical intermediate 1,2,4-triazole-3-carboxylate methyl ester according to claim 1, it is characterized in that, the cyclohexane solution described in step (i) is the cyclohexane solution of massfraction 90-95%.
4. a kind of ribavirin pharmaceutical intermediate 1 according to claim 1,2, the synthetic method of 4-triazole-3-carboxylate methyl ester, is characterized in that, the cyclohexane solution number of times used that joined several times by the solid obtained described in step (i) is 5-9 times.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510981788.3A CN105439968A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate |
| CN201610824164.5A CN106432111A (en) | 2015-12-23 | 2016-09-17 | Method for synthesizing ribavirin drug intermediate 1,2,4-triazole-3-carboxylic acid methyl ester |
| 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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| 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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| CN105439968A true CN105439968A (en) | 2016-03-30 |
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| CN201510981788.3A Pending CN105439968A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of ribavirin drug intermediate methyl 1,2,4-triazolyl-3-carboxylate |
| 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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| 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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822050A (en) * | 2018-09-21 | 2018-11-16 | 浙江诚意药业股份有限公司 | A kind of preparation method of triazole derivatives |
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2015
- 2015-12-23 CN CN201510981788.3A patent/CN105439968A/en active Pending
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- 2016-09-17 CN CN201610824164.5A patent/CN106432111A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822050A (en) * | 2018-09-21 | 2018-11-16 | 浙江诚意药业股份有限公司 | A kind of preparation method of triazole derivatives |
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| CN106432111A (en) | 2017-02-22 |
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Application publication date: 20160330 |