CN100569758C - 3-cyano group-1,2, the preparation method of 4-triazole - Google Patents
3-cyano group-1,2, the preparation method of 4-triazole Download PDFInfo
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- CN100569758C CN100569758C CNB2004100649333A CN200410064933A CN100569758C CN 100569758 C CN100569758 C CN 100569758C CN B2004100649333 A CNB2004100649333 A CN B2004100649333A CN 200410064933 A CN200410064933 A CN 200410064933A CN 100569758 C CN100569758 C CN 100569758C
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- triazole
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Abstract
The invention discloses a kind of separating and make the triazole methane amide with one step of triazole methyl-formiate ammonia, synthetic 3-cyano group-1 then dewaters the triazole methane amide of gained, 2, the method of 4-triazole, the steps include: earlier that the triazole methyl-formiate is soluble in water, airtight logical ammonia is to the pressure of 2.5kg, and ammonia is separated 4～10h, centrifugal dry the triazole methane amide; Add acetonitrile solvent and dissolve, under reflux state, drip phosphorus oxychloride, a complete back continuation reaction 4～8 hours removes solvent under reduced pressure and dewatering agent gets hydrolyzate; Low temperature hydrolysis, methylate isobutyl ketone extraction, concentrate 3-cyano group-1,2,4-triazole crude product, with alcohol refining 3-cyano group-1,2,4-triazole finished product; Operational path of the present invention is short, processing condition require low, acetonitrile, phosphorus oxychloride, mibk are all recyclable in the preparation process applies mechanically, thereby, disposal of pollutants is extremely low, need not use Poisons in whole process of preparation, up to 48%, purity is greater than 99% by the total recovery of the target product that the present invention obtained.
Description
Technical field:
The present invention relates to 3-cyano group-1,2, the preparation method of 4-triazole.
Background technology:
Pfizer Inc. has used 3-cyano group-1,2, and the 4-triazole is developed a kind of PTS, and has entered clinical three trial periods phase, its anticancer brilliance.In a single day this medicine enters the stage of applying, and its market demand can rise significantly, and market outlook are very gratifying, and 3-cyano group-1,2,4-triazole are the key intermediates of this PTS; Also be the raw material of antiviral drug ribavirin, production ribavirin producer is a lot of both at home and abroad at present, thereby 3-cyano group-1,2, and the annual requirement of 4-triazole is very big.
3-cyano group-1,2, the molecular formula of 4-triazole are C
3H
2N
4
Its physico-chemical property is: this strain white crystals body, odorless, tasteless; 185 ℃-187 ℃ of fusing points are soluble in organic solvents such as alcohol, ether.
Its structural formula is:
At present, through the preparation 3-cyano group 1,2 of domestic and foreign literature report and use, the method for 4-triazole has following three kinds:
(1), in English Patent Brit1157256 (BECKER, people such as HEINZ) a kind of employing 3-chloro-1,2 is disclosed, the 4-triazole adds the sodium cyanide one-step synthesis and gets 3-cyano group-1,2, the method for 4-triazole.The steps include: elder generation with 3-chloro-1,2, the 4-triazole is dissolved in the sodium cyanide solution, drips dimethyl formamide, back flow reaction 6 hours, and the vacuum concentration solvent gets crude product, gets finished product with ethyl alcohol recrystallization.Its reaction equation is:
Prepare 3-cyano group-1,2 in this way, though the 4-triazole is simple, but raw material is difficult to obtain, and need to use the extremely strong sodium cyanide of toxicity, not only can influence health of operators, and can produce the discharge of the severe toxicity of serious environmental pollution in producing.Thereby this method should not be used in actual production.
(2), in day disclosure special permission 84-206367, disclose with careless amine hydrazides and methane amide or carbonamidine acetate at high temperature directly cyclization make 1,2,4-triazole-3 methane amide dewaters and synthesizes 3-cyano group-1,2, the 4-triazole, its reaction equation is:
(3), people such as yellow Yongming discloses another kind and has closed method on 21 (10) the 446th pages of nineteen nineties " Chinese Journal of Pharmaceuticals ", it is on the basis of Japanese Patent 84-206367, use ethyl oxamide, hydrazine hydrate and carbonamidine acetate are treated different things alike to operate and are made 1,2,4-triazole-3-methane amide obtains the purpose product through dehydration again.
Above-mentioned (two), (three) described method all exist operational path oversize, and byproduct is many, and the production cycle is long, 3-cyano group-1,2, and the purity of 4-triazole is low, deficiencies such as severe reaction conditions.
Summary of the invention:
The object of the present invention is to provide a kind of 3-cyano group-1,2, the preparation method of 4-triazole.
This method is to utilize triazole methyl-formiate one step ammonia to separate to make the triazole methane amide, the synthetic 3-cyano group-1,2 that then the triazole methane amide of gained dewatered, and the 4-triazole, its reaction equation is:
Its preparation process is as follows:
Step 1: earlier that the triazole methyl-formiate is soluble in water, at the pressure of airtight logical ammonia to 2.5kg, ammonia is separated 4～10h, centrifugal dry the triazole methane amide;
Step 2: get the triazole methane amide and add acetonitrile solvent stirring beginning dissolving, under reflux state, drip phosphorus oxychloride, 3～5h drips complete, continues back flow reaction 4～8h again, removes solvent acetonitrile and dewatering agent POCl under reduced pressure
3, get hydrolyzate.
Step 3, low temperature hydrolysis, methylate isobutyl ketone extraction secondary, concentrated extract gets 3-cyano group-1,2,4-triazole crude product, with alcohol refining 3-cyano group-1,2,4-triazole finished product.
Because the present invention utilizes one step of triazole methyl-formiate ammonia that market easily purchases to separate to make the triazole methane amide, synthetic 3-cyano group-1 then dewaters the triazole methane amide of gained, 2, the 4-triazole, operational path is short, and processing condition require low, acetonitrile, phosphorus oxychloride, mibk are all recyclable in the preparation process applies mechanically, the raw material availability height, thereby disposal of pollutants is extremely low, need not use Poisons in whole process of preparation.Calculate with the triazole methyl-formiate, two step total recoverys reach 48%, and by the 3-cyano group-1,2 that the present invention makes, 4-triazole finished product is analyzed through HPLC, and its purity is between 99%～99.2%.
Description of drawings:
Fig. 1 is a process flow sheet of the present invention;
Concrete mode is as follows:
With preparation 100kg 3-cyano group-1,2, the 4-triazole is an example, and concrete preparation process of the present invention is described:
Embodiment one:
Step 1: get the ammonolysis reaction still that triazole methyl-formiate 400kg places 1000 liters, add pure water 350kg dissolving, logical ammonia is to the pressure of 2.5kg under air-tight state, ammonia is separated 3h, in the time of 30 ℃, takes off liquid with whizzer, and under 90 ℃ of temperature, dry triazole methane amide 450kg
Step 2: the triazole methane amide 450kg that step 1 is obtained places 1000 liters the dehydration reaction still that has the 220kg acetonitrile, and rising temperature for dissolving is under reflux state, drip phosphorus oxychloride 150kg, drip in 3h and finish, successive reaction 4h removes solvent acetonitrile and dewatering agent POCl under reduced pressure
3, recovery set is used.
Step 3: with after the frozen water hydrolysis, methylate isobutyl ketone extraction secondary discards water layer, and with the organic layer dried over mgso, concentrating under reduced pressure gets crude product, with methyl alcohol or ethanol make with extra care finished product 192kg.
With the 3-cyano group-1,2 that gets, 4-triazole finished product carries out HPLC to be analyzed, and its purity is 99.1%, calculates with the triazole methyl-formiate, and two step total recoverys are: 192/400=48%.
Embodiment two:
Step 1: get the ammonolysis reaction still that triazole methyl-formiate 400kg places 1000 liters, add pure water 350kg dissolving, logical ammonia is to the pressure of 2.5kg under air-tight state, ammonia is separated 8h, in the time of 30 ℃, take off liquid with whizzer, and under 90 ℃ of temperature, dry triazole methane amide 460kg;
Step 2: the triazole methane amide 460kg that step 1 is obtained places 1000 liters the dehydration reaction still that has the 220kg acetonitrile, and rising temperature for dissolving is under reflux state, drip phosphorus oxychloride 150kg, drip in 5h and finish, successive reaction 8h removes solvent acetonitrile and dewatering agent POCl under reduced pressure
3, recovery set is used;
Step 3: with after the frozen water hydrolysis, methylate isobutyl ketone extraction secondary discards water layer, and with the organic layer dried over mgso, concentrating under reduced pressure gets crude product, with methyl alcohol or ethanol make with extra care finished product 194kg;
With the 3-cyano group-1,2 that gets, 4-triazole finished product carries out HPLC to be analyzed, and its purity is 99.15%, calculates with the triazole methyl-formiate, and two step total recoverys are 194/400=48.5%.
Claims (1)
1, a kind of 3-cyano group-1,2, the preparation method of 4-triazole, it is characterized in that: this method is that triazole methyl-formiate one step ammonia is separated and made the triazole methane amide, and synthetic 3-cyano group-1,2 then dewaters the triazole methane amide of gained, the 4-triazole, its reaction equation is:
Its preparation process is as follows:
Step 1: earlier that the triazole methyl-formiate is soluble in water, at the pressure of airtight logical ammonia to 2.5kg, ammonia is separated 6～10h, centrifugal dry the triazole methane amide;
Step 2: get the triazole methane amide and add acetonitrile solvent stirring beginning dissolving, under reflux state, drip phosphorus oxychloride, finish for 4～6 hours, the continuation reaction is 4～8 hours again, removes solvent acetonitrile and dewatering agent POCl under reduced pressure
3, get hydrolyzate;
Step 3: low temperature hydrolysis, methylate isobutyl ketone extraction secondary, concentrated extract gets 3-cyano group-1,2,4-triazole crude product, with alcohol refining 3-cyano group-1,2,4-triazole finished product.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100649333A CN100569758C (en) | 2004-10-13 | 2004-10-13 | 3-cyano group-1,2, the preparation method of 4-triazole |
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| CNB2004100649333A CN100569758C (en) | 2004-10-13 | 2004-10-13 | 3-cyano group-1,2, the preparation method of 4-triazole |
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| CN100569758C true CN100569758C (en) | 2009-12-16 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8198461B2 (en) * | 2008-05-08 | 2012-06-12 | Ampac Fine Chemicals Llc. | Process for the preparation of 3-cyano-1,2,4-triazoles |
| CN108863965A (en) * | 2018-06-25 | 2018-11-23 | 青岛科技大学 | The method that one kettle way prepares 1,2,4- triazole -3- formamide |
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2004
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Non-Patent Citations (4)
| Title |
|---|
| Synthesis and Antitumor Activity of Ribavirin Imidates.A NewFacile SynthesisofRibavirinAmidine(1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine Hydrochloride). Ganesh D. Kini,et al.J.Med.Chem.,Vol.32 No.7. 1989 |
| Synthesis and Antitumor Activity of Ribavirin Imidates.A NewFacile SynthesisofRibavirinAmidine(1-β-D-Ribofuranosyl-1,2,4-triazole-3-carboxamidine Hydrochloride). Ganesh D. Kini,et al.J.Med.Chem.,Vol.32 No.7. 1989 * |
| 三氮唑核苷合成研究进展. 郑人华等.浙江工业大学学报，第31卷第3期. 2003 |
| 三氮唑核苷合成研究进展. 郑人华等.浙江工业大学学报，第31卷第3期. 2003 * |
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