CN108033966A - The synthetic method of 5,6 dihydro Triazolopyrazine 3,7 (8H) dioctyl phthalate base ester of 7- tert-butyl group 3- ethyl 8- methyl - Google Patents
The synthetic method of 5,6 dihydro Triazolopyrazine 3,7 (8H) dioctyl phthalate base ester of 7- tert-butyl group 3- ethyl 8- methyl Download PDFInfo
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- CN108033966A CN108033966A CN201810011099.3A CN201810011099A CN108033966A CN 108033966 A CN108033966 A CN 108033966A CN 201810011099 A CN201810011099 A CN 201810011099A CN 108033966 A CN108033966 A CN 108033966A
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- methyl
- triazol
- pyrazine
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- ethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present invention relates to 7 tert-butyl group, 3 ethyl, 8 methyl, 5,6 dihydro [1,2,4] triazol [4,3 a] pyrazine 3,7 (8H) dioctyl phthalate base ester preparation method, mainly solve at present the compound be suitable for industrialized process for preparing technical problem.The present invention prepares 7 tert-butyl group, 3 ethyl, 8 methyl, 5,6 dihydro [1,2,4] triazol [4,3 a] pyrazine, 3,7 (8H) dioctyl phthalate base ester using 2 chlorine, 3 methylpyrazine as starting material, by three-step reaction.Reaction equation is as follows：
Description
Technical field
The present invention relates to the 7- tert-butyl group -3- ethyl -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,
The synthetic method of 7 (8H)-dioctyl phthalate base esters.
Background technology
The 7- tert-butyl group -3- ethyl -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,7 (8H)-diformazan
Acidic group ester (CAS:1174644-71-3) and relevant derivative has important application in pharmaceutical chemistry and organic synthesis, there is pole
Good prospect.But at present there is no complete synthetic route report.Therefore, develop a cheap raw material to be easy to get, easy to operate, reaction is easy
Controlled in batch production, the great meaning of synthetic method that overall yield is adapted to.
The content of the invention
The purpose of the present invention is exploitation one kind has, raw material is cheap, easy to operate, can amplify, three step higher yields uncles 7-
The preparation of butyl -3- ethyl -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester
Method.Mainly solve the technical problem that the compound at present is not suitable for industrialized process for preparing.
Technical scheme：A kind of 7- tert-butyl groups -3- ethyls -8- methyl -5,6- dihydros-[1,2,4] triazol [4,
3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester preparation method, comprise the following steps：Synthesized using 3 footworks, the first step, with 2-
Chloro- 3- methylpyrazines are that starting material by hydrazine hydrate ethanol is that solvent obtains 2- diazanyl -3- methylpyrazines；Second step, 2- hydrazines
Base -3- methylpyrazines obtain ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- first under diethy-aceto oxalate effect
Acidic group ester；3rd step, ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- formic acid base ester are made in 10% palladium carbon hydrogen
It can obtain the 7- tert-butyl group -3- ethyl -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,7 (8H)-two under
Formic acid base ester；
Reaction equation is as follows：
In above-mentioned technique, the first step：Reaction temperature is 90 DEG C；Second step, reaction temperature are 150 DEG C, when the reaction time is 55 small；
3rd step, solvent are ethanol, and reaction temperature is 50 DEG C, when the reaction time 12 is small.
Beneficial effects of the present invention：Reaction process design of the present invention is reasonable, and which employs cheap and easy to get, energy large-scale production
The chloro- 3- methylpyrazines of raw material -2-, by three steps synthesized the 7- tert-butyl group -3- ethyl -8- methyl -5,6- dihydro-[1,2,
4] triazol [4,3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester, has saved synthesis cost, and can be produced on a large scale.
Embodiment
Embodiment
The synthesis of diazanyl -3- methylpyrazines
748 g hydrazine hydrates are added in the ethanol solution of 300 g compounds 1 under 20 degrees Celsius, 90 is Celsius after charging
When degree magnetic agitation 12 is small.Raw material after the reaction was complete reaction solution be concentrated in vacuo, filter cake is beaten stirring with about 1L dichloromethane and removes
Remove unnecessary hydrazine hydrate.Filter cake is transferred in single port bottle and is dried in vacuo.Obtain 400 g yellow solid compounds 2.
The synthesis of ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- formic acid base esters
435 g compounds 2 are dissolved in 5 L diethy-aceto oxalates, when the lower magnetic agitation 5 of 25 degrees Celsius of reaction solution is small.Raw material is with anti-
Reflect complete rear pump or output pump to walk diethy-aceto oxalate rotation, solid about 2L dichloromethane mashing filtering, filter cake is accessory substance 500mL bis-
Chloromethanes rinses twice.Filtrate concentration about 2L ethyl acetate mashing filtering, filter cake is 150 g products.Filtrate is spin-dried for, and silica gel is mixed
Sample obtains yellow solid 50g, and 200.00 g crude Compounds 3 are obtained in reaction.Yield 30%
The synthesis of ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- formic acid base esters
435 g compounds 2 are dissolved in 5 L diethy-aceto oxalates, when the lower magnetic agitation 5 of 50 degrees Celsius of reaction solution is small.Raw material is with anti-
Reflect complete rear pump or output pump to walk diethy-aceto oxalate rotation, solid about 2L dichloromethane mashing filtering, filter cake is accessory substance 500mL bis-
Chloromethanes rinses twice.Filtrate concentration about 2L ethyl acetate mashing filtering, filter cake is 150 g products.Filtrate is spin-dried for, and silica gel is mixed
Sample obtains yellow solid 50g, and 200.00 g crude Compounds 3 are obtained in reaction.Yield 35%
The synthesis of ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- formic acid base esters
435 g compounds 2 are dissolved in 5 L diethy-aceto oxalates, when the lower magnetic agitation 5 of 150 degrees Celsius of reaction solution is small.Raw material with
Reflect that complete rear pump or output pump walks diethy-aceto oxalate rotation, solid about 2L dichloromethane mashing filtering, filter cake is accessory substance 500mL
Dichloromethane rinses twice.Filtrate concentration about 2L ethyl acetate mashing filtering, filter cake is 150 g products.Filtrate is spin-dried for, silica gel
Mix sample and obtain yellow solid 50g, 200.00 g crude Compounds 3 are obtained in reaction.Yield 50%
The synthesis of ethyl -8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- formic acid base esters
435 g compounds 2 are dissolved in 5 L diethy-aceto oxalates, when the lower magnetic agitation 55 of 150 degrees Celsius of reaction solution is small.Raw material with
Reflect that complete rear pump or output pump walks diethy-aceto oxalate rotation, solid about 2L dichloromethane mashing filtering, filter cake is accessory substance 500mL
Dichloromethane rinses twice.Filtrate concentration about 2L ethyl acetate mashing filtering, filter cake is 150 g products.Filtrate is spin-dried for, silica gel
Mix sample and obtain yellow solid 50g, 200.00 g crude Compounds 3 are obtained in reaction.Yield 70%
The 7- tert-butyl group -3- ethyl -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,7 (8H)-diformyl
The synthesis of ester
1.2 L ethanol solutions of 60 g compounds 3 and 10 g Pd/C (10%) are heated to 50 under 50 Psi hydrogen shields
When degree Celsius magnetic agitation 12 is small.Raw material filters filter cake about 12 L alcohol flushings to no product after the reaction was complete.It is concentrated in vacuo
Obtain 180 g crude yellow oilies compounds 4.
Claims (4)
- A kind of 1. 7- tert-butyl groups -3- ethyls -8- methyl -5,6- dihydros-[1,2,4] triazol [4,3-a] pyrazine -3,7 (8H)-two The preparation method of formic acid base ester, it is characterized in that, comprise the following steps：The first step, is led to using the chloro- 3- methylpyrazines of 2- as starting material Cross hydrazine hydrate ethanol and obtain 2- diazanyl -3- methylpyrazines for solvent；Second step, 2- diazanyl -3- methylpyrazines are in diethy-aceto oxalate 2- diazanyl -3- methylpyrazines are obtained under effect；3rd step, ethyl 8- methyl-[1,2,4] triazol [4,3-a] pyrazine -3- first Acidic group ester can obtain ethyl 8- methyl -5,6,7,8- tetrahydrochysenes-[1,2,4] triazol [4,3-a] under the effect of 10% palladium carbon hydrogen Pyrazine -3- formic acid base esters；Reaction equation is as follows：。
- 2. a kind of 7- tert-butyl groups -3- ethyls -8- methyl -5,6- dihydros-[1,2,4] triazol according to claim 1 [4, 3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester preparation method, it is characterized in that：90 DEG C of first step reaction temperature.
- 3. a kind of 7- tert-butyl groups -3- ethyls -8- methyl -5,6- dihydros-[1,2,4] triazol according to claim 1 [4, 3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester preparation method, it is characterized in that：Second step reaction temperature is 150 DEG C, the reaction time For 55 it is small when.
- 4. a kind of 7- tert-butyl groups -3- ethyls -8- methyl -5,6- dihydros-[1,2,4] triazol according to claim 1 [4, 3-a] pyrazine -3,7 (8H)-dioctyl phthalate base ester preparation method, it is characterized in that：3rd step solvent is methanol, pressure 50psi, instead It is 50 DEG C to answer temperature, when the reaction time 12 is small.
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| CN201810011099.3A CN108033966A (en) | 2018-01-05 | 2018-01-05 | The synthetic method of 5,6 dihydro Triazolopyrazine 3,7 (8H) dioctyl phthalate base ester of 7- tert-butyl group 3- ethyl 8- methyl |
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| CN201810011099.3A CN108033966A (en) | 2018-01-05 | 2018-01-05 | The synthetic method of 5,6 dihydro Triazolopyrazine 3,7 (8H) dioctyl phthalate base ester of 7- tert-butyl group 3- ethyl 8- methyl |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620829A (en) * | 2020-05-20 | 2020-09-04 | 上海合全药物研发有限公司 | Synthesis method of 2-methyl-1, 2, 4-triazole-3-amine |
| CN111662287A (en) * | 2020-05-20 | 2020-09-15 | 无锡合全药业有限公司 | Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester |
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| EP2090576A1 (en) * | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
| CN102171213A (en) * | 2008-08-04 | 2011-08-31 | 阿斯利康(瑞典)有限公司 | Pyrazolo [3, 4] pyrimidin-4-yl derivatives and their uses to treat diabetes and obesity |
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| CN105440041A (en) * | 2015-12-30 | 2016-03-30 | 上海药明康德新药开发有限公司 | Synthetic method of 7-tert-butyl-2-ethyl-8-methyl-5,6-glyoxalidine[1,2-a] pyrazine-2,7(8H)-dicarboxylic acid |
| CN107312007A (en) * | 2017-06-29 | 2017-11-03 | 上海合全药业股份有限公司 | The preparation method of the glyoxalidine of 2 (oxoethyl of 2 ethyoxyl 2) 8 methyl 5,6 and the pyrazine carboxylic acid tert-butyl ester |
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| EP2090576A1 (en) * | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
| CN102171213A (en) * | 2008-08-04 | 2011-08-31 | 阿斯利康(瑞典)有限公司 | Pyrazolo [3, 4] pyrimidin-4-yl derivatives and their uses to treat diabetes and obesity |
| CN104892602A (en) * | 2015-06-16 | 2015-09-09 | 浙江工业大学 | Hydrazone derivative containing 1,2,4-triazole [4,3-a] pyridine ring as well as preparation and application of hydrazone derivative |
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| CN107312007A (en) * | 2017-06-29 | 2017-11-03 | 上海合全药业股份有限公司 | The preparation method of the glyoxalidine of 2 (oxoethyl of 2 ethyoxyl 2) 8 methyl 5,6 and the pyrazine carboxylic acid tert-butyl ester |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111620829A (en) * | 2020-05-20 | 2020-09-04 | 上海合全药物研发有限公司 | Synthesis method of 2-methyl-1, 2, 4-triazole-3-amine |
| CN111662287A (en) * | 2020-05-20 | 2020-09-15 | 无锡合全药业有限公司 | Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester |
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