CN107629014A - The synthetic method of the acetic acid of 5 methyl 4H, 1,2,4 triazoles 3 - Google Patents
The synthetic method of the acetic acid of 5 methyl 4H, 1,2,4 triazoles 3 Download PDFInfo
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- CN107629014A CN107629014A CN201711009139.2A CN201711009139A CN107629014A CN 107629014 A CN107629014 A CN 107629014A CN 201711009139 A CN201711009139 A CN 201711009139A CN 107629014 A CN107629014 A CN 107629014A
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Abstract
A kind of acetic acid I of 51,2,4 triazoles of methyl 4H 3 synthetic method, comprises the following steps：1) diethyl malonate and hydrazine hydrate in alcoholic solvent, at room temperature reaction obtain compound 1,2) compound 1 and methyl ethanimidic acid ester hydrochloride 2 in appropriate solvent, in the presence of an organic base and under reflux temperature reaction obtain compound 3,3) compound 3 is in the presence of a base, the hydrolysis of ester bonds with alcoholic solvent, and add after appropriate acid carries out acidification reaction and obtain compound I, see following reaction scheme：
Description
Technical field
The present invention relates to medication chemistry to synthesize field, and in particular to medicine intermediate 5- methyl -4H-1,2,4- triazole -3-
The synthetic method of acetic acid.
Background technology
Triazole heterocycle is a kind of important heteroaromatic, because it easily forms hydrogen bond, coordinate bond etc., and is played a variety of non-
Covalent bond interacts, and can improve the chemical physical properties such as the water solubility of drug molecule；Be widely used in pharmaceutical synthesis,
Functional material and molecular biology etc..It is living that 1,2,4- triazoles in triazole structure show various biologies
Property, such as Itraconazole, triaconazole, posaconazole, albaconazole, Fluconazole, Chinese mugwort Fluconazole, voriconazole etc. are exactly a kind of bag
The medicine of the triazole containing 1,2,4-.
5- methyl -4H-1,2,4- triazole -3- acetic acid, CAS.No. 720706-28-5, its structural formula is shown in formula I；It is
A kind of important pharmaceutical-chemical intermediate, is widely used in medicine and chemical industry synthesis field.Such as document report includes 5-
Methyl -4H-1, recruit's structure of 2,4- triazole -3- acetyl group fragments, is a kind of di-phosphate ester enzyme acceptor, is shown extensive
Antitumor activity.
Khomenko etc. is in " Synthesis and study of novel 1,2,4-triazolylacetic acid
derivatives”(Chem Heterocycl Comp,2016,52(6):402-408.) in a text, it was recently reported that by formylhydrazine A
Back flow reaction obtains corresponding 5- methyl isophthalic acids, 2,4- triazole -3- acetic acid esters 3 in ethanol to acetoxymalonic acid ester list imines ester B；Again
5- methyl -4H-1,2,4- triazole -3- acetic acid I is obtained by ester hydrolysis；See following synthetic route one.
In said synthesis route one [9], acetoxymalonic acid ester list imines ester B is not easy to prepare, and limit this method enters one
Step application.It is contemplated that develop a kind of 5- methyl -4H-1,2,4- triazole -3- second that is simple and convenient, being adapted to industrialized production
Sour I synthetic method.
The content of the invention
The invention provides a kind of 5- methyl -4H-1,2,4- triazole -3- acetic acid I synthetic method, comprises the following steps：
1) diethyl malonate and hydrazine hydrate in alcoholic solvent, at room temperature reaction obtain malonic ester hydrazides 1 (compound 1), 2)
Compound 1 and methyl ethanimidic acid ester hydrochloride 2 are in appropriate solvent, react in the presence of an organic base and under reflux temperature
To 5- methyl -4H-1,2,4- triazole -3- acetic acid esters 3 (compound 3), 3) compound 3 in the presence of a base, hydrolyzes in alcoholic solvent
Ester bond, and add after appropriate acid carries out acidification reaction and obtain 5- methyl -4H-1,2,4- triazole -3- acetic acid esters I, see following reaction
Route two：
5- methyl-the 4H-1 of the present invention, 2,4- triazole -3- acetic acid I synthetic method, wherein, methyl ethylimine ester salt
HCl gases by ice-water bath, being passed through in the mixed solution of acetonitrile, methanol and hexane by hydrochlorate 2 under stirring；In whipping process
Middle reaction obtains.
A kind of preferred embodiment, 5- methyl -4H-1 of the invention, 2,4- triazole -3- acetic acid I synthetic method, its
In, alcoholic solvent described in step 1) is selected from methanol, ethanol or propyl alcohol, preferred alcohol.
A kind of preferred embodiment, 5- methyl -4H-1 of the invention, 2,4- triazole -3- acetic acid I synthetic method, its
In, alcoholic solvent described in step 2) is selected from ethanol, normal propyl alcohol or isopropanol, preferably isopropanol；The organic base is selected from diisopropyl
Base ethylamine, DBU or pyridine, preferably diisopropyl ethyl amine.
A kind of preferred embodiment, 5- methyl -4H-1 of the invention, 2,4- triazole -3- acetic acid I synthetic method, its
In, alcoholic solvent described in step 3) is selected from methanol, ethanol, normal propyl alcohol or isopropanol, preferably methanol or ethanol；The alkali is selected from hydrogen
Sodium oxide molybdena, potassium hydroxide；The appropriate acid is selected from hydrochloric acid, sulfuric acid；It is preferred that HCl gas.
It is initiation material to develop a new diethyl malonate herein, and malonic ester is obtained with hydration hydrazine reaction
Hydrazides 1, then exist with methyl ethanimidic acid ester hydrochloride 2 in Hoenig alkali and carry out condensation reaction and obtain 5- methyl -4H-1,2,4-
Triazole -3- acetic acid esters 3,5- methyl -4H-1,2,4- triazole -3- acetic acid I will be finally obtained after the ester linkage hydrolyzing of compound 3, eventually production
Thing high income.There is the route raw material to be easy to get, cheap, and the synthetic technological condition of each step is gentle, is easy to industrialized production.
Embodiment
The present invention, but the protection domain being not intended to limit the invention will be expanded on further by specific embodiment below.
Without departing from the inventive concept of the premise, those skilled in the art to preparation method and can use instrument within the scope of the claims
Device makes improvements, and these improvement also should be regarded as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended
Claim is defined.
In following embodiments, unless otherwise indicated, described test method is generally built according to normal condition or manufacturer
The condition of view is implemented；Shown raw material, reagent can be obtained by way of commercially available purchase.
The preparation of the malonic ester hydrazides 1 of embodiment 1.
Diethyl malonate (10g, 62.5mmol) is dissolved in 50ml ethanol, then add 85% hydrazine hydrate (1.44g,
1.44mol).Reactant mixture is stirred at room temperature overnight.Stop reaction, filtering, solvent is evaporated off in filtrate decompression.Gained residue
Recrystallized with the mixed solvent of ethyl acetate/petroleum ether, obtain compound 1 (2.10g, 64%), be white solid.1H
NMR (400MHz, DMSO-d6) δ 4.12 (q, J=7.1Hz, 2H), 3.16 (s, 2H), 1.22 (t, J=7.1Hz, 3H)；LC-MS
147(M+H)+。
The preparation of the methyl ethanimidic acid ester hydrochloride 2 of embodiment 2.
In ice-water bath, under stirring by HCl gases be passed through acetonitrile (30g, 0.720mol), methanol (35ml, 0.87mol) and
In the mixed solution of hexane (150ml)；In whipping process, gradually there is white precipitate to be formed.Continue stirring reaction 6h, stop anti-
Should.Reaction solution obtains compound 2 (63.51g, 84%) after removing solvent under reduced pressure.1H NMR(400MHz,CDCl3)δ12.78
(br, 1H), 12.03 (br, 1H), 8.40~7.43 (m, 5H), 4.57 (s, 3H).
The preparation of the ethyl 5- methyl -4H-1,2,4- triazole -3- acetic acid esters 3 of embodiment 3.
Compound 1 (13.08g, 0.09mol) is suspended in isopropanol (70ml), and Hoenig alkali (NEt (i- are then added dropwise
Pr) 2,70ml) and compound 2 (12.6g, 0.16mol).Reactant mixture is stirred at room temperature 10 minutes, then in oil bath
Heating reflux reaction 3 days.Solvent is evaporated off, after the dilution of gained residue with Ethyl acetate, after salt water washing, uses anhydrous sodium sulfate
Dry.Remove ethyl acetate under reduced pressure, the mixed solvent of gained residue with Ethyl acetate/petroleum ether is recrystallized, and obtains mesh
Compound 3 (10.87g, 71%) is marked, is white solid.1H NMR (400MHz, CDCl3) δ 4.24 (q, J=7.1Hz, 2H),
3.82 (s, 2H), 2.41 (s, 3H), 1.29 (t, J=7.1Hz, 3H).
Embodiment 4.5- methyl -4H-1,2,4- triazole -3- acetic acid I preparation
Compound 3 (4g, 23.5mmol) is dissolved in water (30ml) and methanol (20ml), and sodium hydroxide is then added portionwise
(1.22g,1.22mol)；Gained mixture is stirred at room temperature overnight.Remove solvent under reduced pressure, gained residue is dissolved in ether
In (45ml), stirred at 0~5 DEG C and be passed through hydrogen chloride gas, in whipping process, there is white precipitate to be formed；Filter and dry
After obtain target compound I (2.95g, 87%)；1H NMR(400MHz,DMSO-d6):δ3.98(s,2H),2.57(s,3H)；
LC-MS>99% (Purity) 142 (M+H)+.
Claims (7)
1.5- methyl -4H-1,2,4- triazole -3- acetic acid I synthetic method, comprises the following steps：1) diethyl malonate and
Hydrazine hydrate in alcoholic solvent, at room temperature reaction obtain compound 1,2) compound 1 with methyl ethanimidic acid ester hydrochloride 2 appropriate
In solvent, in the presence of an organic base and under reflux temperature reaction obtain compound 3,3) compound 3 in the presence of a base, it is molten in alcohol
Hydrolysis of ester bonds with agent, and add after appropriate acid carries out acidification reaction and obtain compound I, see following reaction scheme：
2. synthetic method according to claim 1, it is characterised in that alcoholic solvent described in step 1) is selected from methanol, ethanol
Or propyl alcohol, preferred alcohol.
3. synthetic method according to claim 1, it is characterised in that alcoholic solvent described in step 2) is selected from ethanol, positive third
Alcohol or isopropanol, preferably isopropanol.
4. synthetic method according to claim 1, it is characterised in that organic base described in step 2) is selected from diisopropyl second
Base amine, DBU or pyridine, preferably diisopropyl ethyl amine.
5. synthetic method according to claim 1, it is characterised in that alcoholic solvent described in step 3) be selected from methanol, ethanol,
Normal propyl alcohol or isopropanol, preferably methanol or ethanol.
6. synthetic method according to claim 1, it is characterised in that alkali described in step 3) is selected from sodium hydroxide, hydrogen-oxygen
Change potassium.
7. synthetic method according to claim 1, it is characterised in that appropriate acid is selected from hydrochloric acid, sulfuric acid described in step 3)；
It is preferred that HCl gas.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387834A (en) * | 2021-06-10 | 2021-09-14 | 苏州工业园区服务外包职业学院 | Continuous synthesis method of 3-oxo-3-hydrazino ethyl propionate |
-
2017
- 2017-10-25 CN CN201711009139.2A patent/CN107629014A/en active Pending
Non-Patent Citations (5)
| Title |
|---|
| DMITRO M. KHOMENKO等: "Synthesis and study of novel 1,2,4-triazolylacetic acid derivatives", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
| HATEM A.ABDEL-AZIZ等: "Synthesis and anticancer potential of certain novel 2-oxo-N-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazodes", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| MARIO DI BRACCIO等: "1,8-Naphthyridines VI. Synthesis and anti-inflammatory activity of 5-(alkylamino)-N,N-diethyl[1,2,4]triazolo[4,3-a][1,8]naphthyridine-6-carboxamides with a new substitution pattern on the triazole ring", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| SCOTT S. WOODARD等: "Combinatorial synthesis of 3,5-dimethylene substituted 1,2,4-triazoles", 《COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING》 * |
| YONGXING TANG等: "Nitramino- and Dinitromethyl-Substituted 1,2,4-Triazole Derivatives as High-Performance Energetic Materials", 《CHEM. EUR. J.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113387834A (en) * | 2021-06-10 | 2021-09-14 | 苏州工业园区服务外包职业学院 | Continuous synthesis method of 3-oxo-3-hydrazino ethyl propionate |
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