CN107629014A - The synthetic method of the acetic acid of 5 methyl 4H, 1,2,4 triazoles 3 - Google Patents

Abstract

A kind of synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I, comprises the following steps: 1) diethyl malonate and hydrazine hydrate react in alcohol solvent, at room temperature Compound 1 is obtained, 2) compound 1 is reacted with methyl acetimidate hydrochloride 2 in a suitable solvent, in the presence of an organic base and at reflux temperature to obtain compound 3, 3) compound 3 is reacted in the presence of a base in alcohol The ester bond is hydrolyzed in a solvent, and compound I is obtained after adding an appropriate acid for acidification reaction, see the following reaction scheme: The synthesis method of the invention has the following advantages: the raw materials of the synthesis route are easy to obtain, the price is cheap, the synthesis process conditions of each step are mild, and the industrial production is easy.

Description

Synthesis of 5-methyl-4H-1,2,4-triazole-3-acetic acid

technical field

The invention relates to the field of pharmaceutical chemical synthesis, in particular to a synthesis method of a pharmaceutical intermediate 5-methyl-4H-1,2,4-triazole-3-acetic acid.

Background technique

Triazole heterocycles are an important class of aromatic heterocycles. Because they are easy to form hydrogen bonds, coordinate bonds, etc., and play a variety of non-covalent interactions, they can improve the chemical and physical properties of drug molecules such as water solubility; It is widely used in drug synthesis, functional materials and molecular biology. The 1,2,4-triazoles in the triazole structure exhibit various biological activities, such as itraconazole, traconazole, posaconazole, abaconazole, fluconazole, Fluconazole, voriconazole, etc. are a class of drugs containing 1,2,4-triazoles.

5-Methyl-4H-1,2,4-triazole-3-acetic acid, CAS.No. is 720706-28-5, its structural formula is shown in formula I; it is an important class of pharmaceutical and chemical intermediates, and is Widely used in the field of pharmaceutical and chemical synthesis. For example, the literature reported a new molecular structure containing 5-methyl-4H-1,2,4-triazole-3-acetyl fragment, which is a kind of phosphodiesterase receptor, showing a wide range of antitumor activities.

In the article "Synthesis and study of novel 1,2,4-triazolylacetic acidderivatives" (Chem Heterocycl Comp, 2016,52(6):402-408.), Khomenko et al. reported the combination of formic hydrazide A and acetic acid malonate Ester monoimide ester B was refluxed in ethanol to obtain the corresponding 5-methyl-1,2,4-triazole-3-acetate 3; and then hydrolyzed to obtain 5-methyl-4H-1,2, 4-triazole-3-acetic acid I; see the following synthetic route 1.

In the above synthetic route 1 [9], malonate monoimide B is not easy to prepare, which limits the further application of this method. The present invention aims to develop a simple and convenient synthesis method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I suitable for industrial production.

Contents of the invention

The invention provides a kind of synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I, comprises the following steps: 1) diethyl malonate and hydrazine hydrate in alcohol solvent , react at room temperature to obtain ethyl malonate hydrazide 1 (compound 1), 2) react compound 1 with methyl acetimidate hydrochloride 2 in a suitable solvent, in the presence of an organic base and at reflux temperature to obtain 5-Methyl-4H-1,2,4-triazole-3-acetate 3 (Compound 3), 3) Compound 3 hydrolyzes the ester bond in an alcohol solvent in the presence of a base, and acidifies by adding an appropriate acid After the reaction, 5-methyl-4H-1,2,4-triazole-3-acetate I was obtained, as shown in the following reaction scheme 2:

The synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I of the present invention, wherein, methyl acetimidate hydrochloride 2 is mixed HCl under stirring in ice-water bath The gas is passed into a mixed solution of acetonitrile, methanol and hexane; the reaction is obtained during stirring.

A preferred embodiment, the synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I of the present invention, wherein, the alcohol solvent described in step 1) is selected from methanol, ethanol or Propanol, preferably ethanol.

A preferred embodiment, the synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I of the present invention, wherein, the alcohol solvent described in step 2) is selected from ethanol, n-propyl Alcohol or isopropanol, preferably isopropanol; The organic base is selected from diisopropylethylamine, DBU or pyridine, preferably diisopropylethylamine.

A preferred embodiment, the synthetic method of 5-methyl-4H-1,2,4-triazole-3-acetic acid I of the present invention, wherein, the alcohol solvent described in step 3) is selected from methanol, ethanol, n-propanol or isopropanol, preferably methanol or ethanol; the base is selected from sodium hydroxide, potassium hydroxide; the appropriate acid is selected from hydrochloric acid, sulfuric acid; preferably hydrochloric acid gas.

This paper developed a new diethyl malonate as the starting material, reacted with hydrazine hydrate to obtain ethyl malonate hydrazide 1, and then reacted with methyl ethyl imidate hydrochloride 2 in the presence of Hoenig base. The condensation reaction gives 5-methyl-4H-1,2,4-triazole-3-acetate 3, and finally the ester bond of compound 3 is hydrolyzed to give 5-methyl-4H-1,2,4-tri Azole-3-acetic acid I, the final product yield is high. The route has the advantages of readily available raw materials, low price, mild synthesis process conditions in each step, and easy industrial production.

detailed description

The following will further illustrate the present invention through specific examples, but it is not intended to limit the protection scope of the present invention. Without departing from the concept of the present invention, those skilled in the art can make improvements to the preparation method and equipment used within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

In the following examples, unless otherwise specified, the test methods are generally implemented under conventional conditions or conditions suggested by the manufacturer; the raw materials and reagents shown can all be obtained through commercially available means.

Embodiment 1. The preparation of ethyl malonate hydrazide 1

Diethyl malonate (10 g, 62.5 mmol) was dissolved in 50 ml of ethanol, then 85% hydrazine hydrate (1.44 g, 1.44 mol) was added. The reaction mixture was stirred overnight at room temperature. Stop the reaction, filter, and evaporate the filtrate to remove the solvent under reduced pressure. The obtained residue was recrystallized from a mixed solvent of ethyl acetate/petroleum ether to obtain compound 1 (2.10 g, 64%) as a white solid. 1HNMR (400MHz, DMSO-d6) δ4.12(q, J=7.1Hz, 2H), 3.16(s, 2H), 1.22(t, J=7.1Hz, 3H); LC-MS147(M+H)+ .

Embodiment 2. The preparation of methyl acetimidate hydrochloride 2

In an ice-water bath, HCl gas was passed into a mixed solution of acetonitrile (30 g, 0.720 mol), methanol (35 ml, 0.87 mol) and hexane (150 ml) with stirring; during stirring, a white precipitate gradually formed. Continue to stir the reaction for 6h, stop the reaction. The solvent was distilled off from the reaction solution under reduced pressure to obtain compound 2 (63.51 g, 84%). 1H NMR (400MHz, CDCl3) δ12.78 (br, 1H), 12.03 (br, 1H), 8.40-7.43 (m, 5H), 4.57 (s, 3H).

Example 3. Preparation of ethyl 5-methyl-4H-1,2,4-triazole-3-acetate 3

Compound 1 (13.08g, 0.09mol) was suspended in isopropanol (70ml), then Hoenig base (NEt(i-Pr)2, 70ml) and compound 2 (12.6g, 0.16mol) were added dropwise. The reaction mixture was stirred at room temperature for 10 minutes, then heated to reflux in an oil bath for 3 days. The solvent was evaporated, and the resulting residue was diluted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting residue was recrystallized from a mixed solvent of ethyl acetate/petroleum ether to obtain the target compound 3 (10.87 g, 71%) as a white solid. 1H NMR (400MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 2.41 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

The preparation of embodiment 4.5-methyl-4H-1,2,4-triazole-3-acetic acid I

Compound 3 (4g, 23.5mmol) was dissolved in water (30ml) and methanol (20ml), then sodium hydroxide (1.22g, 1.22mol) was added in portions; the resulting mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ether (45ml), stirred and passed into hydrogen chloride gas at 0-5°C, during the stirring process, a white precipitate was formed; after filtering and drying, the 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.