CN106588803A - Novel method for preparing 5-acetylisoxazole - Google Patents

Abstract

The invention discloses a method for preparing 5-acetyl isoxazole. The method starts from 2,3-butanedione and undergoes three-step reactions including carbonyl protection, enaminoketolation and ring closure to form isoxazole. The method of the invention has the characteristics of easy-to-obtain raw materials, simple and convenient operation, and easy scale-up production.

Description

A new method for preparing 5-acetylisoxazole

technical field

The present invention specifically relates to a synthesis process of 5-acetylisoxazole compounds or acid salts thereof.

Background technique

Isoxazole compounds are an important class of five-membered heterocyclic heterocyclic compounds. As an important organic synthesis intermediate in the fields of medicine and pesticides, they have great application value. At the same time, this kind of compound has many biological activities, and also has good pharmacological properties. It can reduce human blood sugar, eliminate human pain, resist human inflammation, kill harmful bacteria, control and reduce the harm of HIV, etc. These aspects have a great effect on human beings. In particular, some isoxazole derivatives exhibit agrochemical properties and have the activity of inhibiting the growth of weeds and soil bacteria, so it is also widely used in the fields of pesticides and insecticides. Isoxazole is also widely used in dyes, electrical insulating oils, high-temperature lubricants, and its polymer form is used in semiconductors. In recent years, the research and application of 5-acetylisoxazole compounds in the field of new drug research and development has become increasingly active. The existing synthesis method is to obtain acetyl (carbonyl) from 5-isoxazole formic acid through low-temperature reaction of weinreb amide, and the synthesis cost High, harsh conditions, difficult to industrialized production.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the shortcomings of the existing 5-acetylisoxazole compound preparation methods, such as lack of versatility, high synthesis cost, harsh conditions, and difficulty in industrialized production, etc., and provide A synthesis process of 5-acetylisoxazole compounds and salts thereof completely different from the prior art. The synthesis process of the invention has high yield, simple operation and treatment, is suitable for industrial production, and has universality.

Therefore, the present invention relates to a synthesis process of 5-acetylisoxazole compounds and acid salts thereof as shown in formula III, comprising the following steps:

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For implementation methods that do not indicate specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1 Preparation of Compound 1

Stir and mix (200mmol, 17.22g) 2,3-butanedione and (220mmol, 32.60g) triethyl orthoformate evenly, add 1.00g p-toluenesulfonic acid as a catalyst and stir at room temperature for 18h, take a small amount of the reaction solution and wash it with ethyl acetate Ester extraction TLC spot plate, raw material reaction is complete, and the solvent is removed in vacuo. The obtained product 1 was directly put into the next reaction without purification.

Example 2 Preparation of Compound 2

Add 40ml of N,N-dimethylformamide dimethyl acetal (DMFDMA) to the product 1, reflux in an oil bath at 110°C for more than 24h, TLC monitors that the reaction of the raw material is complete, remove the solvent in vacuo, and add a small amount of ethyl acetate Put 50ml of petroleum ether (ethyl acetate: petroleum ether = 1:9) and let it stand (first use 1:2 to stand still without crystals, then add some petroleum ether), recrystallize black flaky crystals, and suction filter (use Petroleum ether was washed several times to wash away part of the black impurities, and the flaky crystals were metallic silver-gray), and dried at room temperature to obtain the product 2 (1-dimethylamino-4,4-diethoxy-1-pentene-3- ketone). The two-step yields are 55.7%-69.2% in total. LCMS (m/z): 216 (M ⁺ +H).

Example 3 Preparation of compound 3

Take 2.15 g (10 mmol) of product 2 and 0.85 g (12 mmol) of hydroxylamine hydrochloride and dissolve them in 30 mL of methanol, raise the temperature and reflux for 2-3 hours. After the reaction of the raw materials is monitored by TLC, concentrate to remove methanol, add water, and extract with ethyl acetate (30 mL*3 ), the organic phase was concentrated, and column chromatography gave 0.98 g of the product 5-acetylisoxazole hydrochloride, with a yield of 66.4%.

LCMS(m/z):111(M ⁺ +H) ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 11.98 (s, 1H), 8.63(d, J = 1.9 Hz, 1H), 6.79 (d, J = 1.9 Hz,1H), 2.17 (s, 3H).

Claims (8)

1. A synthetic technique for 5-acetylisoxazole (compound 4) or its acid salt as shown in formula I, it comprises the following steps: compound 3 and hydroxylamine under certain acid-base conditions, certain solvent In, the reaction of the method for preparing 5-acetylisoxazole at a suitable temperature, wherein R is methyl or ethyl. 2. The method according to claim 1, wherein said acid-base condition can be acidic, alkaline or neutral. 3. Acidic conditions correspond to hydrochloric acid, sulfuric acid or p-toluenesulfonic acid; alkaline conditions correspond to potassium carbonate or sodium hydroxide. 4. Neutral means that no acid or base is added to the reaction system. 5. The synthesis of compound 3 is shown in formula II. Starting from 2,3-butanedione, a carbonyl group is protected by orthoformic acid triester, and then N,N-dimethylformamide dimethyl acetal is added at a certain temperature. Synthetic enaminone, wherein, the definition of R is the same as that described in claim 1. 6. method as claimed in claim 3, wherein orthoformic acid triester can be methyl ester or ethyl ester, after the first step has reacted, directly carry out next step reaction after the alcohol that spins off generation. 7. The method as claimed in claim 3, wherein the reaction temperature of forming enaminone is 100-130 degrees centigrade. 8. The method according to claim 1, further comprising the step of separating and purifying the reaction product.