D3-Acetylhydrazine, Its Synthesis Method and Application

Abstract

The present invention discloses a D3-acetyl hydrazine, its synthesis method and application, belonging to the fields of organic synthesis and medicine. The synthesis method includes: 1) D3-acetic acid and an alcohol undergo an esterification reaction under acid catalysis to obtain D3-acetate; (2) D3-acetate and acetyl hydrazine undergo an amine-ester exchange reaction to obtain D3-acetyl hydrazine. The method for synthesizing D3-acetyl hydrazine of the present invention has the advantages of short synthesis steps and high yield. At the same time, using D3-acetyl hydrazine as a raw material, a compound D3-2-acetylthiophene acetyl hydrazone with antibacterial activity is synthesized, and it can also provide a solid foundation for the synthesis of other deuterated drugs.

Description

Technical Field

[0001] The present invention relates to the fields of organic synthesis and medicine, and particularly relates to D3-acetylhydrazine, a synthesis method thereof, and applications thereof. Background Art

[0002] Deuterium is an easily obtainable and relatively safe isotope of hydrogen. In the natural distribution, the abundance of deuterium is 0.015%. Since deuterium was fractionated from liquid hydrogen by H.C. Urey in 1931, deuterium has been widely used in various aspects such as medicine, energy, materials, and analytical testing. As is well known, early developed marketed drugs usually have some drawbacks, such as rapid metabolism, poor absorption, unsatisfactory pharmacokinetic parameters, and drug-drug interactions. Often, it is necessary to take the drug multiple times a day or at a large dose to maintain an effective blood drug concentration, resulting in large toxic and side effects. To solve these problems, scientists have also tried some means to modify drug molecules, such as fluorination or methylation, but these strategies often have poor effects or high costs, and deuteration is one of the new means for current drug research and development and modification. Especially after the launch of the world's first deuterated drug, Austedo, it has further accelerated the development of deuterated drugs.

[0003] As a commonly used chemical raw material, acetylhydrazine plays an important role in many fields such as medicine and pesticides. Although the preparation of acetylhydrazine has been reported for a long time, the inventors found that there is no report on the synthesis of deuterated acetylhydrazine. Therefore, designing and developing a synthesis route for deuterated acetylhydrazine with high yield and simple operation has important application value. Summary of the Invention

[0004] One of the purposes of the present invention is to provide a D3-acetylhydrazine to solve the above problems.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows: D3-acetylhydrazine has the following structure:

[0006]

[0007] Another purpose of the present invention is to provide a synthesis method for the above D3-acetylhydrazine. The technical solution adopted is as follows, including the following steps:

[0008] (1) D3-acetic acid and an alcohol undergo an esterification reaction under acid catalysis to obtain D3-acetate;

[0009] (2) D3-acetate and acetylhydrazine undergo an amine-ester exchange reaction to obtain D3-acetylhydrazine;

[0010] The specific synthesis route is as follows:

[0011]

[0012] As a preferred technical solution, in the esterification reaction of step (1), the alcohol is various fatty alcohols.

[0013] As a further preferred technical solution, the fatty alcohol is ethanol. Using ethanol has a lower cost.

[0014] As a preferred technical solution, in the esterification reaction of step (1), the acid is various strong proton acids.

[0015] As a further preferred technical solution, the strong proton acid is sulfuric acid, phosphoric acid or boric acid.

[0016] As an even more preferred technical solution, the acid is sulfuric acid. Using sulfuric acid gives a higher yield.

[0017] In addition, before determining the above reaction route, the inventors also tried other routes to synthesize D3-acetylhydrazine, but the effects were not good. For example: When the inventors used deuterated acetic acid and hydrazine hydrate in a one-step method to synthesize D3-acetylhydrazine, it was found that a violent acid-base neutralization reaction occurred between the two, generating a neutral salt instead of the desired product D3-acetylhydrazine. Even through dilution, cooling, or slow dropping, it was of no avail. In addition, the inventors also tried to first react deuterated acetic acid with oxalyl chloride at low temperature in dichloromethane to prepare highly active deuterated acetyl chloride, and then react deuterated acetyl chloride with hydrazine hydrate to synthesize D3-acetylhydrazine. Although this method can obtain the product D3-acetylhydrazine, the yield is very low (21%). This is mainly because the boiling point of the acyl chloride is relatively low, and there will be a large loss during the post-treatment in the first-step preparation. And in the second-step reaction with hydrazine hydrate, due to the high activity of acetyl chloride, it is easy to undergo a bimolecular substitution reaction with hydrazine hydrate, generating a large amount of by-product D6-N,N'-diacetylhydrazine, further reducing the yield of deuterated acetylhydrazine.

[0018]

[0019] A third object of the present invention is to provide an application of the above D3-acetylhydrazine. The technical solution adopted is: The application is to use D3-acetylhydrazine as a raw material to synthesize a compound D3-2-acetylthiophene acetylhydrazone with antibacterial activity to prove the application value of D3-acetylhydrazine in the medical field. The specific synthesis route is as follows:

[0020]

[0021] Antibacterial activity test:

[0022] Test method: Under aseptic conditions, pour about 10 mL of the culture medium into a 10-cm petri dish and let it stand for 2 hours to harden the culture medium to prepare an agar plate. Pour 1 mL of the inoculum of the cultured microorganism Bacillus subtilis onto a plate containing a fixed agar medium alone. Immerse the prepared sterile filter paper circle in the sample solution, shake well, incubate at 37 °C for 2 days, measure and record the diameter of the corrosion inhibition zone every day, and take the average value. The results are as follows: When the mass of D3-2-acetylthiophene acetylhydrazone is 200 μg, the diameter d of the inhibition zone = 7.0 mm; when the mass of D3-2-acetylthiophene acetylhydrazone is 300 μg, the diameter d of the inhibition zone = 9.0 mm; when the mass of D3-2-acetylthiophene acetylhydrazone is 500 μg, the diameter d of the inhibition zone = 10.0 mm. The antibacterial activity is significantly better than that of non-deuterated 2-acetylthiophene acetylhydrazone (Orient. J. Chem., 2019, 35, 557).

[0023] In addition, using D3-acetylhydrazine as a raw material, the following compounds can also be synthesized (to prove the use of D3-acetylhydrazine)

[0024]

[0025] In addition, as a deuterated product of acetylhydrazine, D3-acetylhydrazine can also be used as an internal standard for qualitative and quantitative detection.

[0026] Compared with the prior art, the advantages of the present invention are as follows: The method for synthesizing D3-acetylhydrazine of the present invention has the advantages of short synthesis steps and high yield; at the same time, using D3-acetylhydrazine as a raw material, a compound D3-2-acetylthiophene acetylhydrazone with antibacterial activity is synthesized, which can also provide a solid foundation for the synthesis of other deuterated drugs. Description of the Drawings

[0027] Figure 1 1H NMR spectrum of D3-acetylhydrazine prepared in Example 1 of the present invention;

[0028] Figure 2 1H NMR spectrum of D3-2-acetylthiophene acetylhydrazone prepared in Example 2 of the present invention;

[0029] Figure 3 13C NMR spectrum of D3-2-acetylthiophene acetylhydrazone prepared in Example 2 of the present invention. Detailed Embodiments

[0030] The present invention will be further described below with reference to the drawings.

[0031] Example 1:

[0032] A method for synthesizing D3-acetylhydrazine, comprising the following steps:

[0033]

[0034] Take a dry and clean 150 mL round-bottom flask, and successively add ethanol (20 mL, 55.00 mol), concentrated sulfuric acid (5 mL, 0.03 mol), and D3-acetic acid (15 mL, 0.24 mol) thereto. Heat to reflux at 120 °C, stir and react for 2 h. After the reaction is completed, cool to room temperature, quench with saturated sodium bicarbonate solution until the solution is neutral, wash once with saturated calcium chloride solution, then heat to 63 °C, distill the obtained mixture to obtain crude ethyl deuterioacetate (16 mL, 0.20 mol, yield 85%);

[0035] Take a dry and clean 150 mL round-bottom flask, successively add crude ethyl deuterioacetate 17 (16 mL, 0.20 mol) and 80% hydrazine hydrate (20 mL, 0.33 mol), heat to reflux at 120 °C, stir and react for 8 h. After the reaction is completed, concentrate under reduced pressure to remove the solvent to obtain crude deuterioacetyl hydrazine, and then recrystallize with dichloromethane and petroleum ether to obtain white crystals (9.93 g, 0.13 mol, yield 70%). The hydrogen spectrum is as Figure 1 shown, 1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 3.97 (s, 2H). HRMS (ESI): Calcd. for C2H3D3NO [M+Na] + 100.0561; found 100.0563.

[0036] Example 2

[0037] Synthesize D3-2-acetylthiophene acetyl hydrazone:

[0038]

[0039] Take a dry and clean 100 mL round-bottom flask, add a hot methanol solution (20 mL) of 2-acetylthiophene (5.03 mL, 0.03 mol), and then add D3-acetyl hydrazine (3.0 g, 0.03 mol) dissolved in methanol (20 mL) thereto. Add a few drops of glacial acetic acid while stirring. Heat the reaction to reflux at 80 °C, stir and react for 2 h, monitor the end point of the reaction by thin layer chromatography (TLC), and after the reaction is completed, cool to room temperature. Concentrate under reduced pressure to remove the solvent, add 30 mL of water, extract with dichloromethane (5 × 30 mL), combine the organic phases, and wash once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a pale yellow solid (4.5 g, yield 81%). The hydrogen spectrum and carbon spectrum are as Figure 2 and Figure 3as shown 1 HNMR(400 MHz, CDCl3) δ 9.65 (s, 1H), 7.30 (s, 1H), 7.25 (d, J = 3.9 Hz, 1H), 7.01 (m, J = 4.2 Hz, 1H), 2.43 (s, 0.08H), 2.28 (s, 3H); 13 C NMR(101 MHz, CDCl3) δ 174.3, 143.8, 143.7, 127.7, 127.3, 126.4, 20.3, 20.1, 19.9, 19.7, 19.5, 13.5。

[0040] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. Application of D3-acetylhydrazine, characterized in that: The application is to synthesize the compound D3-2-acetylthiophene acetylhydrazone with antibacterial activity using D3-acetylhydrazine as a raw material, wherein the D3-acetylhydrazine has the following structure: ； The D3-2-acetylthiophene acetylhydrazone has the following structure: 。

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