CN114763342A - Synthesis method of high-purity 4-methylpiperazine-1-formic ether - Google Patents

Abstract

The invention relates to a synthesis method of high-purity 4-methylpiperazine-1-formic ether, the method comprises the following steps, 1) 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane are mixed, then fatty alcohol is added, the temperature is reduced, sodium cyanide is added in batches, and the room temperature is recovered after the addition, and the stirring is carried out; 2) adding water, adjusting pH to 6-7, stirring at room temperature, separating, and keeping water phase; 3) adjusting pH of the water phase to 8-10 with sodium carbonate aqueous solution, extracting with dichloromethane for 2-3 times, mixing the organic phases, drying, and vacuum spin-drying the organic phase to obtain light yellow transparent oily 4-methylpiperazine-1-formate; the reaction formula of the method is as follows:

Description

A kind of synthetic method of high-purity 4-methylpiperazine-1-formate

technical field

The invention relates to the field of chemical drug synthesis, in particular to a method for preparing 4-methylpiperazine-1-carboxylate.

technical background

Zopiclone is a third-generation sedative-hypnotic drug developed by the French company Rhono-Poulene Rorer for the treatment of sleep disorders. Eszopiclone (Eszopiclone) is a fast-acting, short-acting non-benzodiazepine sedative and hypnotic drug developed by Seprator Company in the United States. It was launched in the United States in April 2005. Its racemate zopiclone has been listed in nearly 100 countries and regions, and eszopiclone is the first drug that can be used for long-term difficulty in falling asleep and maintain quality. Compared with its racemate, eszopiclone has medicinal properties. It has the advantages of fast effect, small side effects and low toxicity.

The zopiclone structure is as follows:

Its synthesis method usually uses 6-(5-chloro-2-pyridyl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine as raw material and 4-Methylpiperazine-1-formyl chloride hydrochloride was condensed to obtain zopiclone. Wherein, the structure of 4-methylpiperazine-1-formyl chloride hydrochloride (A) is as follows:

It can be seen that 4-methylpiperazine-1-formyl chloride hydrochloride is the key raw material for the synthesis of zopiclone.

This raw material is usually purchased from the market, and faces the problems of low purity and impurities, which may be brought in during the synthesis of zopiclone. The relevant impurities include 4-methylpiperazine-1-carboxylate (the present invention) It is abbreviated as compound C) in the text,

In the formula: R is CH ₃ , CH ₃ CH ₂ , (CH ₃ ) ₂ CH.

When R is _CH3 , the compound is methyl 4-methylpiperazine-1-carboxylate (CAS No. 7560-85-2), when it is _CH2CH3 , the compound is ₄ -methyl-1 Ethyl piperazinecarboxylate (CAS No. 59325-11-0), when it is (CH ₃ ) ₂ CH, the compound is isopropyl 4-methyl-1 piperazinecarboxylate.

Compound C is a genotoxic impurity in the quality study of zopiclone. Therefore, there is an urgent need to provide a simple and low-cost method for preparing compound C to provide a high-purity impurity reference substance for the quality control of zopiclone.

The preparation method of 4-methylpiperazine-1-formate in known compound C is as follows: 4-methylpiperazine reacts with methyl chloroformate or ethyl chloroformate to obtain 4-methylpiperazine-1 - Methyl carboxylate or ethyl 4-methyl-1 piperazinecarboxylate.

In the above-mentioned preparation method, the raw materials methyl chloroformate and ethyl chloroformate both belong to toxic components, which are harmful to operators, and the reaction conditions require the participation of strong alkali and sodium cyanide, the reaction is severe, the reaction is not easy to control, and the by-products are relatively low. many. TLC shows that the Rf value between the by-product and the main product is relatively close, and it is difficult to separate by chromatographic column chromatography.

In the post-treatment process, combined with the structural characteristics of such compounds, the inventors found that by adjusting the pH of the system, the by-products of the reaction can be effectively removed, thereby obtaining high-purity compound C.

SUMMARY OF THE INVENTION

The present invention provides a method for synthesizing high-purity zopiclone impurity compound C, which is simple to operate, easy to separate and purify, and the obtained product has high purity.

A kind of high-purity zopiclone impurity compound C synthetic method provided by the invention, described method reaction formula is as follows:

In the formula: R is CH ₃ , CH ₃ CH ₂ , (CH ₃ ) ₂ CH.

The specific operation method is as follows:

1) Mix 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane, then add aliphatic alcohol and then lower the temperature, add sodium cyanide in batches, and restore stirring at room temperature after the addition;

2) After adding water, adjust the pH to 6-7, stir at room temperature, separate liquids, and retain the water phase;

3) The pH of the aqueous phase is adjusted to 8-10 with an aqueous sodium carbonate solution, extracted with dichloromethane for 2-3 times, the organic phases are combined and dried, and the organic phases are spin-dried in vacuo to obtain compound C as a light yellow transparent oil.

In the above method:

In step 1):

The ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride, dichloromethane, fatty alcohol, and sodium cyanide is 5-15g: 40-60ml: 3-6ml: 1-3g, preferably 10g: 50ml : 5ml: 2g (including but not limited to g, kg and ml, L);

The fatty alcohol is selected from methanol, ethanol or isopropanol.

In step 2):

The added amount of the water is equal to the volume of the dichloromethane added in step 1).

The purpose of adding water: one is for stratified extraction, and the other is to adjust the pH value with the participation of water.

The pH value is 6-6.6, preferably 6.4-6.6.

The pH adjusting solvent was 4M dilute hydrochloric acid.

In step 3):

The pH is 8.5-9.1.

The solvent used to adjust the pH value is an aqueous sodium carbonate solution (25% concentration).

The invention also provides the application of compound C, that is to provide a reference substance for research on the quality of zopiclone and its raw materials.

In the above-mentioned content detection method, the impurity compound C synthesized by the method of the present invention can be used as a standard reference substance to be applied in the detection of the impurity content in zopiclone and its raw materials and preparations, so as to qualitatively characterize zopiclone and its raw materials Quantitative analysis.

The method provided by the present invention has the following advantages:

1. The same as the traditional method:

The traditional method uses toxic raw materials, the reaction uses strong base and strong acid, the reaction is violent and difficult to control, the yield is about 59%, and there are many by-products, which must be purified by column chromatography. The reactant of the method of the invention is non-toxic, and secondly, the reaction conditions are mild.

2. The yield of the method provided by the present invention is above 65%, and the purity is above 98.3%, so the method has higher economy.

3. The method provided by the invention has the characteristics of simple operation, short reaction time and high yield, which provides a basis for the research of zopiclone genotoxic impurities.

Description of drawings

Figure 1: Mass spectrum of methyl 4-methylpiperazine-1-carboxylate;

Figure 2: NMR image of methyl 4-methylpiperazine-1-carboxylate;

Figure 3: Mass spectrum of ethyl 4-methylpiperazine-1-carboxylate;

Figure 4: NMR image of ethyl 4-methylpiperazine-1-carboxylate;

Figure 5: Mass spectrum of isopropyl 4-methylpiperazine-1-carboxylate;

Figure 6: NMR image of isopropyl 4-methylpiperazine-1-carboxylate.

specific implementation

The following examples are intended to further illustrate the patent of the present invention, and do not constitute any limitation to the present invention.

Embodiment 1: the preparation method of methyl 4-methylpiperazine-1-carboxylate

1. Add 10 g of -1-formyl chloride hydrochloride and 50 ml of dichloromethane into the reaction flask, then add 5 ml of methanol, then cool down to 0-5°C, add 2 g of sodium cyanide in batches, return to room temperature and stir for 2 hours after the addition.

2. After adding water (50ml) to the system, adjust the pH to 6.4 with 4M dilute hydrochloric acid, stir at room temperature, separate the liquid, and keep the water phase.

3. The aqueous phase was adjusted to pH 9 with an aqueous sodium carbonate solution, extracted twice with 50 ml of dichloromethane, the organic phases were combined and dried, and the organic phase was spin-dried at 40°C in vacuo to obtain 4-methylpiperazine as a light yellow transparent oil. -6.6 g of methyl 1-carboxylate. The yield was 82.5%, and the purity was 98.3%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.70-3.69 (m, 3H), δ 3.49 (s, 4H), δ 2.36 (s, 4H), δ 2.31-2.29 (m, 3H).

4-methylpiperazine-1-carboxylic acid methyl ester mass spectrum and nuclear magnetic resonance diagram are shown in Figures 1 and 2.

Embodiment 2: the preparation method of 4-methylpiperazine-1-ethyl formate

1. Add 10 g of 4-methylpiperazine-1-formyl chloride hydrochloride and 50 ml of dichloromethane into the reaction flask, then add 5 ml of ethanol, and then cool down to 0-5 °C, add 2 g of sodium cyanide in batches, add After completion, return to room temperature and stir for 2h.

2. After adding 50 ml of water to the system, adjust the pH to 6.4 with 4M dilute hydrochloric acid, stir at room temperature, separate the liquid, and keep the water phase.

3. The aqueous phase was adjusted to pH 9 with an aqueous sodium carbonate solution, extracted twice with 50 ml of dichloromethane, the organic phases were combined and dried, and the organic phase was spin-dried at 40°C in vacuo to obtain 4-methylpiperazine as a light yellow transparent oil. -1-ethyl formate 5.7 g. Yield 65.5%, purity 98.8%.

¹ HNMR (400MHz, CDCl ₃ ) δ4.16-4.10(m,2H), δ3.50-3.49(d,4H), δ2.37-2.36(d,4H), δ2.31-2.29(d,3H) ), δ1.28-1.23 (m, 3H).

The mass spectrum and nuclear magnetic resonance image of ethyl 4-methylpiperazine-1-carboxylate are shown in Figures 3 and 4, respectively.

Embodiment 3: the preparation method of 4-methylpiperazine-1-isopropyl carboxylate

1. Add 10 g of 4-methylpiperazine-1-formyl chloride hydrochloride and 50 ml of dichloromethane into the reaction flask, then add 5 ml of isopropanol, and then add 2 g of sodium cyanide in batches at room temperature, and restore after the addition. Stir at 40°C for 2h.

2. After adding 50 ml of water to the system, adjust the pH to 6.6 with 4M dilute hydrochloric acid, stir at room temperature, separate liquids, and retain the water phase.

3. The aqueous phase was then adjusted to pH 9 with an aqueous sodium carbonate solution, extracted twice with 50 ml of dichloromethane, the organic phases were combined and dried, and the organic phases were spin-dried in vacuo at 40°C to obtain a light yellow transparent oil 4-methylpiperazine- Methyl 1-formate 6.1 g. The yield was 64.9%, and the purity was 98.6%.

¹ HNMR (400MHz, CDCl ₃ ) δ4.90-4.84(m,1H), δ3.43-3.42(d,4H), δ2.31(s,4H), δ2.25(d,3H), δ1. 21-1.19 (m, 6H).

The mass spectrum and nuclear magnetic resonance image of isopropyl 4-methylpiperazine-1-carboxylate are shown in Figures 5 and 6, respectively.

Claims (8)

1. A preparation method of high-purity 4-methylpiperazine-1-formic ether comprises the following reaction formula:

in the formula: 4-methylpiperazine-1-carboxylic acid ester, i.e. formula C, R is CH₃，CH₃CH₂，(CH₃)₂CH。

2. The method for preparing the compound of claim 1, comprising the following steps,

1) mixing 4-methylpiperazine-1-formyl chloride hydrochloride and dichloromethane, adding fatty alcohol, cooling, adding sodium cyanide in batches, and recovering to room temperature after adding, and stirring; the fatty alcohol is selected from: methanol, ethanol or isopropanol;

2) adding water, adjusting pH to 6-7, stirring at room temperature, separating, and keeping water phase;

3) adjusting pH of the water phase to 8-10 with sodium carbonate aqueous solution, extracting with dichloromethane for 2-3 times, mixing the organic phases, drying, and vacuum drying to obtain light yellow transparent oil.

3. The method according to claim 1, wherein in step 1): the ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride to the dichloromethane to the fatty alcohol to the sodium cyanide is 5-15 g: 40-60 ml: 3-6 ml: 1-3 g.

4. The method according to claim 1, wherein in step 2): the addition amount of the water is equal to the volume of the dichloromethane added in the step 1), and the pH value is 6-6.6.

5. The method according to claim 1, wherein in step 3): the pH is 8.5-9.1.

6. The method according to claim 1, wherein in step 1): the ratio of the 4-methylpiperazine-1-formyl chloride hydrochloride to the dichloromethane to the fatty alcohol to the sodium cyanide is 10 g: 50 ml: 5 ml: 2g of the total weight of the composition.

7. The method according to claim 1, wherein in step 2): the pH value is 6.4-6.6; the pH adjusting solvent was 4M dilute hydrochloric acid.

8. The method according to claim 1, wherein in step 3): the solvent used for adjusting the pH value is a 25% sodium carbonate aqueous solution.

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