Synthesis method of 1-(1-methylpiperidine-4-yl) piperazine trihydrochloride

Abstract

The invention provides a synthetic method of 1-(1-methylpiperidine-4-yl) piperazine trihydrochloric acid. The 1-(1-methylpiperidine-4-yl) piperazine trihydrochloric acid is used as a The method comprises the following steps: carrying out catalytic hydrogenation on N-methyl-4-piperidone and 1-acetyl piperazine in an alcohol solvent in the presence of palladium on carbon, then carrying out acidic hydrolysis, and refining to obtain the 1-(1-methylpiperidine-4-yl) piperazine trihydrochloride. The method has the advantages of easily available raw materials, simple operation, mild reaction conditions, greatly improved yield and reduced cost.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemical synthesis, and relates to a method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride. Background Art

[0002] 1-(1-Methylpiperidin-4-yl)piperazine trihydrochloride is a key intermediate for the preparation of the drug zavegepant. The structural formula of 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride is: .

[0003] On March 10, 2023, the FDA officially approved Pfizer's zavegepant (Zavzpret) for the acute treatment of migraine in adults, becoming the first and only approved nasal spray CGRP receptor antagonist. This approval provides another relief option for migraine patients who are intolerant of or ineffective with triptans and other acute migraine drugs. This is the first and only calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray specifically for the treatment of acute migraine in adults.

[0004] US5922717A reports a method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine: The method uses benzylpiperazine and N-methylpiperidone as starting materials, and then catalytically hydrogenates them after sodium cyanoborohydride reduction to obtain a free base. In this method, benzylpiperazine is a first-class psychotropic controlled raw material, which is not easy to purchase, and needs to be reduced with sodium cyanoborohydride, which is very expensive and not suitable for industrial production. In addition, the product does not form a salt, and the product is an oily substance, which is not easy to purify and does not meet market demand. Summary of the invention

[0005] The invention provides a new process for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride, which has readily available raw materials, simple operation and low cost.

[0006] The present invention uses 1-acetylpiperazine and N-methyl-4-piperidone as raw materials, catalytically hydrogenates in an alcohol solvent to obtain the compound 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine, and then refluxes hydrolysis with hydrochloric acid to obtain the product. The steps include: (1) Dissolve 1-acetylpiperazine and N-methyl-4-piperidone in an alcohol solvent, add palladium carbon and catalyze hydrogenation at 0.1-1.0 MPa (preferably 0.4-0.5 MPa) and 20-100° C. (preferably 40-50° C.) for 10-24 h, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine; The molar ratio of 1-acetylpiperazine to N-methyl-4-piperidone is 1:1-1:2; the mass ratio of 1-acetylpiperazine to palladium carbon is 1:15-1:25, and the effective substance content of palladium carbon is 5%; the alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-butanol or tert-butanol, preferably methanol.

[0007] (2) Add concentrated hydrochloric acid to 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine, raise the temperature to 60-100°C (preferably 90-100°C) and reflux for 10-15 hours. After cooling, extract with ethyl acetate to remove impurities. Concentrate the aqueous phase to dryness under reduced pressure, add ethanol for crystallization, and recrystallize with a methanol / water mixed solvent to obtain 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride.

[0008] In the methanol / water mixed solvent, the mass ratio of methanol to water is 1:0.05-0.3, preferably 1:0.05. The mass ratio of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine to concentrated hydrochloric acid is 1:2-1:3.

[0009] The synthetic route is as follows: Beneficial effects of the present invention: The invention provides a new method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride, which has the advantages of easy-to-obtain raw materials, simple operation, mild reaction conditions, greatly improved yield and reduced cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is the HNMR spectrum of 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride; Figure 2 This is the HNMR spectrum of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine. DETAILED DESCRIPTION

[0011] The present invention will be further described below through specific implementation modes.

[0012] Example 1 (1) Synthesis of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine 128.17 g (1 mol) of 1-acetylpiperazine and 113.16 g (1 mol) of N-methyl-4-piperidone were added to 1280 g of methanol, and 6.4 g of 5% Pd / C was added. The temperature was controlled at 40-50°C at 0.4-0.5 MPa for catalytic hydrogenation for 12 h until the system no longer absorbed hydrogen. The pressure was maintained for 2 hours, and the mixture was filtered to recover the catalyst. The filtrate was concentrated to dryness under reduced pressure to obtain 233.02 g of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine as a white solid (the yield was greater than 100% because the solvent was not concentrated to dryness). The crude 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride was directly prepared without purification.

[0013] The sample was recrystallized from methyl tert-butyl ether and dried at 40-50°C. The results of HNMR testing were as follows: Figure 2 , indicating that the synthesis was successful.

[0014] (2) Synthesis of crude 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride Add 500g of 37% concentrated hydrochloric acid to the 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine after vacuum concentration, heat to 95°C and reflux for 12 hours, cool to 10-20°C, add 500g of ethyl acetate to extract and remove impurities, concentrate the aqueous phase to dryness under vacuum at 80°C, continue to concentrate under vacuum with 100g of anhydrous ethanol twice, add 500g of anhydrous ethanol, stir at 0-5°C for 2 hours. Filter, rinse with anhydrous ethanol, and dry at 70-80°C to obtain 245.24g of crude product, with a two-step yield of 83.8%.

[0015] (3) Purification of 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride The crude product was added to 934.2g methanol and heated to 65℃ for 1h. 46.7g purified water was added dropwise. The system was dissolved and clear. The temperature was lowered to 0-5℃ and stirred for 2 hours. The product was filtered and dried at 70-80℃ to obtain 205.85g of 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride. The yield was 83.9%, the product purity was 99.73%, and the single impurity was 0.08%. The sample was tested by HNMR. Figure 1 , in line with the product structure.

[0016] Example 2 The methanol in step (1) of Example 1 was replaced by anhydrous ethanol to obtain 238.24 g of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine, with a yield of 100%. The remaining steps were the same as in Example 1.

Claims

1. A method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride, comprising the following steps: (1) Dissolve 1-acetylpiperazine and N-methyl-4-piperidone in an alcohol solvent, add palladium carbon and catalyze hydrogenation at 0.1-1.0 MPa and 20-100° C. for 10-24 h, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine; (2) Add concentrated hydrochloric acid to 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine, raise the temperature to 60-100°C and reflux for 10-15 hours. After cooling, extract with ethyl acetate to remove impurities. Concentrate the aqueous phase to dryness under reduced pressure, add ethanol for crystallization, and recrystallize with a methanol / water mixed solvent to obtain 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride.

2. The method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride according to claim 1, characterized in that: The molar ratio of 1-acetylpiperazine to N-methyl-4-piperidone is 1:1 to 1:

2.

3. The method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride according to claim 1, characterized in that: The mass ratio of 1-acetylpiperazine to palladium carbon is 1:15~1:25, and the effective substance content of palladium carbon is 5%.

4. The method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride according to claim 1, characterized in that: The alcohol solvent is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-butanol or tert-butanol.

5. The method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride according to claim 1, characterized in that: In the methanol / water mixed solvent, the mass ratio of methanol to water is 1:0.05~0.

3.

6. The method for synthesizing 1-(1-methylpiperidin-4-yl)piperazine trihydrochloride according to claim 1, characterized in that: The mass ratio of 1-(1-methylpiperidin-4-yl)-4-acetylpiperazine to concentrated hydrochloric acid is 1:2~1:3.

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