CN108976200B

CN108976200B - Method for preparing pimobendan from side product of pimobendan synthesis

Info

Publication number: CN108976200B
Application number: CN201811091291.4A
Authority: CN
Inventors: 不公告发明人
Original assignee: Qingdao Agricultural University
Current assignee: Qingdao Agricultural University
Priority date: 2018-09-19
Filing date: 2018-09-19
Publication date: 2022-09-20
Anticipated expiration: 2038-09-19
Also published as: CN108976200A

Abstract

The invention discloses a novel method for preparing pimobendan from a by-product of pimobendan synthesis, which comprises the following steps: the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone) is dissolved in a mixed solvent and reacts with Ceric Ammonium Nitrate (CAN) for 2-3 hours at the temperature of 20-25 ℃ to obtain a pimobendan crude product; heating and refluxing the obtained pimobendan crude product in an organic solvent, cooling, filtering and drying to obtain the pimobendan. The invention converts the unnecessary by-products into the required pimobendan product, changes waste into valuable and greatly reduces the production cost.

Description

Method for preparing pimobendan from side product of pimobendan synthesis

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a novel method for preparing pimobendan from a by-product of pimobendan synthesis.

Background

Pimopendan, also known as Pimobendan (Pimobendan), is commercially available under the trade name Acardi, having the chemical name 4, 5-dihydro-6- [2- (4-methoxyphenyl) -1H-benzimidazol-5-yl ] -5-methyl-3 (2H) -pyridazinone, which was developed by Boechringer Ingelhem, Germany, and was first marketed in Japan in 1994. The pimobendan has the pharmacological action characteristic of enhancing the sensitivity of cardiac contractile protein to calcium ions, inhibiting the activity of phosphodiesterase III (PDE-3) and simultaneously expanding blood vessels, so that the pimobendan is an ideal inotropic drug and is clinically used for treating acute and chronic heart failure as a cardiotonic drug.

Currently, the methods for synthesizing pimobendan are classified into three categories according to the initial raw materials used: (1) acetanilide is used as a starting material; (2) p-chlorobenzaldehyde is used as a starting material; (3) benzene chloride is used as a starting material. Since the synthesis process using chlorobenzene as a starting material involves many reaction steps (13-step reaction) and uses unit reaction operations such as liquid bromine and high-pressure ammonification, it is not suitable for industrial production. Therefore, pimobendan is synthesized by using p-chlorobenzaldehyde and acetanilide as starting materials.

The synthetic route using acetanilide as a starting material is as follows:

the synthetic route using p-chlorobenzaldehyde as a starting material is as follows:

respectively taking acetanilide and p-chlorobenzaldehyde as initial raw materials to synthesize pimobendan, and finally, synthesizing pimobendan through the same condensation reaction in the last step, wherein the reaction formula is as follows:

in fact, not only the pimobendan product is produced in this last condensation reaction, but a by-product is inevitably formed, the reaction formula is as follows:

the amount of by-products produced is about 10% of the amount of pimobendan, and since the by-products are unavoidable, it is extremely important whether the by-products produced can be converted into pimobendan. The invention aims to solve the problem of how to convert the generated by-product into pimobendan. The technical route of the invention is as follows:

disclosure of Invention

The invention discloses a novel method for converting a by-product of pimobendan synthesis into pimobendan, which changes waste into valuable and greatly reduces the production cost of the pimobendan.

The method comprises the following steps:

step 1): the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) is dissolved in a mixed solvent, and reacts with Ceric Ammonium Nitrate (CAN) for 2-3 hours at the temperature of 20-25 ℃, and a by-product is oxidized to obtain a pimobendan crude product. Wherein the solvent is mixture of acetone and water, and the amount of the mixture is 5 ml of acetone and 2.5 ml of water/mmol of byproduct (chemical name is (5RS) -6- [1- (4-methyl)Oxybenzyl) -2- (4-methoxyphenyl) -1H-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone), the volume ratio of acetone to water being 2: 1; the by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1)H-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) -pyridazinone) and Ceric Ammonium Nitrate (CAN) in a molar ratio of 1:2 to 3.

Step 2): purifying and refining the pimobendan crude product obtained in the step 1), heating and refluxing in an organic solvent, cooling, filtering and drying to obtain the pimobendan. Wherein the organic solvent is ethyl acetate, and the dosage of the organic solvent is 15 ml of ethyl acetate/g of pimobendan crude product.

The invention has the advantages that: the unnecessary by-products are converted into the required pimobendan product, so that the waste is changed into valuable, and the production cost is greatly reduced.

Detailed Description

Example 1

The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, ceric ammonium nitrate (10.96 g, 20 mmol) was added, and the mixture was stirred at 25 ℃ for 2 hours to precipitate, which was then filtered, collected, and the resulting solid was washed with 100 ml of water and 20 ml of acetone in this order and dried to obtain 3.03 g of a white solid. And adding 45 ml of ethyl acetate into the obtained white solid, stirring, heating and refluxing for 30 minutes, cooling, and filtering to obtain a white precipitate, wherein 2.94 g of pimobendan is obtained, and the yield is 88.1%. m.p. 241.1-242.5 ℃. ¹ H-NMR(500MHz, DMSO-d6)δ: 12.86（br s, 0.5H），12.83（br s, 0.5H），10.91（br s, 0.5H），10.88（br s, 0.5H），8.12（d, J = 9.0, 2H），8.02（br s, 0.5H），7.85（br s, 0.5H），7.73（d, J= 8.5 Hz, 0.5H），7.66（br s, 0.5H），7.64（br s, 0.5H），7.51（d, J= 8.0 Hz, 0.5H），7.11（d, J= 9.0 Hz, 2H），3.83(s, 3H), 3.48～3.51（m, 1H），2.71（d, J= 16.0 Hz, 1H），2.25（d, J= 17.0 Hz, 1H），1.12（d, J= 7.5 Hz, 3H）。

Example 2

The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (9.08 g, 20 mmol) was dissolved in a mixed solvent of 100 ml of acetone and 50 ml of water, ceric ammonium nitrate (32.9 g, 60 mmol) was added, and the mixture was stirred at 22 ℃ for 2.5 hours to precipitate, which was then filtered, collected, and the resulting solid was washed with 200 ml of water and 40 ml of acetone in this order and dried to obtain 6.23 g of a white solid. The obtained white solid is added with 90 ml of ethyl acetate, stirred, heated and refluxed for 30 minutes, cooled and filtered to obtain white precipitate, 6.01 g of pimobendan is obtained, and the yield is 90%.

Example 3

The by-product (chemical name is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1) obtained from the synthesis of pimobendanH-benzimidazol-6-yl]-5-methyl-4, 5-dihydro-3 (2)H) Pyridazinone) (4.54 g, 10 mmol) was dissolved in a mixed solvent of 50 ml of acetone and 25 ml of water, ceric ammonium nitrate (13.7 g, 25 mmol) was added, and the mixture was stirred at 20 ℃ for reaction for 3 hours, to precipitate, and the precipitate was collected by filtration, and the obtained solid was washed with 100 ml of water and 20 ml of acetone in this order and dried to obtain 3.23 g of a white solid. The obtained white solid is added with 45 ml of ethyl acetate, stirred, heated and refluxed for 30 minutes, cooled and filtered to obtain white precipitate, and pimobendan 3.05 g is obtained, and the yield is 91%.

Claims

1. A method for preparing pimobendan from a by-product of pimobendan synthesis, comprising the steps of:

step 1): dissolving a byproduct obtained by pimobendan synthesis, wherein the chemical name of the byproduct is (5RS) -6- [1- (4-methoxybenzyl) -2- (4-methoxyphenyl) -1H-benzimidazole-6-yl ] -5-methyl-4, 5-dihydro-3 (2H) -pyridazinone, dissolving the byproduct in a mixed solvent, adding ammonium ceric nitrate, reacting for 2-3 hours at 20-25 ℃ to obtain a pimobendan crude product, wherein the mixed solvent is acetone and water, the volume ratio of the acetone to the water is 2:1, and the molar ratio of the byproduct to the ammonium ceric nitrate is 1: 2-3;

step 2): purifying and refining the pimobendan crude product obtained in the step 1), heating and refluxing in an organic solvent, cooling, filtering and drying to obtain the pimobendan.

2. The method for producing pimobendan from the by-product of pimobendan synthesis as claimed in claim 1, wherein said step 1) is carried out in the presence of 5 ml of acetone and 2.5 ml of water per mmol of the by-product.

3. The method as claimed in claim 1, wherein the organic solvent used in the refining step 2) is ethyl acetate, and the amount of ethyl acetate used is 15 ml/g.