Method for simply synthesizing m-trifluoromethyl cinnamic acid

Abstract

The invention relates to the technical field of medicine synthesis, and discloses a method for simply synthesizing m-trifluoromethyl cinnamic acid. The m-trifluoromethyl cinnamic acid is prepared by condensing m-trifluoromethyl benzaldehyde and malonic acid under the condition of no solvent or less solvent. The synthesis method has the characteristics of high conversion speed, high yield, low solvent demand, low production cost, large-scale industrial production and the like.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for simply synthesizing m-trifluoromethylcinnamic acid. Background Art

[0002] Cinacalcet is the first drug in a new class of compounds called calcimimetics, which can activate calcium receptors in the parathyroid glands, thereby reducing the secretion of parathyroid hormone. It can be used to treat secondary hyperparathyroidism in chronic kidney disease patients undergoing dialysis and hypercalcemia in patients with parathyroid cancer. The preparation Cinacalcet hydrochloride was developed by NPS Pharmaceuticals in the United States. On March 8, 2004, the FDA approved the marketing of Cinacalcet hydrochloride produced by Amgen (the licensee of NPS Pharmaceuticals' product).

[0003] m-Trifluoromethylcinnamic acid is an important raw material for synthesizing Cinacalcet hydrochloride, and the relatively low-cost synthesis method of m-trifluoromethylcinnamic acid disclosed in the prior art is to synthesize it by Knoevenagel condensation reaction using m-trifluoromethylbenzaldehyde and malonic acid, such as patent US4855086. However, the biggest problem of this method is that it must use relatively expensive solvent pyridine and a small amount of piperidine, which is costly, and in order to remove a small amount of pyridine and piperidine during post-treatment, acid washing is required, which is relatively troublesome.

[0004] Therefore, it is of great practical significance to develop a synthesis process for the large-scale industrial production of trifluoromethylcinnamic acid with low production cost, simple and efficient operation. Summary of the invention

[0005] The purpose of the present invention is to provide a simple method for synthesizing m-trifluoromethylcinnamic acid in order to overcome the defects of the above-mentioned prior art. The core of this method is to prepare the target product without or with less solvent, and the selected solvent is relatively cheap and easy to handle. This method has low production cost, simple and efficient operation, and can be mass-produced industrially.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] Add m-trifluoromethylbenzaldehyde and malonic acid into a reaction container, a solvent with a mass volume ratio of 0 to 0.25 relative to m-trifluoromethylbenzaldehyde, and pyridine with a molar ratio of 0.02 to 0.1 relative to m-trifluoromethylbenzaldehyde, and heat to condense to obtain m-trifluoromethylcinnamic acid, and then simply recrystallize to obtain a product with very high purity. DETAILED DESCRIPTION

[0008] The present invention is described in detail below in conjunction with specific embodiments. It is obvious that the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0009] Example 1

[0010] In a 50mL single-mouth bottle, 5g of trifluoromethylbenzaldehyde, 3.3g of malonic acid and 0.1g of pyridine were added and heated to 100°C. The reaction system was first dissolved and then solidified after about 10 minutes (no obvious residual raw materials were found after testing). 15mL of toluene was added and heated to dissolve. The mixture was slowly cooled to 20°C to precipitate a large amount of white solid. The mixture was filtered and the filter cake was vacuum dried to obtain 4.9g of white solid (liquid phase purity 99.9%, yield 78.9%).

[0011] Example 2

[0012] 100 g of m-trifluoromethylbenzaldehyde, 65.7 g of malonic acid, 2.3 g of pyridine and 25 mL of n-heptane were added to a 1L reaction bottle, heated with stirring and refluxed for 2 hours. The raw materials were basically reacted, 375 mL of n-heptane was added, and the mixture was slowly cooled to 20°C. A large amount of white solid precipitated. The mixture was stirred for 2 hours, filtered, and the filter cake was vacuum dried to obtain 105.5 g of white solid (liquid phase purity 99.6%, yield 85.0%).

[0013] Example 3

[0014] 1000 g of m-trifluoromethylbenzaldehyde, 657.4 g of malonic acid, 22.7 g of pyridine and 250 mL of toluene were added to a 5 L reaction bottle, heated with stirring and refluxed for 4 hours, 2 L of toluene was added, and the mixture was slowly cooled to 20 ° C. A large amount of white solid precipitated. The mixture was stirred for 2 hours, filtered, and the filter cake was vacuum dried to obtain 1014 g of white solid (liquid phase purity 99.9%, yield 81.7%).

[0015] The above descriptions are only some embodiments of the present invention, and are not intended to limit the patent scope of the present invention. Any equivalent structures or equivalent process changes made using the contents of this specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for simply synthesizing m-trifluoromethylcinnamic acid, characterized in that: Under the condition of no solvent or a small amount of solvent, m-trifluoromethylbenzaldehyde and malonic acid are condensed in the presence of a small amount of pyridine to prepare m-trifluoromethylcinnamic acid.

2. The method for synthesizing m-trifluoromethylcinnamic acid as claimed in claim 1, characterized in that The mass volume ratio of the solvent to m-trifluoromethylbenzaldehyde is 0-0.25, and the solvent includes toluene, xylene, chlorobenzene, n-heptane, hexacyclopentane, etc., preferably toluene.

3. The method for synthesizing m-trifluoromethylcinnamic acid as claimed in claim 1, characterized in that: The molar amount of pyridine relative to m-trifluoromethylbenzaldehyde is 0.02 to 0.1, preferably 0.05.