Synthesis method of mirabegron key intermediate

Abstract

According to the preparation method of the mirabegron key intermediate 2-phenylethylamine (I), 2-phenylacetamide serves as a raw material, 2-phenylethylamine is obtained through a reduction reaction of amido, the method is easy to operate, mild in condition, low in catalyst cost, high in reaction yield, remarkably reduced in cost, remarkably reduced in'three wastes', more environmentally friendly and suitable for industrial production. The method is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing a key intermediate of mirabezone. Background Technology

[0002] Mirabelon is a prescription drug used to treat overactive bladder (OAB). It belongs to the β3-adrenergic receptor agonist class and relieves symptoms such as urinary frequency, urgency, and urge incontinence by activating β3 receptors in bladder smooth muscle.

[0003] 2-Phenylacetamine is a key intermediate of Mirabelon, as well as an important pharmaceutical and chemical intermediate and an aromatic amine compound with significant physiological activity and industrial application value. Its core uses are concentrated in pharmaceutical intermediates, food additives, and organic synthesis raw materials.

[0004] The main methods reported for the preparation of 2-phenylethylamine are as follows:

[0005] 1. 2-Phenylacetamide is used as a raw material and reduced to 2-phenylethylamine using lithium aminoide and samarium iodide as catalysts. However, samarium iodide, the reducing agent in this method, is highly sensitive to oxygen, easily oxidizes and becomes ineffective, and is expensive, making it unsuitable for large-scale industrial production.

[0006] 2. Using 2-phenylacetamide as a raw material, 2-phenylethylamine is obtained by reduction with pinacol borane and a special scandium metal complex as a catalyst. However, the scandium metal complex used as a reducing agent in this method is difficult to obtain and expensive, making it unsuitable for large-scale industrial production.

[0007] 3. 2-Phenylacetamide is used as a raw material, and 2-phenylethylamine is obtained by reduction using aminoborane and titanium tetrachloride as catalysts. However, the reducing agents aminoborane and titanium tetrachloride used in this method are also expensive and unsuitable for large-scale industrial production.

[0008] In conclusion, a new synthetic method that is convenient and inexpensive is needed for the synthesis of 2-phenylethylamine, a key intermediate of Mirabelon. Summary of the Invention

[0009] In view of the shortcomings of the prior art, the purpose of this invention is to provide a method for synthesizing 2-phenylethylamine, which has the advantages of simple operation, mild conditions, and low cost, and is suitable for industrial production.

[0010] To achieve the above objectives, the present invention adopts the following technical solution;

[0011] A method for preparing a key intermediate of Miraberon, the structural formula of which is shown in compound (I).

[0012]

[0013] The synthetic route for compound (I) is as follows:

[0014]

[0015] The preparation method includes the following steps:

[0016] Under nitrogen protection, sodium borohydride, sodium hydroxide, ethylene glycol dimethyl ether, and reaction solvent were added to 2-phenylacetamide. The temperature was lowered to 5-10°C, and trimethylchlorosilane was added dropwise, with the temperature controlled not to exceed 20°C during the addition. After the addition was complete, the reaction was carried out for 5-6 hours. After the raw materials had reacted completely, dilute hydrochloric acid was added dropwise to the system. The pH value was measured to be less than 7 while stirring. Ethyl acetate was then added and extracted twice. The organic phase was discarded, and sodium hydroxide was added to the aqueous phase to adjust the pH value to above 10. Ethyl acetate was then added and extracted twice more. The ethyl acetate phases were combined, dried, and recovered under reduced pressure at low temperature. The remaining oily substance was distilled under reduced pressure to obtain the product 2-phenylethylamine (I).

[0017] Furthermore, in the preparation method, the mass ratio of 2-phenylacetamide to sodium borohydride is 1:0.60.

[0018] Furthermore, in the preparation method, the reaction solvents are ethylene glycol dimethyl ether and ethanol.

[0019] Furthermore, in the preparation method, the mass ratio of 2-phenylacetamide to ethylene glycol dimethyl ether and ethanol is 1.0∶4.0∶1.0~1.0∶4.0∶1.5.

[0020] Furthermore, in the preparation method, the mass ratio of 2-phenylacetamide to trimethylchlorosilane is 1.0:1.4 to 1.0:1.6.

[0021] Compared with the prior art, the advantages of the present invention are as follows:

[0022] (1) A method for preparing 2-phenylethylamine, a key intermediate of Mirabell, is provided. It uses an inexpensive catalyst and has mild reaction conditions, resulting in higher yield and significantly reduced cost, making it suitable for large-scale commercial production. (2) The amount of waste generated is significantly reduced compared to traditional methods, greatly reducing the environmental pressure during the production process. Detailed Implementation

[0023] To better understand the technical solution of the present invention, further explanation will be given in conjunction with specific embodiments of the present invention, so that those skilled in the art can better understand the present invention, but this is not intended to be a limitation.

[0024] Example

[0025] 67.5 g of 2-phenylacetamide, 40 g of sodium borohydride, 0.1 g of sodium hydroxide, 270 g of ethylene glycol dimethyl ether, and 80 g of ethanol were placed in a 1 L three-necked flask under nitrogen protection and cooled to 5–10 °C. 100 g of trimethylchlorosilane was added dropwise, with the temperature controlled below 20 °C during addition. After the addition was complete, the reaction was carried out for 5–6 hours. A sample was then spotted onto a TLC plate. Once the reaction was complete, 2 L of 1 mol / L dilute hydrochloric acid was added dropwise, and the pH was measured to be less than 7. Then, 3100 mL of ethyl acetate was added for extraction twice. The organic phase was discarded. Sodium hydroxide was added to the aqueous phase to adjust the pH to above 10, and ethyl acetate was added for extraction twice more, each time using 200 mL of ethyl acetate. The ethyl acetate phases were combined, dried, and filtered. The ethyl acetate phase was recovered under reduced pressure at low temperature. The remaining oily substance was distilled under reduced pressure to obtain 56 g of the product 2-phenylethylamine.

[0026] Although the present invention has been described through embodiments thereof, other embodiments that can be conceived by those skilled in the art involving variations of the present invention are also included within the scope of the present invention and are interpreted and defined by the claims of the present invention.

Claims

1. A method for preparing a key intermediate of Miraberon, characterized in that: 2-Phenylacetamide was used as a starting material and reduced to obtain 2-phenylethylamine (I). The synthetic route is as follows: Its features are: Under nitrogen protection, sodium borohydride, sodium hydroxide, ethylene glycol dimethyl ether, and reaction solvent were added to 2-phenylacetamide. The temperature was lowered to 5-10°C, and trimethylchlorosilane was added dropwise, with the temperature controlled not to exceed 20°C during the addition. After the addition was complete, the reaction was carried out for 5-6 hours. After the raw materials had reacted completely, dilute hydrochloric acid was added dropwise to the system. The pH value was measured to be less than 7 while stirring. Ethyl acetate was then added and extracted twice. The organic phase was discarded, and sodium hydroxide was added to the aqueous phase to adjust the pH value to above 10. Ethyl acetate was then added and extracted twice more. The ethyl acetate phases were combined, dried, and recovered under reduced pressure at low temperature. The remaining oily substance was distilled under reduced pressure to obtain the product 2-phenylethylamine (I). The solvent is ethylene glycol dimethyl ether and ethanol.

2. The preparation method according to claim 1, characterized in that... The mass ratio of 2-phenylacetamide to sodium borohydride is 1:0.

60.

3. The preparation method according to claim 1, characterized in that... The mass ratio of 2-phenylacetamide to trimethylchlorosilane is 1.0:1.4 to 1.0:1.

6.

4. The preparation method according to claim 1, characterized in that... In step S1, the molar ratio of compound II to dimethylamine hydrochloride is 1.0:2.4 to 1.0:2.6.

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