Preparation method of key intermediate epoxide of Lubabbegron
By using 2-(2-bromophenyl)thiophene and epoxy propyl alcohol to prepare the Lubaberon intermediate under a basic catalyst, the problems of high raw materials and high by-products in the prior art are solved, and industrial production with high yields is achieved.
Patent Information
- Application Number
- CN202510885232.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-30
- Publication Date
- 2025-08-22
AI Technical Summary
In the existing Lubaberon synthesis method, the raw material cost is high, the chiral purity is low, and the by-products are many, resulting in high production costs and is not suitable for industrial production.
The lubaberon intermediate 2-((2-thiophene-2-yl)phenoxy)methyl)ethylene oxide was prepared by using 2-(2-bromophenyl)thiophene and epoxy propyl alcohol as starting materials, and the lubaberon intermediate was coupled under the action of an alkaline catalyst to simplify the production process and reduce costs.
The preparation of key epoxides of Lubaberon key intermediates with few by-products and high yields is achieved, which is suitable for industrial production and provides a more economical preparation process choice.
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Figure CN120518601A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing epoxide, a key intermediate of lubabenon. Background Art
[0002] Lubabegron is commonly used as a drug to reduce ammonia and carbon dioxide emissions in bovines. Studies have shown that feeding feed containing lubabegron or its salts significantly reduces ammonia emissions in bovines. Lubabegron is widely used as a feed additive in bovines in developed countries like Europe and the United States. It must be used throughout the cattle's life cycle until marketed, and New Zealand has already legislated its use.
[0003] The synthesis of lubaberon mainly involves the synthesis of two main intermediates A and B. After the synthesis of A and B, lubaberon is obtained through a one-step reaction. The reaction equation is as follows:
[0004]
[0005] Among them, the synthesis of intermediate B mainly adopts the following two methods:
[0006] (1) Reaction of 2-thienylphenol with (S)-glycidyl m-nitrobenzenesulfonate:
[0007]
[0008] (2) Reaction of 2-thienylphenol with (R)-epichlorohydrin
[0009]
[0010] Among them, the (S)-m-nitrobenzenesulfonic acid glycidyl ester used in method (1) has a large molecular weight, a large amount of usage, a high price, and a high unit consumption, which makes the production cost high. Moreover, after experimental verification, the chiral purity of the product is low, and it will contain more than 4% of chiral isomers. At the same time, a large amount of by-products is produced, and the environmental protection treatment cost is high. It is not the best choice for industrial production.
[0011] Method (2) uses (R)-epichlorohydrin, which has a small molecular weight, low unit consumption, and high chiral purity. However, it is easy to produce more than 15% of dipolymers during the preparation process. It affects the quality and yield of the product and is not particularly suitable for industrial production.
[0012] Moreover, both routes use a common precursor compound, 2-thienylphenol, which is synthesized using Suzuki coupling or Grignard reaction. It is difficult to produce and expensive, which together pushes up the production cost of the final product, Lubaberon. Summary of the Invention
[0013] The purpose of the present invention is to provide a method for preparing epoxide, a key intermediate of lubaberon, in order to overcome the deficiencies in the prior art. The method has a simple production process and reduces production costs. The obtained product has few by-products, a high yield and is suitable for industrial production.
[0014] In order to achieve the above-mentioned object of the invention, the preparation method of the key intermediate epoxide of lubaberon of the present invention adopts the following technical scheme:
[0015] A method for preparing a key intermediate epoxide of lubabenon, the synthesis route is as follows:
[0016]
[0017] Preferably, the method comprises the following steps:
[0018] (1) Adding a solvent, 2-(2-bromophenyl)thiophene, and a basic catalyst to a reaction vessel, adding glycidol dropwise with stirring, and continuing the reaction until the 2-(2-bromophenyl)thiophene is completely reacted;
[0019] (2) Cool and filter to remove salt, concentrate the filtrate to dryness, add methanol, heat to dissolve, cool to crystallize, filter, and dry to obtain 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane.
[0020] Preferably, the solvent is a solvent that can form an azeotrope with water.
[0021] Preferably, the solvent is one of toluene, xylene and acetone.
[0022] Preferably, the weight ratio of the solvent to glycidol is 6 to 10.
[0023] Preferably, the molar ratio of 2-(2-bromophenyl)thiophene to glycidol is 1:1.1-1.5.
[0024] Preferably, the alkaline catalyst is one of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium tert-butoxide, and sodium hydrogen sulfide.
[0025] Preferably, the molar ratio of the basic catalyst to 2-(2-bromophenyl)thiophene is 1 to 6:1.
[0026] Preferably, the reaction temperature in step (1) is 50-120°C.
[0027] Preferably, the amount of methanol used is 3 to 6 times the weight of 2-(2-bromophenyl)thiophene.
[0028] Compared with the prior art, the present invention has the following beneficial effects:
[0029] 1. The present invention uses new raw materials and a new synthetic route to prepare the key intermediate epoxide of lubaberon. 2-(2-bromophenyl)thiophene and glycidol are used as starting materials and coupled under the action of a basic catalyst to obtain the lubaberon intermediate 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane. The production process is simple and the production cost is reduced.
[0030] 2. The key intermediate epoxide of lubaberon prepared by the present invention has few by-products and high yield, and is suitable for industrial production;
[0031] 3. The present invention can select the racemate, dextrorotatory or levorotatory isomer of glycidol for reaction to prepare different configurations of epoxides, providing a more feasible process option for the production of lubaberon. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 This is the H-NMR spectrum of the epoxide prepared in Example 1;
[0033] Figure 2 This is the C-NMR spectrum of the epoxide prepared in Example 1;
[0034] Figure 3 The mass spectrum (M+) of the epoxide prepared in Example 1;
[0035] Figure 4 This is the mass spectrum (M-) of the epoxide prepared in Example 1. DETAILED DESCRIPTION
[0036] The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. After reading the present invention, modifications of various equivalent forms of the present invention made by those skilled in the art all fall within the scope defined by the claims attached to this application.
[0037] Example 1:
[0038] A 500 ml reaction flask was added with acetone 240 g, 2-(2-bromophenyl)thiophene 24 g, and potassium carbonate 42 g. The mixture was stirred and heated to 50 ° C. 8.2 g of glycidol was added dropwise. After the addition was complete, the reaction was continued at 50 ° C. The reaction was tracked by TLC until the 2-(2-bromophenyl)thiophene reaction was complete. The temperature was lowered and filtered. The filtrate was concentrated to dryness. The solvent was changed to methanol 72 g. The temperature was raised to 50 ° C to dissolve the material, then the temperature was lowered to below 10 ° C and crystallized for 4 hours. The solid was filtered and dried in vacuo at 50 ° C to dryness to obtain 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane 22 g with a purity of 99.5% and a yield of 95% (based on 2-(2-bromophenyl)thiophene).
[0039] Example 2:
[0040] To a 500 ml reaction flask, 145 g of toluene, 24 g of 2-(2-bromophenyl)thiophene, and 4 g of sodium hydroxide were added, stirred, and the temperature was raised to 110° C. 11 g of glycidol was added dropwise. After the addition was complete, the reaction was continued at 110° C. The reaction was tracked by TLC until the reaction of 2-(2-bromophenyl)thiophene was complete. The temperature was lowered and filtered. The filtrate was concentrated to dryness. The solvent was changed to 96 g of methanol. The temperature was raised to 40° C. to dissolve the material, then the temperature was lowered to below 10° C. and crystallized for 6 hours. The solid was filtered and dried in vacuo at 50° C. to dryness to give 21.8 g of 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane with a purity of 99.7% and a yield of 94% (based on 2-(2-bromophenyl)thiophene).
[0041] Example 3:
[0042] To a 500 ml reaction flask, 190 g of xylene, 24 g of 2-(2-bromophenyl)thiophene, and 12 g of potassium hydroxide were added, stirred, and the temperature was raised to 120° C. 10 g of glycidol was added dropwise. After the addition was complete, the reaction was continued at 120° C. The reaction was tracked by TLC until the reaction of 2-(2-bromophenyl)thiophene was complete. The temperature was lowered and filtered. The filtrate was concentrated to dryness. The solvent was changed to 140 g of methanol. The temperature was raised to 40° C. to dissolve the material, then the temperature was lowered to below 10° C. and crystallized for 10 hours. The solid was filtered and dried in vacuo at 50° C. to give 21 g of 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane with a purity of 99.6% and a yield of 90.5% (based on 2-(2-bromophenyl)thiophene).
[0043] The structure of the key intermediate epoxide of Lubaberon obtained in Example 1 was identified, and the obtained spectrum is shown in the attached Figure 1-4 According to the spectrum, it can be judged that the structure of the obtained product is consistent with the target product.
[0044] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application.
Claims
1. A method for preparing a key intermediate epoxide of lubaberon, characterized in that: The synthesis route is as follows:
2. The method for preparing the key intermediate epoxide of Lubaberon according to claim 1, characterized in that: The steps include: (1) Adding a solvent, 2-(2-bromophenyl)thiophene, and a basic catalyst to a reaction vessel, adding glycidol dropwise with stirring, and continuing the reaction until the 2-(2-bromophenyl)thiophene is completely reacted; (2) Cool and filter to remove salt, concentrate the filtrate to dryness, add methanol, heat to dissolve, cool to crystallize, filter, and dry to obtain 2-((2-thiophen-2-yl)phenoxy)methyl)oxirane.
3. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The solvent is selected to be a solvent that can form an azeotrope with water.
4. The method for preparing the key intermediate epoxide of Lubaberon according to claim 3, characterized in that: The solvent is one of toluene, xylene and acetone.
5. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The weight ratio of the solvent to glycidol is 6 to 10.
6. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The molar ratio of the 2-(2-bromophenyl)thiophene to glycidol is 1:1.1-1.
5.
7. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The alkaline catalyst is one of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium tert-butoxide, and sodium hydrogen.
8. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The molar ratio of the basic catalyst to 2-(2-bromophenyl)thiophene is 1 to 6:
1.
9. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The reaction temperature in step (1) is 50-120°C.
10. The method for preparing the key intermediate epoxide of Lubaberon according to claim 2, characterized in that: The amount of methanol used is 3 to 6 times the weight of 2-(2-bromophenyl)thiophene.