Preparation method of key intermediate of Lubabbegron
Through the new synthesis route, the synthesis of key intermediates of Lubaberon is carried out using a mild process, solving the problem of using highly toxic chemical reagents and hydrogenation reduction in the prior art, and achieving safe and low-cost production.
Patent Information
- Application Number
- CN202411767136.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-04
- Publication Date
- 2025-02-11
AI Technical Summary
The existing synthesis method of Lubaberon intermediate uses the highly toxic chemical reagent nitropropane and requires hydrogenation reduction, which poses safety risks and high production costs.
Using a new synthesis route, solvent, potassium carbonate, phthalimide were added to the reaction bottle, and 2-chloropropane was added dropwise, and parahydroxybenzyl alcohol was added for reflux and water reaction, and finally by hydrolysis or hydrazine. The reaction gave 4-(2-amino-2-methylpropyl)phenol.
The safe production of key intermediates of Lubaberon has been achieved, avoiding the use of highly toxic chemical reagents, reducing production costs, and improving the safety of the process.
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Figure CN119409579A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing a key intermediate of lubabegron. Background Art
[0002] Lubabegron is often used as a drug to reduce ammonia and carbon dioxide emissions from bovines. Studies have shown that feeding bovines with feed containing lubabegron or its salts can significantly reduce ammonia emissions from bovines. Lubabegron is commonly used as a feed additive for bovines in developed countries such as Europe and the United States. It must be used throughout the life cycle of cattle before they are slaughtered, and New Zealand has clearly legislated the use of this product.
[0003] The existing literature on the synthesis of Lubabelong mainly involves the synthesis of two main intermediates. Lubabelong is prepared by condensation of intermediates A and B as shown in the following reaction equation:
[0004]
[0005] The synthesis of intermediate A generally adopts the following reaction:
[0006]
[0007] Among them, 4-(2-amino-2-methylpropyl)phenol is an important intermediate for preparing intermediate A. Its existing synthesis method uses highly toxic chemical reagent nitropropane, and adopts hydrogenation reduction to reduce the nitro group to amino group. Hydrogenation is a key regulated process, which has certain dangers in terms of reaction reagents and reaction types. This puts higher requirements on industrial production and is bound to increase the corresponding production costs. Summary of the invention
[0008] Purpose of the invention: In view of the deficiencies in the prior art, the present application provides a method for preparing a key intermediate of barbaron, which can realize the production of the intermediate with a milder process.
[0009] Technical solution: The synthesis route of the key intermediate of lubabegron described in the present invention is as follows:
[0010]
[0011] The preparation steps of the key intermediate of lubabegron of the present invention are as follows: adding a solvent, potassium carbonate and phthalimide into a reaction flask, dropping 2-chloropropane under stirring, continuing to keep warm after the dropping is completed until the 2-chloropropane reacts completely, adding p-hydroxybenzyl alcohol and continuing to reflux to react with water until no water is removed, cooling, adding water and stirring, separating the layers, concentrating the organic layer to remove the solvent, concentrating to dryness (obtaining compound II), and subjecting the organic layer to hydrazinolysis or hydrolysis to obtain 4-(2-amino-2-methylpropyl)phenol (obtaining compound III).
[0012] Specifically, in the process of obtaining compound II, the reaction temperature is 20-30°C.
[0013] Specifically, the solvent is a solvent that can azeotrope with water, preferably toluene or xylene, and the amount used is 16 to 20 times the weight ratio of 2-chloropropane.
[0014] Specifically, the molar ratio of 2-chloropropane to phthalimide is 1:1.1-1.5, preferably 1:1.1.
[0015] Specifically, the molar ratio of 2-chloropropane to p-hydroxybenzyl alcohol is 1:1-1.2, preferably 1:1.
[0016] Specifically, the molar ratio of 2-chloropropane to potassium carbonate is 1:6-8.
[0017] In the above method steps, compound II can be converted to compound III by hydrolysis or hydrazine hydrolysis.
[0018] Specifically, when the hydrazine hydrolysis method is adopted, the solvent is changed to methanol after concentrating to dryness, hydrazine hydrate is added dropwise at a temperature of 40 °C to carry out hydrazine hydrolysis reaction, and after the reaction is completed, the temperature is lowered and filtered to remove by-products, the filtrate is concentrated to remove methanol, and water is added after concentrating to dryness, and the pH is adjusted to 2-3 with hydrochloric acid to dissolve all the materials, and then the pH is adjusted to 8-9, stirred for crystallization, filtered, and dried to obtain 4-(2-amino-2-methylpropyl)phenol (compound III).
[0019] Specifically, when the hydrolysis method is adopted, the solvent is changed to an alcohol-water mixed solvent after concentration to dryness, and liquid alkali is added to adjust the pH to 10 and maintained, and a hydrolysis reaction is carried out. After the reaction is completed, the temperature is lowered, filtered, and dried to obtain 4-(2-amino-2-methylpropyl)phenol (Compound III). More specifically, the hydrolysis solvent used in the step is preferably a methanol-water or ethanol-water mixed solvent, the weight ratio of alcohol-water is preferably 1:1-2, and the total amount added is 10-20 times the weight of 2-chloropropane.
[0020] Beneficial effects: The present invention uses new raw materials and a new synthesis route to prepare the key intermediates of lubaberon, which solves various problems existing in the processes reported in the literature, such as the high toxicity of nitropropane and the need for hydrogenation reduction of the nitro group, and provides a safe process option for the production of lubaberon intermediates. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 This is the H NMR spectrum of the compound obtained in Example 1.
[0022] Figure 2 This is the NMR carbon spectrum of the compound obtained in Example 1.
[0023] Figure 3 This is the mass spectrum (M-) of the compound obtained in Example 1.
[0024] Figure 4 This is the mass spectrum (M+) of the compound obtained in Example 1. DETAILED DESCRIPTION
[0025] The technical solution of the present application is described in detail below through embodiments, but the protection scope of the present application is not limited to the embodiments.
[0026] Embodiment 1:
[0027] Add 1280g toluene, 828g potassium carbonate, and 162g phthalimide to a 2L reaction bottle, keep the temperature at 10-20°C, add 78.5g 2-chloropropane dropwise, keep the temperature at 20-30°C, stir and react for 20 hours, then add 124g p-hydroxybenzyl alcohol, heat and reflux with water until no water is taken out and the temperature reaches above 110°C, cool to 60°C, add 200ml water, stir for 20min, let stand and separate, discard the water layer, concentrate the toluene layer to dryness, and add 1000g methanol , add 128 g of hydrazine hydrate dropwise at 60°C, continue to keep warm and stir to react after the addition is completed, monitor by TLC until the reaction is complete, cool to room temperature, filter, rinse the solid with methanol, concentrate the filtrate to dryness, add 1200 g of water, adjust the pH to 2-3 with hydrochloric acid, add activated carbon for decolorization, filter, adjust the pH of the filtrate to 8-9 with liquid alkali, cool to 10-20°C, stir and crystallize, filter, and dry the solid to obtain 157 g of compound III with a purity of 98.5% and a yield of 95% (based on 2-chloropropane).
[0028] The product obtained in Example 1 was subjected to structural identification, and the obtained spectrum is shown in the attached figure. According to the spectrum, it can be judged that the structure of the obtained product is consistent with that of the target product.
[0029] Embodiment 2:
[0030] 1400g of xylene, 985g of potassium carbonate and 197g of phthalimide were added to a 2L reaction bottle, 70g of 2-chloropropane was added dropwise at a temperature of 10-20°C, and the reaction was stirred at a temperature of 20-30°C for 20 hours. Then 133g of p-hydroxybenzyl alcohol was added, the temperature was raised and refluxed with water until no water was taken out and the temperature reached above 137°C, the temperature was cooled to 60°C, 200ml of water was added, stirred for 20min, and the mixture was allowed to stand for stratification. The aqueous layer was discarded, the organic layer was concentrated to dryness, 700g of a mixed solvent (methanol: water = 1:1) and 70g of sodium hydroxide were added, and the mixture was kept at a temperature of 60-80°C for hydrolysis reaction. The pH was kept at about 10 for 1 hour during the reaction process, and then the temperature was cooled to 10-20°C and stirred for crystallization, filtered, and the solid was dried to obtain 135.6g of compound III with a purity of 99.7% and a yield of 92% (based on 2-chloropropane).
[0031] Embodiment 3:
[0032] 1200g of toluene, 950g of potassium carbonate and 180g of phthalimide were added to a 2L reaction bottle, 70g of 2-chloropropane was added dropwise at a temperature of 10-20°C, and the reaction was stirred at a temperature of 20-30°C for 20 hours. Then 125g of p-hydroxybenzyl alcohol was added, the temperature was raised to reflux with water until no water was taken out and the temperature reached above 137°C, the temperature was cooled to 60°C, 400ml of water was added, stirred for 20min, allowed to stand for stratification, the aqueous layer was discarded, the organic layer was concentrated to dryness, 1400g of a mixed solvent (methanol: water = 1:1) and 80g of sodium hydroxide were added, and the reaction was hydrolyzed at a temperature of 60-80°C. The pH was kept at about 10 for 1 hour during the reaction, and then the temperature was cooled to 10-20°C and stirred for crystallization, filtered, and the solid was dried to obtain 132.6g of compound III with a purity of 99.8% and a yield of 90% (based on 2-chloropropane).
[0033] The above description is only 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 of lubabegron, characterized in that: The synthesis route is:
2. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: Add solvent, potassium carbonate and phthalimide to the reaction flask, add 2-chloropropane dropwise with stirring, continue to keep warm and react until 2-chloropropane reacts completely, add p-hydroxybenzyl alcohol and continue to reflux and react with water until no water is removed, cool down, add water and stir, then separate the layers, concentrate the organic layer to remove the solvent, concentrate to dryness, and then perform hydrazinolysis or hydrolysis to obtain 4-(2-amino-2-methylpropyl)phenol.
3. The method for preparing the key intermediate of Lubabegron according to claim 1, characterized in that: In the process of obtaining compound II, the reaction temperature is 20-30°C.
4. The method for preparing the key intermediate of Lubabegron according to claim 1, characterized in that: In the process of obtaining compound II, the solvent is toluene and xylene, and the amount used is 16 to 20 times the weight ratio of 2-chloropropane.
5. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: The molar ratio of the 2-chloropropane to phthalimide is 1:1.1-1.
5.
6. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: The molar ratio of the 2-chloropropane to the p-hydroxybenzyl alcohol is 1:1 to 1.
2.
7. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: The molar ratio of the 2-chloropropane to potassium carbonate is 1:6-8.
8. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: When the hydrazine hydrolysis method is adopted, the solvent is changed to methanol after concentrating to dryness, hydrazine hydrate is added dropwise while keeping warm to carry out hydrazine hydrolysis reaction, after the reaction is completed, the temperature is lowered and filtered to remove by-products, the filtrate is concentrated to remove methanol, and water is added after concentrating to dryness, and the pH is adjusted to 2-3 with hydrochloric acid to dissolve all the materials, and then the pH is adjusted to 8-9, stirred for crystallization, filtered, and dried to obtain 4-(2-amino-2-methylpropyl)phenol.
9. The method for preparing the key intermediate of lubabegron according to claim 1, characterized in that: When the hydrolysis method is adopted, the solvent is changed to an alcohol-water mixed solvent after concentration to dryness, and liquid alkali is added to adjust the pH to 10 and maintain it to carry out a hydrolysis reaction. After the reaction is completed, the temperature is lowered, filtered, and dried to obtain 4-(2-amino-2-methylpropyl)phenol.
10. The method for preparing the key intermediate of lubabegron according to claim 9, characterized in that: The hydrolysis solvent used is a mixed solvent of methanol-water and ethanol-water, the weight ratio of alcohol-water is 1:1-2, and the total added amount is 10-20 times the weight of 2-chloropropane.