Synthetic method of rubabbegron intermediate
By using an inexpensive nickel catalyst and a one-pot continuous feeding reaction, the problems of high cost and low efficiency in the synthesis of lubaberon intermediates have been solved, achieving cost reduction and efficiency improvement, making it suitable for commercial production.
Patent Information
- Application Number
- CN202511645518.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-11
- Publication Date
- 2026-01-16
AI Technical Summary
The existing synthesis process for lubaberone intermediates is characterized by high production costs and low efficiency, especially due to the use of precious metal palladium catalysts and column chromatography purification.
The process simplifies the process by replacing the precious palladium catalyst with a cheap nickel catalyst and achieving a two-step reaction through a one-pot continuous feed, eliminating the separation and purification step in the first step. 2-Bromophenol and 2-thiopheneboronic acid are used as raw materials.
It reduces the cost of raw materials and auxiliary materials, improves production efficiency, simplifies the process, and is suitable for commercial production.
Smart Images
Figure CN121342813A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing a lumbaberon intermediate. Background Technology
[0002] Ammonia is the most abundant alkaline gas in the atmosphere, and its emissions have been increasing globally over the past few decades. Ammonia is a significant contributor to the formation of secondary particulate matter in atmospheric haze pollution. Carbon dioxide is a greenhouse gas associated with global warming. Therefore, excessive emissions of ammonia and carbon dioxide will impact the environment and public health. Bovidae are major emitters of ammonia and also significantly contribute to carbon dioxide emissions. Experiments have shown that 2-(3-(2-((2-hydroxy-3-(2-(thiophen-2-yl)phenoxy)propyl)amino)2-methylpropyl)benzyl)nicotinonitrile (lubaberon, CAS: 391920-32-4) and its salts can reduce ammonia and carbon dioxide emissions from bovidae, which is highly beneficial for mitigating environmental pollution and the greenhouse effect.
[0003] The synthesis route of Lubaberon is as follows:
[0004] According to existing technical methods, the preparation of lumbaberon intermediate fragment 2 uses a precious metal palladium catalyst and expensive 2-hydroxyphenylboronic acid, resulting in high production costs for lumbaberon. Moreover, both steps in the synthesis of fragment 2 require column chromatography purification, which is not suitable for commercial production. Summary of the Invention
[0005] The purpose of this invention is to provide a method for synthesizing lumbaberon intermediates, which solves the technical problems of high production cost and low production efficiency in the synthesis of existing intermediates.
[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for synthesizing a lubaberone intermediate, the synthetic route of which is as follows: ; Includes the following steps: 1) 2-Bromophenol and dextrorotatory epichlorohydrin were mixed with a strong base in an organic solvent to carry out a nucleophilic substitution reaction to obtain (S)-2-((2-bromophenoxy)methyl)epoxyethylene; 2) The intermediate (S)-2-((2-bromophenoxy)methyl)ethylene oxide, 2-thiopheneboronic acid, nickel catalyst and phosphine ligand undergo a coupling reaction under the action of a base to obtain the intermediate (S)-2-((2-(thiophene-2-yl)phenoxy)methyl)ethylene oxide.
[0007] Furthermore, the molar ratio of 2-bromophenol, dextrorotatory epichlorohydrin and strong base is 1.0:1.0~1.5:1.0~1.5.
[0008] Furthermore, the strong base comprises one or more of potassium hydroxide, potassium phosphate, and potassium carbonate; the organic solvent comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran.
[0009] Furthermore, the nucleophilic substitution reaction is carried out at a temperature of 50-80°C for 2-14 hours; and the molar concentration of the reactants is 0.05-0.2 M.
[0010] Furthermore, the molar ratio of (S)-2-((2-bromophenoxy)methyl)ethylene oxide, 2-thiophene boric acid, nickel catalyst, phosphine ligand and base is 1.0:1.0~1.4:0.05~0.10:0.11~0.24:1.0~4.0.
[0011] Furthermore, the nickel catalyst comprises one or more of nickel dichloride, nickel dibromide, and nickel aminosulfonate; The phosphine ligand comprises one or more of tricyclohexylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane, and 1,2-bis(diphenylphosphine)propane; The alkali comprises one or more of potassium phosphate, potassium hydroxide, triethylamine, and diisopropylethylamine.
[0012] Furthermore, the coupling reaction is carried out in a solvent; and the concentration of the reactants in the coupling reaction is 0.05~0.2M.
[0013] Furthermore, the coupling reaction is carried out at a temperature of 45-75°C for 10-36 hours.
[0014] The beneficial effects of this invention are: This invention optimizes the synthesis route and conditions for fragment 2 of lubaberon, using cheaper 2-bromophenol and 2-thiopheneboronic acid as main raw materials, thus reducing raw material costs. Furthermore, it replaces the precious palladium catalyst with an inexpensive nickel catalyst, significantly reducing auxiliary material costs. From a process perspective, the two-step synthesis of fragment 2 is achieved through a one-pot continuous feed, eliminating the first-step separation and purification operation and improving production efficiency. Attached Figure Description
[0015] Figure 1 The (prepared in Example 1) S The 1H NMR spectrum of 2-((2-bromophenoxy)methyl)ethylene oxide; Figure 2The image shows the 1H NMR spectrum of the fragment 2 compound prepared in Example 1. Detailed Implementation
[0016] This invention provides a method for synthesizing a lubaberone intermediate, the synthetic route of which is as follows: ; Includes the following steps: 1) 2-Bromophenol and dextrorotatory epichlorohydrin were mixed with a strong base in an organic solvent to carry out a nucleophilic substitution reaction to obtain (S)-2-((2-bromophenoxy)methyl)epoxyethylene; 2) The intermediate (S)-2-((2-bromophenoxy)methyl)ethylene oxide, 2-thiopheneboronic acid, nickel catalyst and phosphine ligand undergo a coupling reaction under the action of a base to obtain the intermediate (S)-2-((2-(thiophene-2-yl)phenoxy)methyl)ethylene oxide.
[0017] In this invention, the molar ratio of 2-bromophenol, dextrorotatory epichlorohydrin and strong base is 1.0:1.0~1.5:1.0~1.5, preferably 1.0:1.2~1.4:1.2~1.4, and more preferably 1.0:1.2~1.3:1.2~1.3.
[0018] In this invention, the strong base comprises one or more of potassium hydroxide, potassium phosphate, and potassium carbonate, preferably potassium hydroxide; the organic solvent comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran, preferably dimethyl sulfoxide.
[0019] In this invention, the temperature of the nucleophilic substitution reaction is 50~80℃, preferably 55~75℃, more preferably 60~65℃; the time of the nucleophilic substitution reaction is 2~14h, preferably 4~10h, more preferably 6~8h; and the molar concentration of the reactants in the nucleophilic substitution reaction is 0.05~0.2M, preferably 0.1~0.15M.
[0020] In this invention, the molar ratio of (S)-2-((2-bromophenoxy)methyl)ethylene oxide, 2-thiopheneboronic acid, nickel catalyst, phosphine ligand and base is 1.0:1.0~1.4:0.05~0.10:0.11~0.24:1.0~4.0, preferably 1.0:1.1:0.1:0.22:2.0.
[0021] In this invention, the nickel catalyst comprises one or more of nickel dichloride, nickel dibromide and nickel aminosulfonate, preferably nickel dichloride; The phosphine ligand comprises one or more of tricyclohexylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphine)ethane and 1,2-bis(diphenylphosphine)propane, preferably tricyclohexylphosphine; The alkali comprises one or more of potassium phosphate, potassium hydroxide, triethylamine, and diisopropylethylamine, preferably potassium phosphate.
[0022] In this invention, the coupling reaction is carried out in a solvent; in the coupling reaction, the concentration of the reactants is 0.05~0.2M, preferably 0.1~0.15M.
[0023] In this invention, the temperature of the coupling reaction is 45~75℃, preferably 50~70℃, and more preferably 55~60℃; the time of the coupling reaction is 10~36h, preferably 15~30h, and more preferably 20~24h.
[0024] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.
[0025] Example 1
[0026] 1) Substitution of 2-bromophenol
[0027] 2-Bromophenol (0.87 g, 5.0 mmol) and potassium hydroxide (0.34 g, 6.0 mmol) were dissolved in 50 mL of dimethyl sulfoxide and heated to 65 °C for 2 h. Then, dextrorotatory epichlorohydrin (0.55 g, 6.0 mmol) was added, and the reaction was continued at 65 °C for 6 h. After cooling to room temperature, 60 mL of water and 60 mL of ethyl acetate were added for extraction. The organic phase was concentrated and purified by column chromatography to obtain (…). S Ethylene oxide (PE:EA = 10:1 elution) was obtained with a yield of 96%. 1 H NMR (600 MHz, Chloroform- d ): δ 7.51 (dd, J = 7.9, 1.7 Hz, 1H), 7.22 (ddd, J = 8.2, 7.4, 1.6Hz, 1H), 6.89 (dd, J = 8.3, 1.5 Hz, 1H), 6.83 (td, J = 7.6, 1.4 Hz, 1H), 4.27(dd, J = 11.2, 2.9 Hz, 1H), 3.99 (dd, J = 11.2, 5.3 Hz, 1H), 3.35 (ddt, J =5.4, 4.1, 2.8 Hz, 1H), 2.87 (dd,J = 5.0, 4.1 Hz, 1H), 2.81 (dd, J = 5.0, 2.7Hz, 1H).
[0028] 2) S Coupling of 2-((2-bromophenoxy)methyl)ethylene oxide with 2-thiopheneboronic acid
[0029] Will( S 2-((2-bromophenoxy)methyl)ethylene oxide (1.15 g, 5.0 mmol), nickel dichloride (64.8 mg, 0.5 mmol), tricyclohexylphosphine (308 mg, 1.1 mmol), and potassium phosphate (2.12 g, 10.0 mmol) were added, and nitrogen was substituted. The mixture was then reacted at 60 °C for 24 h. After cooling to room temperature, 50 mL of ethyl acetate and 60 mL of water were added, and the mixture was extracted and separated. The organic phase was washed with 100 mL of water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 20:1) to give a yellow oily fragment 2 in 92% yield. 1 H NMR (600 MHz, Chloroform- d ): δ 7.69 – 7.65 (m, 1H), 7.52(dd, J = 3.6, 1.2 Hz, 1H), 7.33 (dd, J = 5.2, 1.2 Hz, 1H), 7.27 – 7.21 (m,2H), 7.09 (dd, J = 5.1, 3.7 Hz, 1H), 7.02 (td, J = 7.6, 1.1 Hz, 1H), 6.97(dd, J = 8.3, 1.1 Hz, 1H), 4.31 (dd, J = 10.9, 3.3 Hz, 1H), 4.09 (dd, J =10.8, 5.5 Hz, 1H), 3.46 (dddd, J = 5.8, 4.1, 3.3, 2.6 Hz, 1H), 2.93 (dd, J =4.9, 4.1 Hz, 1H), 2.80 (dd, J = 4.9, 2.6 Hz, 1H).
[0030] Example 2
[0031] 1) Substitution of 2-bromophenol
[0032] 2-Bromophenol (0.87 g, 5.0 mmol), potassium phosphate (1.27 g, 6.0 mmol), and dextrorotatory epichlorohydrin (0.55 g, 6.0 mmol) were dissolved in 50 mL of acetonitrile, heated to 65 °C for 8 h, cooled to room temperature, and extracted with 60 mL of water and 40 mL of ethyl acetate. The organic phase was concentrated and purified by column chromatography to obtain (…). S Ethylene oxide (PE:EA = 10:1 elution) was obtained with a yield of 91%.
[0033] 2) S Coupling of 2-((2-bromophenoxy)methyl)ethylene oxide with 2-thiopheneboronic acid
[0034] Will( S 2-((2-bromophenoxy)methyl)ethylene oxide (1.15 g, 5.0 mmol), nickel aminosulfonate tetrahydrate (162 mg, 0.5 mmol), tricyclohexylphosphine (308 mg, 1.1 mmol) and potassium phosphate (2.12 g, 10.0 mmol) were added, and nitrogen was substituted. The mixture was then reacted at 60 °C for 24 h. After cooling to room temperature, 50 mL of ethyl acetate and 60 mL of water were added, and the mixture was extracted and separated. The organic phase was washed with 100 mL of water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 20:1) to give a colorless oily fragment 2 in 88% yield.
[0035] Example 3
[0036] 1) Substitution of 2-bromophenol
[0037] 2-Bromophenol (0.87 g, 5.0 mmol), potassium carbonate (0.84 g, 6.0 mmol), and dextrorotatory epichlorohydrin (0.55 g, 6.0 mmol) were dissolved in 50 mL of dimethyl sulfoxide and reacted at 65 °C for 6 h. After cooling to room temperature, the mixture was extracted with 60 mL of water and 60 mL of ethyl acetate. The organic phase was concentrated and purified by column chromatography to give (S)-2-((2-bromophenoxy)methyl)epoxyethylene (PE:EA = 10:1 elution), with a yield of 88%.
[0038] 2) S Coupling of 2-((2-bromophenoxy)methyl)ethylene oxide with 2-thiopheneboronic acid
[0039] Will( S2-((2-bromophenoxy)methyl)ethylene oxide (1.15 g, 5.0 mmol), nickel bromide (99 mg, 0.5 mmol), tricyclohexylphosphine (308 mg, 1.1 mmol), and potassium phosphate (2.12 g, 10.0 mmol) were added, and nitrogen was substituted. The mixture was then reacted at 60 °C for 24 h. After cooling to room temperature, 50 mL of ethyl acetate and 60 mL of water were added, and the mixture was extracted and separated. The organic phase was washed with 100 mL of water and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 20:1) to give a colorless oily fragment 2 in 87% yield.
[0040] Example 4: Preparation of Fragment 2 using a two-step, one-pot method
[0041] 2-Bromophenol (0.87 g, 5.0 mmol) and potassium hydroxide (0.34 g, 6.0 mmol) were dissolved in 50 mL of dimethyl sulfoxide and heated to 65 °C for 1.5 h. Then, dextrorotatory epichlorohydrin (0.55 g, 6.0 mmol) was added, and the reaction was continued at 65 °C for 6 h. The mixture was then cooled to room temperature. Nickel dichloride (64.8 mg, 0.5 mmol), tricyclohexylphosphide (308 mg, 1.1 mmol), and potassium phosphate (4.24 g, 20.0 mmol) were added to the solution to replace the nitrogen atmosphere. The mixture was then reacted at 60 °C for 22 h. After cooling to room temperature, 50 mL of ethyl acetate and 60 mL of water were added, and the mixture was extracted and separated. The organic phase was washed with 100 mL of water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 20:1) to obtain a colorless oil. The overall yield of the two steps was 86%.
[0042] As can be seen from the above embodiments, the present invention provides a method for synthesizing lubaberon intermediates. The present invention uses an inexpensive nickel catalyst to replace the precious palladium catalyst, significantly reducing costs in terms of excipients. From a process perspective, the two-step reaction of synthesis fragment 2 is achieved through a one-pot continuous feed, omitting the separation and purification operation in the first step, thus improving production efficiency.
[0043] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method of synthesis of a lubaberon intermediate, characterized by, The synthetic route is as follows: ； The method comprises the following steps: 1) mixing 2-bromophenol, dextrorotatory epichlorohydrin and a strong base in an organic solvent to perform a nucleophilic substitution reaction to obtain (S)-2-((2-bromophenoxy) methyl) oxirane; 2) coupling (S)-2-((2-bromophenoxy) methyl) oxirane, 2-thiophene boronic acid, a nickel catalyst and a phosphine ligand under the action of a base to obtain an intermediate (S)-2-((2-(thiophene-2-yl) phenoxy) methyl) oxirane.
2. The process for synthesis of lubaberon intermediate as claimed in claim 1 wherein, The molar ratio of the 2-bromophenol, dextrorotatory epichlorohydrin and the strong base is 1.0:1.0~1.5:1.0~1.
5.
3. The method of synthesis of lubaberon intermediates according to claim 1 or 2, characterized in that, The strong base comprises one or more of potassium hydroxide, potassium phosphate and potassium carbonate; and the organic solvent comprises one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and tetrahydrofuran.
4. The method of synthesis of lubaberon intermediate as claimed in claim 3 wherein, The nucleophilic substitution reaction is performed at a temperature of 50~80℃ for 2~14h; and the molar concentration of the reactants in the nucleophilic substitution reaction is 0.05~0.2M.
5. The process for synthesis of lubaberon intermediate as claimed in claim 1 or 2 or 4 wherein, The molar ratio of the (S)-2-((2-bromophenoxy) methyl) oxirane, 2-thiophene boronic acid, nickel catalyst, phosphine ligand and base is 1.0:1.0~1.4:0.05~0.10:0.11~0.24:1.0~4.
0.
6. The method of synthesis of lubaberon intermediate as claimed in claim 5 wherein, The nickel catalyst comprises one or more of nickel dichloride, nickel dibromide and nickel sulfamate; The phosphine ligand comprises one or more of tricyclohexylphosphine, triphenylphosphine, 1,2-bis(diphenylphosphino)ethane and 1,2-bis(diphenylphosphino)propane; The base comprises one or more of potassium phosphate, potassium hydroxide, triethylamine and diisopropylethylamine.
7. The method of synthesis of lubaberon intermediates as claimed in claim 1 or 6 wherein, The coupling reaction is performed in a solvent; and the concentration of the reactants in the coupling reaction is 0.05~0.2M.
8. The method of synthesis of lubaberon intermediate as claimed in claim 7, wherein, The coupling reaction is performed at a temperature of 45~75℃ for 10~36h.