A process for the preparation of obisepritide and intermediates thereof
Ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate was directly synthesized by alkylation and aromatic nucleophilic substitution in an aqueous micelle medium. This method solves the problems of long steps, complex post-processing, and high cost in the prior art, and achieves a high-yield and simplified synthesis process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU LIYUAN PHARM CO LTD
- Filing Date
- 2023-06-21
- Publication Date
- 2026-07-14
AI Technical Summary
The existing technology for synthesizing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate involves a long process, complex post-processing, high cost, low yield, and a lot of waste.
Using aqueous micelles as a solvent, the target product is directly synthesized in the presence of alkaline substances via alkylation and aromatic nucleophilic substitution reactions, simplifying the post-processing steps.
The synthesis achieved the advantages of short reaction routes, simple post-processing, high yield, and mild conditions.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of drug synthesis, specifically to a method for preparing obisetropeptide and its intermediates. Background Technology
[0002] Obicetrapib (also known as oxietrapip), with the INN (International Nonpropietary Names for Pharmaceutical Substances) name of Obicetrapib, is an investigational oral selective cholesterol ester transfer protein (CETP) inhibitor developed by New Amsterdam. As a CETP inhibitor, Obicetrapib is being developed to lower LDL-C (low-density lipoprotein cholesterol) and prevent major adverse cardiovascular events. Ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidin-5-oxy)butyrate is an important intermediate in the synthesis of Obicetrapib, and its structural formula is as follows:
[0003]
[0004] The current route for synthesizing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate is:
[0005]
[0006] In this route, 3,5-bis(trifluoromethyl)benzylamine and 2-chloro-5-bromopyrimidine are used as raw materials, and the process involves five steps: aromatic nucleophilic substitution, amino protection, phenolic hydroxylation, etherification, and deprotection. However, this process is lengthy, has complex post-processing, high cost, low yield (total yield of about 33%), and generates a significant amount of waste. Summary of the Invention
[0007] The purpose of this invention is to overcome one or more shortcomings in the prior art and provide a new method for preparing ocbis(trapeptide) intermediate (ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate), which has the advantages of fewer synthetic steps, simple post-processing, and high yield.
[0008] The present invention also provides a novel intermediate for the synthesis of ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate.
[0009] The present invention also provides a method for synthesizing obisetropeptide including the preparation steps of the above-mentioned ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate.
[0010] To achieve the above objectives, the present invention employs the following technical solution:
[0011] A method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0012] Using an aqueous micelle medium as a solvent, 2-chloro-5-hydroxypyrimidine (structural formula: 4-Bromobutyrate ethyl ester (structural formula: In an aqueous micelle medium and in the presence of an alkaline substance, alkylation reaction yields ethyl 4-(2-chloropyrimidin-5-oxy)butyrate. The synthesis route is as follows:
[0013]
[0014] Ethyl 4-(2-chloropyrimidin-5-oxy)butyrate and 3,5-bis(trifluoromethyl)benzylamine (structural formula: In an aqueous micelle medium and in the presence of a basic substance, ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate was generated via an aromatic nucleophilic substitution reaction. The synthetic route is as follows:
[0015]
[0016] The aqueous micelle medium is formed by dispersing a surfactant in water.
[0017] According to some preferred aspects of the invention, the surfactant in the aqueous micelle medium comprises 0.5%-5.0% by mass.
[0018] Furthermore, in the aqueous micelle medium, the surfactant content is 1.0%-2.5% by mass.
[0019] According to one specific aspect of the invention, the surfactant in the aqueous micelle medium comprises 1.8%-2.2% by mass.
[0020] According to some preferred aspects of the invention, the surfactant is one or more selected from Brij-30, polyethylene glycol octylphenyl ether (also known as Triton X-100), hexadecyltrimethylammonium bromide (also known as CTAB), and sodium dodecyl sulfate (also known as SDS).
[0021] In this invention, the surfactant's molecular structure consists of two parts: one end of the molecule is a lipophilic nonpolar group, also known as a hydrophobic group; the other end of the molecule is a hydrophilic polar group or ionic group, also known as a hydrophilic group. As the concentration of the surfactant in the aqueous solution increases, the hydrophobic group of the surfactant molecule aggregates to form a nucleus, while the hydrophilic group expands outward to form micelles. The minimum concentration at which the surfactant produces micelles is called the critical micelle concentration (CMC). Different types of surfactants and solution conditions result in different micelle morphologies, which may be spherical, ellipsoidal, or rod-shaped micelles.
[0022] Furthermore, the surfactant is selected from one or more of lauryl alcohol polyoxyethylene ether (also known as Brij-30), polyethylene glycol octylphenyl ether (also known as Triton X-100), and hexadecyltrimethylammonium bromide (also known as CTAB), which has better effects than sodium dodecyl sulfate (also known as SDS).
[0023] According to some preferred aspects of the invention, in the alkylation reaction and the aromatic nucleophilic substitution reaction, the basic substance used is independently selected from one or more combinations of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, sodium hydroxide, and potassium hydroxide.
[0024] Furthermore, in some preferred embodiments of the present invention, the surfactant is polyethylene glycol octylphenyl ether, and the alkaline substance is one or more combinations selected from potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; or, the surfactant is lauryl polyoxyethylene ether, and the alkaline substance is potassium carbonate and / or sodium carbonate; or, the surfactant is hexadecyltrimethylammonium bromide, and the alkaline substance is triethylamine and / or diisopropylethylamine.
[0025] According to some preferred aspects of the invention, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 40-80°C.
[0026] Furthermore, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 40-70°C.
[0027] Furthermore, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 45-60°C.
[0028] According to some preferred and specific aspects of the invention, the reaction temperature of the alkylation reaction and the reaction temperature of the aromatic nucleophilic substitution reaction are independently 45-55°C.
[0029] According to some preferred aspects of the invention, the alkylation reaction takes 4-16 hours.
[0030] According to some preferred aspects of the invention, the reaction time of the aromatic nucleophilic substitution reaction is 8-24 h.
[0031] According to some preferred aspects of the present invention, in the alkylation reaction, the molar ratio of the ethyl 4-bromobutyrate, the basic substance, and the 2-chloro-5-hydroxypyrimidine is 1:1-2:1-1.5, wherein the concentration of the ethyl 4-bromobutyrate in the aqueous micelle medium is controlled to be 0.1-0.5 mol / L.
[0032] According to some preferred aspects of the present invention, in the aromatic nucleophilic substitution reaction, the molar ratio of the basic substance, the 3,5-bis(trifluoromethyl)benzylamine and the 4-bromobutyrate is controlled to be 1-2:1-1.5:1, based on the amount of ethyl 4-bromobutyrate used in the alkylation reaction.
[0033] According to some preferred and specific aspects of the present invention, the preparation method is a one-pot method, and the embodiments of the one-pot method include:
[0034] Ethyl 4-bromobutyrate and an alkaline substance were added to an aqueous micelle medium. After heating to the preset reaction temperature, 2-chloro-5-hydroxypyrimidine was added dropwise. After the reaction was completed, 3,5-bis(trifluoromethyl)benzylamine and a new alkaline substance were added to the reaction system (no cooling or post-treatment was required). The reaction was then carried out to generate ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-oxy)butyrate.
[0035] According to the present invention, the post-processing of the method is simple. After the reaction is completed, the target product can be obtained by directly using an organic solvent (e.g., ethyl acetate) for extraction, drying, concentration, and silica gel column chromatography, resulting in less waste.
[0036] Another technical solution provided by this invention: an intermediate for synthesizing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, wherein the intermediate is ethyl 4-(2-chloropyrimidine-5-oxy)butyrate, and its structural formula is:
[0037]
[0038] Another technical solution provided by the present invention is a method for synthesizing ocbis(trapeptide), which includes the preparation method of ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate described above.
[0039] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:
[0040] Based on the shortcomings of existing technologies in the preparation of ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the inventors of this invention conducted intensive research and unexpectedly discovered that by using an aqueous micelle medium as a solvent, and using 2-chloro-5-hydroxypyrimidine and ethyl 4-bromobutyrate as raw materials, an intermediate, ethyl 4-(2-chloropyrimidine-5-oxy)butyrate, can be generated through an alkylation reaction. Then, it can be directly reacted with 3,5-bis(trifluoromethyl)benzylamine through an aromatic nucleophilic substitution reaction to generate the corresponding target product. Compared with existing methods, this method has the advantages of a shorter reaction route, simpler post-processing, higher yield, and milder conditions. Attached Figure Description
[0041] Figure 1 The image shows the 1H NMR spectrum of ethyl 4-(2-chloropyrimidin-5-oxy)butyrate, the intermediate prepared in Example 1. Detailed Implementation
[0042] The above-mentioned solution will be further described below with reference to specific embodiments; it should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments; the implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.
[0043] Unless otherwise specified in the following examples, all raw materials are commercially available or prepared by conventional methods in the art.
[0044] In the following text, "wt.%" refers to the weight percentage concentration.
[0045] Polyethylene glycol octylphenyl ether (also known as Triton X-100), purchased from Aladdin, CAS No.: 9002-93-1; lauryl alcohol polyoxyethylene ether (also known as Brij-30), purchased from Aladdin, CAS No.: 9002-92-0; hexadecyltrimethylammonium bromide (also known as CTAB), purchased from Aladdin, CAS No.: 57-09-0; sodium dodecyl sulfate (also known as SDS), purchased from Aladdin, CAS No.: 151-21-3.
[0046] In the following examples, a 2 wt.% Triton X-100 aqueous micelle solution was prepared by adding 2 g of Triton X-100 to 98 mL of distilled water and stirring at room temperature until completely dissolved. (2 wt.% refers to the weight percentage concentration of Triton X-100 in the aqueous micelle medium (Triton X-100 and water)). Other aqueous micelle solutions were prepared using the same method.
[0047] In the following examples, the synthetic route for ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate is as follows:
[0048]
[0049] Example 1
[0050] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0051] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was completed, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of potassium carbonate (2.07 g) were added directly without cooling or post-treatment, and the mixture was reacted at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and subjected to silica gel column chromatography to obtain 3.38 g of the target product, ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-oxy)butyrate, with a purity of 97% and a yield of 75%.
[0052] In this example, the following intermediate process is repeated:
[0053] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C. 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was complete, the reaction solution of the intermediate ethyl 4-(2-chloropyrimidine-5-oxy)butyrate was concentrated, eluted by column chromatography with ethyl acetate-petroleum ether, yielding 95% and purity 97%. The 1H NMR spectrum of the obtained intermediate ethyl 4-(2-chloropyrimidine-5-oxy)butyrate is shown below. Figure 1 As shown.
[0054] Example 2
[0055] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0056] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of NaOH (0.6 g) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was complete, without cooling or post-treatment, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of NaOH (0.6 g) were added directly, and the reaction was carried out at the same temperature for 16 h. After the reaction was complete, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and purified by silica gel column chromatography to obtain 3.43 g of the target product with a purity of 95% and a yield of 76%.
[0057] Example 3
[0058] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0059] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of triethylamine (2.08 mL) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was complete, without cooling or post-treatment, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of triethylamine (2.08 mL) were added directly, and the reaction was carried out at the same temperature for 16 h. After the reaction was complete, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and purified by silica gel column chromatography to obtain 2.80 g of the target product with a purity of 97% and a yield of 62%.
[0060] Example 4
[0061] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0062] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of triethylamine (2.08 mL) were added to 10 mL of 2 wt.% SDS aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was completed, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of triethylamine (2.08 mL) were added directly without cooling or post-treatment, and the reaction was carried out at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and purified by silica gel column chromatography to obtain 2.16 g of the target product with a purity of 97% and a yield of 48%.
[0063] Example 5
[0064] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0065] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of 2 wt.% Brij-30 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was complete, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of potassium carbonate (2.07 g) were added directly without cooling or post-treatment, and the reaction was carried out at the same temperature for 16 h. After the reaction was complete, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and purified by silica gel column chromatography to obtain 3.24 g of the target product with a purity of 97% and a yield of 72%.
[0066] Example 6
[0067] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0068] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 40 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was completed, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of potassium carbonate (2.07 g) were added directly without cooling or post-treatment, and the reaction was carried out at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and subjected to silica gel column chromatography to obtain 2.97 g of the target product, ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-oxy)butyrate, with a purity of 95% and a yield of 66%.
[0069] Example 7
[0070] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0071] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of 2 wt.% Triton X-100 aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 60 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was completed, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of potassium carbonate (2.07 g) were added directly without cooling or post-treatment, and the reaction was carried out at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and subjected to silica gel column chromatography to obtain 3.33 g of the target product, ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-oxy)butyrate, with a purity of 96% and a yield of 74%.
[0072] Example 8
[0073] This example provides a method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, the method comprising:
[0074] 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of triethylamine (2.08 mL) were added to 10 mL of 2 wt.% CTAB aqueous micelle medium. The mixture was stirred at room temperature for 5 min, then heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction was continued for 16 h. After the reaction was complete, without cooling or post-treatment, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of triethylamine (2.08 mL) were added directly, and the reaction was carried out at the same temperature for 16 h. After the reaction was complete, the mixture was cooled to room temperature, extracted (15 mL × 3 times with ethyl acetate), dried, concentrated, and purified by silica gel column chromatography to obtain 3.52 g of the target product with a purity of 97% and a yield of 78%.
[0075] Comparative Example 1
[0076] The process is basically the same as in Example 8, except that water is used directly as the solvent to replace the 2 wt.% CTAB aqueous micelle medium.
[0077] The specific steps are as follows: 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of triethylamine (2.08 mL) were added to 10 mL of water, stirred at room temperature for 5 min, heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction continued for 16 h. After the reaction was completed, without cooling or post-treatment, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of triethylamine (2.08 mL) were added directly, and the reaction was carried out at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and purified by silica gel column chromatography to obtain 1.04 g of the target product with a purity of 97% and a yield of 23%.
[0078] Comparative Example 2
[0079] The method is basically the same as in Example 8, except that water is used directly as the solvent to replace the 2 wt.% CTAB aqueous micelle medium, and triethylamine is replaced with an equal molar amount of potassium carbonate.
[0080] The specific steps are as follows: 10 mmol of ethyl 4-bromobutyrate (1.94 g) and 15 mmol of potassium carbonate (2.07 g) were added to 10 mL of water, stirred at room temperature for 5 min, heated to 50 °C, and 11 mmol of 2-chloro-5-hydroxypyrimidine (1.43 g) was added dropwise, and the reaction continued for 16 h. After the reaction was completed, without cooling or post-treatment, 11 mmol of 3,5-bis(trifluoromethyl)benzylamine (2.67 g) and 15 mmol of potassium carbonate (2.07 g) were added directly, and the reaction was carried out at the same temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and purified by silica gel column chromatography to obtain 1.71 g of the target product with a purity of 93% and a yield of 38%.
[0081] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.
[0082] The endpoints and any values of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
Claims
1. A method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate, characterized in that, The preparation method includes: Using an aqueous micelle medium as a solvent, 2-chloro-5-hydroxypyrimidine and ethyl 4-bromobutyrate were subjected to an alkylation reaction in the aqueous micelle medium in the presence of an alkaline substance to generate ethyl 4-(2-chloropyrimidine-5-oxy)butyrate. Ethyl 4-(2-chloropyrimidin-5-oxy)butyrate and 3,5-bis(trifluoromethyl)benzylamine were subjected to an aromatic nucleophilic substitution reaction in an aqueous micelle medium in the presence of an alkaline substance to generate ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidin-5-oxy)butyrate. The aqueous micelle medium is formed by dispersing a surfactant in water; The surfactant is polyethylene glycol octylphenyl ether, and the alkaline substance is one or more combinations selected from potassium carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide; or, the surfactant is lauryl alcohol polyoxyethylene ether, and the alkaline substance is potassium carbonate and / or sodium carbonate; or, the surfactant is hexadecyltrimethylammonium bromide, and the alkaline substance is triethylamine and / or diisopropylethylamine.
2. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The surfactant in the aqueous micelle medium is 0.5%-5.0% by mass.
3. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The surfactant in the aqueous micelle medium has a mass percentage content of 1.0%-2.5%.
4. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The surfactant in the aqueous micelle medium contains 1.8%-2.2% by mass.
5. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The reaction temperature for the alkylation reaction and the reaction temperature for the aromatic nucleophilic substitution reaction are independently 40-80°C.
6. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The alkylation reaction takes 4-16 hours, and the aromatic nucleophilic substitution reaction takes 8-24 hours.
7. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, In the alkylation reaction, the molar ratio of ethyl 4-bromobutyrate, the basic substance, and the 2-chloro-5-hydroxypyrimidine is 1:1-2:1-1.5, wherein the concentration of ethyl 4-bromobutyrate in the aqueous micelle medium is controlled to be 0.1-0.5 mol / L. In the aromatic nucleophilic substitution reaction, the molar ratio of the basic substance, the 3,5-bis(trifluoromethyl)benzylamine, and the 4-bromobutyrate is controlled to be 1-2:1-1.5:1, based on the amount of ethyl 4-bromobutyrate used in the alkylation reaction.
8. The method for preparing ethyl 4-(2-((3,5-bis(trifluoromethylbenzyl)amino)pyrimidine-5-oxy)butyrate according to claim 1, characterized in that, The preparation method is a one-pot method, and the implementation of the one-pot method includes: Ethyl 4-bromobutyrate and the alkaline substance were added to an aqueous micelle medium. After heating to a preset reaction temperature, 2-chloro-5-hydroxypyrimidine was added dropwise. After the reaction was completed, 3,5-bis(trifluoromethyl)benzylamine and a new alkaline substance were added to the reaction system. The reaction was carried out to generate ethyl 4-(2-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-5-oxy)butyrate.