Synthesis method of (3-chlorophenethyl) glycine benzyl ester
By optimizing the synthesis method of (3-chlorophenethyl) glycine benzyl ester, using sodium carbonate catalyst and low temperature reaction, the problems of low yield and high purification cost in the prior art were solved, and efficient and low-cost drug intermediate production was achieved.
Patent Information
- Application Number
- CN202510772282.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-11
- Publication Date
- 2025-07-22
AI Technical Summary
The synthesis yield of existing (3-chlorophenethyl) glycine benzyl ester is low and is not easy to amplify production, has low raw material utilization rate, many side reactions, and high purification cost, which limits its application in drug industrialization.
Sodium carbonate was used as the basic catalyst to control the molar ratio of 3-chlorophenethylamine, sodium carbonate and benzyl bromoacetate to be 1:1.2:1.2, the reaction temperature was 0-10℃, and dichloromethane was used as the solvent, and the reaction time was 3-6h, which optimized the reaction path and suppressed side reactions.
The target product yield has been increased to 85%, the raw material cost has been reduced, the production cycle has been shortened, the purification has been simplified, and it is in line with the concept of green chemistry, providing practical solutions for the industrial production of drug intermediates.
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Figure CN120349255A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of synthesizing benzyl (3-chlorophenethyl) glycinate, and specifically to a method for synthesizing benzyl (3-chlorophenethyl) glycinate. Background Art
[0002] As a pharmaceutical intermediate, benzyl (3-chlorophenethyl) glycinate plays a key role in the synthesis of bioactive molecules such as gastrin receptor modulators and novel anti-ulcer drugs. The chlorophenethyl fragment and the benzyl glycinate skeleton in its structure provide an important molecular recognition basis for the design of drugs targeting the gastrin receptor.
[0003] Patent AU1993037645 first revealed the core role of this type of compound in the development of gastrin receptor antagonists. By specifically binding to the receptor, it blocks the signal pathway of excessive gastric acid secretion, providing a new paradigm for the treatment of diseases such as peptic ulcer and Zollinger-Ellison syndrome. However, the reductive amination process adopted in this patent has significant technical bottlenecks: the hydrogen released during the reaction is flammable and explosive, requiring a supporting high-pressure inert gas protection system, which greatly increases the safety control cost of industrial production; at the same time, the process relies on precious metal catalysts such as palladium-carbon and high-purity aldehyde raw materials, with high raw material costs and a complex catalyst recovery system, restricting the economy of this route.
[0004] Currently, the mainstream traditional synthesis route still mainly involves the direct condensation reaction of 3-chlorophenethylamine and benzyl bromoacetate (as reported in the literature 10.1016 / j.bmcl.2006.05.010), but this method has two technical defects: First, the reaction system lacks an efficient exogenous basic catalyst and relies on 3-chlorophenethylamine itself as the base reagent, resulting in insufficient substrate utilization. Approximately 30%-40% of the amine does not participate in the target bonding reaction and is only consumed as a proton acceptor, with an atom economy of only 50%-60%, causing raw material waste; Second, it is difficult to effectively inhibit the hydrolysis side reaction of the benzyl ester group and the self-condensation between amine molecules in the reaction system. Liquid chromatography monitoring shows that the by-product ratio can reach 15%-25%, forcing the subsequent use of complex purification methods such as column chromatography, and the purification cost accounts for 25%-30% of the total production cost. Limited by the above technical bottlenecks, the large-scale preparation yield of this compound is generally lower than 60%, severely restricting its application and promotion in the industrialization of drugs. Therefore, developing a green synthesis process with low risk, high atom economy, and capable of inhibiting side reactions has become the core technical requirement for breaking through the industrial production barriers of this intermediate. Summary of the Invention
[0005] To solve the above problems, that is, to solve the problems raised in the above background art, the present invention proposes a method for synthesizing benzyl (3-chlorophenethyl) glycinate, which comprises the following steps: 3-chlorophenethylamine reacts with benzyl bromoacetate in dichloromethane under the action of sodium carbonate to form benzyl (3-chlorophenethyl) glycinate, and the reaction formula is as follows: 。
[0006] A further setting of the present invention is that the molar ratio of the 3-chlorophenethylamine, sodium carbonate and benzyl bromoacetate is 1:1.2:1.2.
[0007] A further setting of the present invention is that the reaction temperature is 0°C - 10°C, the reaction time is 3 - 6 h, preferably 5 h.
[0008] A further setting of the present invention is that the reaction solvent is an aprotic solvent, including but not limited to one or a combination of dichloromethane, acetone, DMF or tetrahydrofuran, preferably dichloromethane.
[0009] The beneficial technical effects of the present invention are as follows: By introducing sodium carbonate as a basic catalyst, the reaction path is optimized. By precisely controlling the molar ratio of 3-chlorophenethylamine, sodium carbonate and benzyl bromoacetate (1:1.2:1.2) and adopting a low-temperature (0 - 10°C) reaction condition, side reactions are effectively inhibited, and the yield of the target product is increased to 85%, which is more than 40% higher than that of the prior art; using dichloromethane as the reaction solvent, which has both high solubility and low boiling point characteristics, simplifies the post-treatment steps, and the organic phase can be directly separated by extraction, greatly shortening the production cycle; sodium carbonate, as an inexpensive and readily available inorganic base, reduces the raw material cost and conforms to the concept of green chemistry; by controlling the reaction time of 5 h, the reaction is ensured to be complete and the product purity reaches the chromatographic grade standard, providing a high-quality intermediate for subsequent drug development. The present invention not only overcomes the efficiency bottleneck of the prior art, but also provides a practical technical solution for the industrial production of benzyl (3-chlorophenethyl) glycinate. BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Figure 1 Shows the NMR spectrum of benzyl (3-chlorophenethyl) glycinate. DETAILED DESCRIPTION OF THE INVENTION
[0011] The following describes the preferred embodiments of the present invention with reference to the attached Figure 1 Those skilled in the art should understand that these embodiments are only used to explain the technical principle of the present invention and are not intended to limit the protection scope of the present invention. EXAMPLE
[0012] Under ice bath conditions, add 300 mL of dichloromethane to a three-necked flask, start stirring, and adjust the rotation speed to 200 r / min. Subsequently, add 15.5 g (0.1 mol) of 3-chlorophenethylamine and 10.2 g (0.12 mol) of sodium carbonate in sequence, and control the temperature of the reaction system at 0-10 °C. After the system is stable, add 27.5 g (0.12 mol) of benzyl bromoacetate to the reaction solution and continue the reaction for 5 h. After the reaction is completed, under ice bath conditions, slowly pour the reaction solution into 75 mL of pure water, and extract the aqueous phase three times with ethyl acetate (45 mL each time). Combine the organic phases obtained from the three extractions, add 30 g of anhydrous sodium sulfate for drying. After drying, concentrate the organic phase, and then separate and purify it by column chromatography. Select 200 g (100-200 mesh) of silica gel powder as the stationary phase, and perform gradient elution with a petroleum ether solution containing 10% ethyl acetate. When the amount of the mobile phase reaches 1 L, the target product begins to appear. When the cumulative amount of the mobile phase reaches 2.2 L, the product collection is completed, and finally 25.7 g of benzyl (3-chlorophenethyl)glycinate is obtained. The calculated yield is 85%.
[0013] Although the present invention has been described with reference to the preferred embodiments, various modifications can be made to it without departing from the scope of the present invention, and components therein can be replaced with equivalents. In particular, as long as there is no structural conflict, the technical features mentioned in each embodiment can be combined in any manner. The present invention is not limited to the specific embodiments disclosed in the text, but includes all technical solutions falling within the scope of the claims.
[0014] In the description of the present invention, the terms such as "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., which indicate directions or positional relationships, are based on the directions or positional relationships shown in the drawings. This is only for the convenience of description, rather than indicating or implying that the device or element must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be construed as a limitation of the present invention. In addition, the terms "first", "second", "third" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance.
[0015] In addition, it should be noted that in the description of the present invention, unless otherwise clearly specified and limited, the terms "mounted", "connected", "connected" should be understood in a broad sense. For example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be directly connected or indirectly connected through an intermediate medium, and it can be the internal communication of two elements. For those skilled in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.
[0016] The term "comprising" or any other similar term is intended to cover non-exclusive inclusion, such that a process, article, or apparatus / device that comprises a series of elements includes not only those elements but also other elements not expressly listed, or elements that are inherent to those processes, articles, or apparatus / devices.
[0017] So far, the technical solution of the present invention has been described in conjunction with the preferred embodiments shown in the accompanying drawings. However, it is readily understood by those skilled in the art that the protection scope of the present invention is obviously not limited to these specific embodiments. Without departing from the principle of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will fall within the protection scope of the present invention.
Claims
1. A method for synthesizing benzyl (3-chlorophenethyl) glycinate, characterized in that: It includes the following steps: 3-chloro-phenethylamine reacts with benzyl bromoacetate in a reaction solvent under the action of sodium carbonate to form benzyl (3-chloro-phenethyl) glycinate, and the reaction formula is as follows: 。 2. The synthesis method of benzyl (3-chlorophenethyl) glycinate according to claim 1, wherein: The molar ratio of the 3-chloro-phenethylamine, sodium carbonate and benzyl bromoacetate is 1:1.2:1.
2.
3. The synthesis method of benzyl (3-chlorophenethyl) glycinate according to claim 1, wherein: The reaction temperature is 0°C - 10°C, and the reaction time is 3 - 6 h.
4. The synthetic method of benzyl (3-chlorophenethyl) glycinate according to claim 1, characterized in that: The reaction solvent is an aprotic solvent, including but not limited to one or a combination of dichloromethane, acetone, DMF or tetrahydrofuran.