Synthesis method of N alpha-fluorenylmethoxycarbonyl-L-threonine ethyl ester
The first intermediate was prepared by p-toluenesulfonyl chloride, ethanol, and triethylamine, and reacted with Nα-fluorene methoxycarbonyl-L-threonine and potassium carbonate, and the synthesis of Nα-fluorene methoxycarbonyl-L-threonine ethyl ester was achieved in a one-pot method, which solved the problems of numerous synthesis processes, complex operations and serious pollution in the prior art, and achieved efficient and simple synthesis processes and high-purity products.
Patent Information
- Application Number
- CN202510333986.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-20
- Publication Date
- 2025-06-20
AI Technical Summary
The existing synthesis method of Nα-fluorene methoxycarbonyl-L-threonine ethyl ester has problems such as numerous reaction processes, complex operations, and serious odor pollution. The three waste treatment volume is large, and the yield and product purity are low.
A new synthesis method is adopted to prepare the first intermediate by p-toluenesulfonyl chloride, ethanol, and triethylamine, and react with Nα-fluorene methoxycarbonyl-L-threonine and potassium carbonate to realize the one-pot synthesis of Nα-fluorene methoxycarbonyl-L-threonine ethyl ester, simplifying the process flow, reducing the intermediate purification and the back and forth operation of the reaction device.
The synthesis of Nα-fluorene methoxycarbonyl-L-threonine ethyl ester with fast reaction speed, simple operation, small three-waste treatment volume, high yield and high product purity is achieved, which is suitable for industrial production.
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Figure CN120172883A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, and particularly relates to a method for synthesizing Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester. Background Art
[0002] Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester is an important raw material for synthesizing polypeptide drugs. Therefore, the research on the synthesis of Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester is particularly important. The existing synthesis methods are mainly as follows:
[0003] The first synthesis method: L - threonine is suspended in absolute ethanol, and anhydrous hydrogen chloride is introduced until saturation. L - threonine gradually dissolves. After the reaction ends, it is concentrated under reduced pressure, and anhydrous ethyl ether is added for crystallization to obtain the intermediate L - threonine ethyl ester hydrochloride. Further reaction with fluorenylmethoxycarbonyl succinimide gives the product Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester.
[0004] The second synthesis method: L - threonine is suspended in absolute ethanol, and thionyl chloride is added dropwise at low temperature. After the addition is completed, the mixture is heated under reflux for reaction. After the reaction ends, it is concentrated under reduced pressure, and anhydrous ethyl ether is added for crystallization to obtain the intermediate L - threonine ethyl ester hydrochloride. Further reaction with fluorenylmethoxycarbonyl succinimide gives the product Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester.
[0005] The third synthesis method: L - threonine, p - toluenesulfonic acid, and ethanol are added to a carbon tetrachloride solution, and the mixture is heated under reflux for water separation. After the reaction ends, it is concentrated under reduced pressure, and anhydrous ethyl ether is added for crystallization to obtain the intermediate L - threonine ethyl ester p - toluenesulfonate. Further reaction with fluorenylmethoxycarbonyl succinimide gives the product Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester.
[0006] There are problems in the prior art such as numerous synthesis steps, complex operations, large odor and serious pollution in the production of intermediates. For example, flammable and explosive ethyl ether is used, and thionyl chloride is used, etc., consuming a large amount of energy in treating the three wastes. Therefore, there is an urgent need for a synthesis method of Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester with a relatively fast reaction rate, simple operation, small amount of three - waste treatment, high yield and high product purity. Summary of the Invention
[0007] The technical problem to be solved by the present invention is: to overcome the defects in the prior art and provide a synthesis method of Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester with a relatively fast reaction rate, simple operation, small amount of three - waste treatment, high yield and high product purity.
[0008] To solve the above problems, the technical solution provided by the present invention is as follows:
[0009] A synthesis method of Nα - fluorenylmethoxycarbonyl - L - threonine ethyl ester, comprising the following steps:
[0010] Step S1: Prepare a first intermediate by adding an organic solvent, p-toluenesulfonyl chloride, ethanol, and triethylamine; the state of the first intermediate is a mixed solution containing the organic solvent.
[0011] Step S2: React the first intermediate with Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate to obtain a mixed solution, and perform post-treatment on the mixed solution to obtain Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester.
[0012] The reaction formula for Step S1 is:
[0013]
[0014] The reaction formula for Step S2 is:
[0015]
[0016] Further, Step S1 includes dissolving p-toluenesulfonyl chloride and ethanol in the organic solvent, stirring for dissolution; dropping triethylamine for reaction; adding water to the reaction solution, standing for liquid separation; washing, drying, and filtering the organic phase in sequence to obtain the first intermediate.
[0017] Further, in Step S1, the molar ratio of p-toluenesulfonyl chloride, ethanol, and triethylamine is 1:0.9 - 2:0.9 - 3.
[0018] Further, in Step S1, the molar ratio of p-toluenesulfonyl chloride, ethanol, and triethylamine is 1:1.0 - 1.1:1.0 - 1.2.
[0019] Further, in Step S1, the mass ratio of p-toluenesulfonyl chloride to the organic solvent is 1:5 - 50.
[0020] Further, in Step S1, the mass ratio of p-toluenesulfonyl chloride to the organic solvent is 1:10 - 20.
[0021] Further, the organic solvent is dichloromethane or dichloroethane.
[0022] Further, Step S2 includes adding Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate to the mixed solution containing the organic solvent of the first intermediate for reaction; adding water to the reaction solution, standing for liquid separation; washing, drying, filtering, and concentrating under reduced pressure the organic phase in sequence; adding petroleum ether to precipitate a solid; and filtering and drying to obtain Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester.
[0023] Further, in Step S2, based on p-toluenesulfonyl chloride in Step S1, the molar ratio of p-toluenesulfonyl chloride, Nα-fluorenylmethoxycarbonyl-L-threonine, and potassium carbonate is 1:0.9 - 2:0.9 - 3.
[0024] Further, the molar ratio of the p-toluenesulfonyl chloride, Nα-fluorenylmethoxycarbonyl-L-threonine, and potassium carbonate is 1: 1.0-1.1: 1.0-1.2.
[0025] Further, in step S2, based on the p-toluenesulfonyl chloride in step S1, the mass ratio of the p-toluenesulfonyl chloride to petroleum ether is 1: 1-20.
[0026] Further, the mass ratio of the p-toluenesulfonyl chloride to petroleum ether is 1: 3-10.
[0027] In the present invention, if there is a conflict between the Chinese name and the structural formula of the compound, the structural formula shall prevail, except when the structural formula has obvious errors.
[0028] The beneficial effects of the present invention are that the Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester, its synthesis method, and raw material formula of the present invention prepare a first intermediate through p-toluenesulfonyl chloride, ethanol, and triethylamine; then, the product Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester is prepared through the first intermediate, Nα-fluorenylmethoxycarbonyl-L-threonine, and potassium carbonate. The product is synthesized by a one-pot method. The whole preparation process does not require purification of the intermediate, nor does it require switching the reaction device back and forth. The reaction time is shortened, and the operation efficiency is improved. It has the advantages of simple process, low pressure of three-waste treatment, convenient operation, high product purity and yield, and is especially suitable for industrial production. Description of the Drawings
[0029] Figure 1 It is the nuclear magnetic resonance spectrum of Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester obtained by the specific embodiment of the present application;
[0030] Figure 2 It is the high performance liquid chromatography of Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester obtained by the specific embodiment of the present application;
[0031] Figure 3 It is the mass spectrum of Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester obtained by the specific embodiment of the present application;
[0032] Figure 4 It is the infrared spectrum of Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester obtained by the specific embodiment of the present application. Specific Embodiments
[0033] The following examples illustrate the present invention, but do not limit the present invention. In the art, simple substitutions or improvements made by those skilled in the art to the present invention fall within the scope of the technical solutions protected by the present invention.
[0034] The present invention provides a method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester, which comprises the following steps: Step S1, preparing a first intermediate from p-toluenesulfonyl chloride, ethanol and triethylamine; Step S2, preparing the Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester from the first intermediate, Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate.
[0035] As an alternative embodiment for preparing the first intermediate.
[0036] The preparation of the first intermediate from p-toluenesulfonyl chloride, ethanol and triethylamine includes: dissolving solid p-toluenesulfonyl chloride and liquid ethanol in dichloromethane solution, and stirring until fully dissolved; first controlling the temperature of the reaction system at 0-10 °C, and then dropping liquid triethylamine for the first reaction, the time of the first reaction being 2-3 hours; after the reaction is completed, adding water and standing for liquid separation; washing, drying and filtering the oil phase in sequence to obtain the first intermediate.
[0037] Optionally, the organic solvent such as, but not limited to, dichloromethane is immiscible with water;
[0038] As an alternative embodiment for preparing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester.
[0039] The preparation of Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester from the first intermediate, Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate includes: first controlling the temperature of the reaction system at 0-10 °C, and then adding solid Nα-fluorenylmethoxycarbonyl-L-threonine and solid potassium carbonate to the first intermediate for reaction, that is, the second reaction, the reaction time being 2-3 hours; after the reaction is completed, adding water and standing for liquid separation; washing, drying, filtering and concentrating under reduced pressure the oil phase in sequence; adding petroleum ether to precipitate a solid; and filtering and drying to obtain the Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester.
[0040] Example 1:
[0041] Dissolve 100 g (0.525 mol) of solid p-toluenesulfonyl chloride and 24.2 g (0.525 mol) of liquid ethanol in 2000 g of an organic solvent dichloroethane solution, stir until fully dissolved, slowly drop 53.1 g (0.525 mol) of liquid triethylamine, control the temperature of the reaction system at about 5 °C during the dropping process, after the dropping is completed, stir at room temperature for 3 hours; after the reaction is completed, add water and stand for liquid separation; wash, dry and filter the oil phase to obtain the first intermediate (in the form of a mixed solution containing dichloroethane).
[0042] To the first intermediate, 179.1 g (0.525 mol) of solid Nα-Fmoc-L-threonine and 72.5 g (0.525 mol) of solid potassium carbonate were added successively. During the addition process, the temperature of the reaction system was controlled at about 5 °C. After the addition was completed, the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added and the mixture was allowed to stand for liquid separation. The oil phase was washed, dried, filtered, and concentrated under reduced pressure to dryness. 600 g of petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 145.3 g of the product Nα-Fmoc-L-threonine ethyl ester, with a yield of 74.99%, HPLC: 98.70%, melting point: 100.4 - 100.9 °C, specific rotation [α] 20 D = -13.0 (C = 1 DMF).
[0043] Example 2:
[0044] 100 g (0.525 mol) of solid p-toluenesulfonyl chloride and 21.7 g (0.471 mol) of liquid ethanol were dissolved in 1000 g of an organic solvent dichloromethane solution. The mixture was stirred until completely dissolved, and 47.8 g (0.472 mol) of liquid triethylamine was slowly added dropwise. During the addition process, the temperature of the reaction system was controlled at about 10 °C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added and the mixture was allowed to stand for liquid separation. The oil phase was washed, dried, filtered, to obtain the first intermediate (in the state of a mixed solution containing dichloromethane).
[0045] To the first intermediate, 161.1 g (0.472 mol) of solid Nα-Fmoc-L-threonine and 65.2 g (0.472 mol) of solid potassium carbonate were added successively. During the addition process, the temperature of the reaction system was controlled at about 10 °C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added and the mixture was allowed to stand for liquid separation. The oil phase was washed, dried, filtered, and concentrated under reduced pressure to dryness. 1000 g of petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 130.3 g of the product Nα-Fmoc-L-threonine ethyl ester, with a yield of 67.24%, HPLC: 98.26%, melting point: 100.5 - 101.0 °C, specific rotation [α] 20 D = -12.8 (C = 1 DMF).
[0046] Example 3:
[0047] Dissolve 100 g (0.525 mol) of solid p-toluenesulfonyl chloride and 26.6 g (0.577 mol) of liquid ethanol in 1500 g of an organic solvent dichloromethane solution, stir well to dissolve, and slowly add dropwise 63.7 g (0.630 mol) of liquid triethylamine. During the addition process, control the temperature of the reaction system at about 0 °C. After the addition is completed, stir at room temperature for 2 hours; after the reaction is completed, add water and let it stand for liquid separation; wash, dry, and filter the oil phase to obtain the first intermediate (in the state of a mixed solution containing dichloromethane).
[0048] Add 197.0 g (0.577 mol) of solid Nα-Fmoc-L-threonine and 87.0 g (0.629 mol) of solid potassium carbonate to the first intermediate in sequence. During the addition process, control the temperature of the reaction system at about 0 °C. After the addition is completed, stir at room temperature for 2 hours; after the reaction is completed, add water and let it stand for liquid separation; wash, dry, filter, and concentrate under reduced pressure to dryness; add 300 g of petroleum ether to precipitate a solid; filter and dry to obtain 135.9 g of the product Nα-Fmoc-L-threonine ethyl ester, with a yield of 70.14%, HPLC: 98.49%, melting point: 100.1 - 100.7 °C, specific rotation [[α] 20 D =-13.5 (C = 1 DMF).
[0049] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention.
Claims
1. A method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester, characterized in that: The steps include: Step S1, preparing a first intermediate by adding an organic solvent, p-toluenesulfonyl chloride, ethanol, and triethylamine; the first intermediate is in a mixed liquid containing an organic solvent; Step S2, obtaining a mixed solution by reacting the first intermediate with Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate, and post-treating the mixed solution to obtain the Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester; The reaction formula of step S1 is: The reaction formula of step S2 is:
2. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 1, characterized in that: The step S1 comprises dissolving p-toluenesulfonyl chloride and ethanol in an organic solvent and stirring to dissolve; adding triethylamine dropwise to react; adding water to the reaction solution and standing to separate the layers; and washing, drying and filtering the organic phase in sequence to obtain a mixed solution containing the first intermediate and the organic solvent.
3. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 2, characterized in that: In the step S1, the molar ratio of p-toluenesulfonyl chloride, ethanol and triethylamine is 1:0.9-2:0.9-3.
4. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 3, characterized in that: In the step S1, the molar ratio of p-toluenesulfonyl chloride, ethanol and triethylamine is 1:1.0-1.1:1.0-1.
2.
5. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 4, characterized in that: In the step S1, the mass ratio of p-toluenesulfonyl chloride to the organic solvent is 1:5-50.
6. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 5, characterized in that: In the step S1, the mass ratio of p-toluenesulfonyl chloride to the organic solvent is 1:10-20.
7. A method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to any one of claims 1 to 6, characterized in that: The organic solvent is dichloromethane or dichloroethane.
8. The method for synthesizing Nα-Fmoc-L-threonine ethyl ester according to claim 7, characterized in that: The step S2 comprises adding Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate to a mixed solution containing an organic solvent of the first intermediate for reaction; adding water to the reaction solution and standing to separate the layers; washing, drying, filtering and concentrating the organic phase in sequence; adding petroleum ether to precipitate solids; and filtering and drying to obtain the Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester.
9. The method for synthesizing Nα-Fmoc-L-threonine ethyl ester according to claim 8, characterized in that: In step S2, the molar ratio of p-toluenesulfonyl chloride, Nα-fluorenylmethoxycarbonyl-L-threonine and potassium carbonate is 1:0.9-2:0.9-3 based on the p-toluenesulfonyl chloride in step S1.
10. The method for synthesizing Nα-fluorenylmethoxycarbonyl-L-threonine ethyl ester according to claim 9, characterized in that: In step S2, the p-toluenesulfonyl chloride in step S1 is used as a reference, and the mass ratio of p-toluenesulfonyl chloride to petroleum ether is 1:1-20.