Method for the preparation of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Abstract

The application discloses a preparation method of a compound of formula 1, and the method is shown in the following reaction flow. The method of the application obtains a compound of formula 3 from a compound of formula 2 by a one-pot method, and the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and triethylamine at a suitable temperature to generate a compound of formula 4, and finally the compound of formula 4 is salted by hydrogen chloride gas in a suitable solvent at a suitable temperature to generate the compound of formula 1. The method of the application is simple in operation, mild in reaction condition, high in reaction yield, and convenient for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis. Specifically, this invention relates to a method for preparing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Background Technology

[0002] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is a water-soluble peptide coupling agent and a general carbonyl activator. It can be used to bond amides with secondary amines, prepare products such as immunocrosslinkers, protein and nucleic acid crosslinks, and modify carbonyl groups in proteins.

[0003] Chinese patent document CN104193654A discloses a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Formula 1), and the specific synthetic route is shown below.

[0004]

[0005] This method uses N,N-dimethyl-1,3-propanediamine as the starting material. It first reacts with carbon disulfide to obtain an intermediate, which is then reacted with ethyl chloroformate through oxidation, condensation, oxidative desulfurization, and finally salt formation—a total of five steps with an overall yield of approximately 80%. This method is lengthy and cumbersome, complex to operate, and involves a hazardous production environment.

[0006] Japanese patent document JPH08198836A also reports a synthesis method for Formula 1. The specific synthesis route is shown below.

[0007]

[0008] This method uses ethylamine as the starting material, first reacting it with carbon disulfide to obtain an intermediate, then reacting it with ethyl chloroformate through oxidation, condensation, oxidative desulfurization, and finally salt formation—a total of five steps with an overall yield of approximately 32%. However, this method is lengthy and cumbersome, complex to operate, and involves a hazardous production environment.

[0009] Therefore, there is an urgent need in the field for a method to synthesize 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride that is simple to operate, environmentally friendly, safe for production personnel, and has a high yield. Summary of the Invention

[0010] The purpose of this invention is to provide a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, which should have the advantages of simple operation, environmental friendliness, safety for production personnel, and high yield.

[0011] In a first aspect, the present invention provides a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the method being illustrated in the following reaction flow:

[0012]

[0013] The method includes the following steps:

[0014] 1) The compound of formula 2 was reacted with triphosgene, dimethylamine and ethylamine to give the compound of formula 3;

[0015] 2) Dehydrating the compound of formula 3 yields the compound of formula 4;

[0016] 3) Salting the compound of formula 4 yields 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1.

[0017] In a specific implementation, in step 1), compound 2 is reacted with triphosgene, dimethylamine and ethylamine in a one-pot process to obtain compound 3.

[0018] In a specific implementation, in step 2), compound 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate compound 4.

[0019] In a specific implementation, in step 3), hydrogen chloride gas is used to salt the compound of formula 4 to obtain the compound of formula 1.

[0020] In a specific embodiment, in step 2), the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate the compound of formula 4 at -5°C to 30°C; preferably at 0°C to 5°C.

[0021] In a specific embodiment, in step 2), the molar ratio of the compound of formula 3 to dibromotriphenylphosphine is 1:1 to 1:1.5; preferably 1:1.05.

[0022] In a specific implementation, in step 2), the base is diisopropylethylamine, triethylamine, or N,N-dimethylaniline; preferably diisopropylethylamine.

[0023] In a specific embodiment, in step 3), the salt formation of compound 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride of formula 1 is carried out at a temperature of 5°C to 40°C; preferably 20°C to 25°C.

[0024] In a specific embodiment, in step 3), the compound of formula 4 is salted to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride of formula 1 in a solvent of tetrahydrofuran, acetonitrile, and dichloromethane, preferably tetrahydrofuran.

[0025] In a specific embodiment, the yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 90% or more, preferably 95% or more, and more preferably 98% or more.

[0026] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0027] Through extensive and in-depth research, the inventors unexpectedly discovered a synthetic method for producing compound 1. The synthetic route and reaction formula of this invention are shown below:

[0028]

[0029] The method of this invention uses compound of formula 2 as a starting material to obtain compound of formula 3 via a one-pot process. Then, compound of formula 3 is dehydrated at temperature T1 using dibromotriphenylphosphine and base B1 to generate compound of formula 4. Finally, compound of formula 4 is salted with hydrogen chloride gas in solvent S1 at temperature T2 to obtain compound of formula 1. The inventors have optimized the reaction conditions of this method, improving the reaction yield. The method of this invention has mild reaction conditions, which is beneficial for industrial production. The method of this invention avoids the use of sulfur-containing compounds, thus avoiding environmental pollution caused by sulfur-containing compounds. The method of this invention achieves a high yield in preparing compound of formula 1. Based on these findings, this invention was completed.

[0030] definition

[0031] The scientific and technical terms used herein are consistent with the conventional understanding of those skilled in the art to which this invention pertains. For clarity of understanding, the content of this invention is defined as follows:

[0032] One-pot method

[0033] The term "one-pot synthesis" as used herein refers to the "one-pot synthesis" conventionally understood in the art. This method of synthesizing compounds involves mixing all raw materials and reagents in one container and then converting them into the desired compound through a chemical reaction. However, one-pot synthesis typically requires strict experimental conditions and control because it involves complex chemical reactions.

[0034] The method of the present invention

[0035] This invention provides a method for synthesizing 1,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in the reaction route above, the method comprising the following steps:

[0036] 1) The compound of formula 2 was reacted with triphosgene, dimethylamine and ethylamine to give the compound of formula 3;

[0037] 2) Dehydrating the compound of formula 3 yields the compound of formula 4;

[0038] 3) Salting the compound of formula 4 yields 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1.

[0039] In the method of the present invention, the compound of formula 2, triphosgene, dimethylamine and ethylamine can be reacted in a "one-pot" process to obtain the compound of formula 3.

[0040] Based on the teachings of this invention, those skilled in the art will know how to dehydrate a compound of formula 3 to obtain a compound of formula 4. In a specific embodiment, the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate compound 4. In a specific embodiment, the dehydration of the compound of formula 3 under the action of dibromotriphenylphosphine and a base to generate compound 4 can be carried out at a suitable temperature, for example, between -5°C and 30°C; preferably between 0°C and 5°C. In a specific embodiment, the molar ratio of the compound of formula 3 to dibromotriphenylphosphine can be 1:1 to 1:1.5; preferably 1:1.05. In a specific embodiment, the base can be diisopropylethylamine, triethylamine, or N,N-dimethylaniline; preferably diisopropylethylamine.

[0041] Based on the teachings of this invention, those skilled in the art will also know how to salt the compound of formula 4 to obtain the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1. For example, those skilled in the art can use hydrogen chloride gas to salt the compound of formula 4 to obtain the compound of formula 1. In specific embodiments, the salt formation of the compound of formula 4 to obtain the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1 is carried out at a synthesis temperature, for example, 5°C to 40°C; preferably 20°C to 25°C. In specific embodiments, the salt formation of the compound of formula 4 to obtain the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1 can be carried out in a suitable solvent, for example, in tetrahydrofuran, acetonitrile, or dichloromethane, preferably tetrahydrofuran.

[0042] The method of the present invention yields very high amounts of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. In specific embodiments, the yield of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride prepared by the method of the present invention is 90% or more, preferably 95% or more, and more preferably 98% or more.

[0043] Advantages of this invention:

[0044] 1. This invention provides a novel method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0045] 2. The method of the present invention is simple to operate and environmentally friendly;

[0046] 3. The method of this invention is safe for production personnel;

[0047] 4. The method of the present invention yields a high yield of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0048] The technical solution of the present invention is further described below with reference to specific implementation examples. However, the following embodiments do not constitute a limitation of the present invention. All application methods based on the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0049] Example 1: One-pot synthesis of compound 3

[0050] 75.11 g (1 mol) of 3-aminopropanol, 300 mL of toluene, and 98.92 g (0.33 mol) of triphosgene were added to the reaction flask. After the addition was complete, the temperature was lowered to 0°C, and then 7.9 g (0.1 mol) of pyridine was added dropwise at 0-5°C. After the addition was complete, the reaction was carried out at 0-5°C for 1 hour, and then slowly heated to reflux for 4 hours. After the temperature was lowered to 0°C, 90.2 g (2 mol) of dimethylamine was introduced and the reaction was carried out at 0-5°C for 4 hours. The reaction was checked to ensure completeness, and the reaction solution was heated to 20-25°C. 64.4 g (1 mol) of 70% ethylamine solution was added dropwise. After the addition was complete, the reaction was checked to ensure completeness, and the mixture was filtered and dried to obtain 166.4 g of compound 3, with a yield of 96.0%.

[0051] Example 2: Synthesis of Compound 4

[0052] Three reaction flasks were filled with 0.75 L of dichloromethane. In flask 1, 211.1 g (0.5 mol) of dibromotriphenylphosphine was added; in flask 2, 221.7 g (0.525 mol) of dibromotriphenylphosphine was added; and in flask 3, 316.7 g (0.75 mol) of dibromotriphenylphosphine was added. After the additions, the internal temperature was controlled at 0–5 °C under nitrogen protection, and then 101.2 g (1 mol) of triethylamine was added dropwise. After the additions were complete, the temperature in all three reaction flasks was controlled at 20–25 °C, and 86.6 g (0.5 mol) of compound 3 was added. The reaction was carried out for 4 hours. After the reaction was complete, the dichloromethane was removed by distillation. The residue was added to 500 mL of n-hexane, stirred, and filtered to remove insoluble matter. The filtrate was then distilled off to obtain compound 4. Calculate the yields of the three reactions.

[0053] Table 1

[0054]

[0055] Example 3: Synthesis of Compound 4

[0056] Take three reaction flasks and add 211.1 g (0.5 mol) of dibromotriphenylphosphine and 0.75 L of dichloromethane to each flask. After the addition is complete, maintain the internal temperature at 0–5 °C under nitrogen protection, and then begin adding 101.2 g (1 mol) of triethylamine dropwise. In reaction flask 1, 82.3 g (0.475 mol) of compound 3 is added while maintaining the temperature at 0–5 °C; in reaction flask 2, 82.3 g (0.475 mol) of compound 3 is added while maintaining the temperature at 10–15 °C; and in reaction flask 3, 82.3 g (0.475 mol) of compound 3 is added while maintaining the temperature at 20–25 °C. After the addition is complete, the three groups of experiments are allowed to react for 4 hours. After the reaction is complete, distill off the dichloromethane. Add 500 mL of n-hexane to the residue, stir, filter to remove insoluble matter, and distill off the n-hexane from the filtrate to obtain compound 4. Calculate the yields of the three reactions.

[0057] Table 2

[0058]

[0059] Example 4: Synthesis of Compound 4

[0060] Take three reaction flasks and add 211.1 g (0.5 mol) of dibromotriphenylphosphine and 0.75 L of dichloromethane to each flask. After the addition is complete, under nitrogen protection, the temperature is lowered to an internal temperature of 0–5 °C. Then, 101.2 g (1 mol) of triethylamine is added dropwise to reaction flask 1; 129.3 g (1 mol) of diisopropylethylamine is added dropwise to reaction flask 2; and 121.2 g (1 mol) of N,N-dimethylaniline is added dropwise to reaction flask 3. After the addition of all three reactions is complete, 82.3 g (0.475 mol) of compound 3 is added while maintaining the temperature at 0–5 °C. The reaction is allowed to proceed for 4 hours. After the reaction is complete, dichloromethane is removed by distillation. The residue is added to 500 mL of n-hexane, stirred, and filtered to remove insoluble matter. The filtrate is then distilled off to obtain compound 4. Calculate the yields of the three reactions.

[0061] Table 3

[0062]

[0063] Example 5: Synthesis of Compound 4

[0064] 1.5 L of dichloromethane and 422.1 g (1 mol) of dibromotriphenylphosphine were added to the reaction flask. After the addition was complete, the mixture was cooled to an internal temperature of 0–5 °C under nitrogen protection. Then, 258.5 g (2 mol) of diisopropylethylamine was added dropwise. After the addition was complete, 165 g (0.95 mol) of compound 3 was added while maintaining the temperature at 0–5 °C. The reaction was carried out for 4 hours. After the reaction was complete, the dichloromethane was removed by distillation. The residue was added to 1 L of n-hexane, stirred, and filtered to remove insoluble matter. The filtrate was then distilled with n-hexane to obtain 133.3 g of compound 4, with a yield of 99.4%.

[0065] Example 6: Synthesis of Compound 1

[0066] Add 141.2 g (1 mol) of Formula 4 to each of three reaction flasks. Then, add 670 mL of dichloromethane to reaction flask 1; 670 mL of tetrahydrofuran to reaction flask 2; and 670 mL of acetonitrile to reaction flask 3. Simultaneously, control the temperature of all three reactions at 35–40 °C and introduce 46 g (1.26 mol) of HCl gas into the reaction solution. After the gas is introduced, stir the three reaction solutions for 30 minutes to allow the salt formation reaction to complete. Crystallize at room temperature, filter under nitrogen protection, and dry the solid under vacuum to obtain a white solid of Formula 1. Calculate the yields of the three reactions.

[0067] Table 4

[0068] experimental group reaction solvent reaction temperature yield 1 dichloromethane 35～40℃ 90.6％ 2 Tetrahydrofuran 35～40℃ 94.0％ 3 Acetonitrile 35～40℃ 89.8％

[0069] Example 7: Synthesis of Compound 1

[0070] Add 141.2 g (1 mol) of Formula 4 to each of three reaction flasks, followed by 670 mL of tetrahydrofuran. After the addition, in reaction flask 1, 46 g (1.26 mol) of HCl gas was introduced into the reaction solution while maintaining the temperature at 5–10 °C; in reaction flask 2, 46 g (1.26 mol) of HCl gas was introduced into the reaction solution while maintaining the temperature at 20–25 °C; and in reaction flask 3, 46 g (1.26 mol) of HCl gas was introduced into the reaction solution while maintaining the temperature at 35–40 °C. After the gas was introduced, the three reaction solutions were stirred for 30 minutes to allow the salt formation reaction to complete. Crystallization was performed at room temperature, filtered under nitrogen protection, and the solid was dried under vacuum to obtain a white solid of Formula 1. Calculate the yields of the three reactions.

[0071] Table 5

[0072] experimental group reaction solvent reaction temperature yield 1 Tetrahydrofuran 5～10℃ 95.5％ 2 Tetrahydrofuran 20～25℃ 97.2％ 3 Tetrahydrofuran 35～40℃ 93.9％

[0073] Example 8: Synthesis of Compound 1

[0074] In a 5L reaction flask, 423.6 g (3 mol) of compound 4 was added, followed by 2L of tetrahydrofuran for dissolution. While maintaining the temperature at 20–25°C, 138 g (3.78 mol) of HCl gas was introduced into the reaction solution. After the gas was completely introduced, the mixture was stirred for 30 minutes until the salt formation reaction was complete. Crystallization was carried out at room temperature, and the solution was filtered under nitrogen protection. The solid was then dried under vacuum to obtain 523 g of compound 1, with a yield of 98.1% (HPLC: 99.8%).

[0075] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

A method for synthesizing 1.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, the method being illustrated in the following reaction flow: The method includes the following steps: 1) The compound of formula 2 was reacted with triphosgene, dimethylamine and ethylamine to give the compound of formula 3; 2) Dehydrating the compound of formula 3 yields the compound of formula 4; 3) Salting the compound of formula 4 yields 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1; In step 1), compound 2 is reacted with triphosgene, dimethylamine and ethylamine in a one-pot process to obtain compound 3; In step 2), compound 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate compound 4.

2. The method as described in claim 1, characterized in that, In step 3), hydrogen chloride gas is used to salt the compound of formula 4 to obtain the compound of formula 1.

3. The method as described in claim 1 or 2, characterized in that, In step 2), the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate the compound of formula 4 at -5°C to 30°C.

4. The method as described in claim 3, characterized in that, In step 2), the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate the compound of formula 4 at 0°C to 5°C.

5. The method as described in claim 3, characterized in that, In step 2), the molar ratio of compound 3 to dibromotriphenylphosphine is 1:1 to 1:1.

5.

6. The method as described in claim 5, characterized in that, In step 2), the molar ratio of compound 3 to dibromotriphenylphosphine is 1:1.

05.

7. The method as described in claim 3, characterized in that, In step 2), the base is diisopropylethylamine, triethylamine, N,N-dimethylaniline, or a mixture thereof.

8. The method as described in claim 7, characterized in that, In step 2), the base is diisopropylethylamine.

9. The method as described in claim 1 or 2, characterized in that, In step 3), the salt formation of compound 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1 is carried out at a temperature of 5°C to 40°C.

10. The method as described in claim 9, characterized in that, In step 3), the salt formation of compound 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1 is carried out at a temperature of 20-25°C.

11. The method as described in claim 1 or 2, characterized in that, In step 3), the salt formation of compound 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride of formula 1 is carried out in a solvent selected from tetrahydrofuran, acetonitrile, dichloromethane or mixtures thereof.

12. The method as described in claim 11, characterized in that, In step 3), the salt formation of compound 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride of formula 1 is carried out in a solvent, namely tetrahydrofuran.

13. The method as described in claim 1, characterized in that, The yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is above 90%.

14. The method as described in claim 13, characterized in that, The yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is above 95%.

15. The method as described in claim 14, characterized in that, The yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is above 98%.

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