Method for preparing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Abstract

Disclosed in the present invention is a method for preparing a compound of formula (1). The method is as shown in the following reaction process. The method of the present invention comprises: using a compound of formula (2) as a starting raw material to obtain a compound of formula (3) by a "one-pot method", dehydrating the compound of formula (3) with dibromotriphenylphosphorane and triethylamine at a suitable temperature to generate a compound of formula (4), and finally, in a suitable solvent, salifying the compound of formula (4) with hydrogen chloride gas at a suitable temperature to obtain the compound of formula (1). The method of the present invention is simple to operate, involves mild reaction conditions, has a high reaction yield, and is convenient for industrial production.

Description

Preparation method of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for preparing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Background Art

[0002] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is a water-soluble peptide coupling agent and a universal carbonyl activation reagent. It can be used to form bonds between amides and secondary amines, prepare immunocrosslinks, crosslink proteins and nucleic acids, and be used for carbonyl modification in proteins.

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

[0004] This method uses N,N-dimethyl-1,3-propylenediamine as the starting material, first reacting it with carbon disulfide to obtain an intermediate, which is then reacted with ethyl chloroformate through five steps of oxidation, condensation, oxidative desulfurization, and finally salt formation, with an overall yield of approximately 80%. This method is long and tedious, with complex operations and high production environmental and risk factors.

[0005] Japanese patent document JPH08198836A also reports a synthesis method of Formula 1. The specific synthesis route is shown below.

[0006] This method uses ethylamine as the starting material, first reacting it 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 about 32%. However, this method is also long and cumbersome, with complex operations and high production environment and risks.

[0007] Therefore, there is an urgent need in the art for a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride that is simple to operate, environmentally friendly, safe for production personnel, and has a high yield.

[0008] Summary of the Invention

[0009] The object of the present 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, high yield, etc.

[0010] In a first aspect, the present invention provides a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, as shown in the following reaction scheme:

[0011] The method comprises the following steps:

[0012] 1) reacting the compound of formula 2 with triphosgene, dimethylamine and ethylamine to obtain a compound of formula 3;

[0013] 2) dehydrating the compound of formula 3 to obtain the compound of formula 4;

[0014] 3) The compound of formula 4 is salified to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1.

[0015] In a specific embodiment, in step 1), the compound of formula 2 is reacted with triphosgene, dimethylamine and ethylamine through a "one-pot process" to obtain the compound of formula 3.

[0016] In a specific embodiment, in step 2), the compound of formula 3 is dehydrated under the action of dibromotriphenylphosphine and a base to generate a compound of formula 4.

[0017] In a specific embodiment, in step 3), hydrogen chloride gas is used to form a salt of the compound of formula 4 to obtain the compound of formula 1.

[0018] 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 0°C to 5°C.

[0019] In a specific embodiment, in step 2), the molar ratio of the compound of formula 3 to dibromotriphenylphosphine is 1:1-1:1.5; preferably 1:1.05.

[0020] In a specific embodiment, in step 2), the base is diisopropylethylamine, triethylamine, or N,N-dimethylaniline; preferably diisopropylethylamine.

[0021] In a specific embodiment, in step 3), the salification of the compound of formula 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 to 25°C.

[0022] In a specific embodiment, in step 3), the compound of formula 4 is salified to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1 in a solvent of tetrahydrofuran, acetonitrile, dichloromethane, preferably tetrahydrofuran.

[0023] In a specific embodiment, the yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is above 90%, preferably above 95%, and more preferably above 98%.

[0024] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail 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 listed here one by one. DETAILED DESCRIPTION

[0025] After extensive and in-depth research, the inventors unexpectedly discovered a synthetic method for producing the compound of formula 1. The synthetic route reaction formula of the method of the present invention is as follows:

[0026] The method of the present invention uses the compound of formula 2 as the starting material, obtains the compound of formula 3 through a "one-pot process", then dehydrates the compound of formula 3 with dibromotriphenylphosphine and base B1 at temperature T1 to produce the compound of formula 4, and finally salts the compound of formula 4 with hydrogen chloride gas in a solvent S1 at temperature T2 to obtain the compound of formula 1. The inventors have optimized the reaction process conditions of the method of the present invention, thereby improving the reaction yield. The method of the present invention has mild reaction conditions and is conducive to industrial production. The method of the present invention avoids the use of sulfur-containing compounds, thereby preventing sulfur-containing compounds from polluting the environment. The method of the present invention produces the compound of formula 1 in high yield. Based on this, the present invention was completed.

[0027] definition

[0028] The scientific and technical terms used herein are consistent with those commonly understood by those skilled in the art to which the present invention belongs. For the purpose of a clear understanding of the present invention, the following definitions are made for the present invention:

[0029] One-pot method

[0030] The term "one-pot method" as used herein refers to what is commonly understood in the art as a "one-pot synthesis." This method of synthesizing a compound involves combining all raw materials and reagents in a single container and then converting them into the desired compound through a chemical reaction. However, one-pot synthesis often requires rigorous experimental conditions and control due to the complex chemical reactions involved.

[0031] Method of the present invention

[0032] The present invention provides a method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in the reaction scheme shown above, the method comprising the following steps:

[0033] 1) reacting the compound of formula 2 with triphosgene, dimethylamine and ethylamine to obtain a compound of formula 3;

[0034] 2) dehydrating the compound of formula 3 to obtain the compound of formula 4;

[0035] 3) The compound of formula 4 is salified to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as shown in formula 1.

[0036] In the method of the present invention, the compound of formula 2 can be reacted with triphosgene, dimethylamine and ethylamine to obtain the compound of formula 3 through a "one-pot process".

[0037] Based on the teachings of the present invention, those skilled in the art will understand how to dehydrate the compound of Formula 3 to obtain the compound of Formula 4. In a specific embodiment, the compound of Formula 3 is dehydrated in the presence of dibromotriphenylphosphine and a base to produce the compound of Formula 4. In a specific embodiment, the dehydration of the compound of Formula 3 in the presence of dibromotriphenylphosphine and a base to produce the compound of Formula 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 from 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.

[0038] Based on the teachings of the present invention, those skilled in the art 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 a specific embodiment, 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 of, for example, 5°C to 40°C; preferably 20 to 25°C. In a specific embodiment, 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, such as tetrahydrofuran, acetonitrile, dichloromethane, preferably tetrahydrofuran.

[0039] The yield of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride prepared by the method of the present invention is very high. In a specific embodiment, the yield of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride prepared by the method of the present invention is greater than 90%, preferably greater than 95%, and more preferably greater than 98%.

[0040] Advantages of the present invention:

[0041] 1. The present invention provides a novel method for synthesizing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0042] 2. The method of the present invention is simple to operate and environmentally friendly;

[0043] 3. The method of the present invention is safe for production personnel;

[0044] 4. The yield of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride obtained by the method of the present invention is high.

[0045] The technical solutions of the present invention are further described below with reference to specific implementation examples. However, the following examples do not constitute a limitation of the present invention. All various application methods adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, where specific conditions are not specified, generally follow conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0046] Example 1: One-pot synthesis of compound 3

[0047] 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. The temperature was cooled to 0°C after the addition was completed, and then 7.9 g (0.1 mol) of pyridine was added dropwise at 0-5°C under controlled temperature. After the addition was complete, the mixture was slowly heated to reflux for 4 hours and then cooled to 0°C under controlled temperature. 90..2 g (2 mol) of dimethylamine was added after the addition was complete and the mixture was reacted at 0-5°C for 4 hours. After the reaction was completed, the reaction solution was heated to 20-25°C and the temperature was controlled to add 64.4 g (1 mol) of 70% ethylamine solution dropwise. After the addition was complete and the reaction was completed for 1 hour, the reaction was filtered and dried to give 166.4 g of the compound of formula 3 in a yield of 96.0%.

[0048] Example 2: Synthesis of Compound 4

[0049] Add 0.75L of dichloromethane to three reaction flasks. Add 211.1g (0.5 mol) of dibromotriphenylphosphine to reaction flask #1; 221.7g (0.525 mol) of dibromotriphenylphosphine to reaction flask #2; and 316.7g (0.75 mol) of dibromotriphenylphosphine to reaction flask #3. After the additions are complete, control the internal temperature at 0-5°C under nitrogen protection, and then begin the dropwise addition of 101.2g (1 mol) of triethylamine. After the additions are complete, control the temperature at 20-25°C to add 86.6g (0.5 mol) of the compound of Formula 3 to the three reaction flasks. After the additions are complete, allow the three groups of experiments to react for 4 hours. After the reaction is complete, dichloromethane is distilled off. The residual liquid is added with 500ml of n-hexane, stirred, and filtered to remove insoluble matter. The filtrate is then distilled from n-hexane to obtain the compound of Formula 4. Calculate the yields of the three reactions.

[0050] Table 1

[0051] Example 3: Synthesis of Compound 4

[0052] Take three reaction flasks and add 211.1 g (0.5 mol) of dibromotriphenylphosphine and 0.75 L of dichloromethane, respectively. After the additions are complete, control the internal temperature at 0-5°C under nitrogen, and then begin the dropwise addition of 101.2 g (1 mol) of triethylamine. Control the temperature of reaction flask No. 1 at 0-5°C and add 82.3 g (0.475 mol) of compound 3; control the temperature of reaction flask No. 2 at 10-15°C and add 82.3 g (0.475 mol) of compound 3; and control the temperature of reaction flask No. 3 at 20-25°C and add 82.3 g (0.475 mol) of compound 3. After the additions are complete, the three groups of experiments react for 4 hours. After the reaction is complete, dichloromethane is distilled off. The residual liquid is added with 500 ml of n-hexane, stirred, and filtered to remove insoluble matter. The filtrate is then distilled off the n-hexane to obtain compound 4. Calculate the yields of the three reactions.

[0053] Table 2

[0054] Example 4: Synthesis of Compound 4

[0055] Add 211.1 g (0.5 mol) of dibromotriphenylphosphine and 0.75 L of dichloromethane to three reaction flasks, respectively. After addition, cool to an internal temperature of 0-5°C under nitrogen. Then, begin dropwise adding 101.2 g (1 mol) of triethylamine to reaction flask #1; 129.3 g (1 mol) of diisopropylethylamine to reaction flask #2; and 121.2 g (1 mol) of N,N-dimethylaniline to reaction flask #3. After the three reaction sets are complete, add 82.3 g (0.475 mol) of the compound of Formula 3, controlling the temperature at 0-5°C. After addition, react for 4 hours. After completion of the reaction, dichloromethane is distilled off. The residual solution is added with 500 ml of n-hexane, stirred, filtered to remove insoluble matter, and the filtrate is distilled from n-hexane to obtain the compound of Formula 4. Calculate the yields of the three reactions.

[0056] Table 3

[0057] Example 5: Synthesis of Compound 4

[0058] 1.5 L of dichloromethane and 422.1 g (1 mol) of dibromotriphenylphosphine were added to the reaction flask. After the addition, the temperature was lowered to 0-5 ° C under nitrogen protection, and 258.5 g (2 mol) of diisopropylethylamine was added dropwise. After the addition was completed, the temperature was controlled at 0-5 ° C. 165 g (0.95 mol) of the compound of formula 3 was added and the reaction was continued for 4 hours. After the reaction was completed, dichloromethane was distilled off, and the residual liquid was added with 1 L of n-hexane and stirred, and then filtered to remove insoluble matter. The filtrate was distilled into n-hexane to obtain 133.3 g of the compound of formula 4 with a yield of 99.4%.

[0059] Example 6: Synthesis of Compound 1

[0060] Add 141.2 g (1 mol) of Formula 4 to each of three reaction flasks. Then, add 670 ml of dichloromethane to flask 1; 670 ml of tetrahydrofuran to flask 2; and 670 ml of acetonitrile to flask 3. Simultaneously, control the temperature at 35-40°C while passing 46 g (1.26 mol) of HCl gas through the reaction mixtures. After completion of the gasification, stir the reaction mixtures for 30 minutes to complete the salt-forming reaction. Crystallize at room temperature, filter under nitrogen, and vacuum dry to obtain the compound of Formula 1 as a white solid. Calculate the yields of the three reactions.

[0061] Table 4

[0062] Example 7: Synthesis of Compound 1

[0063] Take three reaction flasks and add 141.2 g (1 mol) of Formula 4 to each, followed by 670 ml of tetrahydrofuran. After the addition is complete, control the temperature of reaction flask No. 1 at 5-10°C and pass 46 g (1.26 mol) of HCl gas into the reaction solution; control the temperature of reaction flask No. 2 at 20-25°C and pass 46 g (1.26 mol) of HCl gas into the reaction solution; and control the temperature of reaction flask No. 3 at 35-40°C and pass 46 g (1.26 mol) of HCl gas into the reaction solution. After the completion of the pass, stir the three reaction solutions for 30 minutes to complete the salt formation reaction. Crystallize at room temperature, filter under nitrogen protection, and vacuum dry the solid to obtain the white solid compound of Formula 1. Calculate the yield of the three reactions.

[0064] Table 5

[0065] Example 8: Synthesis of Compound of Formula 1

[0066] To a 5L reaction flask, 423.6 g (3 mol) of the compound of Formula 4 was added, followed by dissolution in 2L of tetrahydrofuran. 138 g (3.78 mol) of HCl gas was introduced into the reaction solution at a temperature of 20-25°C. After completion of the addition, the solution was stirred for 30 minutes to allow the salt formation reaction to complete. Crystallization was carried out at room temperature, filtered under nitrogen, and the solid was vacuum dried to obtain 523 g of the compound of Formula 1, with a yield of 98.1% and an HPLC yield of 99.8%.

[0067] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. The synthesis method of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the method is as shown in the following reaction process: The method comprises the following steps: 1) Reacting the compound of formula 2 with triphosgene, dimethylamine and ethylamine to obtain the compound of formula 3; 2) Dehydrating the compound of formula 3 to obtain the compound of formula 4; 3) Salifying the compound of formula 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1.

2. The method according to claim 1, characterized in that, In step 1), the compound of formula 2 reacts with triphosgene, dimethylamine and ethylamine to obtain the compound of formula 3 by a "one-pot method".

3. The method according to claim 1, wherein 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.

4. The method according to any one of claims 1 to 3, characterized in that, In step 3), the compound of formula 4 is salified with hydrogen chloride gas to obtain the compound of formula 1.

5. The method according to any one of claims 1-3, characterized in that, In step 2), the dehydration of the compound of formula 3 under the action of dibromotriphenylphosphine and a base to generate the compound of formula 4 is carried out at -5°C to 30°C; preferably at 0°C to 5°C.

6. The method according to claim 5, wherein In step 2), the molar ratio of the compound of formula 3 to dibromotriphenylphosphine is 1:1 - 1:1.5; preferably 1:1.

05.

7. The method according to claim 5, wherein In step 2), the base is diisopropylethylamine, triethylamine, N,N-dimethylaniline or a mixture thereof; preferably diisopropylethylamine.

8. The method according to any one of claims 1 to 3, characterized in that, In step 3), the salification of the compound of formula 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1 is carried out at a temperature of 5°C to 40°C; preferably 20°C to 25°C.

9. The method according to any one of claims 1-3, characterized in that, In step 3), the salification of the compound of formula 4 to obtain 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride shown in formula 1 is carried out in a solvent selected from tetrahydrofuran, acetonitrile, dichloromethane or a mixed solvent thereof; preferably tetrahydrofuran.

10. The method according to any one of claims 1 to 3, characterized in that, The yield of the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is above 90%, preferably above 95%, more preferably above 98%.

Images