CN107987123B - Liquid phase synthesis method of tetradecyl amino butyryl valinamide butyrate trifluoroacetate - Google Patents

Liquid phase synthesis method of tetradecyl amino butyryl valinamide butyrate trifluoroacetate Download PDF

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CN107987123B
CN107987123B CN201711307541.9A CN201711307541A CN107987123B CN 107987123 B CN107987123 B CN 107987123B CN 201711307541 A CN201711307541 A CN 201711307541A CN 107987123 B CN107987123 B CN 107987123B
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dab
boc
val
tetrahydrofuran
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CN107987123A (en
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张忠旗
苏晨灿
王万科
李乾
黄峰涛
王俊杰
杨小琳
赵金礼
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Shaanxi HuiKang Bio Tech Co Ltd
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
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Abstract

The invention discloses a liquid phase synthesis method of tetradecyl amino butyryl valinamide butyric urea trifluoroacetate, which comprises the steps of synthesizing tetradecyl carbamic acid by taking tetradecyl tetramine and ethyl chloroformate as raw materials, and synthesizing CH with H-DAB (Boc) -OH3(CH2)12CH2NH-CO-DAB (Boc) -OH; synthesizing H-Val-DAB (Boc) -OH by Fmoc-Val-OH and H-DAB (Boc) -OH, and then reacting with CH3(CH2)12CH2NH-CO-DAB (Boc) -OH to obtain CH3(CH2)12CH2NH-CO-DAB (Boc) -Val-DAB (Boc) -OH, and the tetradecyl amino butyryl valinamide butyrate urea trifluoroacetate with the purity of more than 95 percent is obtained through deprotection, HPLC purification and freeze-drying. The invention abandons expensive Fmoc-DAB (Boc) -OH and H-DAB (Boc) -OMe & HCl as raw materials, and selects H-DAB (Boc) -OH as a raw material, thereby having the advantages of simple and convenient synthesis and low cost.

Description

Liquid phase synthesis method of tetradecyl amino butyryl valinamide butyrate trifluoroacetate
Technical Field
The invention belongs to the technical field of cosmetics, and particularly relates to a method for synthesizing short peptides in polypeptides.
Background
Tetradecyl aminobutyryl valinamide butyric urea trifluoroacetate also known as hyaluronic acid peptideThe sequence of which is CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH is tripeptide modified by tetradecyl carbamoyl, can act on the dermis layer, improves the synthesis of collagen fibers by promoting the synthesis of hyaluronic acid of natural skin, thereby improving the phenomenon of skin relaxation, and is widely applied to various high-grade cosmetic products.
At present, the synthesis method of tetradecyl amino butyryl valinamide butyrate urea trifluoroacetate is rarely reported, so that the synthesis method of tetradecyl amino butyryl valinamide butyrate urea trifluoroacetate with a simple development process has practical significance.
Disclosure of Invention
The invention provides a synthesis method of tetradecyl amino butyryl valinamide butyrate urea trifluoroacetate, which has the advantages of simple and convenient process and low cost.
The technical scheme adopted for solving the technical problems comprises the following steps:
(1) synthesis of tetradecanoic acid
The preparation method comprises the following steps of taking trichloromethane as a solvent, stirring 1-tetradecylamine, triethylamine and ethyl chloroformate to react for 1-3 hours at room temperature, washing the reaction solution with dilute hydrochloric acid after the reaction is finished, removing the trichloromethane through rotary evaporation, and drying to obtain the tetradecyl ethyl carbamate.
And taking a mixed solution of tetrahydrofuran and methanol in a volume ratio of 2:1 as a solvent, stirring and reacting ethyl tetradecyl carbamate and a 10% lithium hydroxide aqueous solution at 0-5 ℃ for 2-4 hours, adjusting the pH value to 4-5 with hydrochloric acid, performing rotary evaporation to remove tetrahydrofuran and methanol, extracting with ethyl acetate, drying an ethyl acetate phase with anhydrous sodium sulfate, and performing rotary evaporation to dryness to obtain the tetradecyl carbamate.
(2) Synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-OH
Tetrahydrofuran is used as a solvent, tetradecyl carbamic acid, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide are stirred and react for 2-4 hours at room temperature, and precipitate is removed by filtration to obtain CH3(CH2)12CH2NH-COOSu in tetrahydrofuran.
② dissolving H-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding into CH3(CH2)12CH2Reacting NH-COOSu in tetrahydrofuran solution at room temperature for 1.5-2.5 hr under stirring, concentrating by rotary evaporation, dissolving the concentrated product in ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, and rotary evaporation to obtain CH3(CH2)12CH2NH-CO-DAB(Boc)-OH。
(3) Synthesis of H-Val-DAB (Boc) -OH
The method comprises the steps of taking tetrahydrofuran as a solvent, carrying out stirring reaction on Fmoc-Val-OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide for 2-4 hours at room temperature, and filtering to remove precipitates to obtain a tetrahydrofuran solution of Fmoc-Val-OSu.
Dissolving H-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding the solution into tetrahydrofuran solution of Fmoc-Val-OSu, stirring and reacting for 1.5-2.5 hours at room temperature, performing rotary evaporation and concentration, dissolving the concentrated product in ethyl acetate, washing the ethyl acetate phase with diluted hydrochloric acid, drying with anhydrous sodium sulfate, and performing rotary evaporation and evaporation to obtain Fmoc-Val-DAB (Boc) -OH.
③ adding a mixed solution of piperidine and tetrahydrofuran in a volume ratio of 1:4 into Fmoc-Val-DAB (Boc) -OH, stirring and reacting for 20-40 minutes at room temperature, carrying out rotary evaporation and concentration, adding the concentrated solution into cold ether to separate out a precipitate, centrifuging to remove a supernatant, washing the precipitate with ether, centrifuging, and carrying out vacuum drying at room temperature to obtain H-Val-DAB (Boc) -OH.
(4) Synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-Val-DAB(Boc)-OH
Taking tetrahydrofuran as a solvent, and reacting CH3(CH2)12CH2NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide are stirred and reacted for 2-4 hours at room temperature, and precipitate is removed by filtration to obtain CH3(CH2)12CH2NH-CO-DAB (Boc) -OSu in tetrahydrofuran.
② dissolving H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding into CH3(CH2)12CH2Reacting NH-CO-DAB (Boc) -OSu in tetrahydrofuran solution at room temperature for 1.5-3 hr under stirring, rotary evaporating for concentration, dissolving the concentrated product in ethyl acetate, washing the ethyl acetate phase with dilute hydrochloric acid, drying with anhydrous sodium sulfate, and rotary evaporating for evaporation to obtain CH3(CH2)12CH2NH-CO-DAB(Boc)-Val-DAB(Boc)-OH。
(5) Synthesis of CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH·2CF3COOH
Will CH3(CH2)12CH2Adding NH-CO-DAB (Boc) -Val-DAB (Boc) -OH into a cutting liquid, wherein the cutting liquid is a mixed liquid of trifluoroacetic acid and water in a volume ratio of 95:5, stirring and reacting at room temperature for 1-2 hours, performing suction filtration, performing reduced pressure concentration on a filtrate, adding a concentrated solution into cold ethyl ether to separate out a precipitate, centrifuging to remove a supernatant, washing the precipitate with ethyl ether, centrifuging, and performing vacuum drying at room temperature to obtain CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH crude product; crude product is processed by C18Purifying by reversed phase high performance liquid chromatography, concentrating under reduced pressure, and freeze drying to obtain CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH, tetradecylaminobutylamidobutanamide urea trifluoroacetate.
In the step (1), the molar ratio of 1-tetradecylamine, ethyl chloroformate, and triethylamine is preferably 1:1 to 1.2:2 to 4.
In the step (2), the molar ratio of tetradecanoic acid, N-hydroxysuccinimide, and N, N' -dicyclohexylcarbodiimide is preferably 1:1 to 1.2, and the molar ratio of tetradecanoic acid, H-DAB (Boc) -OH, and N, N-diisopropylethylamine is preferably 1:1 to 1.2:1.5 to 2.5.
In the step (3), it is preferable that the molar ratio of Fmoc-Val-OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide is 1:1 to 1.2, and the molar ratio of Fmoc-Val-OH, H-DAB (Boc) -OH and N, N-diisopropylethylamine is 1:1 to 1.2:1.5 to 2.5.
In the above step (4), CH is preferred3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide is 1: 1-1.2, and CH3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine is 1: 1-1.2: 1.5-2.5.
The invention synthesizes tetradecyl carbamic acid (CH) from tetradecyl tetramine, ethyl chloroformate and triethylamine by a liquid phase method3(CH2)12CH2NH-COOH)，CH3(CH2)12CH2NH-COOH and H-DAB (Boc) -OH react to synthesize CH3(CH2)12CH2NH-CO-DAB (Boc) -OH; Fmoc-Val-OH and H-DAB (Boc) -OH are reacted to synthesize H-Val-DAB (Boc) -OH, CH3(CH2)12CH2NH-CO-DAB (Boc) -OH and H-Val-DAB (Boc) -OH are synthesized, deprotected and purified by a liquid phase fragment synthesis method to obtain tetradecyl amino butyryl valinamide butyrate urea trifluoroacetate with the purity of more than 95%. The invention abandons the use of Fmoc-DAB (Boc) -OH and H-DAB (Boc) -OMe.HCl which have high material price as raw materials, and uses H-DAB (Boc) -OH as a raw material, thereby providing a simple, convenient and low-cost synthesis method for tetradecyl amino butyryl valinamide butyric urea trifluoroacetate.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
(1) Synthesis of tetradecanoic acid
Adding 21.34g (0.1mol) of 1-tetradecylamine into 350mL of trichloromethane, adding 41.6mL (0.3mol) of triethylamine, dissolving until the mixture is clear, dropwise adding a mixed solution of 10.5mL (0.11mol) of ethyl chloroformate and 40mL of trichloromethane under the stirring condition, continuously stirring and reacting for 1 hour at room temperature after dropwise adding, washing the reaction solution for 3 times by using 0.5mol/L hydrochloric acid after the reaction is finished, rotationally evaporating at 30-40 ℃ to remove the trichloromethane, and drying in vacuum at room temperature to obtain 27.79g of tetradecyl ethyl Carbamate (CH)3(CH2)12CH2NH-CO-OCH2CH3)。
② adding the tetradecane ethyl carbamate obtained in the step I into a mixed solution of 550mL tetrahydrofuran and 275mL methanol, stirring and dissolving, then adding 275mL lithium hydroxide aqueous solution with the mass concentration of 10% at the temperature of 0-5 ℃, stirring and reacting for 3 hours, adjusting the pH value to 4-5 with 1mol/L hydrochloric acid, rotary evaporating to remove tetrahydrofuran and methanol, extracting with ethyl acetate (250mL multiplied by 3 times), combining ethyl acetate phases, drying with anhydrous sodium sulfate, rotary evaporating to dryness to obtain 23.01g tetradecane ethyl Carbamate (CH)3(CH2)12CH2NH-COOH), yield 89.39%.
(2) Synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-OH
(ii) preparation of 23.01g (0.08945mol) CH3(CH2)12CH2NH-COOH and N-hydroxysuccinimide (HOSu)11.32g (0.09840mol) were dissolved in 450mL of tetrahydrofuran under stirring, 20.30g (0.09840mol) of N, N' -dicyclohexylcarbodiimide was added and reacted at room temperature for 3 hours under stirring, and the precipitate was removed by filtration to obtain CH3(CH2)12CH2NH-COOSu in tetrahydrofuran.
② 21.47g (0.09840mol) H-DAB (Boc) -OH was added to 210mL tetrahydrofuran, 30.0mL (0.1789mol) N, N-diisopropylethylamine was added thereto after stirring and dissolving3(CH2)12CH2Reacting NH-COOSu in tetrahydrofuran solution at room temperature for 1.5 hr under stirring, concentrating at 30-40 deg.C by rotary evaporation to obtain oil, dissolving in 400mL ethyl acetate, washing organic phase with 0.5% hydrochloric acid for 3 times, drying with anhydrous sodium sulfate, and rotary evaporating at 30-40 deg.C to obtain 30.68g CH3(CH2)12CH2NH-CO-DAB (Boc) -OH, yield 75.01%.
(3) Synthesis of H-Val-DAB (Boc) -OH
[ solution ] 33.94g (0.1mol) of Fmoc-Val-OH and 12.66g (0.11mol) of N-hydroxysuccinimide (HOSu) were added to 450mL of tetrahydrofuran, and the mixture was dissolved by stirring, 22.70g (0.11mol) of N, N' -dicyclohexylcarbodiimide was added thereto, and the mixture was reacted by stirring at room temperature for 3 hours, and the precipitate was removed by filtration to obtain a tetrahydrofuran solution of Fmoc-Val-OSu.
Adding 21.83g (0.1mol) of H-DAB (Boc) -OH into 210mL of tetrahydrofuran, adding 33.0mL (0.2mol) of N, N-diisopropylethylamine, stirring for dissolving, adding the mixture into a tetrahydrofuran solution of Fmoc-Val-OSu, stirring for reacting for 1.5 hours at room temperature, performing rotary evaporation and concentration at 30-40 ℃ to obtain oil, adding 400mL of ethyl acetate for dissolving, washing an organic phase for 3 times by using hydrochloric acid with the mass fraction of 0.5%, drying by using anhydrous sodium sulfate, performing rotary evaporation and evaporation at 30-40 ℃ to obtain Fmoc-Val-DAB (Boc) -OH.
③ adding 300mL of mixed solution of piperidine and tetrahydrofuran with the volume ratio of 1:4 into Fmoc-Val-DAB (Boc) -OH, stirring and reacting for 30 minutes at room temperature, carrying out rotary evaporation and concentration at 30-40 ℃ to obtain oily liquid, adding 300mL of anhydrous ether to separate out precipitate, centrifuging to remove supernatant, washing the precipitate with ether, centrifuging, and carrying out vacuum drying at room temperature to obtain 25.07g H-Val-DAB (Boc) -OH with the yield of 78.98%.
(4) Synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-Val-DAB(Boc)-OH
(iii) 30.68g (0.06706mol) of CH3(CH2)12CH2NH-CO-DAB (Boc) -OH and 8.49g (0.07377mol) N-hydroxysuccinimide (HOSu) were dissolved in 390mL tetrahydrofuran under stirring, 15.22g (0.07377mol) N, N' -dicyclohexylcarbodiimide was added and reacted at room temperature for 3 hours under stirring, and the precipitate was removed by filtration to obtain CH3(CH2)12CH2NH-CO-DAB (Boc) -OSu in tetrahydrofuran.
② 23.41g (0.07377mol) H-Val-DAB (Boc) -OH was added to 240mL tetrahydrofuran, 22.1mL (0.13412mol) N, N-diisopropylethylamine was added thereto after stirring and dissolving3(CH2)12CH2Stirring NH-CO-DAB (Boc) -OSu in tetrahydrofuran solution for 2 hours at room temperature, concentrating by rotary evaporation at 30-40 ℃, adding 600mL of ethyl acetate for dissolving, washing the organic phase with 0.5% hydrochloric acid for 3 times, drying with anhydrous sodium sulfate, and rotary evaporating to dryness at 30-40 DEG CTo give 38.14g of CH3(CH2)12CH2NH-CO-DAB (Boc) -Val-DAB (Boc) -OH with a yield of 73.40%.
(5) Synthesis of CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH·2CF3COOH
The CH obtained in the step (4)3(CH2)12CH2Adding NH-CO-DAB (Boc) -Val-DAB (Boc) -OH into 330mL of cutting fluid, wherein the cutting fluid is a mixed solution of trifluoroacetic acid and water in a volume ratio of 95:5, stirring at room temperature for reaction for 1 hour, performing suction filtration, concentrating the filtrate at 30-40 ℃ under reduced pressure, adding the concentrated solution into 800mL of cold diethyl ether to separate out a precipitate, centrifuging to remove the supernatant, washing the precipitate with diethyl ether, centrifuging for 2 times, and performing vacuum drying at room temperature to obtain 23.56g of CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH crude product, using C to make said crude product be used18Purifying by reversed phase high performance liquid chromatography (under the purification conditions of GLP-ID50mm × 450mm column specification, detection wavelength of 215nm, flow rate of 30mL/min, mobile phase A of trifluoroacetic acid aqueous solution with volume fraction of 0.1%, mobile phase B of trifluoroacetic acid methanol solution with volume fraction of 0.1%, elution gradient of B phase of 10% -20% 30min and B phase of 20% -25% 30min), concentrating under reduced pressure, and freeze drying to obtain 19.47g CH with purity of 96.23%3(CH2)12CH2NH-CO-DAB-Val-DAB-OH, namely tetradecylaminobutylamidobutanamide urea trifluoroacetate, yield 52.14%.
Example 2
In the step (1) of this example, the molar ratio of 1-tetradecylamine, ethyl chloroformate, and triethylamine is 1:1:2, and in the step (1) and the step (2), the reaction time is 3 hours and 4 hours, respectively, in the step (2) of this example, the molar ratio of tetradecylcarbamic acid, N-hydroxysuccinimide, and N, N' -dicyclohexylcarbodiimide is 1:1:1, the molar ratio of tetradecylcarbamic acid, H-dab (boc) -OH, and N, N-diisopropylethylamine is 1:1: 1:1.5, and in the step (2) and the step (2), the reaction time is 4 hours and 2.5 hours, respectively; in step (3) of this example, Fmoc-Val-OH, N-hydroxysuccinimide, and N, N' -dicyclohexylcarbodiimide were used in a molar ratio of 1:1:1, and FThe mol ratio of moc-Val-OH, H-DAB (Boc) -OH and N, N-diisopropylethylamine is 1:1:1.5, and in the step (3), the reaction time is 4 hours, 2.5 hours and 40 minutes respectively; in step (4) of this embodiment, the CH3(CH2)12CH2NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide, N' -dicyclohexylcarbodiimide in a molar ratio of 1:1:1, CH3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine is 1:1:1.5, and in the step (4), the reaction time is 4 hours and 3 hours respectively; in step (5) of this example, the reaction time was 2 hours; the other steps were carried out in the same manner as in example 1 to obtain 17.54g of tetradecylaminobutylamidobutanamide urea trifluoroacetate having a purity of 96.71% in a yield of 46.97%.
Example 3
In the step (1) of this example, the molar ratio of 1-tetradecylamine, ethyl chloroformate, and triethylamine is 1:1.2:4, and in the step (1) and the step (2), the reaction time is 2 hours and 2 hours, respectively, in the step (2) of this example, the molar ratio of tetradecanecarbamic acid, N-hydroxysuccinimide, and N, N' -dicyclohexylcarbodiimide is 1:1.2:1.2, the molar ratio of tetradecanecarbamic acid, H-dab (boc) -OH, and N, N-diisopropylethylamine is 1:1.2:2.5, and in the step (2) and the step (2), the reaction time is 2 hours and 1.5 hours, respectively; in step (3) of this example, the molar ratio of Fmoc-Val-OH, N-hydroxysuccinimide, N' -dicyclohexylcarbodiimide is 1:1.2:1.2, the molar ratio of Fmoc-Val-OH, H-dab (boc) -OH, N-diisopropylethylamine is 1:1.2:2.5, and in (i), (ii), and (iii) of step (3), the reaction time is 2 hours, 1.5 hours, and 20 minutes, respectively; in step (4) of this embodiment, the CH3(CH2)12CH2NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide, N' -dicyclohexylcarbodiimide in a molar ratio of 1:1.2:1.2, CH3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine is 1:1.2:2.5, and in the step (4), the reaction time is 2 hours and 1.5 hours respectively; of the present embodimentIn the step (5), the reaction time is 1.5 hours; the other steps were carried out in the same manner as in example 1 to obtain 19.05g of tetradecylaminobutylamidobutanamide urea trifluoroacetate having a purity of 95.77% in 51.01% yield.

Claims (5)

1. A liquid phase synthesis method of tetradecyl aminobutyroylvalinamide butyric urea trifluoroacetate, which is characterized by comprising the following steps of:
(1) synthesis of tetradecanoic acid
Using trichloromethane as a solvent, stirring 1-tetradecylamine, triethylamine and ethyl chloroformate to react for 1-3 hours at room temperature, washing the reaction solution with dilute hydrochloric acid after the reaction is finished, removing the trichloromethane by rotary evaporation, and drying to obtain ethyl tetradecylcarbamate;
taking a mixed solution of tetrahydrofuran and methanol in a volume ratio of 2:1 as a solvent, stirring and reacting ethyl tetradecyl carbamate and a 10% lithium hydroxide aqueous solution at 0-5 ℃ for 2-4 hours, adjusting the pH value to 4-5 with hydrochloric acid, performing rotary evaporation to remove tetrahydrofuran and methanol, extracting with ethyl acetate, drying an ethyl acetate phase with anhydrous sodium sulfate, and performing rotary evaporation to dryness to obtain tetradecyl carbamate;
(2) synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-OH
Tetrahydrofuran is used as a solvent, tetradecyl carbamic acid, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide are stirred and react for 2-4 hours at room temperature, and precipitate is removed by filtration to obtain CH3(CH2)12CH2A solution of NH-COOSu in tetrahydrofuran;
② dissolving H-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding into CH3(CH2)12CH2Reacting NH-COOSu in tetrahydrofuran solution at room temperature for 1.5-2.5 hr under stirring, concentrating by rotary evaporation, dissolving the concentrated product in ethyl acetate, washing with dilute hydrochloric acid, drying with anhydrous sodium sulfate, and rotary evaporation to obtain CH3(CH2)12CH2NH-CO-DAB(Boc)-OH；
(3) Synthesis of H-Val-DAB (Boc) -OH
Taking tetrahydrofuran as a solvent, carrying out stirring reaction on Fmoc-Val-OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide for 2-4 hours at room temperature, and filtering to remove precipitates to obtain a tetrahydrofuran solution of Fmoc-Val-OSu;
dissolving H-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding the tetrahydrofuran solution into a tetrahydrofuran solution of Fmoc-Val-OSu, stirring and reacting for 1.5-2.5 hours at room temperature, performing rotary evaporation and concentration, dissolving a concentrated product in ethyl acetate, washing an ethyl acetate phase with diluted hydrochloric acid, drying with anhydrous sodium sulfate, and performing rotary evaporation to dryness to obtain Fmoc-Val-DAB (Boc) -OH;
③ adding a mixed solution of piperidine and tetrahydrofuran in a volume ratio of 1:4 into Fmoc-Val-DAB (Boc) -OH, stirring and reacting for 20-40 minutes at room temperature, carrying out rotary evaporation and concentration, adding the concentrated solution into cold ether to separate out a precipitate, centrifuging to remove a supernatant, washing the precipitate with ether, centrifuging, and carrying out vacuum drying at room temperature to obtain H-Val-DAB (Boc) -OH;
(4) synthesis of CH3(CH2)12CH2NH-CO-DAB(Boc)-Val-DAB(Boc)-OH
Taking tetrahydrofuran as a solvent, and reacting CH3(CH2)12CH2NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide are stirred and reacted for 2-4 hours at room temperature, and precipitate is removed by filtration to obtain CH3(CH2)12CH2A solution of NH-CO-DAB (Boc) -OSu in tetrahydrofuran;
② dissolving H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine in tetrahydrofuran, adding into CH3(CH2)12CH2Reacting NH-CO-DAB (Boc) -OSu in tetrahydrofuran solution at room temperature for 1.5-3 hr under stirring, rotary evaporating for concentration, dissolving the concentrated product in ethyl acetate, washing the ethyl acetate phase with dilute hydrochloric acid, drying with anhydrous sodium sulfate, and rotary evaporating for evaporation to obtain CH3(CH2)12CH2NH-CO-DAB(Boc)-Val-DAB(Boc)-OH；
(5) Synthesis of CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH·2CF3COOH
Will CH3(CH2)12CH2Adding NH-CO-DAB (Boc) -Val-DAB (Boc) -OH into a cutting liquid, wherein the cutting liquid is a mixed liquid of trifluoroacetic acid and water in a volume ratio of 95:5, stirring and reacting at room temperature for 1-2 hours, performing suction filtration, performing reduced pressure concentration on a filtrate, adding a concentrated solution into cold ethyl ether to separate out a precipitate, centrifuging to remove a supernatant, washing the precipitate with ethyl ether, centrifuging, and performing vacuum drying at room temperature to obtain CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH crude product; crude product is processed by C18Purifying by reversed phase high performance liquid chromatography, concentrating under reduced pressure, and freeze drying to obtain CH3(CH2)12CH2NH-CO-DAB-Val-DAB-OH, tetradecylaminobutylamidobutanamide urea trifluoroacetate.
2. The liquid phase synthesis process of tetradecylaminobutylamidobutyric acid urea trifluoroacetate according to claim 1, characterized in that: in the step (1), the molar ratio of the 1-tetradecylamine, the ethyl chloroformate and the triethylamine is 1: 1-1.2: 2-4.
3. The liquid phase synthesis process of tetradecylaminobutylamidobutyric acid urea trifluoroacetate according to claim 1, characterized in that: in the step (2), the molar ratio of the tetradecanoic acid, the N-hydroxysuccinimide and the N, N' -dicyclohexylcarbodiimide is 1: 1-1.2, and the molar ratio of the tetradecanoic acid, the H-DAB (Boc) -OH and the N, N-diisopropylethylamine is 1: 1-1.2: 1.5-2.5.
4. The liquid phase synthesis process of tetradecylaminobutylamidobutyric acid urea trifluoroacetate according to claim 1, characterized in that: in the step (3), the molar ratio of Fmoc-Val-OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide is 1: 1-1.2, and the molar ratio of Fmoc-Val-OH, H-DAB (Boc) -OH and N, N-diisopropylethylamine is 1: 1-1.2: 1.5-2.5.
5. The liquid phase synthesis process of tetradecylaminobutylamidobutyric acid urea trifluoroacetate according to claim 1, characterized in that: in step (4), the CH3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, N-hydroxysuccinimide and N, N' -dicyclohexylcarbodiimide is 1: 1-1.2, and CH3(CH2)12CH2The mol ratio of NH-CO-DAB (Boc) -OH, H-Val-DAB (Boc) -OH and N, N-diisopropylethylamine is 1: 1-1.2: 1.5-2.5.
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