CN107857796B - Synthesis method of trifluoroacetyl tripeptide-2 - Google Patents
Synthesis method of trifluoroacetyl tripeptide-2 Download PDFInfo
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Abstract
The invention discloses a method for synthesizing trifluoroacetyl tripeptide-2, which comprises the step of synthesizing NH by Wang Resin2The method comprises the following steps of (1) preparing a Resin peptide of (E) -Val-Tyr (tBu) -Val-Wang Resin peptide, reacting the Resin peptide with 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, 1-hydroxy phenylpropyl triazole, trifluoroacetic acid and N, N' -diisopropylethylamine to synthesize N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin, and finally performing cutting treatment, purification and freeze-drying on the Resin peptide to obtain trifluoroacetyl tripeptide-2. The invention adopts low-cost, simple and easily-obtained trifluoroacetic acid to replace expensive trifluoroacetic acid ethyl ester or trifluoroacetyl chloride, and simultaneously adopts a process of firstly activating the trifluoroacetic acid and then neutralizing the acid, thereby overcoming the defect that the trifluoroacetic acid can neutralize NH2The influence of the-Val-Tyr (tBu) -Val-Wang Resin peptide has the advantages of low cost, high efficiency and simple method, and is an ideal synthesis method of trifluoroacetyl tripeptide-2.
Description
Technical Field
The invention belongs to the technical field of cosmetics, and particularly relates to a synthesis method of trifluoroacetyl tripeptide-2.
Background
The trifluoroacetyl tripeptide-2 is an active polypeptide consisting of three amino acids, the sequence of the polypeptide is N- (2,2, 2-trifluoroacetyl) -Val-Tyr-Val-OH, and the polypeptide can stimulate the generation of ECM by inhibiting MMP-1 and is used for resisting wrinkles and ageing. Therefore, it is widely used as a matrix protector in cosmetics.
At present, the defects related to the synthesis of trifluoroacetyl tripeptide-2 mainly include that ethyl trifluoroacetate or trifluoroacetyl chloride is mostly adopted as an acylation reagent during trifluoroacetylation, the material cost is high, the efficiency is low, and the synthesis process is complex. The trifluoroacetyl tripeptide-2 is used as a cosmetic raw material, so that the production cost is reduced, the production efficiency is improved, and the research of a synthetic process is simplified, and the trifluoroacetyl tripeptide-2 has important significance.
Disclosure of Invention
The invention aims to overcome the defects of high synthesis cost, low efficiency and complex process of the existing trifluoroacetyl tripeptide-2 and provide a solid-phase synthesis method of trifluoroacetyl tripeptide-2, which has low cost, high efficiency and simple synthesis process.
The technical scheme adopted for solving the technical problems comprises the following steps:
(1) synthesis of NH2-Val-Tyr(tBu)-Val-Wang Resin
② Fmoc-Val-Wang Resin synthesis
Swelling Wang Resin with N, N-dimethylformamide, adding dichloromethane, Fmoc-Val-OH, 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide, stirring at normal temperature for reaction for 3-5 hours under the protection of nitrogen, and washing with isopropanol and N, N-dimethylformamide sequentially to obtain Fmoc-Val-Wang Resin.
② Fmoc-Tyr (tBu) -Val-Wang Resin
Removing Fmoc once from Fmoc-Val-Wang Resin by using mixed solution of piperidine and N, N-dimethylformamide in a volume ratio of 1:4, washing with isopropanol and N, N-dimethylformamide respectively, adding N, N-dimethylformamide, Fmoc-Tyr (tBu) -OH, 1-hydroxybenzotriazole and N, N-diisopropylcarbodiimide, stirring at normal temperature for 1-3 hours under the protection of nitrogen, and washing with isopropanol and N, N-dimethylformamide sequentially to obtain Fmoc-Tyr (tBu) -Val-Wang Resin.
③ Fmoc-Val-Tyr (tBu) -Val-Wang Resin
Connecting Fmoc-Val-OH to Fmoc-Tyr (tBu) -Val-Wang Resin according to the method of the step II to obtain Fmoc-Val-Tyr (tBu) -Val-Wang Resin.
Synthesis of NH2-Val-Tyr(tBu)-Val-Wang Resin
Mixing Fmoc-Val-Tyr (tBu) -Val-Wang Resin with piperidine and N, N-dimethylRemoving Fmoc once from the mixed solution with the volume ratio of the dimethylformamide of 1:4, and washing with isopropanol and N, N-dimethylformamide in sequence to obtain NH2-Val-Tyr(tBu)-Val-Wang Resin。
(2) Synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin
Dissolving 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate and 1-hydroxybenzotriazole in N, N-dimethylformamide, adding trifluoroacetic acid, stirring at normal temperature for reaction for 15-30 min, adding N, N' -diisopropylethylamine, stirring for 20-40 min, adding NH into the obtained reaction solution2Reacting in the-Val-Tyr (tBu) -Val-Wang Resin for 1-3 hours at normal temperature under the protection of nitrogen, washing with isopropanol, N-dimethylformamide and anhydrous methanol in sequence, and drying to obtain N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin.
(3) Synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr-Val-OH
And (3) adding a cutting fluid into the N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin obtained in the step (2), stirring at normal temperature for 1-3 hours, and separating and purifying to obtain trifluoroacetyl tripeptide-2.
The cutting fluid comprises the following components in percentage by mass: trifluoroacetic acid 83%, phenol 5%, thioanisole 4%, water 3%, and triisopropylsilane 5%.
In the step (1), the molar ratio of Wang resin to Fmoc-Val-OH, 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide is preferably 1: 8-12: 1-1.3: 4-6.
In the step (1), the molar ratio of the addition amount of Fmoc-Tyr (tBu) -OH, 1-hydroxybenzotriazole and N, N-diisopropylcarbodiimide to the amount of Wang resin in the step (i) is preferably 2: 2.5-3: 1.
In the third step (1), the molar ratio of the addition amount of Fmoc-Val-OH, 1-hydroxybenzotriazole and N, N-diisopropylcarbodiimide to the amount of Wang resin in the first step is preferably 2: 2.5-3: 1.
In the step (2), the molar ratio of the addition amount of the 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, the 1-hydroxybenzotriazole and the trifluoroacetic acid to the amount of Wang resin in the step (i) is preferably 3-7: 2-6: 1.
The invention firstly adopts a solid phase method to synthesize NH2And (3) carrying out trifluoroacetylation on the-Val-Tyr (tBu) -Val-Wang Resin by using trifluoroacetic acid as a raw material to obtain a trifluoroacetyl tripeptide-2 product. The invention overcomes the defects of high cost, low efficiency and complex synthesis process existing in the conventional trifluoroacetylation reaction by adopting ethyl trifluoroacetate or trifluoroacetyl chloride, and simultaneously adopts the process of firstly activating trifluoroacetic acid and then neutralizing the acid, thereby overcoming the defect that the trifluoroacetic acid can neutralize NH2The influence of the-Val-Tyr (tBu) -Val-Wang Resin peptide has the advantages of low synthesis cost, high efficiency and simple process, and is a relatively ideal method for synthesizing trifluoroacetyl tripeptide-2.
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 NH2-Val-Tyr(tBu)-Val-Wang Resin
Synthesizing Fmoc-Val-Wang Resin
Adding 20.0g Wang Resin (with the substitution degree of 0.5mmol/g) into a synthesizer, adding 200mL of N, N-dimethylformamide, soaking for 4 hours to fully swell the Resin, removing the N, N-dimethylformamide by suction filtration, adding 200mL of dichloromethane, 33.94g of Fmoc-Val-OH, 1.22g of 4-dimethylaminopyridine, 7.79mL of N, N-diisopropylcarbodiimide into the synthesizer, stirring and reacting at normal temperature for 4 hours under the protection of nitrogen, carrying out suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times, and washing with 180mL of N, N-dimethylformamide each time to obtain Fmoc-Val-Wang Resin, wherein the molar ratio of the Wang Resin to the Fmoc-Val-OH, 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide is 1:10:1: 5.
② Fmoc-Tyr (tBu) -Val-Wang Resin
Adding the Fmoc-Val-Wang Resin obtained in the step I into a synthesizer, adding 200mL of mixed solution of piperidine and N, N-dimethylformamide in a volume ratio of 1:4, stirring and reacting at normal temperature for 40 minutes under the protection of nitrogen, performing suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times, 200mL each time, adding the washed Resin into the synthesizer, adding 200mL of N, N-dimethylformamide, adding 9.19g of Fmoc-Tyr (tBu) -OH, 4.05g of 1-hydroxybenzotriazole, 4.67mL of N, N-diisopropylcarbodiimide, Fmoc-Tyr (tBu) -OH, 1-hydroxybenzotriazole, N-diisopropylcarbodiimide in a molar ratio of 2:3:3:1, stirring and reacting at normal temperature for 2 hours under the protection of nitrogen, performing suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times of 200mL each time to obtain Fmoc-Tyr (tBu) -Val-Wang Resin.
③ Fmoc-Val-Tyr (tBu) -Val-Wang Resin
Adding the Fmoc-Tyr (tBu) -Val-Wang Resin obtained in the step (2) into a synthesizer, adding 200mL of mixed solution of piperidine and N, N-dimethylformamide in the volume ratio of 1:4, stirring at normal temperature under the protection of nitrogen for reaction for 40 minutes, performing suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times, 200mL each time, adding the washed Resin into the synthesizer, adding 200mL of N, N-dimethylformamide, adding 6.87g of Fmoc-Val-OH, 4.05g of 1-hydroxybenzotriazole, 4.67mL of N, N-diisopropylcarbodiimide, Fmoc-Val-OH, 1-hydroxybenzotriazole, N-diisopropylcarbodiimide in the molar ratio of 2:3:3:1, stirring at normal temperature under the protection of nitrogen for reaction for 2 hours, suction filtration, washing with isopropanol and N, N-dimethylformamide respectively for 2 times, 200mL each time, obtaining Fmoc-Val-Tyr (tBu) -Val-Wang Resin.
Synthesis of NH2-Val-Tyr(tBu)-Val-Wang Resin
Adding the Fmoc-Val-Tyr (tBu) -Val-Wang Resin obtained in the step (c) into a synthesizer, adding 200mL of mixed solution of piperidine and N, N-dimethylformamide in a volume ratio of 1:4, stirring at normal temperature under the protection of nitrogen for reaction for 40 minutes, performing suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times respectively, and obtaining NH (NH) with 200mL each time2-Val-Tyr(tBu)-Val-Wang Resin。
(2) Synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin
28.96g of 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate and 9.46g of 1-hydroxybenzotriazole are dissolved in 200mL of N, N-dimethylformamide, 4.5mL of trifluoroacetic acid is added, the mixture is stirred at normal temperature for reaction for 20 minutes, and then 17.5mL of N, N' -diisopropylethylamine is added dropwiseContinuously stirring for 30 minutes to obtain reaction liquid; NH obtained in the step (iv)2Adding Val-Tyr (tBu) -Val-Wang Resin into the reaction liquid, stirring and reacting 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole, trifluoroacetic acid and Wang Resin at a molar ratio of 7:7:6:1 under the protection of nitrogen at normal temperature for 2 hours, carrying out suction filtration, washing with isopropanol and N, N-dimethylformamide for 2 times respectively, washing with methanol for 3 times, 200mL each time, carrying out suction filtration, and drying at 40 ℃ to obtain 27.5g N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin.
(3) Synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr-Val-OH
Adding the N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin obtained in the step (2) into 300mL of cutting fluid (the mass percentage of the cutting fluid is composed of 83% of trifluoroacetic acid, 5% of phenol, 4% of thioanisole, 3% of water and 5% of triisopropylsilane), stirring at normal temperature for reaction for 2 hours, performing suction filtration to obtain a brown yellow liquid, performing reduced pressure concentration to obtain a yellow oily substance, pouring the concentrated solution into 500mL of frozen methyl tert-butyl ether, uniformly stirring, standing at 4 ℃ to obtain a white precipitate, filtering, washing for 2 times by using the methyl tert-butyl ether, and performing vacuum drying at room temperature to obtain 5.0g of a crude product of trifluoroacetyl tripeptide-2; and (2) purifying the crude trifluoroacetyl tripeptide-2 by reverse phase chromatography (a reverse phase polymer column: MCI GEL reverse phase chromatography filler, the specification of the column is 5cm multiplied by 45cm, the flow rate is 30mL/min, the wavelength is 215nm, a mobile phase A is trifluoroacetic acid aqueous solution with the volume concentration of 0.1%, a mobile phase B is trifluoroacetic acid methanol solution with the volume concentration of 0.1%, the elution gradient is B18% -26% for 50min), and freeze-drying to obtain 4.2g of trifluoroacetyl tripeptide-2 freeze-dried powder, wherein the yield is 86.31%, and the purity is more than 95%.
Example 2
In the case of the step (1) and the step (3) of this example, the molar ratio of 1-hydroxybenzotriazole, N-diisopropylcarbodiimide to Wang resin was 2.5:2.5:1, and the other steps of this step were the same as in example 1. In the step (2) of this embodiment, the molar ratio of 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole, trifluoroacetic acid and Wang resin is 3:3:2:1, and the other steps of this step are the same as those of the example 1. The procedure in step (3) of this example was performed in the same manner as in example 1 to obtain 3.6g of trifluoroacetyl tripeptide-2 lyophilized powder with a yield of 74.00%.
Example 3
In the step (2) of this embodiment, the molar ratio of 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole, trifluoroacetic acid and Wang resin is 5:5:4:1, and the other steps of this step are the same as those of example 1. Steps (1) and (3) of this example were carried out in the same manner as in example 1 to obtain 4.1g of trifluoroacetyl tripeptide-2 lyophilized powder with a yield of 84.25%.
Claims (5)
1. A method for synthesizing trifluoroacetyl tripeptide-2 is characterized by comprising the following steps:
(1) synthesis of NH2-Val-Tyr(tBu)-Val-Wang Resin
Synthesizing Fmoc-Val-Wang Resin
Swelling Wang Resin with N, N-dimethylformamide, adding dichloromethane, Fmoc-Val-OH, 4-dimethylaminopyridine and N, N-diisopropylcarbodiimide, stirring at normal temperature for reaction for 3-5 hours under the protection of nitrogen, and washing with isopropanol and N, N-dimethylformamide sequentially to obtain Fmoc-Val-Wang Resin;
② Fmoc-Tyr (tBu) -Val-Wang Resin
Removing Fmoc-once from the Fmoc-Val-Wang Resin obtained in the step I by using mixed solution of piperidine and N, N-dimethylformamide in a volume ratio of 1:4, washing the Fmoc-once by using isopropanol and N, N-dimethylformamide respectively, then adding N, N-dimethylformamide, Fmoc-Tyr (tBu) -OH, 1-hydroxybenzotriazole and N, N-diisopropyl carbodiimide, stirring the mixture at normal temperature for reaction for 1 to 3 hours under the protection of nitrogen, and washing the mixture by using isopropanol and N, N-dimethylformamide sequentially to obtain Fmoc-Tyr (tBu) -Val-Wang Resin;
③ Fmoc-Val-Tyr (tBu) -Val-Wang Resin
Connecting Fmoc-Val-OH to the obtained Fmoc-Tyr (tBu) -Val-Wang Resin according to the method of the step II to obtain Fmoc-Val-Tyr (tBu) -Val-Wang Resin;
synthesis of NH2-Val-Tyr(tBu)-Val-Wang Resin
Piperidine and N, N-dimethyl methyl are used for Fmoc-Val-Tyr (tBu) -Val-Wang Resin obtained in the step threeRemoving Fmoc once from the mixed solution with the amide volume ratio of 1:4, and washing with isopropanol and N, N-dimethylformamide in sequence to obtain NH2-Val-Tyr(tBu)-Val-Wang Resin；
(2) Synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin
Dissolving 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate and 1-hydroxybenzotriazole in N, N-dimethylformamide, adding trifluoroacetic acid, stirring at normal temperature for reaction for 15-30 minutes, adding N, N' -diisopropylethylamine, continuing stirring for 20-40 minutes, adding NH obtained in the step (iv) into the obtained reaction solution2Reacting in-Val-Tyr (tBu) -Val-Wang Resin for 1-3 hours at normal temperature under the protection of nitrogen, washing with isopropanol, N-dimethylformamide and anhydrous methanol in sequence, and drying to obtain N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin;
(3) synthesis of N- (2,2, 2-trifluoroacetyl) -Val-Tyr-Val-OH
Adding a cutting fluid into the N- (2,2, 2-trifluoroacetyl) -Val-Tyr (tBu) -Val-Wang Resin obtained in the step (2), stirring at normal temperature for 1-3 hours, and separating and purifying to obtain trifluoroacetyl tripeptide-2;
the cutting fluid comprises the following components in percentage by mass: trifluoroacetic acid 83%, phenol 5%, thioanisole 4%, water 3%, and triisopropylsilane 5%.
2. The method for synthesizing trifluoroacetyl tripeptide-2 according to claim 1, wherein: in the step (1), the molar ratio of Wang resin to Fmoc-Val-OH, 4-dimethylaminopyridine to N, N-diisopropylcarbodiimide is 1: 8-12: 1-1.3: 4-6.
3. The method for synthesizing trifluoroacetyl tripeptide-2 according to claim 1, wherein: in the step (1), the molar ratio of the addition amount of Fmoc-Tyr (tBu) -OH, 1-hydroxybenzotriazole and N, N-diisopropylcarbodiimide to the amount of Wang resin in the step (i) is 2: 2.5-3: 1.
4. The method for synthesizing trifluoroacetyl tripeptide-2 according to claim 1, wherein: in the third step of the step (1), the molar ratio of the addition amount of Fmoc-Val-OH, 1-hydroxybenzotriazole and N, N-diisopropylcarbodiimide to the amount of Wang resin in the first step is 2: 2.5-3: 1.
5. The method for synthesizing trifluoroacetyl tripeptide-2 according to claim 1, wherein: in the step (2), the molar ratio of the addition amount of the 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, the 1-hydroxybenzotriazole and the trifluoroacetic acid to the amount of Wang resin in the step (i) is 3-7: 2-6: 1.
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