CN107857796A - A kind of synthetic method of trifluoroacetyl tripeptides 2 - Google Patents
A kind of synthetic method of trifluoroacetyl tripeptides 2 Download PDFInfo
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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Abstract
The invention discloses a kind of synthetic method of trifluoroacetyl tripeptides 2, this method first passes through Wang Resin synthesis NH2Val Tyr (tBu) Val Wang Resin resin peptides; then by the resin peptide and 6 Chloro-Benzotriazoles 1; 1; 3,3 tetramethylurea hexafluorophosphoric acid esters, 1 hydroxyl azimidobenzene, trifluoroacetic acid, N, N ' diisopropylethylamine reaction synthesis N (2; 2; 2 trifluoroacetyl groups) Val Tyr (tBu) Val Wang Resin, cutting process, purifying are finally carried out to it, is freezed, obtains trifluoroacetyl tripeptides 2.The present invention overcomes trifluoroacetic acid to NH using cheap, the simple and easy to get trifluoroacetic acid fictitious hosts of cost more expensive Trifluoroacetic Acid Ethyl Ester or trifluoro-acetyl chloride, while using trifluoroacetic acid antacid technique again is activated in advance2The influence of Val Tyr (tBu) Val Wang Resin resin peptides, there is the advantages of low cost, efficiency high, simple method, be that a kind of preferably trifluoroacetyl tripeptides is 2-in-1 into method.
Description
Technical field
The invention belongs to cosmetic technical field, and in particular to a kind of synthetic method of trifluoroacetyl tripeptides -2.
Background technology
Trifluoroacetyl tripeptides -2 is a kind of active peptides of three amino acid composition, and its sequence is N- (2,2,2- trifluoro second
Acyl group)-Val-Tyr-Val-OH, this polypeptide can stimulate ECM generation by suppressing MMP-1, for crease-resistant and anti-aging.Cause
This, is used in cosmetics as matrix shield element.
At present, relevant trifluoroacetyl tripeptides -2-in-1 into the shortcomings that Trifluoroacetic Acid Ethyl Ester is mainly used in trifluoroacetylation more
Or trifluoro-acetyl chloride does acylating reagent, material cost is high, and efficiency is low, and synthesis technique is complicated.Trifluoroacetyl tripeptides -2 is as cosmetic
Product raw material, production cost is reduced, improve production efficiency, the research for simplifying synthesis technique is significant.
The content of the invention
The technical problems to be solved by the invention be to overcome existing trifluoroacetyl tripeptides -2-in-1 into cost is high, efficiency is low,
The shortcomings that complex process, there is provided a kind of cost is low, efficiency high, the simple synthesis in solid state side of trifluoroacetyl tripeptides -2 of synthesis technique
Method.
Technical scheme is made up of following step used by solving above-mentioned technical problem：
(1) NH is synthesized2-Val-Tyr(tBu)-Val-Wang Resin
2. synthesize Fmoc-Val-Wang Resin
After Wang Resin are swelled with DMF, dichloromethane, Fmoc-Val-OH, 4- diformazan are added
Aminopyridine, N, N- DICs, under nitrogen protection, stirring at normal temperature react 3~5 hours, use isopropanol successively
Washed with DMF, obtain Fmoc-Val-Wang Resin.
2. synthesize Fmoc-Tyr (tBu)-Val-Wang Resin
It is 1 by Fmoc-Val-Wang Resin piperidines and N,N-dimethylformamide volume ratio:4 mixed liquor removing
Fmoc- once, is washed respectively with isopropanol and DMF, adds DMF, Fmoc-Tyr
(tBu)-OH, I-hydroxybenzotriazole, N, N- DICs, under nitrogen protection, stirring at normal temperature reaction 1~3 are small
When, washed successively with isopropanol and DMF, obtain Fmoc-Tyr (tBu)-Val-Wang Resin.
3. synthesize Fmoc-Val-Tyr (tBu)-Val-Wang Resin
Obtained according to the method for step 2. to connection Fmoc-Val-OH on Fmoc-Tyr (tBu)-Val-Wang Resin
Fmoc-Val-Tyr(tBu)-Val-Wang Resin。
4. synthesize NH2-Val-Tyr(tBu)-Val-Wang Resin
It is 1 by Fmoc-Val-Tyr (tBu)-Val-Wang Resin piperidines and N,N-dimethylformamide volume ratio:4
Mixed liquor take off Fmoc- once, washed successively with isopropanol and DMF, obtain NH2-Val-Tyr(tBu)-
Val-Wang Resin。
(2) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (tBu)-Val-Wang Resin are synthesized
By 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, I-hydroxybenzotriazole N, N- diformazan
After base formyl amine solvent, trifluoroacetic acid is added, stirring at normal temperature is reacted 15~30 minutes, adds N, N '-diisopropylethylamine, after
Continuous stirring 20~40 minutes, gained reaction solution adds NH2In-Val-Tyr (tBu)-Val-Wang Resin, protected in nitrogen
Under, stirring at normal temperature is reacted 1~3 hour, is washed successively with isopropanol, DMF, absolute methanol, dry N-
(2,2,2- trifluoroacetyl groups)-Val-Tyr (tBu)-Val-Wang Resin.
(3) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr-Val-OH is synthesized
Added in N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (the tBu)-Val-Wang Resin that step (2) is obtained
Cutting liquid, stirring at normal temperature 1~3 hour, is isolated and purified, and obtains trifluoroacetyl tripeptides -2.
The mass percent of above-mentioned cutting liquid forms：Trifluoroacetic acid 83%, phenol 5%, thioanisole 4%, water 3%,
Tri isopropyl silane 5%.
Above-mentioned steps (1) 1. in, preferably Wang resin and Fmoc-Val-OH, DMAP, N, N- bis- is different
The mol ratio of propyl group carbodiimide is 1:8~12:1~1.3:4~6.
Above-mentioned steps (1) 2. in, preferably Fmoc-Tyr (tBu)-OH, I-hydroxybenzotriazole, N, N- diisopropyl carbon
The mol ratio 2 of the addition of diimine and step 1. middle Wang resin dosages:2.5~3:2.5~3:1.
Above-mentioned steps (1) 3. in, preferably Fmoc-Val-OH, I-hydroxybenzotriazole, N, N- DICs
Addition and step 1. middle Wang resin dosages mol ratio 2:2.5~3:2.5~3:1.
In above-mentioned steps (2), preferred 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters, 1- hydroxy benzenes
And the mol ratio of triazole, the addition of trifluoroacetic acid and step 1. middle Wang resin dosages is 3~7:3~7:2~6:1.
The present invention first uses Solid phase synthesis NH2- Val-Tyr (tBu)-Val-Wang Resin, then made with trifluoroacetic acid
Trifluoroacetylation is carried out for raw material, the product of trifluoroacetyl tripeptides -2 is made.In being reacted instant invention overcomes conventional trifluoroacetylation
Using the shortcomings that cost existing for Trifluoroacetic Acid Ethyl Ester or trifluoro-acetyl chloride is high, efficiency is low, synthesis technique is complicated, while using first
Row activates trifluoroacetic acid antacid technique again, overcomes trifluoroacetic acid to NH2-Val-Tyr(tBu)-Val-Wang
The influence of Resin resin peptides, there is the advantages of low synthesis cost, efficiency high, simple technique, be a kind of trifluoro second of relative ideal
Acyl tripeptides -2-in-1 into method.
Embodiment
With reference to embodiment, the present invention is described in more detail, but protection scope of the present invention is not limited only to these realities
Apply example.
Embodiment 1
(1) NH is synthesized2-Val-Tyr(tBu)-Val-Wang Resin
1. synthesize Fmoc-Val-Wang Resin
20.0g Wang Resin (substitution value 0.5mmol/g) are added in synthesizer, add 200mL N, N- dimethyl
Formamide is soaked 4 hours, it is fully swelled, and filters and removes DMF, and 200mL dichloros are added into synthesizer
Methane, 33.94g Fmoc-Val-OH, 1.22g DMAPs, 7.79mL N, N- DICs, Wang
Resin and Fmoc-Val-OH, DMAP, N, the mol ratio of N- DICs is 1:10:1:5, in nitrogen
Under gas shielded, stirring at normal temperature is reacted 4 hours, is filtered, with respectively washing 2 times of isopropanol and DMF, every time
180mL, obtain Fmoc-Val-Wang Resin.
2. synthesize Fmoc-Tyr (tBu)-Val-Wang Resin
1. Fmoc-Val-Wang Resin that step is obtained are added in synthesizer, and add 200mL piperidines and N, N- bis-
NMF volume ratio is 1:4 mixed liquor, under nitrogen protection stirring at normal temperature react 40 minutes, filter, with isopropanol and
DMF respectively washing 2 times, each 200mL, the resin after washing is added in synthesizer, adds 200mL N, N-
Dimethylformamide, and it is different to add 9.19g Fmoc-Tyr (tBu)-OH, 4.05g1- hydroxybenzotriazoles, 4.67mL N, N- bis-
Propyl group carbodiimide, Fmoc-Tyr (tBu)-OH, I-hydroxybenzotriazole, N, N- DICs and Wang resin
Mol ratio 2:3:3:1, stirring at normal temperature reaction 2 hours, is filtered, with isopropanol and DMF under nitrogen protection
Each washing 2 times, each 200mL, obtains Fmoc-Tyr (tBu)-Val-Wang Resin.
3. synthesize Fmoc-Val-Tyr (tBu)-Val-Wang Resin
2. Fmoc-Tyr (tBu)-Val-Wang Resin that step is obtained are added in synthesizer, and add 200mL piperazines
Pyridine is 1 with N,N-dimethylformamide volume ratio:4 mixed liquor, stirring at normal temperature reaction 40 minutes, is filtered under nitrogen protection,
With the respectively washing 2 times, each 200mL of isopropanol and DMF, the resin after washing is added in synthesizer, added
200mL DMFs, and 6.87g Fmoc-Val-OH, 4.05g I-hydroxybenzotriazoles, 4.67mL N are added,
N- DICs, Fmoc-Val-OH, I-hydroxybenzotriazole, N, N- DICs and Wang
Resin mol ratio 2:3:3:1, stirring at normal temperature reaction 2 hours, is filtered, with isopropanol and N, N- dimethyl under nitrogen protection
Formamide respectively washing 2 times, each 200mL, obtains Fmoc-Val-Tyr (tBu)-Val-Wang Resin.
4. synthesize NH2-Val-Tyr(tBu)-Val-Wang Resin
3. Fmoc-Val-Tyr (tBu)-Val-Wang Resin that step is obtained are added in synthesizer, and are added
200mL piperidines is 1 with N,N-dimethylformamide volume ratio:4 mixed liquor, under nitrogen protection 40 points of stirring at normal temperature reaction
Clock, filter, with isopropanol and DMF respectively washing 2 times, each 200mL, obtain NH2-Val-Tyr(tBu)-
Val-Wang Resin。
(2) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (tBu)-Val-Wang Resin are synthesized
By 28.96g 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, 9.46g 1- hydroxy benzos three
Azoles is dissolved in 200mL DMFs, adds 4.5mL trifluoroacetic acids, stirring at normal temperature is reacted 20 minutes, then is added dropwise
17.5mL N, N '-diisopropylethylamine, continue stirring 30 minutes, obtain reaction solution；4. NH that step is obtained2-Val-Tyr
(tBu)-Val-Wang Resin are added in reaction solution, 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters, 1-
The mol ratio of hydroxybenzotriazole, trifluoroacetic acid and Wang resin is 7:7:6:1, stirring at normal temperature reaction 2 under nitrogen protection
Hour, filter, respectively washed 2 times, washed with methanol 3 times, each 200mL with isopropanol and DMF, filtered, 40
DEG C drying, obtains 27.5g N- (2,2,2- trifluoroacetyl group)-Val-Tyr (tBu)-Val-Wang Resin.
(3) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr-Val-OH is synthesized
N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (the tBu)-Val-Wang Resin that step (2) is obtained are added to
(mass percent of cutting liquid forms 300mL cutting liquids：Trifluoroacetic acid 83%, phenol 5%, thioanisole 4%, water 3%,
Tri isopropyl silane 5%) in, stirring at normal temperature is reacted 2 hours, is filtered to obtain brown color liquid, is concentrated under reduced pressure into yellow oil, dense
Contracting liquid is poured into the 500mL methyl tertiary butyl ether(MTBE)s of freezing, is stirred, and 4 DEG C of standings have white precipitate, filtering, uses methyl- tert
Butyl ether is washed 2 times, and room temperature in vacuo is dried, and obtains the crude product of 5.0g trifluoroacetyls tripeptides -2；The crude product of trifluoroacetyl tripeptides -2 is passed through
Reverse phase chromatography (inverted polymer post：MCI GEL reverse-phase chromatography fillers, pillar specification 5cm × 45cm, flow velocity 30mL/min,
Wavelength 215nm, mobile phase A：Volumetric concentration be 0.1% trifluoroacetic acid aqueous solution, Mobile phase B：Volumetric concentration is the three of 0.1%
Fluoroacetic acid methanol solution, gradient：18%~26%50min of B), freeze-drying, obtain the freeze-dried powder of trifluoroacetyl tripeptides -2
4.2g, yield 86.31%, purity>95%.
Embodiment 2
The step of the present embodiment (1) 2. and 3. in, I-hydroxybenzotriazole, N, N- DICs and Wang
Resin mol ratio 2.5:2.5:1, other steps of the step are same as Example 1.In the step of this implementation (2), 6- chlorobenzenes
And triazole -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, I-hydroxybenzotriazole, trifluoroacetic acid and Wang resin mole
Than for 3:3:2:1, other steps of the step are same as Example 1.The step of this implementation (3), is same as Example 1, obtains 3.6g
The freeze-dried powder of trifluoroacetyl tripeptides -2, yield 74.00%.
Embodiment 3
In the step of this implementation (2), 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters, 1- hydroxy benzenes
And the mol ratio of triazole, trifluoroacetic acid and Wang resin is 5:5:4:1, other steps of the step are same as Example 1.This
The step of implementation (1) and (3) are same as Example 1, obtain the freeze-dried powder of 4.1g trifluoroacetyls tripeptides -2, yield 84.25%.
Claims (5)
1. a kind of synthetic method of trifluoroacetyl tripeptides -2, it is characterised in that it is made up of following step：
(1) NH is synthesized2-Val-Tyr(tBu)-Val-Wang Resin
1. synthesize Fmoc-Val-Wang Resin
After Wang Resin are swelled with DMF, dichloromethane, Fmoc-Val-OH, 4- dimethylamino are added
Pyridine, N, N- DICs, under nitrogen protection, stirring at normal temperature react 3~5 hours, successively with isopropanol and N,
Dinethylformamide washs, and obtains Fmoc-Val-Wang Resin；
2. synthesize Fmoc-Tyr (tBu)-Val-Wang Resin
1. Fmoc-Val-Wang Resin piperidines that step is obtained is 1 with N,N-dimethylformamide volume ratio:4 it is mixed
Close liquid removing Fmoc- once, washed respectively with isopropanol and DMF, add DMF,
Fmoc-Tyr (tBu)-OH, I-hydroxybenzotriazole, N, N- DICs, under nitrogen protection, stirring at normal temperature is anti-
Answer 1~3 hour, washed successively with isopropanol and DMF, obtain Fmoc-Tyr (tBu)-Val-Wang
Resin；
3. synthesize Fmoc-Val-Tyr (tBu)-Val-Wang Resin
Obtained according to the method for step 2. to connection Fmoc-Val-OH on obtained Fmoc-Tyr (tBu)-Val-Wang Resin
Fmoc-Val-Tyr(tBu)-Val-Wang Resin；
4. synthesize NH2-Val-Tyr(tBu)-Val-Wang Resin
3. Fmoc-Val-Tyr (tBu)-Val-Wang Resin piperidines that step is obtained and N,N-dimethylformamide body
Product is than being 1:4 mixed liquor takes off Fmoc- once, is washed successively with isopropanol and DMF, obtains NH2-Val-
Tyr(tBu)-Val-Wang Resin；
(2) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (tBu)-Val-Wang Resin are synthesized
By 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, I-hydroxybenzotriazole N, N- dimethyl methyl
After acid amides dissolving, trifluoroacetic acid is added, stirring at normal temperature is reacted 15~30 minutes, adds N, N '-diisopropylethylamine, continue to stir
Mix 20~40 minutes, gained reaction solution adds 4. NH that step obtains2In-Val-Tyr (tBu)-Val-Wang Resin, in nitrogen
Under gas shielded, stirring at normal temperature is reacted 1~3 hour, is washed successively with isopropanol, DMF, absolute methanol, is dried
Obtain N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (tBu)-Val-Wang Resin；
(3) N- (2,2,2- trifluoroacetyl groups)-Val-Tyr-Val-OH is synthesized
Cutting is added in N- (2,2,2- trifluoroacetyl groups)-Val-Tyr (the tBu)-Val-Wang Resin that step (2) is obtained
Liquid, stirring at normal temperature 1~3 hour, is isolated and purified, and obtains trifluoroacetyl tripeptides -2；
The mass percent of above-mentioned cutting liquid forms：Trifluoroacetic acid 83%, phenol 5%, thioanisole 4%, water 3%, three are different
Propyl silane 5%.
2. the synthetic method of trifluoroacetyl tripeptides -2 according to claim 1, it is characterised in that：Step (1) 1. in,
Wang resin and Fmoc-Val-OH, DMAP, N, the mol ratio of N- DICs is 1:8~12:
1~1.3:4~6.
3. the synthetic method of trifluoroacetyl tripeptides -2 according to claim 1, it is characterised in that：Step (1) 2. in,
Fmoc-Tyr (the tBu)-OH, I-hydroxybenzotriazole, N, the additions of N- DICs and step 1. in
The mol ratio 2 of Wang resin dosages:2.5~3:2.5~3:1.
4. the synthetic method of trifluoroacetyl tripeptides -2 according to claim 1, it is characterised in that：Step (1) 3. in,
The Fmoc-Val-OH, I-hydroxybenzotriazole, N, the additions of N- DICs and step 1. middle Wang
The mol ratio 2 of resin dosages:2.5~3:2.5~3:1.
5. the synthetic method of trifluoroacetyl tripeptides -2 according to claim 1, it is characterised in that：It is described in step (2)
6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, I-hydroxybenzotriazole, the addition and step of trifluoroacetic acid
The mol ratio of rapid 1. middle Wang resin dosages is 3~7:3~7:2~6:1.
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| CN112121145A (en) * | 2020-10-28 | 2020-12-25 | 广州赛莱拉生物基因工程有限公司 | Use of trifluoroacetyl tripeptide-2 |
| CN113214168A (en) * | 2021-04-29 | 2021-08-06 | 陕西慧康生物科技有限责任公司 | Method for synthesizing cyclic dipeptide containing glutamic acid and aspartic acid by solid-liquid combination |
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| CN113214168A (en) * | 2021-04-29 | 2021-08-06 | 陕西慧康生物科技有限责任公司 | Method for synthesizing cyclic dipeptide containing glutamic acid and aspartic acid by solid-liquid combination |
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| CN107857796B (en) | 2021-05-04 |
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