CN107857799A - A kind of liquid-phase synthesis process of tetrapeptide 21 - Google Patents
A kind of liquid-phase synthesis process of tetrapeptide 21 Download PDFInfo
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- CN107857799A CN107857799A CN201711160534.0A CN201711160534A CN107857799A CN 107857799 A CN107857799 A CN 107857799A CN 201711160534 A CN201711160534 A CN 201711160534A CN 107857799 A CN107857799 A CN 107857799A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of liquid-phase synthesis process of tetrapeptide 21; Gly Glu and Lys Gly full guard fragment Boc Gly Glu (OtBu) OMe, Fmoc Lys (Boc) Gly OH are respectively synthesized using liquid phase synthesizing method; then condensation reaction generation Boc Gly Glu (OtBu) Lys (Boc) Gly OH will be carried out with Boc Gly Glu (OtBu) OMe after Fmoc Lys (Boc) Gly OH removing Fmoc groups; finally remove all blocking groups and obtain H Gly Glu Lys Gly OH, i.e. tetrapeptide 21.The present invention uses liquid phase synthesizing method, raw materials used cheap and easily-available, avoids the vector resin used in synthesis in solid state, and intermediate purity is high, integrated cost is cheap, environmentally friendly, is adapted to large-scale production.
Description
Technical field
The invention belongs to the synthesis technical field of peptide, and in particular to a kind of liquid-phase synthesis process of tetrapeptide -21.
Background technology
Skin aging is a global problem, and it causes the change of many skin components average levels.These change
The quality epidermis cohesive force of dermal extracellular matrix is influenceed, so as to induce the generation of wrinkle and skin fragility.(the sequence of tetrapeptide -21
For H-Gly-Glu-Lys-Gly-OH) it is a kind of four peptases, it is present in some extracellular matrix proteins, its part
Using inducing the most important structure of skin --- the recovery of skin components.
Tetrapeptide -21 promotes collagen, hyaluronic acid and fibrin enhancing activity, so as to improve skin elasticity, reduces
Skin roughness.Skin is minimized by consumingly smooth and fixation, various wrinkles.Tetrapeptide -21 has high anti-aging
Potentiality, it is particularly suitable for anti-wrinkle and the eye health of anti-aging.Experiment shows, with similar cosmetics peptide such as palm fibre in the market
Palmitic acid acyl pentapeptide -4 is compared, and 10ppm tetrapeptides -21 are better than 10ppm Matrixyl -4, as a kind of cosmetics peptide, is had significant
Anti-aging potential.
The synthetic method of tetrapeptide -21 is mostly solid phase polypeptide synthesis at present, and resin price used is expensive, and cost is higher and not
Easy scale.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of high efficiency, low cost, the tetrapeptide -21 of easy scale
Liquid-phase synthesis process.
Technical scheme is used by solving the above problems：Gly-Glu full guard is respectively synthesized using liquid phase synthesizing method
Fragment Boc-Gly-Glu (OtBu)-OMe and Lys-Gly full guard fragment Fmoc-Lys (Boc)-Gly-OH, then will
Condensation reaction generation Boc- is carried out after Fmoc-Lys (Boc)-Gly-OH removing Fmoc groups with Boc-Gly-Glu (OtBu)-OMe
Gly-Glu (OtBu)-Lys (Boc)-Gly-OH, finally removes all blocking groups and obtains H-Gly-Glu-Lys-Gly-OH, i.e.,
Tetrapeptide -21.
Above-mentioned Boc-Gly-Glu (OtBu)-OMe synthetic method is：Using tetrahydrofuran as solvent, by Boc-Gly-OH with
N, N '-dicyclohexylcarbodiimide, N- hydroxysuccinimides react 2~5 hours under the conditions of 0~10 DEG C, filtering, to filtrate
Middle addition H-Glu (OtBu)-OMeHCl and sodium bicarbonate aqueous solution, after being reacted 1~2 hour under the conditions of 0~10 DEG C, rise to
Room temperature reaction 8~14 hours, isolated and purified after having reacted, obtain Boc-Gly-Glu (OtBu)-OMe, wherein Boc-Gly-OH,
N, N '-dicyclohexylcarbodiimide, N- hydroxysuccinimides, H-Glu (OtBu)-OMeHCl, the mol ratio of sodium acid carbonate
It is preferred that 1:1.3~1.5:1.1~1.3:1.05~1.10:3.0~4.0.
Above-mentioned Fmoc-Lys (Boc)-Gly-OH synthetic method is：Using tetrahydrofuran as solvent, by Fmoc-Lys
(Boc)-OH and N, N '-dicyclohexylcarbodiimide, I-hydroxybenzotriazole, N, N '-diisopropylethylamine are in -5~0 DEG C of condition
Lower reaction 2~4 hours, filtering, H-Gly-OH and organic base is added into filtrate, after being reacted 1~2 hour at 0~5 DEG C, is risen
To room temperature reaction 8~10 hours, isolated and purified after having reacted, obtain Fmoc-Lys (Boc)-Gly-OH, wherein Fmoc-Lys
(Boc)-OH, N, N '-dicyclohexylcarbodiimide, I-hydroxybenzotriazole, N, N '-diisopropylethylamine, H-Gly-OH, organic
The mol ratio of alkali preferably 1:1.2~1.5:2.0~3.0:2.0~3.0:1.0~1.3:3.0~4.0, described organic base is N-
Any one in methylmorpholine, 1-METHYLPYRROLIDONE, N, N '-diisopropylethylamine.
Contracted after the above-mentioned removing Fmoc groups by Fmoc-Lys (Boc)-Gly-OH with Boc-Gly-Glu (OtBu)-OMe
Closing the concrete operations reacted is：Fmoc-Lys (Boc)-Gly-OH is dissolved in DMF, the room under piperidines effect
2~3 hours removing Fmoc groups of temperature reaction, then reacted with Boc-Gly-Glu (OtBu)-OMe, reaction solution is poured into after having reacted
In water, extraction, pickling, dry, removed under reduced pressure solvent, obtain Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH；Then exist
Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH all blocking groups are removed in cutting liquid, isolates and purifies, obtains H-
Gly-Glu-Lys-Gly-OH, i.e. tetrapeptide -21, wherein Fmoc-Lys (Boc)-Gly-OH, Boc-Gly-Glu (OtBu)-OMe,
The mol ratio of piperidines preferably 1:1.0~1.3:3~5, the preferred trifluoroacetic acid of described cutting liquid and tri isopropyl silane, pure water body
Product is than being 90:5:5 mixed liquor.
The present invention uses liquid phase synthesizing method, by the way of fragment condensation, improves peptide symthesis transformation efficiency, raw materials used
It is cheap and easily-available, the vector resin used in synthesis in solid state is avoided, intermediate purity is high, integrated cost is cheap, environmentally friendly, fits
Close large-scale production.
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
1st, Boc-Gly-Glu (OtBu)-OMe is synthesized
17.5g (0.1mol) Boc-Gly-OH and 300mL tetrahydrofurans are added into 1000mL there-necked flasks, are stirred to solid
Dissolving, system are cooled to 0 DEG C, add 13.6g (0.12mol) N- hydroxysuccinimides, 30.9g (0.15mol) ring of N, N '-two
Hexyl carbodiimide, reacted 3 hours under the conditions of 0~10 DEG C, TLC display reactions are complete, filter out insoluble matter, add into filtrate
Enter 27.9g (0.11mol) H-Glu (OtBu)-OMeHCl, 33.6g (0.4mol) sodium acid carbonate, 60mL pure water, at 0~10 DEG C
Under the conditions of react 2 hours after, warm naturally to room temperature reaction 10 hours, TLC monitoring reactions are complete, stop reaction, removed under reduced pressure
100mL water is added after solvent, 3 times (each 200mL) are extracted with ethyl acetate, organic phase is through saturated common salt water washing, anhydrous sulphur
Sour sodium filters after drying, and is dissolved in after filtrate decompression desolvation in dichloromethane, through silica gel column chromatography, (eluant, eluent is ethyl acetate
It is 1 with petroleum ether volume ratio:3 mixed liquors) after obtain 33.6g Boc-Gly-Glu (OtBu)-OMe, purity is more than 95%, yield
89.8%.
2nd, Fmoc-Lys (Boc)-Gly-OH is synthesized
46.8g (0.1mol) Fmoc-Lys (Boc)-OH and 500mL tetrahydrofurans, stirring are added into 1000mL there-necked flasks
Be cooled to 0 DEG C after dissolving, add 27g (0.2mol) I-hydroxybenzotriazoles and 32mL (0.2mol) N, N '-diisopropylethylamine,
26.7g (0.13mol) N, N '-dicyclohexylcarbodiimide, react 3 hours, filter under the conditions of -5~0 DEG C, add into filtrate
Enter the tetrahydrofuran solution that 80mL contains 9.8g (0.13mol) H-Gly-OH and 50mL (0.3mol) N, N '-diisopropylethylamine,
After being reacted 2 hours at 0~5 DEG C, room temperature reaction 10 hours is warmed naturally to, TLC shows no starting material left, stops reaction, decompression
After desolvation, add 300mL water, with dichloromethane extract 3 times (each 200mL), organic phase through saturated common salt water washing, subtract
52g white solids Fmoc-Lys (Boc)-Gly-OH is obtained after pressure-off is molten.
3rd, H-Gly-Glu-Lys-Gly-OH is synthesized
39.3g (74.7mmol) Fmoc-Lys (Boc)-Gly-OH, 100mL N, N- bis- are added into 1000mL there-necked flasks
NMF, 25mL (0.25mol) piperidines is added after dissolving completely, is stirred at room temperature 3 hours, removes Fmoc groups, TLC is shown
Removing is complete, then adds the DMF that 50mL contains 33.6g (89.7mmol) Boc-Gly-Glu (OtBu)-OMe
Solution, reaction 24 hours is stirred at room temperature, stops reaction, pour into 2500mL water, (500mL × 4 time) are extracted with ethyl acetate, have
Machine mutually do by the aqueous hydrochloric acid solution washing (400mL × 2 time) through 0.5mol/L, saturated common salt water washing organic phase, anhydrous sodium sulfate
Filtered after dry, filtrate decompression desolvation, obtain 52g Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH.
By 52g Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH add cutting liquid in (by 180mL trifluoroacetic acids,
10mL tri isopropyl silanes, 10mL pure water composition), it is stirred at room temperature 2 hours, is concentrated under reduced pressure into no trifluoroacetic acid cut and overflows, slightly
Product are first using RPLC purifying (mobile phase A：Volume fraction is 0.05% trifluoroacetic acid aqueous solution；Mobile phase
B：Volume fraction be 0.05% trifluoroacetic acid methanol solution, gradient：Mobile phase B 3%5min, 3%-15%60min,
15% constant current；Detection wavelength 215nm, flow velocity 15mL/min, chromatographic column specification：5cm × 45cm, filler：GEL inverted polymers),
Then using ion exchange, (volume fraction is 2% acetic acid aqueous solution constant current, Detection wavelength 215nm, flow velocity except trifluoroacetic acid
5mL/min, chromatographic column specification：5cm × 45cm, filler DEAE), finally it is freeze-dried, obtains 31g H-Gly-Glu-Lys-
Gly-OH, i.e. tetrapeptide -21, purity are more than 97%, yield 79.8%.
Embodiment 2
1st, Boc-Gly-Glu (OtBu)-OMe is synthesized
45.5g (0.26mol) Boc-Gly-OH and 600mL tetrahydrofurans are added into 2000mL there-necked flasks, are stirred to solid
Body dissolves, and system is cooled to 0 DEG C, adds 33.3g (0.29mol) N- hydroxysuccinimides, 70g (0.34mol) ring of N, N '-two
Hexyl carbodiimide, reacted 3 hours under the conditions of 0~10 DEG C, TLC display reactions are complete, filter out insoluble matter, add into filtrate
Enter 72.5g (0.286mol) H-Glu (OtBu)-OMeHCl, 65.5g (0.78mol) sodium acid carbonate, 150mL pure water, 0~
After being reacted 2 hours under the conditions of 10 DEG C, room temperature reaction 10 hours is warmed naturally to, TLC monitoring reactions are complete, stop reaction, decompression
400mL water is added after desolvation, 3 times (each 300mL) are extracted with ethyl acetate, organic phase is through saturated common salt water washing, nothing
Aqueous sodium persulfate filters after drying, and is dissolved in after filtrate decompression desolvation in dichloromethane, through silica gel column chromatography, (eluant, eluent is acetic acid
Ethyl ester is 1 with petroleum ether volume ratio:3 mixed liquors) after obtain 87.5g Boc-Gly-Glu (OtBu)-OMe, purity is more than 95%,
Yield 90%.
2nd, Fmoc-Lys (Boc)-Gly-OH is synthesized
140.6g (0.3mol) Fmoc-Lys (Boc)-OH and 1000mL tetrahydrofurans are added into 2000mL there-necked flasks, is stirred
0 DEG C is cooled to after mixing dissolving, adds 81g (0.6mol) I-hydroxybenzotriazoles and 99mL (0.6mol) N, N '-diisopropyl second
Amine, 80.3g (0.39mol) N, N '-dicyclohexylcarbodiimide, react 3 hours under the conditions of -5~0 DEG C, filtering, into filtrate
The tetrahydrofuran solution that 150mL contains 29.2g (0.39mol) H-Gly-OH and 98mL (0.9mol) N- methylmorpholines is added, 0
After being reacted 2 hours at~5 DEG C, room temperature reaction 10 hours is warmed naturally to, TLC shows no starting material left, stops reaction, and decompression is de-
After solvent, add 1000mL water, with dichloromethane extract 3 times (each 350mL), organic phase through saturated common salt water washing, subtract
126g white solids Fmoc-Lys (Boc)-Gly-OH is obtained after pressure desolvation.
3rd, H-Gly-Glu-Lys-Gly-OH is synthesized
120.8g (0.23mol) Fmoc-Lys (Boc)-Gly-OH, 300mL N, N- bis- are added into 1000mL there-necked flasks
NMF, 84mL (0.92mol) piperidines is added after dissolving completely, is stirred at room temperature 3 hours, removes Fmoc groups, TLC is shown
Removing is complete, then adds the DMF that 100mL contains 87.5g (0.23mol) Boc-Gly-Glu (OtBu)-OMe
Solution, reaction 24 hours is stirred at room temperature, stops reaction, pour into 5000mL water, (1000mL × 4 time) are extracted with ethyl acetate,
Aqueous hydrochloric acid solution washing (600mL × 2 time) of the organic phase through 0.5mol/L, saturated common salt water washing organic phase, anhydrous sodium sulfate
Filtered after drying, filtrate decompression desolvation, obtain 145g Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH.
By 145g Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH add cutting liquid in (by 450mL trifluoroacetic acids,
25mL tri isopropyl silanes, 25mL pure water composition), it is stirred at room temperature 2 hours, is concentrated under reduced pressure into no trifluoroacetic acid cut and overflows, slightly
Product are first using RPLC purifying (mobile phase A：Volume fraction is 0.05% trifluoroacetic acid aqueous solution；Mobile phase
B：Volume fraction be 0.05% trifluoroacetic acid methanol solution, gradient：Mobile phase B 3%5min, 3%-15%60min,
15% constant current；Detection wavelength 215nm, flow velocity 15mL/min, chromatographic column specification：5cm × 45cm, filler：GEL inverted polymers),
Then using ion exchange, (volume fraction is 2% acetic acid aqueous solution constant current, Detection wavelength 215nm, flow velocity except trifluoroacetic acid
5mL/min, chromatographic column specification：5cm × 45cm, filler DEAE), finally it is freeze-dried, obtains 74g H-Gly-Glu-Lys-
Gly-OH, i.e. tetrapeptide -21, purity are more than 98%, yield 73%.
Claims (7)
- A kind of 1. liquid-phase synthesis process of tetrapeptide -21, it is characterised in that：The complete of Gly-Glu is respectively synthesized using liquid phase synthesizing method Protected fragment Boc-Gly-Glu (OtBu)-OMe and Lys-Gly full guard fragment Fmoc-Lys (Boc)-Gly-OH, then will Condensation reaction generation Boc- is carried out after Fmoc-Lys (Boc)-Gly-OH removing Fmoc groups with Boc-Gly-Glu (OtBu)-OMe Gly-Glu (OtBu)-Lys (Boc)-Gly-OH, finally removes all blocking groups and obtains H-Gly-Glu-Lys-Gly-OH, i.e., Tetrapeptide -21；Above-mentioned Boc-Gly-Glu (OtBu)-OMe synthetic method is：Using tetrahydrofuran as solvent, by Boc-Gly-OH and N, N '-dicyclohexylcarbodiimide, N- hydroxysuccinimides react 2~5 hours under the conditions of 0~10 DEG C, filtering, into filtrate H-Glu (OtBu)-OMeHCl and sodium bicarbonate aqueous solution are added, after being reacted 1~2 hour under the conditions of 0~10 DEG C, rises to room Temperature reaction 8~14 hours, isolates and purifies after having reacted, obtains Boc-Gly-Glu (OtBu)-OMe；Above-mentioned Fmoc-Lys (Boc)-Gly-OH synthetic method is：Using tetrahydrofuran as solvent, by Fmoc-Lys (Boc)-OH With N, N '-dicyclohexylcarbodiimide, I-hydroxybenzotriazole, N, N '-diisopropylethylamine react 2 under the conditions of -5~0 DEG C ~4 hours, filtering, H-Gly-OH and organic base are added into filtrate, after being reacted 1~2 hour at 0~5 DEG C, be warmed to room temperature anti- Answer 8~10 hours, isolated and purified after having reacted, obtain Fmoc-Lys (Boc)-Gly-OH.
- 2. the liquid-phase synthesis process of the tetrapeptide -21 according to claims 1, it is characterised in that：The Boc-Gly-Glu (OtBu) in-OMe synthetic method, Boc-Gly-OH, N, N '-dicyclohexylcarbodiimide, N- hydroxysuccinimides, H- Glu (OtBu)-OMeHCl, the mol ratio of sodium acid carbonate are 1:1.3~1.5:1.1~1.3:1.05~1.10:3.0~4.0.
- 3. the liquid-phase synthesis process of the tetrapeptide -21 according to claims 1, it is characterised in that：The Fmoc-Lys (Boc) in-Gly-OH synthetic method, Fmoc-Lys (Boc)-OH, N, N '-dicyclohexylcarbodiimide, 1- hydroxy benzos three Azoles, N, N '-diisopropylethylamine, H-Gly-OH, the mol ratio of organic base are 1:1.2~1.5:2.0~3.0:2.0~3.0: 1.0~1.3:3.0~4.0.
- 4. the liquid-phase synthesis process of the tetrapeptide -21 according to claims 1 or 3, it is characterised in that：Described organic base is Any one in N- methylmorpholines, 1-METHYLPYRROLIDONE, N, N '-diisopropylethylamine.
- 5. the liquid-phase synthesis process of the tetrapeptide -21 according to claims 1, it is characterised in that by Fmoc-Lys (Boc) - Gly-OH removing Fmoc groups after with Boc-Gly-Glu (OtBu)-OMe carry out condensation reaction concrete operations be：By Fmoc- Lys (Boc)-Gly-OH is dissolved in DMF, and 2~3 hours removing Fmoc groups are reacted at room temperature under piperidines effect, React with Boc-Gly-Glu (OtBu)-OMe, be poured into water reaction solution again after having reacted, extract, pickling, dry, decompression is de- Except solvent, Boc-Gly-Glu (OtBu)-Lys (Boc)-Gly-OH is obtained；Then Boc-Gly-Glu is removed in cutting liquid (OtBu)-Lys (Boc)-Gly-OH all blocking groups, isolate and purify, obtain H-Gly-Glu-Lys-Gly-OH, i.e., four Peptide -21.
- 6. the liquid-phase synthesis process of tetrapeptide -21 according to claim 5, it is characterised in that：The condensation reaction it is specific In operation, Fmoc-Lys (Boc)-Gly-OH, Boc-Gly-Glu (OtBu)-OMe, the mol ratio of piperidines are 1:1.0~1.3:3 ~5.
- 7. the liquid-phase synthesis process of tetrapeptide -21 according to claim 5, it is characterised in that：Described cutting liquid is trifluoro Acetic acid is 90 with tri isopropyl silane, pure water volume ratio:5:5 mixed liquor.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1715295A (en) * | 2004-07-03 | 2006-01-04 | 兰州大学 | Liquid phase synthetic method for endomorphine -1 and endomorphine -2 |
| CN103613642A (en) * | 2013-11-20 | 2014-03-05 | 陕西东大生化科技有限责任公司 | Liquid-phase segmented synthesis method of argireline |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| CN105189531A (en) * | 2013-03-13 | 2015-12-23 | 新科蒂斯公司 | Peptides for skin rejuvenation and methods of using the same |
-
2017
- 2017-11-20 CN CN201711160534.0A patent/CN107857799B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1715295A (en) * | 2004-07-03 | 2006-01-04 | 兰州大学 | Liquid phase synthetic method for endomorphine -1 and endomorphine -2 |
| CN105189531A (en) * | 2013-03-13 | 2015-12-23 | 新科蒂斯公司 | Peptides for skin rejuvenation and methods of using the same |
| CN104109189A (en) * | 2013-04-18 | 2014-10-22 | 中国人民解放军军事医学科学院毒物药物研究所 | Liquid-phase synthetic method of Thr-Pro-Pro-Thr tetrapiptide |
| CN103613642A (en) * | 2013-11-20 | 2014-03-05 | 陕西东大生化科技有限责任公司 | Liquid-phase segmented synthesis method of argireline |
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