CN103665102A - Synthesis method for GHK tripeptide - Google Patents
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Abstract
The invention discloses a synthesis method for GHK tripeptide. A conventional liquid-phase synthesis method is adopted. The method comprises the following steps of protecting lysine by using p-nitrophenyl acetate, protecting dipeptide obtained by enabling Boc-Gly-OH to react with histidine by using di-tert-butyl dicarbonate, and enabling the protected dipeptide to react with the protected lysine to obtain the GHK tripeptide. According to the method, the p-nitrophenyl acetate is used for protecting the lysine, and can selectively acylate amino groups farther away from carboxylic acid functional groups, and compared with a conventional protecting method, the p-nitrophenyl acetate protecting method has the advantages that the operating steps are simple, and the production cost is lowered; the di-tert-butyl dicarbonate is used for protecting the dipepetide, so that the generation of other byproducts is reduced, the lipophicity of a chemical compound is improved, the separation and purification of a product are facilitated, the yield of the product is improved, and meanwhile, the generation of a recemization product can also be reduced.
Description
Technical field
The invention belongs to makeup technical field, be specifically related to a kind of by the method for the synthetic GHK tripeptides of liquid phase means.
Background technology
GHK tripeptides is a kind of three amino acid whose active polypeptide that contain, aminoacid sequence is H-Gly-His-Lys-OH, GHK-Cu is medically the earliest for promoting wound healing and promoting skin elasticity, recent part Study is thought can improve microgroove, PAL-GHK has the effect of rich lip, uses in the production of lipstick, makes lip seem plump soft bright after use, having unique lip scape, is also the indispensable raw material of safe chest enlarge product.
At present, the synthetic method of GHK mainly adopts classical solid phase synthesis.Solid phase synthesis is about to protected amino acid and is extended one by one to N end by C end, by condensation, deprotection, condensation again, cutting resin, centrifugal, freeze-drying and high performance liquid phase, prepares purity higher than 90% GHK product.In the method, needed resin market value is comparatively expensive, and its exchange activity is little, and in synthetic the condensing agent that uses and alkali all obviously excessive, caused increasing of GHK raw materials cost, therefore, the processing method research of reduction GHK production cost is significant.
Summary of the invention
Technical problem to be solved by this invention is to overcome the shortcoming that existing GHK tripeptides preparation method exists, provide a kind of simple to operate, cost is low, the synthetic method of the GHK tripeptides of the easily separated purifying of product
Solving the problems of the technologies described above adopted technical scheme is comprised of following step:
1, synthetic H-Lys (Ac)-OH
Methionin is dissolved in distilled water completely, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 10～11, add acetic acid p-nitrophenyl acetate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) be 1g:5～10mL than being the mixed solution of 1:2～5, the mol ratio of Methionin and acetic acid p-nitrophenyl acetate is 1:1.0～2, stirring at room reaction 2～5 hours, separation and purification product, obtains H-Lys (Ac)-OH.
2, synthetic Boc-Gly-COOSu
By Boc-Gly-OH and 1, 4-dioxane or tetrahydrofuran (THF) are that 1g:8～10mL mixes by quality-volume ratio, stirring at room, add N-maloyl imines, be stirred to dissolving, drip N, N'-dicyclohexylcarbodiimide and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixing solutions of 1g:2～5mL, Boc-Gly-OH and N-maloyl imines, N, the mol ratio of N'-dicyclohexylcarbodiimide is 1:1～1.5:1～2, room temperature reaction 2～3 hours, filtration under diminished pressure is removed solid insoluble, obtain 1 of Boc-Gly-COOSu, 4-dioxane or tetrahydrofuran solution.
3, synthetic Boc-Gly-His (Boc)-OH
Histidine and sodium bicarbonate are dissolved in distilled water completely, and gained solution is added drop-wise in the Isosorbide-5-Nitrae-dioxane or tetrahydrofuran solution of the Boc-Gly-COOSu that step 2 obtains, stirring at room reaction 12～24 hours; Drip tert-Butyl dicarbonate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1g:3～10mL, add sodium hydroxide, the mol ratio of Boc-Gly-OH and Histidine, sodium bicarbonate, tert-Butyl dicarbonate, sodium hydroxide is 1:1.0～2:1.0～2:1.0～2:1.5～4, room temperature reaction 3～5 hours, separation and purification product, obtains Boc-Gly-His (Boc)-OH.
4, synthetic Boc-Gly-His (Boc)-COOSu
By Boc-Gly-His (Boc)-OH and 1, 4-dioxane or tetrahydrofuran (THF) are that 1g:8～10mL mixes by quality-volume ratio, stirring at room, add N-maloyl imines, be stirred to dissolving, drip N, N'-dicyclohexylcarbodiimide and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixing solutions of 1g:2～5mL, Boc-Gly-His (Boc)-OH and N-maloyl imines, N, the mol ratio of N'-dicyclohexylcarbodiimide is 1:1～1.5:1～2, room temperature reaction 2～3 hours, filtration under diminished pressure is removed solid insoluble, obtain 1 of Boc-Gly-His (Boc)-COOSu, 4-dioxane or tetrahydrofuran solution.
5, synthetic Boc-Gly-His (Boc)-Lys (Ac)-OH
H-Lys (Ac)-OH and sodium bicarbonate are dissolved in distilled water completely, gained solution is added drop-wise to 1 of Boc-Gly-His (Boc)-COOSu that step 4 obtains, in 4-dioxane or tetrahydrofuran solution, the mol ratio of H-Lys (Ac)-OH and sodium bicarbonate, Boc-Gly-His (Boc)-OH is 1.1～1.5:1.1～1.5:1, stirring at room reaction 18～20 hours, separation and purification product, obtains Boc-Gly-His (Boc)-Lys (Ac)-OH.
6, synthetic GHK tripeptides
Boc-Gly-His (Boc)-Lys (Ac)-OH is added in the mixed solution that the volume ratio of trifluoroacetic acid and distilled water is 1:1, quality-the volume ratio of Boc-Gly-His (Boc)-Lys (Ac)-OH and mixed solution is 1g:8～10mL, stirring at room reaction 2～3 hours, be extracted with ethyl acetate, water is evaporated to dry, obtains GHK tripeptides.
The optimum condition of synthetic H-Lys of the present invention (Ac)-OH step 1 is: Methionin is dissolved in distilled water completely, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 10～11, add acetic acid p-nitrophenyl acetate and 1, the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1:3, and the mol ratio of Methionin and acetic acid p-nitrophenyl acetate is 1:1.0～1.3, stirring at room reaction 3～4 hours, separation and purification product, obtains H-Lys (Ac)-OH.
The optimum condition of synthetic Boc-Gly-His of the present invention (Boc)-OH step 3 is: Histidine and sodium bicarbonate are dissolved in distilled water completely, gained solution is added drop-wise to 1 of Boc-Gly-COOSu that step 2 obtains, in 4-dioxane or tetrahydrofuran solution, stirring at room reaction 18～20 hours; Drip tert-Butyl dicarbonate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1g:5～8mL, add sodium hydroxide, the mol ratio of Boc-Gly-OH and Histidine, sodium bicarbonate, tert-Butyl dicarbonate, sodium hydroxide is 1:1.1～1.5:1.1～1.5:1.3～1.5:2～3, room temperature reaction 3～5 hours, separation and purification product, obtains Boc-Gly-His (Boc)-OH.
The present invention adopts acetic acid p-nitrophenyl acetate to protect Methionin, this protecting group optionally acidylate from carboxylic acid functional the amino away from, compare with existing guard method, operation steps is obviously simple, also can reduce production costs.Meanwhile, adopt tert-Butyl dicarbonate to protect dipeptides, can increase the close ester of compound, contribute to the separation and purification of product, can also reduce the generation of racemization product.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of the synthetic GHK tripeptides of embodiment 1.
Fig. 2 is the liquid chromatogram of the synthetic GHK tripeptides of embodiment 1.
Embodiment
Below in conjunction with drawings and Examples, the present invention is described in more detail, but the invention is not restricted to these embodiment.
Embodiment 1
1, synthetic H-Lys (Ac)-OH
By 10g(0.07mol) Methionin and 40mL distilled water adds in reaction flask, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 10, slowly add 15.2g(0.08mol) acetic acid p-nitrophenyl acetate (Pu Zhen bio tech ltd provides by Shanghai) and 80mL1, the mixed solution of 4-dioxane, stirring at room reaction 4 hours, filter, concentrating under reduced pressure filtrate, be extracted with ethyl acetate, the aqueous citric acid solution that water is 10% with massfraction regulates pH value to 3, be extracted with ethyl acetate, filtration under diminished pressure after anhydrous sodium sulfate drying for organic phase, filtrate decompression is concentrated into dry, obtain H-Lys (Ac)-OH, yield is 96%.
2, synthetic Boc-Gly-COOSu
By 10g(0.057mol) Boc-Gly-OH and 100mL1,4-dioxane adds in reaction flask, and stirring at room adds 7.2g(0.063mol) N-maloyl imines, be stirred to dissolving, slowly drip 12.9g(0.063mol) N, N'-dicyclohexylcarbodiimide and 50mL1, the mixing solutions of 4-dioxane, room temperature reaction 3 hours, filtration under diminished pressure is removed solid insoluble, obtains Isosorbide-5-Nitrae-dioxane solution of Boc-Gly-COOSu.
3, synthetic Boc-Gly-His (Boc)-OH
By 10.6g(0.068mol) Histidine and 5.7g(0.068mol) sodium bicarbonate is dissolved in 30mL distilled water, gained solution is added drop-wise to 1 of Boc-Gly-COOSu that step 2 obtains, in 4-dioxane solution, stirring at room reaction 20 hours, then drip 14.8g(0.068mol) tert-Butyl dicarbonate and 50mL1, the mixed solution of 4-dioxane, add again 4.6g(0.114mol) sodium hydroxide, room temperature reaction 5 hours, filter, concentrating under reduced pressure filtrate, be extracted with ethyl acetate, the aqueous citric acid solution that water is 10% with massfraction regulates pH value to 3, be extracted with ethyl acetate, organic phase is successively through washing, saturated common salt washing, anhydrous sodium sulfate drying, filtration under diminished pressure, concentrating under reduced pressure, obtain Boc-Gly-His (Boc)-OH, yield is 90%.
4, synthetic Boc-Gly-His (Boc)-COOSu
By 10g(0.057mol) Boc-Gly-His (Boc)-OH and 100mL1,4-dioxane adds in reaction flask, and then stirring at room adds 7.8g(0.068mol) N-maloyl imines, be stirred to dissolving, slowly drip again 14g(0.068mol) N, N'-dicyclohexylcarbodiimide and 30mL1, the mixing solutions of 4-dioxane, room temperature reaction 3 hours, filtration under diminished pressure is removed solid insoluble, obtains Isosorbide-5-Nitrae-dioxane solution of Boc-Gly-His (Boc)-COOSu.
5, synthetic Boc-Gly-His (Boc)-Lys (Ac)-OH
By 12.8g(0.068mol) H-Lys (Ac)-OH and 5.7g(0.068mol) sodium bicarbonate is dissolved in 50mL distilled water, gained solution is added drop-wise to 1 of Boc-Gly-His (Boc)-COOSu that step 4 obtains, in 4-dioxane solution, stirring at room reaction 20 hours, the aqueous citric acid solution that is 10% with massfraction regulates pH value to 3, be extracted with ethyl acetate, organic phase is successively through washing, saturated common salt washing, anhydrous sodium sulfate drying, filtration under diminished pressure, concentrating under reduced pressure, obtain Boc-Gly-His (Boc)-Lys (Ac)-OH, yield is 90%.
6, synthetic H-Gly-His-Lys-OH
10g Boc-Gly-His (Boc)-Lys (Ac)-OH is added in the mixed solution that the volume ratio of 100mL trifluoroacetic acid and distilled water is 1:1, stirring at room reaction 3 hours, be extracted with ethyl acetate, water is evaporated to dry, with reverse high performance liquid chromatography, (filler is that F type particle diameter is the SBC MCI GEI reverse-phase chromatography filler of 30～50 μ m, by Chengdu section, composing biological company limited provides, the ammonia soln that mobile phase A is is 28% with massfraction regulates the ultrapure water of pH value to 8.5, the ammonia soln that Mobile phase B is is 28% with massfraction regulates the methyl alcohol of pH value to 8.5, eluent gradient is chosen as 0～40 minute, A:B by 83:17 to 73:27) carry out separation and purification, obtain GHK tripeptides, yield is 90%.
Contriver adopts mass spectrograph to carry out structural characterization to the product obtaining, and the results are shown in Figure 1.As seen from Figure 1, the molecular weight of products therefrom and molecular ion peak are consistent with GHK tri-peptide molecular weights and molecular ion peak, illustrate that preparing product is GHK tripeptides.Adopt liquid chromatograph to measure the purity of the product obtaining, liquid chromatogram is shown in Fig. 2.As seen from Figure 2, the purity of prepared GHK tripeptides is greater than 90%.
Embodiment 2
In synthetic H-Lys (the Ac)-OH step 1 of the present embodiment, by 10g(0.07mol) Methionin and 40mL distilled water adds in reaction flask, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 11, slowly add 26.6g(0.0.14mol) acetic acid p-nitrophenyl acetate (Pu Zhen bio tech ltd provides by Shanghai) and 250mL1, the mixed solution of 4-dioxane, stirring at room reaction 5 hours, other steps of this step are identical with embodiment 1, obtain H-Lys (Ac)-OH.Other steps are identical with embodiment 1, obtain GHK tripeptides.
Embodiment 3
In synthetic Boc-Gly-His (the Boc)-OH step 3 of the present embodiment, by 17.8g(0.0.114mol) Histidine and 9.6g(0.114mol) sodium bicarbonate is dissolved in 30mL distilled water, gained solution is added drop-wise to 1 of Boc-Gly-COOSu that step 2 obtains, in 4-dioxane solution, stirring at room reaction 20 hours, then drip 24.6g(0.114mol) tert-Butyl dicarbonate and 200mL1, the mixed solution of 4-dioxane, add again 9.3g(0.228mol) sodium hydroxide, room temperature reaction 3 hours, other steps of this step are identical with embodiment 1, obtain Boc-Gly-His (Boc)-OH.Other steps are identical with embodiment 1, obtain GHK tripeptides.
Embodiment 4
In embodiment 1～3, Isosorbide-5-Nitrae-dioxane used is replaced with isopyknic tetrahydrofuran (THF), and other steps are identical with corresponding embodiment, obtain GHK tripeptides.
Claims (3)
1. a synthetic method for GHK tripeptides, is characterized in that it is comprised of following step:
(1) synthetic H-Lys (Ac)-OH
Methionin is dissolved in distilled water completely, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 10～11, add acetic acid p-nitrophenyl acetate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1g:5～10mL, and the mol ratio of Methionin and acetic acid p-nitrophenyl acetate is 1:1～2, stirring at room reaction 2～5 hours, separation and purification product, obtains H-Lys (Ac)-OH;
(2) synthetic Boc-Gly-COOSu
By Boc-Gly-OH and 1, 4-dioxane or tetrahydrofuran (THF) are that 1g:8～10mL mixes by quality-volume ratio, stirring at room, add N-maloyl imines, be stirred to dissolving, drip N, N'-dicyclohexylcarbodiimide and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixing solutions of 1g:2～5mL, Boc-Gly-OH and N-maloyl imines, N, the mol ratio of N'-dicyclohexylcarbodiimide is 1:1～1.5:1～2, room temperature reaction 2～3 hours, filtration under diminished pressure is removed solid insoluble, obtain 1 of Boc-Gly-COOSu, 4-dioxane or tetrahydrofuran solution,
(3) synthetic Boc-Gly-His (Boc)-OH
Histidine and sodium bicarbonate are dissolved in distilled water completely, and gained solution is added drop-wise in the Isosorbide-5-Nitrae-dioxane or tetrahydrofuran solution of the Boc-Gly-COOSu that step (2) obtains, stirring at room reaction 12～24 hours; Drip tert-Butyl dicarbonate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1g:3～10mL, add sodium hydroxide, the mol ratio of Boc-Gly-OH and Histidine, sodium bicarbonate, tert-Butyl dicarbonate, sodium hydroxide is 1:1～2:1～2:1～2:1.5～4, room temperature reaction 3～5 hours, separation and purification product, obtains Boc-Gly-His (Boc)-OH;
(4) synthetic Boc-Gly-His (Boc)-COOSu
By Boc-Gly-His (Boc)-OH and 1, 4-dioxane or tetrahydrofuran (THF) are that 1g:8～10mL mixes by quality-volume ratio, stirring at room, add N-maloyl imines, be stirred to dissolving, drip N, N'-dicyclohexylcarbodiimide and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixing solutions of 1g:2～5mL, Boc-Gly-His (Boc)-OH and N-maloyl imines, N, the mol ratio of N'-dicyclohexylcarbodiimide is 1:1～1.5:1～2, room temperature reaction 2～3 hours, filtration under diminished pressure is removed solid insoluble, obtain 1 of Boc-Gly-His (Boc)-COOSu, 4-dioxane or tetrahydrofuran solution,
(5) synthetic Boc-Gly-His (Boc)-Lys (Ac)-OH
H-Lys (Ac)-OH and sodium bicarbonate are dissolved in distilled water completely, gained solution is added drop-wise to 1 of Boc-Gly-His (Boc)-COOSu that step (4) obtains, in 4-dioxane or tetrahydrofuran solution, the mol ratio of H-Lys (Ac)-OH and sodium bicarbonate, Boc-Gly-His (Boc)-OH is 1.1～1.5:1.1～1.5:1, stirring at room reaction 18～20 hours, separation and purification product, obtains Boc-Gly-His (Boc)-Lys (Ac)-OH;
(6) synthetic GHK tripeptides
Boc-Gly-His (Boc)-Lys (Ac)-OH is added in the mixed solution that the volume ratio of trifluoroacetic acid and distilled water is 1:1, quality-the volume ratio of Boc-Gly-His (Boc)-Lys (Ac)-OH and mixed solution is 1g:8～10mL, stirring at room reaction 2～3 hours, be extracted with ethyl acetate, water is evaporated to dry, obtains GHK tripeptides.
2. the synthetic method of GHK tripeptides according to claim 1, it is characterized in that: in described synthetic H-Lys (Ac)-OH step (1), Methionin is dissolved in distilled water completely, stirring at room, the aqueous sodium hydroxide solution that is 10% with massfraction regulates pH value to 10～11, add acetic acid p-nitrophenyl acetate and 1, the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1:3, the mol ratio of Methionin and acetic acid p-nitrophenyl acetate is 1:1.0～1.3, stirring at room reaction 3～4 hours, separation and purification product, obtains H-Lys (Ac)-OH.
3. the synthetic method of GHK tripeptides according to claim 1, it is characterized in that: in described synthetic Boc-Gly-His (Boc)-OH step (3), Histidine and sodium bicarbonate are dissolved in distilled water completely, gained solution is added drop-wise to 1 of Boc-Gly-COOSu that step (2) obtains, in 4-dioxane or tetrahydrofuran solution, stirring at room reaction 18～20 hours; Drip tert-Butyl dicarbonate and 1, quality-the volume ratio of 4-dioxane or tetrahydrofuran (THF) is the mixed solution of 1g:5～8mL, add sodium hydroxide, the mol ratio of Boc-Gly-OH and Histidine, sodium bicarbonate, tert-Butyl dicarbonate, sodium hydroxide is 1:1.1～1.5:1.1～1.5:1.3～1.5:2～3, room temperature reaction 3～5 hours, separation and purification product, obtains Boc-Gly-His (Boc)-OH.
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| CN111732628A (en) * | 2020-06-24 | 2020-10-02 | 浙江天台药业有限公司 | Synthetic method of GHK tripeptide |
| CN111732628B (en) * | 2020-06-24 | 2022-04-05 | 中国计量大学 | Synthetic method of GHK tripeptide |
| CN111690037A (en) * | 2020-07-31 | 2020-09-22 | 广州赛莱拉干细胞科技股份有限公司 | Method for synthesizing GHK acetate |
| CN113045472A (en) * | 2021-03-11 | 2021-06-29 | 成都诺优肽生物科技有限公司 | boc-gly. osu, tripeptide-1 and tripeptide-1 copper, and preparation method thereof |
| CN113943343A (en) * | 2021-10-15 | 2022-01-18 | 广州奥利生物科技有限公司 | Blue copper peptide with anti-aging and repairing effects and preparation method and application thereof |
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