CN107857797A - The liquid-phase fragment synthetic method of one species snake venom tripeptides - Google Patents

The liquid-phase fragment synthetic method of one species snake venom tripeptides Download PDF

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Publication number
CN107857797A
CN107857797A CN201711284541.1A CN201711284541A CN107857797A CN 107857797 A CN107857797 A CN 107857797A CN 201711284541 A CN201711284541 A CN 201711284541A CN 107857797 A CN107857797 A CN 107857797A
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China
Prior art keywords
boc
pro
dab
bzl
fmoc
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CN201711284541.1A
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Inventor
张忠旗
李乾
李晨
王慧
王斌
张佳旭
杨小琳
赵金礼
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Shaanxi HuiKang Bio Tech Co Ltd
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Shaanxi HuiKang Bio Tech Co Ltd
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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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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

Abstract

The invention discloses the liquid-phase fragment synthetic method of a species snake venom tripeptides, this method is with the Fmoc Pro OH of low cost, H DAB (Boc) OH, benzylamine is that raw material first synthesizes protected fragment H Pro DAB (Boc) NH Bzl, then by Boc β Ala OH, H Pro DAB (Boc) NH Bzl synthesis Boc β Ala Pro DAB (Boc) NH Bzl, Boc β Ala Pro DAB (Boc) NH Bzl are isolated and purified after trifluoroacetic acid Deprotection, it is lyophilized, obtain the H β Ala Pro DAB NH Bzl that purity is more than 95%, that is class snake venom tripeptides.The inventive method is simple and easy, cost is low, and a kind of simple process, lower-cost liquid-phase fragment synthetic method are provided for the synthesis of class snake venom tripeptides.

Description

The liquid-phase fragment synthetic method of one species snake venom tripeptides
Technical field
The invention belongs to cosmetic technical field, and in particular to the liquid-phase synthesis process of the small peptide into polypeptide.
Background technology
Class snake venom tripeptides (H- β-Ala-Pro-DAB-NH-Bzl) is a kind of simulation venom toxin Waglerin I activity Small peptide, Waglerin I are found in the venom (Tripidolaemus wagleri) of Temple Viper poisonous snakes, are muscle nicotine Acetylcholinergic receptor (nmAChR) antagonist.H- β-Ala-Pro-DAB-NH-Bzl are that DSM dutch royal DSMs group is wholly-owned By biochemical science and technology, the fragment for imitating effective molecule protein (Waglerin1) synthesizes to obtain subsidiary PENTAPHARM Small molecule tripeptides, its chemical constitution is similar to poisonous snake serum, but safer and more effective compared to clostridium botulinum, therefore can safety applications Into cosmetics, there is outstanding glabrous skin, rapid anti-wrinkle performance.
At present, the method that the method for class snake venom tripeptides is combined using solid phase, liquid phase mostly is conventionally synthesized, i.e., first by 2- CTC Resin synthesis in solid state fragment Boc- β-Ala-Pro-DAB (Boc)-OH or Fmoc- β-Ala-Pro-DAB (Boc)-OH, then By fragment Boc- β-Ala-Pro-DAB (Boc)-OH or Fmoc- β-Ala-Pro-DAB (Boc)-OH and benzylamine synthesize Boc- β- Ala-Pro-DAB (Boc)-NH-Bzl or Fmoc- β-Ala-Pro-DAB (Boc)-NH-Bzl, is produced through deprotection group Thing, building-up process is more numerous and diverse, cost is high, therefore development technology is easy, the lower-cost peptide symthesis method of class snake venom three is to wide It is general be used in cosmetics class snake venom tripeptides it is significant.
The content of the invention
It is low, the simple class snake venom tripeptides of method that the technical problems to be solved by the invention are to provide a kind of synthesis cost Liquid-phase fragment synthetic method.
Technical scheme is made up of following step used by solving above-mentioned technical problem：
(1) H-Pro-DAB (Boc)-NH-Bzl is synthesized
1. using tetrahydrofuran as solvent, by Fmoc-Pro-OH and n-hydroxysuccinimide, N, N'- dicyclohexyl phosphinylidynes Imines stirring reaction 2~4 hours at ambient temperature, are filtered to remove precipitation, obtain Fmoc-Pro-OSu tetrahydrofuran solution.
2. after H-DAB (Boc)-OH and DIPEA are dissolved in into tetrahydrofuran, it is added to step and 1. obtains Fmoc-Pro-OSu tetrahydrofuran solution in, reaction is stirred at room temperature 1~2 hour, obtains Fmoc-Pro-DAB (Boc)-OH.
3. using tetrahydrofuran as solvent, by Fmoc-Pro-DAB (Boc)-OH, I-hydroxybenzotriazole, N, N'- diisopropyls Base carbimide, benzylamine stirring reaction 2~4 hours at ambient temperature, obtain Fmoc-Pro-DAB (Boc)-NH-Bzl.
It is 4. Fmoc-Pro-DAB (Boc)-NH-Bzl is molten with the tetrahydrofuran for the piperidines that volume fraction is 15%~20% Liquid removes Fmoc protection groups, obtains H-Pro-DAB (Boc)-NH-Bzl.
(2) Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl is synthesized
Using tetrahydrofuran as solvent, by Boc- β-Ala-OH, I-hydroxybenzotriazole, N, N'- diisopropylcarbodiimides, H-Pro-DAB (Boc)-NH-Bzl stirring reaction 2~4 hours at ambient temperature, obtain Boc- β-Ala-Pro-DAB (Boc)- NH-Bzl。
(3) H- β-Ala-Pro-DAB-NH-Bzl are synthesized
Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl are removed with the trifluoroacetic acid aqueous solution that volume fraction is 95% Fmoc protection groups, obtain H- β-Ala-Pro-DAB-NH-Bzl crude products；H- β-Ala-Pro-DAB-NH-Bzl crude products are pure through HPLC Change, freeze-drying, obtain H- β-Ala-Pro-DAB-NH-Bzl, i.e. class snake venom tripeptides.
Above-mentioned steps (1) 1. in, preferably Fmoc-Pro-OH, n-hydroxysuccinimide, N, N'- dicyclohexyl phosphinylidynes The mol ratio of imines is 1:1.0~1.2:1.0~1.2.
Above-mentioned steps (1) 2. in, preferred Fmoc-Pro-OH, H-DAB (Boc)-OH, DIPEA rub You are than being 1:1.0~1.2:1.5~2.5.
Above-mentioned steps (1) 3. in, preferably Fmoc-Pro-DAB (Boc)-OH, benzylamine, I-hydroxybenzotriazole, N, N'- The mol ratio of diisopropylcarbodiimide is 1:1.5~3:1.5~3:1.5~3.
In above-mentioned steps (2), preferably H-Pro-DAB (Boc)-NH-Bzl, Boc- β-Ala-OH, I-hydroxybenzotriazole, The mol ratio of N, N'- diisopropylcarbodiimide is 1:1.1~1.3:1.5~3:1.5~3.
The present invention using Fmoc-Pro-OH, H-DAB (Boc)-OH, benzylamine and Boc- β-Ala-OH cheap and easy to get as raw material, Synthesis cost is low, and method is simply easy, and a kind of reason is provided for class snake venom tripeptides (H- β-Ala-Pro-DAB-NH-Bzl) synthesis The liquid-phase fragment synthetic method thought.
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) H-Pro-DAB (Boc)-NH-Bzl is synthesized
1. 16.87g (0.05mol) Fmoc-Pro-OH and 6.33g (0.055mol) n-hydroxysuccinimide is weighed in appearance In device, 230mL tetrahydrofuran stirring and dissolvings are added, add 11.35g (0.055mol) N, N'- Dicyclohexylcarbodiimide, room Warm stirring reaction 3 hours, is filtered to remove precipitation, obtains Fmoc-Pro-OSu tetrahydrofuran solution.
2. 12.00g (0.055mol) H-DAB (Boc)-OH is added in 120mL tetrahydrofurans, 16.5mL is added (0.10mol) DIPEA, the Fmoc-Pro-OSu of step 1. tetrahydrofuran is added it to after stirring and dissolving In solution, reaction 1.5 hours is stirred at room temperature, 30~40 DEG C of rotary evaporation concentrations, 350mL ethyl acetate is added into concentrate, With the salt acid elution organic phase 3 times that mass fraction is 0.5%, anhydrous sodium sulfate drying, 30~40 DEG C of rotary evaporations concentrations, second is used Ether separates out precipitation, filters, and dries, obtains 21.86g Fmoc-Pro-DAB (Boc)-OH.
3. by 21.86g (0.04065mol) Fmoc-Pro-DAB (Boc)-OH, 10.98g (0.08130mol) 1- hydroxy benzenes And triazole is dissolved in 320mL tetrahydrofurans, 13.5mL (0.08130mol) N, N'- diisopropylcarbodiimide is added, stirring is anti- Answer 5 minutes, then add the solution of 8.71g (0.08130mol) benzylamines and 90mL tetrahydrofurans, reaction 3 hours is stirred at room temperature, 30~40 DEG C of rotary evaporation concentrations, 400mL ethyl acetate is added into concentrate, with the salt acid elution that mass fraction is 0.5% Organic phase 3 times, 30~40 DEG C of rotary evaporation concentrations, obtains Fmoc-Pro-DAB (Boc)-NH-Bzl.
4. 3. Fmoc-Pro-DAB (Boc)-NH-Bzl that step is obtained adds the piperidines that 300mL volume fractions are 20% Tetrahydrofuran solution in, be stirred at room temperature reaction 30 minutes, the concentration of 30~40 DEG C of rotary evaporations, add 400mL ether separate out it is heavy Form sediment, filtering, washed 2 times with ether, dry, obtain 12.01gH-Pro-DAB (Boc)-NH-Bzl.
(2) Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl is synthesized
6.74g (0.03563mol) Boc- β-Ala-OH, 8.03g (0.05938mol) I-hydroxybenzotriazole are dissolved in In 150mL tetrahydrofurans, and 9.2mL (0.05938mol) N, N'- diisopropylcarbodiimide is added, stirring reaction 5 minutes, so The solution of 12.01g (0.02969mol) H-Pro-DAB (Boc)-NH-Bzl and 180mL tetrahydrofurans is added afterwards, is stirred at room temperature anti- Answer 3 hours, 30~40 DEG C of rotary evaporation concentrations, 350mL ethyl acetate is added into concentrate, is 0.5% salt with mass fraction Acid elution organic phase 3 times, 30~40 DEG C of rotary evaporation concentrations, is separated out with ether and precipitated, filtered, dried, obtain 11.28gBoc- β-Ala-Pro-DAB(Boc)-NH-Bzl。
(3) H- β-Ala-Pro-DAB-NH-Bzl are synthesized
It is 95% that Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl that step (2) is obtained, which adds 110mL volume fractions, In trifluoroacetic acid aqueous solution, reaction 1 hour is stirred at room temperature, concentration of reaction solution, concentrate is added to separate out in 500mL ether and sunk Form sediment, be centrifuged off supernatant, precipitation is washed with ether, centrifuged 2 times, be dried in vacuo, obtain 6.80g H- β-Ala-Pro-DAB-NH- Bzl crude products.6.80g H- β-Ala-Pro-DAB-NH-Bzl crude products are purified through HPLC, purification condition：Pillar specification is GLP- ID50mm × 450mm, Detection wavelength 215nm, flow velocity 30mL/min, mobile phase A are water-soluble for the trifluoroacetic acid of volume fraction 0.1% Liquid, Mobile phase B are the acetonitrile solution of the trifluoroacetic acid of volume fraction 0.1%, and gradient is：B 35%~45%60min of phase, Refined solution obtains the H- β-Ala-Pro-DAB-NH-Bzl of 5.72g purity 97.4%, i.e. class snake through being concentrated under reduced pressure, being freeze-dried Malicious tripeptides, yield 51.30%.
Embodiment 2
The present embodiment step (1) 1. in, Fmoc-Pro-OH, n-hydroxysuccinimide, N, N'- dicyclohexyl phosphinylidynes The mol ratio of imines is 1:1.2:1.2, step (1) 2. in, Fmoc-Pro-OH, H-DAB (Boc)-OH, N, N- diisopropyls The mol ratio of ethamine is 1:1.2:2.5, step (1) 3. in, Fmoc-Pro-DAB (Boc)-OH, benzylamine, 1- hydroxy benzos three Azoles, N, the mol ratio of N'- diisopropylcarbodiimides is 1:3:3:3, in step (2), H-Pro-DAB (Boc)-NH-Bzl, Boc- β-Ala-OH, I-hydroxybenzotriazole, N, the mol ratio of N'- diisopropylcarbodiimides is 1:1.3:3:3, other steps It is same as Example 1, obtain the H- β-Ala-Pro-DAB-NH-Bzl of 5.35g purity 96.7%, i.e. class snake venom tripeptides, yield 47.98%.
Embodiment 3
The present embodiment step (1) 1. in, Fmoc-Pro-OH, n-hydroxysuccinimide, N, N'- dicyclohexyl phosphinylidynes The mol ratio of imines is 1:1:1, step (1) 2. in, Fmoc-Pro-OH, H-DAB (Boc)-OH, DIPEA Mol ratio be 1:1:1.5, step (1) 3. in, Fmoc-Pro-DAB (Boc)-OH, benzylamine, I-hydroxybenzotriazole, N, The mol ratio of N'- diisopropylcarbodiimides is 1:1.5:1.5:1.5, in step (2), H-Pro-DAB (Boc)-NH-Bzl, Boc- β-Ala-OH, I-hydroxybenzotriazole, N, the mol ratio of N'- diisopropylcarbodiimides is 1:1.1:1.5:1.5, other Step is same as Example 1, obtains the H- β-Ala-Pro-DAB-NH-Bzl of 5.79g purity 97.3%, i.e. class snake venom tripeptides, receives Rate 51.92%.

Claims (5)

1. the liquid-phase fragment synthetic method of a species snake venom tripeptides, it is characterised in that methods described comprises the steps of：
(1) H-Pro-DAB (Boc)-NH-Bzl is synthesized
1. using tetrahydrofuran as solvent, by Fmoc-Pro-OH and n-hydroxysuccinimide, N, N'- Dicyclohexylcarbodiimides Stirring reaction 2~4 hours at ambient temperature, precipitation is filtered to remove, obtains Fmoc-Pro-OSu tetrahydrofuran solution；
2. after H-DAB (Boc)-OH and DIPEA are dissolved in into tetrahydrofuran, it is added to what 1. step obtained In Fmoc-Pro-OSu tetrahydrofuran solution, reaction is stirred at room temperature 1~2 hour, obtains Fmoc-Pro-DAB (Boc)-OH；
3. using tetrahydrofuran as solvent, by Fmoc-Pro-DAB (Boc)-OH, I-hydroxybenzotriazole, N, N'- diisopropyl carbon Acid imide, benzylamine stirring reaction 2~4 hours at ambient temperature, obtain Fmoc-Pro-DAB (Boc)-NH-Bzl；
4. Fmoc-Pro-DAB (Boc)-NH-Bzl are taken off with the tetrahydrofuran solution for the piperidines that volume fraction is 15%~20% Except Fmoc protection groups, H-Pro-DAB (Boc)-NH-Bzl is obtained；
(2) Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl is synthesized
Using tetrahydrofuran as solvent, by Boc- β-Ala-OH, I-hydroxybenzotriazole, N, N'- diisopropylcarbodiimides, H- Pro-DAB (Boc)-NH-Bzl stirring reaction 2~4 hours at ambient temperature, obtain Boc- β-Ala-Pro-DAB (Boc)- NH-Bzl；
(3) H- β-Ala-Pro-DAB-NH-Bzl are synthesized
Boc- β-Ala-Pro-DAB (Boc)-NH-Bzl are removed into Fmoc with the trifluoroacetic acid aqueous solution that volume fraction is 95% to protect Base is protected, obtains H- β-Ala-Pro-DAB-NH-Bzl crude products；H- β-Ala-Pro-DAB-NH-Bzl crude products are purified through HPLC, freezed Dry, obtain H- β-Ala-Pro-DAB-NH-Bzl, i.e. class snake venom tripeptides.
2. the liquid-phase fragment synthetic method of class snake venom tripeptides according to claim 1, it is characterised in that：The step (1) 1. in, Fmoc-Pro-OH, n-hydroxysuccinimide, N, the mol ratio of N'- Dicyclohexylcarbodiimides are 1:1.0~ 1.2:1.0~1.2.
3. the liquid-phase fragment synthetic method of class snake venom tripeptides according to claim 1, it is characterised in that：The step (1) 2. in, Fmoc-Pro-OH, H-DAB (Boc)-OH, DIPEA mol ratio be 1:1.0~1.2:1.5~ 2.5。
4. the liquid-phase fragment synthetic method of class snake venom tripeptides according to claim 1, it is characterised in that：The step (1) 3. in, Fmoc-Pro-DAB (Boc)-OH, benzylamine, I-hydroxybenzotriazole, N, the mol ratio of N'- diisopropylcarbodiimides For 1:1.5~3:1.5~3:1.5~3.
5. the liquid-phase fragment synthetic method of class snake venom tripeptides according to claim 1, it is characterised in that：The step (2) In, H-Pro-DAB (Boc)-NH-Bzl, Boc- β-Ala-OH, I-hydroxybenzotriazole, N, N'- diisopropylcarbodiimides Mol ratio is 1:1.1~1.3:1.5~3:1.5~3.
CN201711284541.1A 2017-12-07 2017-12-07 The liquid-phase fragment synthetic method of one species snake venom tripeptides Pending CN107857797A (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110950926A (en) * 2019-12-31 2020-04-03 山东济肽生物科技有限公司 Liquid phase synthesis method of snake venom-like tripeptide
CN112321674A (en) * 2020-10-30 2021-02-05 润辉生物技术（威海）有限公司 Snake venom-like tripeptide fatty acid derivative and preparation method and application thereof
CN112409445A (en) * 2020-11-24 2021-02-26 浙江湃肽生物有限公司 Solid-phase synthesis method of snake venom-like tripeptide
CN112430253A (en) * 2020-11-24 2021-03-02 浙江湃肽生物有限公司 Liquid phase synthesis method of snake venom-like tripeptide
CN113045623A (en) * 2019-12-27 2021-06-29 深圳翰宇药业股份有限公司 Liquid phase synthesis method of snake venom peptide SYN-AKE
CN113896763A (en) * 2021-12-10 2022-01-07 浙江湃肽生物有限公司深圳分公司 Synthesis method of snake venom-like tripeptide
CN113912672A (en) * 2021-11-08 2022-01-11 汉肽生物医药集团有限公司 Synthesis method of dipeptide diaminobutyrylbenzylamide
CN114369139A (en) * 2020-10-14 2022-04-19 成都泰莱康科技有限公司 Preparation method of snake venom-like tripeptide
CN114380887A (en) * 2021-12-09 2022-04-22 深圳翰宇药业股份有限公司 Liquid phase fragment synthesis method of snake venom-like tripeptide
CN115043903A (en) * 2022-05-07 2022-09-13 浙江湃肽生物股份有限公司 Liquid phase synthesis method of snake venom-like tripeptide

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WO2009138801A2 (en) * 2008-05-14 2009-11-19 Nb Labs Limited Cosmetic formulation
CN103570804A (en) * 2013-09-11 2014-02-12 深圳市维琪医药研发有限公司 Synthetic method of polypeptide with skin activity

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CN101061134A (en) * 2004-11-02 2007-10-24 彭特法姆股份公司 Novel topical application agents against mimic and age-related wrinkles
WO2009138801A2 (en) * 2008-05-14 2009-11-19 Nb Labs Limited Cosmetic formulation
CN103570804A (en) * 2013-09-11 2014-02-12 深圳市维琪医药研发有限公司 Synthetic method of polypeptide with skin activity

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045623A (en) * 2019-12-27 2021-06-29 深圳翰宇药业股份有限公司 Liquid phase synthesis method of snake venom peptide SYN-AKE
CN110950926A (en) * 2019-12-31 2020-04-03 山东济肽生物科技有限公司 Liquid phase synthesis method of snake venom-like tripeptide
CN110950926B (en) * 2019-12-31 2020-10-16 山东济肽生物科技有限公司 Liquid phase synthesis method of snake venom-like tripeptide
CN114369139A (en) * 2020-10-14 2022-04-19 成都泰莱康科技有限公司 Preparation method of snake venom-like tripeptide
CN114369139B (en) * 2020-10-14 2024-04-19 成都泰莱康科技有限公司 Preparation method of snake venom tripeptide
CN112321674A (en) * 2020-10-30 2021-02-05 润辉生物技术（威海）有限公司 Snake venom-like tripeptide fatty acid derivative and preparation method and application thereof
CN112409445A (en) * 2020-11-24 2021-02-26 浙江湃肽生物有限公司 Solid-phase synthesis method of snake venom-like tripeptide
CN112430253A (en) * 2020-11-24 2021-03-02 浙江湃肽生物有限公司 Liquid phase synthesis method of snake venom-like tripeptide
CN113912672A (en) * 2021-11-08 2022-01-11 汉肽生物医药集团有限公司 Synthesis method of dipeptide diaminobutyrylbenzylamide
CN114380887A (en) * 2021-12-09 2022-04-22 深圳翰宇药业股份有限公司 Liquid phase fragment synthesis method of snake venom-like tripeptide
CN113896763A (en) * 2021-12-10 2022-01-07 浙江湃肽生物有限公司深圳分公司 Synthesis method of snake venom-like tripeptide
CN115043903A (en) * 2022-05-07 2022-09-13 浙江湃肽生物股份有限公司 Liquid phase synthesis method of snake venom-like tripeptide

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Application publication date: 20180330