CN112430253A - Liquid phase synthesis method of snake venom-like tripeptide - Google Patents
Liquid phase synthesis method of snake venom-like tripeptide Download PDFInfo
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- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
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Abstract
The invention discloses a liquid phase synthesis method of snake venom tripeptide, which takes Fmoc-dab (Boc) -OH, benzylamine, Boc-beta-Ala-OH, H-Pro-OMe.HCl/H-Pro-OBzl.HCl as raw materials, DIC/HOBt, DIC/HOAt, EDC/HOBt, HATU, HBTU and the like as reagents to synthesize polypeptide H-beta-Ala-Pro-dab (Boc) -NHBzl, and then a bar protecting group Boc is cut off and purified under an acidic condition to obtain a product. The invention uses a solid-phase synthesis method to directly obtain a product H-beta-Ala-Pro-Dab (Boc) -NHBzl, overcomes the stability problem of CTC resin in the product, adopts a method of connecting Fmoc-Dab (Boc) -OH and benzylamine to avoid the racemization problem of Dab, and has the advantages of short synthesis process route, very short production period, suitability for large-scale production, good method stability and suitability for large-scale production.
Description
Technical Field
The present invention relates to a method for producing a polypeptide. More particularly, the invention relates to a method for preparing H-beta-Ala-Pro-Dab-NHBzl.
Background
The H-beta-Ala-Pro-Dab-NHBzl is a small molecular polypeptide simulating the activity of snake venom toxin Waglerin I, clinical tests show that the polypeptide can reduce wrinkle generation by inhibiting muscle contraction, has excellent smooth and rapid wrinkle removing performance, and the H-beta-Ala-Pro-Dab-NH-Bzl acts on a postsynaptic membrane and is a reversible antagonist of muscle nicotinic acetylcholine receptor (mmAChR), so that the search for a proper synthetic method has important significance for industrialization of the small molecular polypeptide.
The common chemical synthesis methods for polypeptide synthesis comprise liquid phase synthesis and solid phase synthesis, and for small molecular polypeptides, polypeptides with amino acids smaller than 10 amino acids are generally synthesized by a liquid phase synthesis method, but the liquid phase synthesis method has more steps and is relatively complex, the purity of crude products obtained by completely adopting the liquid phase synthesis method is not high, the total yield is not high, the solid phase synthesis method is adopted, the removal difficulty is relatively high, the cost-benefit ratio is extremely low, and the limitation of each method cannot be avoided by completely adopting the solid phase synthesis or completely adopting the liquid phase synthesis method.
The method used in the invention patent publication No. CN107936108A, entitled liquid phase fragment Synthesis of a Snake venom-like tripeptide, used two hydrolysis reactions with a possibility of racemization, especially hydrolysis of Dab-OMe, but with a very low possibility of racemization for Pro-OMe. In addition, in the reaction for linking Boc- β -Ala-Pro-Dab (Boc) -OH to benzylamine, Dab (Boc) main chain amino acid is not an oxycarbonyl-based protecting group, racemization of Dab is very likely to occur in the condensation reaction, and the product quality is greatly affected.
In the technical route mentioned in the patent publication No. CN107857797A, the patent name of the invention is a liquid phase fragment synthesis method of snake venom tripeptide, firstly, Fmoc-Pro-OH is prepared to react with H-dab (Boc) -OH to form Fmoc-Pro-dab (Boc) -OH, during the reaction process of Fmoc-Pro-OSu and H-dab (Boc) -OH, the reaction is difficult and the yield is low due to the larger steric hindrance of Pro amino acid; in addition, in the Fmoc-Pro-Dab (Boc) -OH and benzylamine linking reaction, Dab (Boc) main chain amino acid is not an oxycarbonyl-based protecting group, racemization of Dab is very easily generated in the condensation reaction, and the product quality is greatly influenced.
In the technical route mentioned in the patent publication No. CN103570804A, namely the invention patent of a liquid-phase fragment synthesis method of snake-like venom tripeptide, the snake-like venom tripeptide is obtained by a solid-liquid combination method, and in the technical route, CTC resin is used, so that the CTC resin has a very high stability problem and the process control is difficult. In the Boc-beta-Ala-Pro-Dab (Boc) -OH coupling reaction with benzylamine, Dab (Boc) main chain amino acid is not an oxycarbonyl protecting group, so that racemization of Dab is very easily generated in the condensation reaction, and the product quality is greatly influenced.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a liquid phase synthesis method of snake venom-like tripeptide, which can avoid racemization of Dab, has short process route, very short production period and stable resin and is suitable for large-scale production.
In order to achieve the purpose, the invention provides the following technical scheme:
a liquid phase synthesis method of snake venom-like tripeptide is characterized by comprising the following steps:
(1) synthesis of Fmoc-dab (Boc) -NHBzl
Adding DMF into a reactor, adding Fmoc-dab (Boc) -OH, benzylamine and NMM, adding DMF for washing, stirring for dissolving, slowly adding EDCI, and stirring at room temperature for reacting completely;
after the reaction is completed, adding a large amount of water into the reaction liquid to separate out a viscous solid, then removing a supernatant, washing the solid with water, adding DCM into the solid to dissolve, layering after dissolution, removing a water phase, drying a DCM layer with magnesium sulfate, filtering to obtain a DCM solution, and removing DCM by rotary evaporation to obtain a white solid product;
(2) synthesis of H-dab (Boc) -NHBzl
Dissolving the white solid product obtained in the step (1) by using a 20% Pip/DCM solution, stirring and reacting until the reaction is completely carried out, and starting to treat the reaction;
after the reaction is completed, adding water into the reaction liquid, extracting and layering to obtain an organic phase, washing twice, drying the organic phase with magnesium sulfate, filtering, collecting filtrate, removing the solvent by rotary evaporation to obtain a solid, pulping and washing the solid with petroleum ether ethyl acetate twice, and filtering to obtain an oily product;
(3) synthesis of Boc-beta-Ala-Pro-OMe
Uniformly stirring Boc-beta-Ala-OH, H-Pro-OMe.HCI and HoBT with a DCM solution, slowly adding NMM, finally slowly adding EDCI, and stirring for reaction until the reaction is complete;
adding the reaction solution into water, layering to obtain an organic phase, washing the organic phase with a sodium bicarbonate aqueous solution and a hydrochloric acid aqueous solution once respectively, washing with water once, drying with anhydrous magnesium sulfate, filtering, and selectively removing the solvent from the filtrate to obtain an oily substance;
(4) synthesis of Boc-beta-Ala-Pro-OH
Adding methanol into the oily substance obtained in the step (3) to dissolve, adding water into NaOH to dissolve, and slowly adding the NaOH into the methanol solution to stir for reaction;
after the reaction is completed, concentrating to remove part of methanol, adding ethyl acetate and petroleum ether, stirring, standing for layering, collecting a water phase, extracting the water phase with petroleum ether and ethyl acetate once again, collecting a lower-layer water phase, adjusting the pH value of the water phase to 3-4 with concentrated hydrochloric acid and water, extracting with DCM, collecting an organic phase, washing with saturated NaCl, drying with anhydrous Na2SO4, filtering, and removing DCM by rotary evaporation to obtain an oily product;
(5) synthesis of Boc-beta-Ala-Pro-dab (Boc) -NHBzl
Respectively dissolving the oily products obtained in the step (4) and the step (2) with DMF, uniformly mixing the two solutions, adding HoBT, then slowly adding EDCI, and stirring to react completely;
after the reaction is completed, adding water and ethyl acetate, stirring, extracting and layering, washing an organic phase with a Na2CO3 aqueous solution, washing with a hydrochloric acid solution once, washing with water once, washing with saturated NaCl once, drying with magnesium sulfate, filtering, and removing ethyl acetate by rotary evaporation to obtain an oily product;
(6) synthesis of H-beta-Ala-Pro-Dab-NHBzl
And (5) adding a hydrochloric acid aqueous solution into the oily product obtained in the step (5), stirring to react completely, performing rotary evaporation to remove water to obtain a product, and purifying and inverting the product to obtain the product.
In summary, the following steps:
in the technical route, a full liquid phase synthesis method is adopted, Fmoc-Dab (Boc) -OH is used as a raw material, a snake venom tripeptide product is finally obtained through 6 steps of reaction, the racemization problem of Dab is not involved, the route is reliable, the stability problem of CTC resin is overcome, the racemization problem of Dab is avoided by adopting a method of connecting Fmoc-Dab (Boc) -OH and benzylamine, the synthesis process route is short, the production period is very short, the method is suitable for large-scale production, the method is good in stability, and the method is suitable for large-scale production.
Drawings
FIG. 1 is a schematic representation of the liquid phase synthesis scheme of a snake venom-like tripeptide according to the present invention;
FIG. 2 is a synthetic scheme of step (1) of the present invention;
FIG. 3 is a synthetic route to step (2) of the present invention;
FIG. 4 is a synthetic route diagram of step (3) of the present invention;
FIG. 5 is a synthetic route diagram of step (4) of the present invention;
FIG. 6 is a synthetic route to step (5) of the present invention;
FIG. 7 is a synthetic route to step (6) of the present invention;
FIG. 8 is the hplc profile of the H- β -Ala-Pro-Dab-NHBzl product in accordance with an embodiment of the present invention.
Detailed Description
The liquid phase synthesis method of the snake venom-like tripeptide of the invention is further illustrated by the following examples:
(1) synthesis of Fmoc-dab (Boc) -NHBzl
18L of DMF was added to a 100L reaction vessel, Fmoc-dab (Boc) -OH (200.0 g, 454 mmol) and HoBT (79.9 g, 590mmol), BnNH2 (48.6 g, 454 mmol), NMM (59.7g, 590mmol) were added, 2L of DMF was added and the solution was dissolved by stirring, EDCI (1132.2 g, 5906 mmol) was slowly added and the reaction was stirred at room temperature overnight.
TLC detects that the raw material is completely reacted, the reaction solution is added into a large amount of water to separate out a viscous solid, then the supernatant is discarded, and the solid is washed by water. The solid was dissolved in DCM, and after dissolution the aqueous phase was removed. The DCM layer was dried over magnesium sulfate and filtered to give a DCM solution. DCM was removed by rotary evaporation to give the product as a white solid (Fmoc-dab (Boc) -NHBzl) 200g, 83% yield.
(2) Synthesis of H-dab (Boc) -NHBzl
Fmoc-dab (Boc) -NHBzl was dissolved in 2L of 20% Pip/DCM solution and the reaction was stirred for 2 hours and the starting material reaction was complete and the workup was started. Adding 1L of water into the reaction liquid, extracting and layering to obtain an organic phase, washing twice, drying the organic phase with magnesium sulfate and filtering, collecting filtrate, carrying out rotary evaporation to remove the solvent to obtain a solid, pulping and washing the solid with petroleum ether ethyl acetate twice, and filtering to obtain 109g of an oily product (Boc-beta-Ala-OH) with the yield of 94%.
(3) Synthesis of Boc-beta-Ala-Pro-OMe
Uniformly stirring Boc-beta-Ala-OH (67.3 g, 407.6 mmol), H-Pro-OMe.HCI (734.1 g, 387.2 mmol) and HoBT (551.2 g, 407.6 mmol) with DCM (7L), slowly adding NMM (41.3 g, 407.6 mmol), slowly adding EDCI (78.1 g, 407.6 mmol), stirring for overnight reaction, detecting the remaining small amount of raw materials by TLC, supplementing EDCI (0.3 eq, 122 g), continuously stirring for 2 hours until the raw materials are basically completely reacted, adding the reaction solution into water, layering to obtain an organic phase, washing the organic phase once with aqueous sodium bicarbonate solution and aqueous hydrochloric acid solution, washing once with water, drying over anhydrous magnesium sulfate for 20 minutes, filtering, and selectively removing the solvent from the filtrate to obtain an oily substance (Boc-beta-Ala-Pro-OMe) 120g with a yield of 103%
(4) Synthesis of Boc-beta-Ala-Pro-OH
Boc-beta-Ala-Pro-OMe (120g, 387mmol) was dissolved in 120mL of methanol, 21.7g of NaOH was weighed and dissolved in 542mL of water, and slowly added to the methanol solution and stirred for 2 hours.
After TLC detection reaction is completed, concentrating to remove part of methanol, adding ethyl acetate and petroleum ether (1: 1,150 ML), stirring for 10min, standing for layering, and collecting water phase. The aqueous phase was extracted once more with petroleum ether and ethyl acetate, the lower aqueous phase was collected, the aqueous phase was adjusted to pH 3-4 with 500ml concentrated HCl +3500ml water, extracted 3 times with 3L DCM, and the organic phase was collected. Washed with saturated NaCl, dried over anhydrous Na2SO4, filtered, and the DCM was removed by rotary evaporation to give 115g of an oily product (Boc-. beta. -Ala-Pro-OH) in 104% yield.
(5) Synthesis of Boc-beta-Ala-Pro-dab (Boc) -NHBzl
Boc- β -Ala-Pro-OH (120g, 387mmol) was dissolved in DMF (600 ml), Boc- β -Ala-OH (109 g, 371 mol) was dissolved in DMF (600 ml), the solution of Boc- β -Ala-Pro-OH and Boc- β -Ala-OH in DMF was mixed well, HoBT (60.8 g, 44.5 mmol) was added followed by slow addition of EDCI (853.1 g, 4450 mmol) and the reaction stirred for 3 h.
The TLC detection reaction was almost complete, 3L water and 3L ethyl acetate were added, stirring was carried out for 10min, extraction was carried out for delamination, the organic phase was washed 2 times with 5% Na2CO3 aqueous solution, washed once with 1M hydrochloric acid solution, washed once with water, washed once with saturated NaCl, dried over magnesium sulfate, filtered, and the ethyl acetate was removed by rotary evaporation to give 208g of an oily product with a yield of 97.7%.
(6) Synthesis of H-beta-Ala-Pro-Dab-NHBzl
Adding 1L of hydrochloric acid aqueous solution (6 mol/L) into Boc-beta-Ala-Pro-Dab (Boc) -NHBzl (208 g, 361 mmol), stirring for reacting for 3 hours, removing water by rotary evaporation to obtain a product, and purifying and carrying out reversed phase preparation on the product to obtain 48.2g of product (H-beta-Ala-Pro-Dab-NHBzl) with the yield of 35.7%.
The purity is detected by HPLC, and reaches more than 98%, and in the product of our batch, the maximum single impurity of the product is 0.1952%, and the purity is 99.6083%.
The above description is provided for further details of the present invention with reference to specific modified embodiments, and it should not be considered that the present invention is limited to these specific embodiments, and it should be understood that those skilled in the art may make several simple deductions or substitutions without departing from the spirit of the present invention, and all such alternatives are deemed to fall within the scope of the present invention.
Claims (1)
1. A liquid phase synthesis method of snake venom-like tripeptide is characterized by comprising the following steps:
synthesis of Fmoc-dab (Boc) -NHBzl
a. Adding DMF into a reactor, adding Fmoc-dab (Boc) -OH, benzylamine and NMM, adding DMF for washing, stirring for dissolving, slowly adding EDCI, and stirring at room temperature for reacting completely;
b. after the reaction is completed, adding a large amount of water into the reaction liquid to separate out a viscous solid, then removing a supernatant, washing the solid with water, adding DCM into the solid to dissolve, layering after dissolution, removing a water phase, drying a DCM layer with magnesium sulfate, filtering to obtain a DCM solution, and removing DCM by rotary evaporation to obtain a white solid product;
synthesis of H-dab (Boc) -NHBzl
Dissolving the white solid product obtained in the step (1) by using a 20% Pip/DCM solution, stirring and reacting until the reaction is completely carried out, and starting to treat the reaction;
after the reaction is completed, adding water into the reaction liquid, extracting and layering to obtain an organic phase, washing twice, drying the organic phase with magnesium sulfate, filtering, collecting filtrate, removing the solvent by rotary evaporation to obtain a solid, pulping and washing the solid with petroleum ether ethyl acetate twice, and filtering to obtain an oily product;
synthesis of Boc-beta-Ala-Pro-OMe
Uniformly stirring Boc-beta-Ala-OH, H-Pro-OMe.HCI and HoBT with a DCM solution, slowly adding NMM, finally slowly adding EDCI, and stirring for reaction until the reaction is complete;
adding the reaction solution into water, layering to obtain an organic phase, washing the organic phase with a sodium bicarbonate aqueous solution and a hydrochloric acid aqueous solution once respectively, washing with water once, drying with anhydrous magnesium sulfate, filtering, and selectively removing the solvent from the filtrate to obtain an oily substance;
synthesis of Boc-beta-Ala-Pro-OH
Adding methanol into the oily substance obtained in the step (3) to dissolve, adding water into NaOH to dissolve, and slowly adding the NaOH into the methanol solution to stir for reaction;
after the reaction is completed, concentrating to remove part of methanol, adding ethyl acetate and petroleum ether, stirring, standing for layering, collecting a water phase, extracting the water phase with petroleum ether and ethyl acetate once again, collecting a lower-layer water phase, adjusting the pH value of the water phase to 3-4 with concentrated hydrochloric acid and water, extracting with DCM, collecting an organic phase, washing with saturated NaCl, drying with anhydrous Na2SO4, filtering, and removing DCM by rotary evaporation to obtain an oily product;
synthesis of Boc-beta-Ala-Pro-dab (Boc) -NHBzl
Respectively dissolving the oily products obtained in the step (4) and the step (2) with DMF, uniformly mixing the two solutions, adding HoBT, then slowly adding EDCI, and stirring to react completely;
after the reaction is completed, adding water and ethyl acetate, stirring, extracting and layering, washing an organic phase with a Na2CO3 aqueous solution, washing with a hydrochloric acid solution once, washing with water once, washing with saturated NaCl once, drying with magnesium sulfate, filtering, and removing ethyl acetate by rotary evaporation to obtain an oily product;
synthesis of H-beta-Ala-Pro-Dab-NHBzl
And (5) adding a hydrochloric acid aqueous solution into the oily product obtained in the step (5), stirring to react completely, performing rotary evaporation to remove water to obtain a product, and purifying and inverting the product to obtain the product.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
CN114213503A (en) * | 2021-12-31 | 2022-03-22 | 上海予利生物科技股份有限公司 | Synthesis 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 |
CN117486968A (en) * | 2024-01-03 | 2024-02-02 | 深圳创元生物医药科技有限公司 | Preparation method of snake venom peptide |
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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 |
CN107857797A (en) * | 2017-12-07 | 2018-03-30 | 陕西慧康生物科技有限责任公司 | The liquid-phase fragment synthetic method of one species snake venom tripeptides |
CN107936108A (en) * | 2017-12-05 | 2018-04-20 | 陕西慧康生物科技有限责任公司 | The liquid-phase synthesis process of one species snake venom tripeptides |
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 |
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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 |
CN107936108A (en) * | 2017-12-05 | 2018-04-20 | 陕西慧康生物科技有限责任公司 | The liquid-phase synthesis process of one species snake venom tripeptides |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
CN114213503A (en) * | 2021-12-31 | 2022-03-22 | 上海予利生物科技股份有限公司 | 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 |
CN117486968A (en) * | 2024-01-03 | 2024-02-02 | 深圳创元生物医药科技有限公司 | Preparation method of snake venom peptide |
CN117486968B (en) * | 2024-01-03 | 2024-03-29 | 深圳创元生物医药科技有限公司 | Preparation method of snake venom peptide |
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