CN115368221B - Small molecule carrier, preparation method thereof and application thereof in polypeptide synthesis - Google Patents
Small molecule carrier, preparation method thereof and application thereof in polypeptide synthesis Download PDFInfo
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Abstract
The invention discloses a small molecular carrier shown in a formula I, which has a structural formula shown in the specification, wherein R is a linear chain or branched chain alkyl of C18-C26. Further, R is a C18-C26 linear alkyl group, such as C18, C19, C20, C21, C22, C23, C24, C25, C26 linear alkyl groups. In another aspect, the invention discloses the use of and methods for synthesizing polypeptides using small molecule vectors of formula I. The polypeptide synthesis method has mild reaction conditions, low cost and easy synthesis of the carrier, and the purity of the obtained product is obviously improved compared with the prior art, so that the method is a green and efficient synthesis method.
Description
Technical Field
The invention belongs to the technical field of polypeptide synthesis, and particularly relates to a small molecule carrier shown in a formula I, a preparation method thereof and application of the small molecule carrier in polypeptide synthesis.
Background
The polypeptide is a special compound formed by connecting less than 100 amino acids through amide bonds, and has special physiological activity, so that the polypeptide has wider application in the fields of pharmacy, biology, cosmetics and the like, and a research hot spot of chemistry family is formed by how to synthesize the polypeptide in a large scale and high efficiency. Generally, the liquid phase synthesis (LPPS) and the solid phase synthesis (SPPS) are adopted, the liquid phase synthesis has high reaction speed and large reaction scale, but the liquid phase synthesis is only suitable for synthesizing the polypeptide with less than 5 amino acids because the polypeptide intermediate is difficult to purify. In 1963, merrifield first proposed a solid-phase polypeptide synthesis method (SPPS) in which amino acids were immobilized on a resin via chemical bonds, which reduced the problem of purification of the synthesized polypeptide intermediates. The solid-phase synthesis technology of the polypeptide is developed vigorously, and the solid-phase synthesis technology of the polypeptide is the mainstream method for synthesizing the polypeptide on a large scale in industry at present, but the solid-phase synthesis technology of the polypeptide has the limitations, and firstly, the resin has limited loading capacity, and the resin has high price and is not recyclable, so that the polypeptide synthesis efficiency is low, and the cost is high. In the second step, in the peptide bond generation reaction, reactants are in solid-liquid phases, so that the reaction speed is low, the required amino acid feeding proportion is high, and the waste of materials is caused. Based on the obvious disadvantages of solid phase synthesis, scientists have continuously explored new solutions, developed many new liquid phase synthesis methods, have the advantage of easy purification of solid phase synthesis, and are applied to synthesis of long chain polypeptides.
Takahashi et al, 2012, published an effective liquid phase synthesis method:
(org. Lett.2012,14, 4514-4517.) the core of this method consists in the synthesis of polypeptides with an amide bond end, such as eptifibatide, using a long chain alkoxy substituted benzhydrylamine as a carrier. Takahashi et al in 2017 further improved
Methods (Angew. Chem. Inter. Ed.2017,56,7803-7807.&CN107011132 a), the linear alkoxy substituent group in the benzhydryl carrier is replaced by branched alkoxy phytol group, this change increases the solubility of the carrier, so that the by-product generated can be removed only by washing with sodium carbonate aqueous solution after the reaction is completed, and the product is left in solution for the connection of the next amino acid, thereby greatly simplifying the post-reaction treatment process. />
The method combines the advantages of polypeptide liquid phase synthesis and solid phase synthesis, so as to makeThe problem of difficult synthesis of polypeptides with strong hydrophobicity is solved, but there are also some obvious disadvantages such as: the used benzhydryl derivative carrier has poor solubility, needs to react in chloroform, has gelation phenomenon along with the increase of the number of amino acids, and has complicated carrier synthesis steps and high cost.
A polypeptide liquid phase synthesis method (CN 112175002A & CN 111269261A) taking diphenyl phosphonooxy substituted benzhydryl derivative as a carrier is developed by light transmission and the like of national northwest industrial university, an ethyl acetate/normal hexane solvent system is adopted to precipitate and separate intermediates, and the solvent system has low polarity and poor solubility for some high-polarity impurities and reagents, so that the impurities possibly remain in the synthesized intermediates, thereby influencing the next reaction.
Disclosure of Invention
In order to overcome the defects of the existing polypeptide liquid phase synthesis technology, the application provides a small molecule carrier shown in the formula I, and the small molecule carrier is applied to polypeptide liquid phase synthesis, so that a satisfactory effect is obtained. The method takes low-toxicity dichloromethane as a reaction solvent, and after the reaction is finished, polypeptide intermediates are precipitated and separated in a high-polarity solvent such as acetonitrile or N, N-dimethylformamide, so that excessive raw materials, condensation reagents, catalysts and other high-polarity impurities used in the reaction can be fully dissolved in the solvent for removal, the reaction condition is mild, the carrier is low in cost and easy to synthesize, the purity of the obtained product is obviously improved compared with the prior art, and the method is a green and efficient synthesis method.
The invention comprises the following technical scheme:
in a first aspect, the present invention provides a small molecule carrier of formula I, which has the following structural formula:
wherein R is a C18-C26 linear or branched alkyl group.
Preferably, R is a C18-C26 linear alkyl group, such as C18, C19, C20, C21, C22, C23, C24, C25, C26 linear alkyl.
In a specific embodiment of the invention, the small molecule carrier has the following structural formula:
in a second aspect, the present invention provides a method for preparing a small molecule carrier of formula i, the method comprising:
(1) Reacting hydroxynaphthalene formaldehyde shown in a formula III with alkyl halide RX under a base condition to obtain alkoxy naphthalene formaldehyde shown in a formula II;
(2) The alkoxyl naphthaldehyde shown in the formula II is prepared into the micromolecular carrier shown in the formula I under the condition of borohydride or catalytic hydrogenation reducing agent.
Wherein R is a C18-C26 linear or branched alkyl group, and X is Cl, br or I.
Preferably, R is a C18-C26 linear alkyl group, such as C18, C19, C20, C21, C22, C23, C24, C25, C26 linear alkyl.
Preferably, the alkali in the step (1) is selected from one or more than two of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
Preferably, the borohydride in the step (2) is selected from one or more than two of sodium borohydride, potassium borohydride and lithium borohydride.
Preferably, the catalytic hydrogenation reducing agent in step (2) is selected from palladium on carbon. One or more of palladium hydroxide/carbon and Raney nickel.
In a third aspect, the invention provides a use of a small molecule vector of formula I in polypeptide synthesis.
Preferably, the polypeptide is a compound formed by connecting less than or equal to 100 amino acids through an amide bond.
In a specific embodiment of the invention, the polypeptide is carnosine.
In a fourth aspect, the present invention provides a method for synthesizing a polypeptide using a small molecule carrier of formula I, comprising the steps of:
(1) In an organic solvent, carrying out esterification reaction on a small molecular carrier and Fmoc-protected amino acid under the action of a condensing agent, adding a quenching agent to quench the reaction after 3-4 hours, adding a Fmoc-removing reagent to react for 3-4 hours, concentrating, adding acetonitrile or DMF into a concentrated solution, precipitating, and filtering to obtain an amino acid carrier compound;
(2) Dissolving the amino acid carrier complex obtained in the step (1) in an organic solvent, adding Fmoc-protected amino acid to be connected, carrying out esterification reaction under the action of a condensing agent, adding a quencher to quench the reaction after 3-4 hours, adding a Fmoc-removing reagent to react for 3-4 hours, concentrating, adding acetonitrile or DMF into a concentrated solution, precipitating, filtering to obtain two amino acid carrier complexes, and repeating the above operation until all amino acids of a target polypeptide are connected;
(3) And (3) adding a cracking reagent into the polyamino acid carrier complex obtained in the step (2), and recovering the micromolecular carrier to obtain the target polypeptide.
The organic solvents include, but are not limited to, methylene chloride, ethanol, acetonitrile.
The condensing agent is selected from one or more than two of Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), 2- (1H-benzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HBTU), 4-Dimethylaminopyridine (DMAP) and 1-Hydroxybenzotriazole (HOBT).
The quenching agent is water or amine compound, such as n-propylamine, isopropylamine or butylamine.
The Fmoc protecting group removing reagent is selected from one or more than two of diethylamine, piperidine, 1, 8-diazabicyclo [5.4.0] -7-undecene (DBU), morpholine and 3-mercaptopropionic acid.
The cleavage reagent is trifluoroacetic acid (CF) 3 CO 2 H) The mass ratio of the mixture of Triisopropylsilane (TIS) and water is 95:2.5:2.5.
In the reaction process for synthesizing the polypeptide by utilizing the small molecular carrier, the small molecular carrier and Fmoc-protected amino acid are subjected to esterification reaction under the action of a condensing agent, fmoc-protected groups are removed after the reaction is quenched, the exposed amino acid carrier compound is precipitated in a high-polarity solvent such as acetonitrile or N, N-dimethylformamide, excessive condensing agent, amino acid and reaction byproducts are dissolved in the solvent, and the amino acid carrier compound with extremely high purity can be obtained by separation through simple filtration.
The small molecular carrier shown in the formula I is used for polypeptide liquid phase synthesis, overcomes the defects of poor solubility, high carrier cost, difficult impurity removal and the like in the current polypeptide liquid phase synthesis, and has the advantages of simplicity, high efficiency and low cost.
Drawings
FIG. 1 Small molecule Carrier Compounds prepared in example 1 1 H NMR spectrum
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1Synthesis of small molecule vectors
The synthetic route is shown in the following diagram:
experimental operation:
s1: 100mL of N, N-dimethylformamide, 4.02g of 2-hydroxy-1-naphthaldehyde, 10g of 1-bromobehenyl, 6.45g of anhydrous potassium carbonate and the like are sequentially added into a dry reaction bottle, the temperature is raised to 80 ℃ after the addition to react for 8 hours, and TLC detection (developing agent: N-hexane: ethyl acetate=10:1) is finished. Cooling to room temperature, slowly adding the reaction solution into a mixed solution of 1M hydrochloric acid (120 mL) and water (60 mL) at 0-10 ℃, adding Bi Jiaoban h, filtering, washing a filter cake to be neutral by water, fully washing by methanol, and drying under reduced pressure to obtain 10.87g of behenyl dialkoxy naphthalene formaldehyde with the yield of 97%;
s2: 200mL of tetrahydrofuran, 66mL of methanol and 10.0g of behenyl naphthacene formaldehyde are sequentially added into a dry reaction bottle, stirred and dissolved at room temperature, then 4.0g of sodium borohydride is slowly added, stirred and reacted at room temperature for 2 hours after the completion of the reaction, TLC (developing agent is n-hexane: ethyl acetate=10:1) is adopted to detect the completion of the reaction, the reaction solution is added into 400mL of ice water, 180mL of 1M hydrochloric acid is slowly added dropwise at the temperature below 10 ℃, the stirring is carried out for 0.5 hour, the obtained solution is concentrated and distilled under reduced pressure at the temperature of 40 ℃ to remove the tetrahydrofuran, then 1M hydrochloric acid is added to adjust the pH to 5-7, suction filtration is carried out, 80mL of methanol is used for fully stirring and washing, and suction drying is carried out to obtain 9.9g of behenyl naphthacene methanol, and the yield is 98%.
The prepared target compound is subjected to 1 H nuclear magnetism identification, using Bruker Avance II-400 nuclear magnetic spectrometer to measure, CDCl3 as solvent, TMS as internal standard, obtaining 1 The H nuclear magnetic spectrum is as follows: 1 H NMR(CDCl3,400MHz)δ8.11(d,1H)，7.79(t,2H)，7.51(t,1H)，7.35(t,1H)，7.26(d,1H)，5.19(s,2H)，4.13(t,2H)，1.94(s,1H)，1.81～1.88(m,2H)，1.46～1.53(m,2H)，1.20～1.40(m,36H)，0.87(t,3H)。 1 the H NMR spectrum is shown in figure 1 of the specification.
Example 2Synthesis of carnosine Using Small molecule vectors
1.0g of the target compound (carrier I) prepared in example 1 was dissolved in 15mL of methylene chloride, and Fmoc-His (Trt) -OH 1.93g, N-Diisopropylcarbodiimide (DIC) 0.63g and 4-Dimethylaminopyridine (DMAP) 0.06g were sequentially added with stirring to react at 25℃for 3 hours. After the completion of the TLC monitoring reaction, 2mL of water was added to quench the reaction, the reaction solution was washed with 15mL of water, and the organic phase was dried over anhydrous sodium sulfate and filtered. To the filtrate was added 6mL of piperidine, 1mL1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) and 3-mercaptopropionic acid, stirring for 4 hr, concentrating under reduced pressure after TLC monitoring reaction, adding 20mL acetonitrile into the concentrated solution, stirring for crystallization, suction filtering, and drying the obtained solid under reduced pressure
1.69g, yield 95%.
Adding into a dry reaction bottle
1.55g of Fmoc-beta-Ala-OH 1.29g, N-Diisopropylcarbodiimide (DIC) 0.63g and 1-Hydroxybenzotriazole (HOBT) 0.67g were dissolved in 15mL of methylene chloride and stirred to react for 3 hours at 25℃followed by TLC monitoring the completion of the reaction. 2mL of water was added to quench the reaction, the reaction mixture was washed with 15mL of water, and the organic phase was dried over anhydrous sodium sulfate and filtered. To the filtrate was added 6mL of piperidine, 1mL of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) and 3-mercaptopropionic acid, stirring for 4 hours, concentrating under reduced pressure after TLC monitoring reaction is completed, adding 20mL acetonitrile into the concentrated solution, stirring for crystallization, suction filtering, and drying the obtained solid under reduced pressure to obtain +.>
1.6g, yield 95%.
Adding into a dry reaction bottle
1.5g, then trifluoroacetic acid was added: water: triisopropylsilane=95:2.5:2.5 (mass ratio) in a mixed solution of 10g, the reaction was stirred at room temperature overnight. Concentrating under reduced pressure, adding 10mL isopropyl ether for crystallization, filtering to obtain a crude product, refluxing and washing the crude product with absolute ethyl alcohol, and filtering while the crude product is hot to obtain 0.33g of carnosine pure product with the yield of 90% and the purity of 99.3%.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The small molecule carrier shown in the formula I has the following structural formula:
wherein R is a C18-C26 linear or branched alkyl group.
2. The small molecule carrier of claim 1, wherein R is a C18-C26 linear alkyl group.
3. The small molecule carrier of claim 1, wherein the small molecule carrier has the following structural formula:
4. a process for preparing a small molecule carrier of formula i according to claim 1, said process comprising:
(1) Reacting hydroxynaphthalene formaldehyde shown in a formula III with alkyl halide RX under a base condition to obtain alkoxy naphthalene formaldehyde shown in a formula II;
(2) Preparing an alkoxyl naphthaldehyde shown in a formula II into a small molecular carrier shown in a formula I under the condition of borohydride or catalytic hydrogenation reducing agent;
wherein R is a C18-C26 linear or branched alkyl group, and X is Cl, br or I.
5. The method according to claim 4, wherein the alkali in the step (1) is one or a combination of two or more selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide;
the borohydride in the step (2) is selected from one or more than two of sodium borohydride, potassium borohydride and lithium borohydride;
the catalytic hydrogenation reducing agent in the step (2) is selected from one or more than two of palladium/carbon, palladium hydroxide/carbon and Raney nickel.
6. Use of a small molecule vector of formula i according to claim 1 in the synthesis of a polypeptide.
7. A method for synthesizing a polypeptide using the small molecule vector of formula i of claim 1, comprising the steps of:
(1) In an organic solvent, carrying out esterification reaction on a small molecular carrier and Fmoc-protected amino acid under the action of a condensing agent, adding a quenching agent to quench the reaction after 3-4 hours, adding a Fmoc-removing reagent to react for 3-4 hours, concentrating, adding acetonitrile or DMF into a concentrated solution, precipitating, and filtering to obtain an amino acid carrier compound;
(2) Dissolving the amino acid carrier complex obtained in the step (1) in an organic solvent, adding Fmoc-protected amino acid to be connected, carrying out esterification reaction under the action of a condensing agent, adding a quencher to quench the reaction after 3-4 hours, adding a Fmoc-removing reagent to react for 3-4 hours, concentrating, adding acetonitrile or DMF into a concentrated solution, precipitating, filtering to obtain two amino acid carrier complexes, and repeating the above operation until all amino acids of a target polypeptide are connected;
(3) And (3) adding a cracking reagent into the polyamino acid carrier complex obtained in the step (2), and recovering the micromolecular carrier to obtain the target polypeptide.
8. The method of synthesizing a polypeptide according to claim 7, wherein the organic solvent includes, but is not limited to, dichloromethane, ethanol, acetonitrile; the condensing agent is selected from one or more than two of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 2- (1H-benzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 4-dimethylaminopyridine and 1-hydroxybenzotriazole.
9. The method of synthesizing a polypeptide according to claim 7, wherein the quencher is water or an amine compound; the Fmoc removal reagent is selected from one or more than two of diethylamine, piperidine, 1, 8-diazabicyclo [5.4.0] -7-undecene, morpholine and 3-mercaptopropionic acid.
10. The method of synthesizing a polypeptide according to claim 7, wherein the cleavage reagent is a mixture of trifluoroacetic acid, triisopropylsilane and water in a mass ratio of 95:2.5:2.5.
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| WO2019127919A1 (en) * | 2017-12-29 | 2019-07-04 | 深圳翰宇药业股份有限公司 | Carrier compound for liquid phase synthesis of polypeptide, preparation method therefor and use thereof |
| CN112979763A (en) * | 2021-03-03 | 2021-06-18 | 山东大学 | Liquid phase synthesis method of antimicrobial peptide Oreoch-2 based on soluble hydrophobic carrier |
| CN114315538A (en) * | 2021-12-31 | 2022-04-12 | 杭州澳赛诺生物科技有限公司 | Benzyl alcohol phenol ether compound used as polypeptide liquid phase synthesis carrier and preparation method and application thereof |
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| JP2000336054A (en) * | 1999-05-26 | 2000-12-05 | Mitsubishi Chemicals Corp | Production of hydroxynaphthaldehyde |
| WO2016135071A1 (en) * | 2015-02-23 | 2016-09-01 | Universität Wien | A compound for preparing polypeptides |
| WO2019127921A1 (en) * | 2017-12-29 | 2019-07-04 | 深圳翰宇药业股份有限公司 | Compound for polypeptide liquid-phase synthesis carrier, preparation method therefor and use thereof |
| WO2019127919A1 (en) * | 2017-12-29 | 2019-07-04 | 深圳翰宇药业股份有限公司 | Carrier compound for liquid phase synthesis of polypeptide, preparation method therefor and use thereof |
| CN112979763A (en) * | 2021-03-03 | 2021-06-18 | 山东大学 | Liquid phase synthesis method of antimicrobial peptide Oreoch-2 based on soluble hydrophobic carrier |
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