Soluble liquid phase carrier for polypeptide liquid phase synthesis and application thereof

Abstract

The invention belongs to the technical field of polypeptide liquid-phase synthesis carriers, and discloses a soluble liquid-phase carrier for polypeptide liquid-phase synthesis and application of the soluble liquid-phase carrier. The structural formula of the soluble liquid phase carrier for polypeptide liquid phase synthesis is shown in the specification, in the formula, 1-3 groups R are selected from H, methoxyl, halogen, alkyl, aldehyde group and nitryl; the number of the group Linker-Tag is 1 to 3; when the soluble liquid-phase carrier is applied to polypeptide liquid-phase synthesis, the soluble liquid-phase carrier not only shows excellent performance in the aspects of improving the operation efficiency, conveniently monitoring the reaction process and the like, but also has the advantages of economical efficiency and sustainable use, can remarkably improve the efficiency and controllability of the polypeptide liquid-phase synthesis process, and has extremely high practicability.

Description

Technical Field

[0001] This invention relates to the technical field of peptide liquid-phase synthesis carriers, and more specifically, to a soluble liquid-phase carrier for peptide liquid-phase synthesis and its application. Background Technology

[0002] Chemically synthesized peptides refer to the process of forming peptide bonds by dehydration condensation between amino acids using chemical means, gradually elongating the peptide chain. The main methods for chemically synthesizing peptides are solid-phase synthesis and liquid-phase synthesis.

[0003] The main steps of solid-phase synthesis are as follows: First, the amino group of the amino acid is protected using a protecting agent such as Fmoc or Boc. Then, the carboxyl terminus of the first amino acid is bound to the resin, and the protecting agent at the amino terminus is removed. The second amino acid is then linked, and this process is repeated to condense the desired amino acid sequence in a specific order. Finally, the peptide is cleaved from the resin under acidic conditions and purified to obtain the desired peptide. Solid-phase synthesis has advantages in speed and exhibits a pseudo-dilution effect, effectively reducing side reactions and easily controlling the racemic nature of amino acids. Therefore, solid-phase synthesis is currently a commonly used method for peptide synthesis. However, due to the high cost of solid-phase synthesis carriers and the extensive use of reagents for washing during the synthesis process, solid-phase synthesis has certain limitations.

[0004] Conventional liquid-phase synthesis involves coupling amino acids in a specific solvent to obtain the corresponding peptides. This is generally a homogeneous reaction with good reactivity. The reagents used are typically only required in equivalence or slightly excess amounts. Intermediates can be further purified to the required purity through washing, crystallization, chromatography, or preparative chromatography. Conventional liquid-phase synthesis offers advantages such as cost-effectiveness and flexibility, but it is labor-intensive and has the disadvantage of being difficult to synthesize long-chain amino acids.

[0005] In recent years, to address the issue of high cost of solid-phase synthesis supports, research has been conducted on liquid-phase synthesis of peptides using liquid-phase synthesis supports with specific structures, combined with solid-phase synthesis methods. This method involves attaching reactants to a soluble liquid-phase synthesis support for the reaction, which takes place in a homogeneous system. After the reaction, the carrier-product complex is precipitated by changing solvent polarity, temperature, and other conditions, thereby achieving product separation. This method can significantly improve the purity of liquid-phase synthesized peptides or their intermediates, effectively reduce amino acid racemization, lower the production cost of peptide drugs, and improve production efficiency.

[0006] However, current methods for peptide liquid-phase synthesis based on liquid-phase synthesis carriers have two main drawbacks. Firstly, they require highly soluble liquid-phase synthesis carriers. Poor carrier solubility leads to incomplete reactions and peptide aggregation and precipitation, limiting the synthetic length and disrupting the "precipitation-dissolution" purification process, resulting in impurity accumulation and significantly reducing the final yield and purity. Secondly, as the peptide chain length increases, the crystal precipitation state deteriorates, leading to washing difficulties and prolonged washing time, and even incomplete washing, which is detrimental to producing high-quality peptides.

[0007] For example, Ajimo Co., Ltd.'s liquid phase carrier AJIPHASE is mainly composed of benzene rings and aliphatic chains, which can be used for the synthesis of long peptide chains, offering advantages such as cost-effectiveness and high flexibility. However, AJIPHASE has the two drawbacks mentioned above: poor solubility in conventional reagents, requiring the use of chloroform, a highly toxic and regulated solvent, as the liquid phase; and poor compatibility with some polar or ultra-long peptide chains; after peptide chain precipitation, it presents as a paste, making filtration very difficult and requiring a long washing time, which can easily lead to insufficient washing, resulting in high impurity content and low purity of the peptides. Summary of the Invention

[0008] The technical problem to be solved by this invention is to provide a soluble liquid carrier for polypeptide liquid-phase synthesis that has good solubility in conventional reagents, good crystal precipitation state, is easy to wash, low cost, and high synthesis efficiency, and its application. The technical solution is as follows:

[0009] A soluble liquid carrier for polypeptide liquid-phase synthesis has the structure shown in formula (I):

[0010]

[0011] (I)

[0012] in:

[0013] The group R is selected from H, methoxy, halogen, alkyl, aldehyde, and nitro, and the number is 1-3;

[0014] The number of Linker-Tag groups is 1-3;

[0015] Linker is selected from the divalent group formed by removing hydrogen atoms from the hydroxyl and amino groups of the compounds shown in the following structural formulas:

[0016] ;

[0017] Tag is selected from the monovalent group formed after removing group X from the compounds shown in the following structural formulas:

[0018]

[0019] ;

[0020] Wherein, the group X is selected from F, Cl, Br, I, trifluoromethanesulfonic acid group, p-toluenesulfonic acid group, and p-toluenesulfonyl group.

[0021] As a further improvement to the above-mentioned soluble liquid carrier, the soluble liquid carrier is selected from the following structural formulas:

[0022]

[0023]

[0024] .

[0025] As a further improvement to the above-mentioned soluble liquid carrier: structural formula A is selected from the following structural formulas:

[0026]

[0027]

[0028] .

[0029] As a further improvement to the above-mentioned soluble liquid carrier, structural formula B is selected from the following structural formulas:

[0030]

[0031]

[0032] .

[0033] As a further improvement to the above-mentioned soluble liquid carrier: structural formula C is selected from the following structural formulas:

[0034] .

[0035] As a further improvement to the above-mentioned soluble liquid carrier: structural formula D is selected from the following structural formulas:

[0036] .

[0037] As a further improvement to the above-mentioned soluble liquid carrier: structural formula E is selected from the following structural formulas:

[0038] .

[0039] As a further improvement to the aforementioned soluble liquid carrier:

[0040] The specific structural formula F is as follows: ;

[0041] The specific structural formula G is as follows: .

[0042] The application of the aforementioned soluble liquid carrier in the liquid-phase synthesis of peptides is preferably performed where the peptide is a teriparatide fragment with the sequence Fmoc-Ser(tBu)-Val-Ser(tBu)-Glu(trt)-Ile-Gln(trt)-Leu-Met-His(trt)-Asn(trt)-Leu-OH. Using a coupling precursor linked to the carboxyl terminus of an amino acid at the functional group of the compound shown in formula (I) as the starting material, the synthesis proceeds through deprotection, condensation of single amino acid residues or peptides (dipeptides, tripeptides, etc.), and similar cycles until the synthesis of the last amino acid is completed. Finally, the target peptide is obtained by cleavage of the liquid-phase synthesis carrier and removal of the protecting group.

[0043] The soluble liquid carrier for polypeptide liquid-phase synthesis of the present invention and its application have been verified to have the following advantages:

[0044] (1) Excellent solubility and wide solvent applicability: The soluble liquid carrier of the present invention has good solubility in a variety of conventional organic solvents (such as dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylformamide, toluene, 1,4-dioxane, etc.), avoiding the use of solvents such as chloroform, which are highly toxic and regulated, and providing a more environmentally friendly, stable and flexible solution for polypeptide liquid phase synthesis.

[0045] (2) Good product precipitation state, easy to filter and wash: The "carrier-product" complex prepared using the soluble liquid carrier of the present invention precipitates directly after the reaction and presents a good solid particle state, rather than a viscous paste or gel compound. The complex is very easy to filter, which can significantly improve the operational efficiency of the filtration and washing process, making the entire synthesis process smoother and more efficient.

[0046] (3) High linkage stability and mild and controllable lysis conditions: The linkage between the soluble liquid carrier and the polypeptide of the present invention has excellent stability and can maintain structural integrity during the polypeptide chain elongation assembly process; at the same time, the linkage site of the soluble liquid carrier is sensitive to weak acid, and can achieve controllable detachment and separation of polypeptide under mild conditions without destroying the amino acid side chain protecting groups, and can be reused.

[0047] (4) Strong UV absorption facilitates reaction tracking: The soluble liquid carrier of the present invention has very obvious reaction indication characteristics on thin layer chromatography (TLC). The reaction process can be clearly monitored under UV light and is compatible with conventional analytical instruments (HPLC, etc.). Operators can intuitively and conveniently track the reaction process. Especially in complex synthesis systems, it can quickly determine whether the reaction is complete, which significantly improves the accuracy and efficiency of the experiment.

[0048] In summary, the soluble liquid carrier of the present invention, when applied to the liquid-phase synthesis of peptides, not only exhibits excellent performance in improving operational efficiency and facilitating reaction monitoring, but also possesses advantages in terms of economy and sustainable use. It can significantly improve the efficiency and controllability of the peptide liquid-phase synthesis process and has strong practicality.

[0049] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0050] The accompanying drawings, which form part of this invention, are used to aid in understanding the invention. The content provided in the drawings and their related descriptions can be used to explain the invention, but do not constitute an undue limitation of the invention. In the drawings:

[0051] Figure 1 These are photographs of compound A1 in different solvents according to Example 1 of the present invention.

[0052] Figure 2 This is the NMR spectrum of compound A1 from Example 1 of the present invention.

[0053] Figure 3 This is the NMR spectrum of compound B1 from Example 2 of the present invention.

[0054] Figure 4 This is a photograph of the solid-liquid mixture in step 350 of Embodiment 3 of the present invention. Detailed Implementation

[0055] The present invention will now be clearly and completely described in conjunction with the accompanying drawings. Those skilled in the art will be able to implement the present invention based on these descriptions. Before describing the present invention in conjunction with the accompanying drawings, it should be particularly noted that:

[0056] The technical solutions and features provided in the various parts of this invention, including the following description, can be combined with each other without conflict.

[0057] Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0058] Regarding the terminology and units used in this invention: The terms "comprising," "having," and any variations thereof in the specification, claims, and related parts of this invention are intended to cover non-exclusive inclusion.

[0059] In this specification and in the following embodiments, the following abbreviations represent substances as follows:

[0060] DMF: N,N-dimethylformamide;

[0061] THF: Tetrahydrofuran;

[0062] DCM: Dichloromethane;

[0063] TCM: Chloroform;

[0064] In this specification and in the following embodiments, the following terms have the following meanings:

[0065] Room temperature: refers to 20-25℃.

[0066] Substitution: refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0067] Alkyl: refers to a straight-chain or branched hydrocarbon group in an alkane molecule, such as methyl-CH3, ethyl-CH2CH3, methylene-CH2-; alkyl can also be part of other groups, such as C1-C6 alkoxy groups and C1-C6 alkylamino groups.

[0068] Example 1

[0069] In this embodiment, the soluble liquid carrier for polypeptide liquid-phase synthesis is compound A1 with a piperidine methanol structure, named 4-(2,3,4-tris(octadecyloxy)benzyl)-2-(3-methoxy-4-(hydroxymethyl)phenoxy)piperidine, and its synthesis steps are as follows:

[0070]

[0071]

[0072]

[0073] Step 110, Synthesis of intermediate 3b (methyl 3,4,5-tris(octadecyloxy)benzoate)

[0074] First, 30g of raw material 3a (methyl gallate) was added to a 2000mL three-necked flask, followed by 1000mL of DMF, 168.37g of bromooctadecane, and 225.16g of potassium carbonate. The mixture was heated to 80℃ and reacted for 2 days. After the reaction was completed by TLC monitoring, 1L of water was added, and the mixture was cooled before adding 2L of chloroform for extraction. The mixture was separated, and a large amount of solid precipitated directly from the organic phase. After filtration, 1L of ethyl acetate was added to the solid, and the mixture was stirred overnight before filtration again to remove impurities. The solid was dried to obtain 124g of light brown solid, which is intermediate 3b.

[0075] Step 120, Synthesis of intermediate 3C (3,4,5-tris(octadecyloxy)phenylmethanol)

[0076] 110g of intermediate 3b was added to 200mL of ultra-dry THF. 8.87g of lithium aluminum hydride was added in batches while the temperature was controlled below 5℃. After the addition was complete, the reaction was carried out at room temperature for 6h. After the reaction was completed by TLC monitoring, excess sodium sulfate was added to quench the reaction. After stirring for 1h, the mixture was filtered. The filtrate was concentrated and dried to obtain 91.9g of white solid, which is intermediate 3c.

[0077] Step 130, Synthesis of Tag-7 (5-(bromomethyl)-1,2,3-tris(octadecyloxy)benzene)

[0078] Dissolve 50g of intermediate 3c in 200mL of TCM, cool to 0℃, and slowly add 45g of phosphorus tribromide. After the addition is complete, react at room temperature for 2h. The TLC starting material disappears and a new small polarity spot is generated. Then add 500mL of acetonitrile, and a white solid precipitates. Filter and dry to obtain 50g of solid, which is Tag-7.

[0079] Step 140, Synthesis of Intermediate 1b (4-((2-formyl-5-methoxyphenoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester)

[0080] 10g of starting material 1a1 (2-hydroxy-4-methoxybenzaldehyde), 27g of starting material 1a2 (1-N-BOC-4-(4-methylbenzenesulfonyloxymethyl)piperidine), and 27g of potassium carbonate were added to 100mL of LDM and stirred overnight at 80°C. The TLC reaction showed the disappearance of the starting material spot and the appearance of a new spot, which was the target product. After the reaction was complete, saturated brine and ethyl acetate were added for separation. The organic phase was collected, washed five times with saturated brine, combined, and concentrated. The concentrate was directly used for the next step.

[0081] Step 150, Synthesis of Intermediate 1c (4-methoxy-2-(piperidin-4-ylmethoxy)benzaldehyde)

[0082] The concentrate from step 140 was dissolved in 50 mL of 4 mol / L ethyl hydrochloride solution and stirred at room temperature for 2 h. A solid precipitated out, which was then filtered and dried to obtain 12 g of solid, which is intermediate 1c.

[0083] Step 160, Synthesis of intermediate 1d (4-methoxy-2-((1-(3,4,5-tris(octadecoxy)benzyl)piperidin-4-yl)methoxy)benzaldehyde)

[0084] Dissolve 12g of intermediate 1c and 20g of potassium carbonate in DCM, add 52g of Tag-7, react at room temperature for 3h, the TLC starting material disappears and a new spot is generated, filter the potassium carbonate and concentrate the organic phase to a small volume, add methanol to precipitate the solid, filter and dry to obtain 45g of solid, which is intermediate 1d.

[0085] Step 170, Synthesis of Compound A1

[0086] 50g of intermediate 1d was dissolved in 200mL of THF solution, kept in an ice bath at a temperature below 10℃, 20mL of methanol solution was added, and 3.3g of sodium borohydride was slowly added. The mixture was stirred continuously for 3h. When the starting material spot disappeared as monitored by TLC, 20mL of ice water was added to quench the reaction. The organic phase was directly evaporated to dryness, and the solid precipitated. After filtration, the byproducts of the sodium borohydride reaction were removed by simple column chromatography, yielding 45g of the product, which is compound A1.

[0087] Figure 1 The images show solutions of compound A1 in different solvents from this embodiment. From left to right, the solvents used are DCM, THF, 2-methyltetrahydrofuran, ethyl acetate, and DMF. The concentrations of the DCM, THF, and 2-methyltetrahydrofuran solutions are 50 mg / mL, while the concentrations of the ethyl acetate and DMF solutions are 30 mg / mL. Figure 1 It can be seen that all solutions are clear and transparent, indicating that compound A1 has good solubility in these solvents.

[0088] Figure 2 The NMR spectrum of compound A1 is shown below, and the corresponding NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.20-7.13 (m, 1H), 6.51 (s, 2H), 6.44 (dq, J=4.5, 2.4Hz, 2H), 4.61 (d, J=6.3Hz, 2H), 3.94 (dt, J=14.7, 6.5Hz, 6H), 3.82 (d, J=18.6Hz, 5H), 3.41 (s,2H), 2.92 (d, J=11.2Hz, 2H), 2.25 (t, J=6.4Hz, 1H), 1.84-1.71 (m, 10H), 1.46(hept, J=6.2, 5.7Hz, 8H), 1.30 (s, 84H), 0.88 (t, J=6.7Hz, 9H).

[0089] Based on the above synthetic approach, compounds A2-A9 can be synthesized with simple modifications.

[0090] Example 2

[0091] In this embodiment, the soluble liquid carrier for polypeptide liquid-phase synthesis is compound B1 having a piperidine methanol structure, named 2,4-dimethoxy-6-(1-(3,4,5-tris(octadecoxy)benzyl)piperidin-4-yl)methoxy)phenyl)methanol, and its synthesis steps are as follows:

[0092]

[0093]

[0094] Step 210, Synthesis of intermediate 2b (tert-butyl-4-((2-formyl-3,5-dimethoxyphenoxy)methyl)piperidine-1-carboxylate)

[0095] 12g of starting material 2a1 (4,6-dimethoxysalicylaldehyde), 27g of starting material 2a2 (1-N-BOC-4-(4-methylbenzenesulfonyloxymethyl)piperidine), and 27g of potassium carbonate were added to 100mL of DMF. The mixture was stirred overnight at 80°C. The starting material disappeared on TLC, and a new spot appeared, which was the target product. After the reaction was complete, saturated brine and ethyl acetate were added for separation. The organic phase was collected, washed five times with saturated brine, combined, and concentrated. The concentrate was directly used for the next step.

[0096] Step 220, Synthesis of intermediate 2C (2,4-dimethoxy-6-(piperidin-4-methyleneoxy)benzaldehyde)

[0097] The concentrate from step 210 was dissolved in 50 mL of 4 mol / L ethyl hydrochloride solution, stirred at room temperature for 2 h, and a solid precipitated. The solid was filtered and dried to obtain 10 g of solid, which is intermediate 2c.

[0098] Step 230, Synthesis of intermediate 2d (2,4-dimethoxy-6-((1-(3,4,5-tris(octadecoxy)benzyl)piperidin-4-yl)methoxy)benzaldehyde)

[0099] 10g of intermediate 2c and 15g of potassium carbonate were placed in DCM, and 50g of Tag-7 was added. The reaction was carried out at room temperature for 3h. The TLC starting material disappeared and a new spot was generated. After filtering out the potassium carbonate with diatomaceous earth, the organic phase was concentrated to a small volume. Acetonitrile was added to precipitate the solid. After filtration and drying, 34g of solid was obtained, which is intermediate 2d.

[0100] 1 H NMR (400 MHz, Chloroform-d) δ 10.38 (s, 1H), 6.52 (s, 2H), 6.10-5.99 (m, 2H), 3.95 (dt, J=13.8, 6.5Hz, 6H), 3.87 (d, J=7.5Hz, 8H), 3.43 (s,2H), 2.93 (s, 2H), 2.27-2.05 (m, 1H), 1.64 (s, 10H), 1.46 (p, J=7.0Hz, 8H), 1.26 (s, 84H), 0.88 (t, J=6.8Hz, 9H).

[0101] Step 240, Synthesis of Compound B1

[0102] 34g of intermediate 2d was dissolved in 200mL of THF solution. The mixture was kept in an ice bath at a temperature below 10°C. 3g of sodium borohydride was slowly added, followed by 10mL of methanol. The mixture was stirred continuously for 3 hours. When the starting material spot disappeared as monitored by TLC, 20mL of ice water was added to quench the reaction. The organic phase was directly evaporated to dryness, and the solid precipitated. After filtration, the byproducts of the sodium borohydride reaction were removed by simple column chromatography, yielding 30g of the product, which is compound B1.

[0103] Figure 3 The NMR spectrum of compound B1 is shown below, and the corresponding NMR data are as follows: 1H NMR (400 MHz, Chloroform-d) δ 6.52 (s, 2H), 6.11 (d, J=11.9 Hz, 2H), 4.70 (s, 2H), 3.94 (dt, J=15.9,6.5 Hz, 6H), 3.81 (d, J=7.9 Hz, 8H), 3.42 (s, 2H), 2.94 (d, J=10.7 Hz, 2H), 2.19 – 2.16 (m, 1H), 1.82=1.81 (m, 10H), 1.46 (dd, J=13.1, 6.7 Hz, 8H), 1.29 (d, J=11.2 Hz, 84H), 0.88 (t, J=6.7 Hz, 9H).

[0104] Based on the above synthetic approach, compounds B2-B7 can be synthesized with simple modifications.

[0105] Example 3

[0106] Teriparatide fragments were synthesized using compound A1, and their sequences and structural formulas are as follows:

[0107] Fmoc-Ser(tBu)-Val-Ser(tBu)-Glu(trt)-Ile-Gln(trt)-Leu-Met-His(trt)-Asn(trt)-Leu-OH

[0108]

[0109] The synthesis steps are as follows:

[0110] Step 310: Dissolve 5g of compound A1 in 50mL of DCM, add 1.85g of Fmoc-Leu-OH, 1.35g of dicyclohexylcarbodiimide, and 0.8g of 4-dimethylaminopyridine, and stir continuously for 1.5h. Monitor the reaction by TLC until complete. Then add 150mL of methanol solution. Dicyclohexylurea (DCU) dissolves first, then a solid precipitates. Filter the solid and wash it with 150mL of acetonitrile to obtain Fmoc-Leu-A1.

[0111] Step 320, First Fmoc Removal: Dissolve Fmoc-Leu-A1 in 50 mL of DCM, then add 2.5 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), stir at room temperature for 30 minutes, and add acetonitrile after the reaction is complete by TLC monitoring. The solid precipitates, is filtered, and the filter cake is washed twice with acetonitrile. The TLC spot test is used to check whether the washing is clean, and the ninhydrin product after Fmoc removal can be visualized.

[0112] Step 330: Dissolve the product from step 320 in 50 mL of DCM, add 3.1 g Fmoc-Asn(trt)-OH, 1.1 mL N,N'-diisopropylcarbodiimide (DIC), 0.9 g 1-hydroxybenzotriazole (HOBt), and 0.8 g 4-dimethylaminopyridine (DMAP), and stir continuously for 1.5 h. Monitor the reaction for completion by TLC. Then add acetonitrile to precipitate the solid, filter, and wash the filter cake twice with acetonitrile.

[0113] Step 340: Repeat steps 320-330 above until all amino acids of the complete teriparatide fragment are linked.

[0114] Step 350: Dissolve the precipitated solid in 50 mL of DCM, add 2.5 mL of 5 wt% trifluoroacetic acid, stir for 2 h, and monitor the reaction completion by TLC. Then add 5 g of sodium bicarbonate solid, monitor the pH of the solution to ensure it has become weakly alkaline (pH≈8), and then add 150 mL of acetonitrile to precipitate the solid, obtaining a solid-liquid mixture.

[0115] Figure 4 This is a photograph of a solid-liquid mixture. (Example:) Figure 4 As shown, the solid-liquid mixture separates into layers after standing, indicating that no gel-like compound forms. It has been verified that vacuum filtration can be easily performed using 11μm filter paper.

[0116] The filtrate obtained by vacuum filtration was subjected to low-temperature rotary evaporation to obtain crude teriparatide fragment with a purity of 82.53%. The crude product was then purified by reverse phase preparation to obtain 2.7g of teriparatide fragment.

[0117] The filter residue obtained by vacuum filtration was dissolved in DCM and filtered through diatomaceous earth. A mixture of acetonitrile and water in a volume ratio of 90:1 was added to the filtrate. After the solid precipitated, it was filtered and dried to obtain 3.9 g of compound A1, with a recovery rate of 78%, which can be directly reused.

[0118] The foregoing has described the relevant content of the present invention. Those skilled in the art will be able to implement the present invention based on these descriptions. All other embodiments obtained by those skilled in the art based on the above description of the present invention without inventive effort should fall within the scope of protection of the present invention.

Claims

1. A soluble liquid carrier for polypeptide liquid-phase synthesis, the structure of which is shown in formula (I): (I) in: The group R is selected from H, methoxy, halogen, alkyl, aldehyde, and nitro, and the number is 1-3; The number of Linker-Tag groups is 1-3; Linker is selected from the divalent group formed by removing hydrogen atoms from the hydroxyl and amino groups of the compounds shown in the following structural formulas: ； Tag is selected from the monovalent group formed after removing group X from the compounds shown in the following structural formulas: ； ； Wherein: group X is selected from F, Cl, Br, I, trifluoromethanesulfonic acid group, p-toluenesulfonic acid group, p-toluenesulfonyl group.

2. The soluble liquid carrier as described in claim 1, characterized in that: Soluble liquid carriers are selected from the following structural formulas: ； ； 。 3. The soluble liquid carrier as described in claim 2, characterized in that: Structural formula A is selected from the following structural formulas: ； ； 。 4. The soluble liquid carrier as described in claim 2, characterized in that: Structural formula B is selected from the following structural formulas: ； ； 。 5. The soluble liquid carrier as described in claim 2, characterized in that: Structural formula C is selected from the following structural formulas: 。 6. The soluble liquid carrier as described in claim 2, characterized in that: Structural formula D is selected from the following structural formulas: 。 7. The soluble liquid carrier as described in claim 2, characterized in that: Structural formula E is selected from the following structural formulas: 。 8. The soluble liquid carrier as described in claim 2, characterized in that: The specific structural formula F is as follows: ; The specific structural formula G is as follows: .

9. The application of the soluble liquid carrier according to any one of claims 1-8 in the liquid-phase synthesis of peptides.

10. The application as described in claim 9, characterized in that: The polypeptide is a teriparatide fragment with the sequence Fmoc-Ser(tBu)-Val-Ser(tBu)-Glu(trt)-Ile-Gln(trt)-Leu-Met-His(trt)-Asn(trt)-Leu-OH.

Images