A compound for polypeptide liquid phase synthesis carrier and application thereof

Abstract

The application discloses a compound for a polypeptide liquid-phase synthesis carrier and application thereof, and belongs to the technical field of the polypeptide liquid-phase synthesis carrier. The compound contains a ferrocene structure, and a structural formula of the compound is. The compound is used as the polypeptide liquid-phase synthesis carrier, and the compound not only has excellent performance in improving operation efficiency, reducing emulsification, facilitating monitoring of a reaction process and the like, but also has advantages of economy and sustainable use, can significantly improve efficiency and controllability of a polypeptide liquid-phase synthesis process, and has extremely strong practicability.

Description

Technical Field

[0001] This invention relates to the technical field of peptide liquid-phase synthesis carriers, and more specifically, to a compound used as a peptide liquid-phase synthesis carrier 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 false dilution effect, effectively reducing the racemization problem of amino acids. Therefore, it is currently a commonly used method for peptide synthesis. However, the high cost of solid-phase synthesis carriers and the extensive use of reagents for washing during the synthesis process limit its effectiveness.

[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 carriers, research has been conducted on liquid-phase synthesis of peptides using liquid-phase synthesis carriers with specific structures, combined with solid-phase synthesis methods. This significantly improves the purity of liquid-phase synthesized peptides or their intermediates, effectively reduces amino acid racemization, lowers the production cost of peptide drugs, and increases production efficiency. However, this synthesis method also suffers from the problem of deteriorating crystal precipitation as the peptide chain increases, leading to washing difficulties, prolonged washing time, and incomplete washing, which is detrimental to the production of high-quality peptides.

[0006] For example, Ajimo Co., Ltd.'s liquid-phase synthesis carrier AJIPHASE is mainly composed of benzene rings and aliphatic chains. It can be dissolved in solution for amino acid coupling, and after the reaction, the carrier can be precipitated using a highly polar solvent. This allows for the synthesis of long peptide chains and offers advantages such as cost-effectiveness and high flexibility. However, after peptide chain precipitation, AJIPHASE presents as a paste, making filtration very difficult and requiring a long washing time. This can easily lead to insufficient washing, resulting in high impurity content and low purity of the peptides. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a compound for use as a carrier for polypeptide liquid-phase synthesis, which has good crystal precipitation state, is easy to wash, has low cost and high synthesis efficiency, and its application.

[0008] To achieve the above objectives, the present invention first provides a compound for use as a support for polypeptide liquid-phase synthesis, the compound containing a ferrocene structure, the structure of which is shown in formula (I):

[0009] ;

[0010] in:

[0011] X is selected from OH, NH2, halogens, and 5-8 membered aromatic rings;

[0012] R is selected from C1-C100 alkyl, C2-C100 alkenyl, C2-C100 alkynyl, C3-C100 cycloalkyl, C3-C100 cycloalkyl substituted with C1-C100 alkyl, C3-C100 cycloalkyl substituted with C1-C50 alkoxy substituted with C3-C100 cycloalkyl, and substituted C1-C100 alkyl.

[0013] Y is selected from H, phenyl, halophenyl, aliphatic chain phenyl, and nitrobenzene.

[0014] As a further improvement to the above-mentioned compound: the structural formula of the compound is as follows:

[0015] .

[0016] As a further improvement to the above-mentioned compound: the structural formula of the compound is as follows:

[0017] ;

[0018] in:

[0019] R1 is selected from C1-C100 alkyl, C2-C100 alkenyl, C2-C100 alkynyl, C3-C100 cycloalkyl, C3-C100 cycloalkyl substituted with C1-C100 alkyl, C3-C100 cycloalkyl substituted with C1-C50 alkoxy substituted with C3-C100 cycloalkyl, and substituted C1-C100 alkyl.

[0020] As a further improvement to the above-mentioned compound: the compound is selected from the following structural formulas:

[0021] .

[0022] As a further improvement to the above-mentioned compound: the structural formula of the compound is as follows:

[0023] ;

[0024] in:

[0025] R1 is selected from C1-C100 alkyl, C2-C100 alkenyl, C2-C100 alkynyl, C3-C100 cycloalkyl, C3-C100 cycloalkyl substituted with C1-C100 alkyl, C3-C100 cycloalkyl substituted with C1-C50 alkoxy, and substituted C1-C100 alkyl.

[0026] R2 is selected from OH, NH2, halogen, C1-C100 alkyl, C2-C100 alkenyl, C2-C100 alkynyl, C3-C100 cycloalkyl, C3-C100 cycloalkyl substituted with C1-C100 alkyl, C3-C100 cycloalkyl substituted with C1-C50 alkoxy, and substituted C1-C100 alkyl.

[0027] As a further improvement to the above-mentioned compound: the structural formula of the compound is as follows:

[0028] .

[0029] As a further improvement to the above-mentioned compound: the compound is selected from the following structural formulas:

[0030] .

[0031] To achieve the above objectives, the present invention further provides the application of the compound described in the first aspect as a carrier in the liquid-phase synthesis of peptides, preferably, the peptide being Gly-Ala-Pro-Pro-Pro-Ser-NH2 or Fmoc-Tyr(tBu)-Phe-Ser(tBu)-Ala-Pro-Gly-OH. A coupling precursor linked to the carboxyl terminus of an amino acid on the functional group of the compound shown in formula (I) is used as the starting material. This process involves deprotection, condensation of a single amino acid residue or peptide (dipeptide, tripeptide, 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.

[0032] Verification has shown that the ferrocene-containing compounds of the present invention, when used as peptide liquid-phase synthesis supports (hereinafter referred to as ferrocene supports), have the following advantages when applied to peptide liquid-phase synthesis:

[0033] Significantly Improved Operational Efficiency: In peptide liquid-phase synthesis, traditional carriers tend to form clumps or paste-like gels during the precipitation stage, increasing the difficulty and time required for filtration and washing. This invention uses compounds containing ferrocene structures as a component of the carrier, effectively avoiding the formation of paste-like gel crystals, significantly improving the operational efficiency of filtration and washing processes, and making the entire synthesis process smoother and more efficient.

[0034] Reducing emulsification: In the presence of long fatty chains, emulsification often occurs due to their lipophilic nature, thus affecting the efficiency of separation or filtration. The ferrocene carrier of this invention can significantly reduce the probability of emulsification, effectively avoiding separation or filtration difficulties caused by emulsification, ensuring smooth operation, thereby reducing the potential risk of experimental failure and improving the overall reliability and repeatability of the experiment.

[0035] Facilitates reaction progress monitoring: The ferrocene support of this invention exhibits very clear reaction indication characteristics on thin-layer chromatography (TLC), clearly showing the color spots of the support under natural light. This feature allows operators to conveniently monitor the reaction progress, especially in complex synthetic systems, enabling rapid determination of whether the reaction has proceeded completely, significantly improving the convenience and accuracy of experiments, and reducing experimental errors and wasted time.

[0036] (4) Economical and easy to recycle and reuse: The ferrocene carrier of the present invention requires a wide range of raw materials with low cost. After synthesis, it can be reused by simple recycling and treatment, which reduces production costs and has high economic and environmental benefits. This makes the carrier have a good cost performance in practical applications and can greatly reduce the use of monomer materials, reagents and solvents. It is suitable for promotion and application in large-scale peptide synthesis.

[0037] In summary, this invention uses compounds containing ferrocene structures as carriers for polypeptide liquid-phase synthesis. This not only demonstrates excellent performance in improving operational efficiency, reducing emulsification, 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 polypeptide liquid-phase synthesis process and has strong practicality.

[0038] 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

[0039] The accompanying drawings, which form part of this invention, are used to aid in understanding the invention. The contents provided in the drawings and their descriptions in relation to the invention can be used to explain the invention, but do not constitute an improper limitation of the invention.

[0040] Figure 1 This is a photograph of the actual intermediate 4c.

[0041] Figure 2 A photograph of the actual product after reacting intermediate 4c with 0.5% TFA / TCM and separating it using an aqueous solution. Detailed Implementation

[0042] 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:

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In this specification and in the following embodiments, the following abbreviations represent substances as follows:

[0047] DMF: N,N-dimethylformamide;

[0048] DCM: Dichloromethane;

[0049] THF: Tetrahydrofuran;

[0050] 1-Bromooctadecane: 1-Bromooctadecane.

[0051] In this specification and in the following embodiments, the following terms have the following meanings:

[0052] Room temperature: refers to 20-25℃.

[0053] Substitution: refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0054] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes. For example, the prefix (Ca~Cb)alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, C1~C20 alkyl refers to straight-chain or branched alkyl groups containing 1 to 20 carbon atoms.

[0055] 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.

[0056] Alkoxy group: refers to an alkyl group that is attached to an oxygen atom to form a substituent, such as methoxy group -OCH3.

[0057] Cycloalkyl: refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no heterocyclic atoms, and having a single ring or multiple rings (including fused, bridged and spirocyclic systems).

[0058] 5-8 membered aromatic rings / groups: These refer to aromatic single rings or multiple cyclic groups composed of C atoms without heteroatoms.

[0059] Alkenyl groups: including straight-chain or branched alkenyl groups.

[0060] Alkyne group: including straight-chain or branched alkynyl groups. Example 1

[0061] The specific steps for synthesizing compound B1 (1-(4'-chloro-2-fluoro-4-eicosanoyloxybiphenyl)ferrocene), which is used as a support for polypeptide liquid-phase synthesis and contains a ferrocene structure, are as follows:

[0062]

[0063] Step 110, Synthesis of Intermediate 1b (m-methoxybenzoyl chloride)

[0064] First, add 30 mL of LDM and 4 mL of LMF to a 50 mL flask, then add 5 g of starting material 1a (3-methoxybenzoic acid), and slowly add thionyl chloride (1.5 eq). Cool and reflux for 4 h to obtain intermediate 1b. After rotary evaporation and concentration, no purification process is required, and it can be directly used in the next step.

[0065] Step 120, Synthesis of intermediate 1c ((4-methoxyphenyl)ferrocene)

[0066] 11.6 g of aluminum chloride and 40 mL of dichloromethane were added to a 100 mL single-necked flask. 4.5 g of 3-methoxybenzoyl chloride or 4-methoxybenzoyl chloride was slowly added in an ice bath. After stirring for 30 min, 4.1 g of ferrocene was slowly added. After reacting at 0 °C for 12 h, 20 mL of water was added to quench the reaction. The reaction mixture was washed three times with saturated sodium bicarbonate and dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and subjected to column chromatography with an eluent ratio of petroleum ether:ethyl acetate = 9:1 to give intermediate 1c.

[0067] 1 HNMR (400MHz, Chloroform-d) δ7.49 (dt, J=7.6, 1.2Hz, 1H), 7.45-7.40 (m, 1H), 7.36 (t, J=8.0Hz, 1H), 7. 08 (ddd, J=8.4, 2.7, 1.0Hz, 1H), 4.91 (t, J=2.0Hz, 2H), 4.58 (t, J=2.0Hz, 2H), 4.21 (s, 5H), 3.87 (s, 3H).

[0068] Step 130, Synthesis of intermediate 1d ((4-hydroxyphenyl)ferrocene)

[0069] A 1M BBr3 (2 eq) dichloromethane solution was added dropwise to a 30 mL dichloromethane solution of compound 1c at 0 °C, and the mixture was stirred at room temperature for 12 h. After the reaction was completed by TLC monitoring, the reaction mixture was washed with a saturated sodium bicarbonate aqueous solution, the organic extract was dried on anhydrous sodium sulfate, filtered, and evaporated to give intermediate 1d.

[0070] 1 HNMR (400MHz, Chloroform-d) δ7.88-7.80 (m, 2H), 6.89-6.82 (m, 2H), 4.84 (t, J=2.0Hz, 2H), 4.51 (t, J=2.0Hz, 2H), 4.13 (s, 5H).

[0071] Step 210, Synthesis of intermediate 2e(1-(4'-hydroxy-2-fluoro-4-eicosyloxybiphenyl)ferrocene)

[0072] 5 g of intermediate 1d was dissolved in THF, placed in an ice bath under nitrogen protection, and then 4 eq of 65.3 ml of 3-fluorophenyl magnesium bromide (1 mmol / L) was gradually added. The mixture was then gradually brought to room temperature and stirred for 4 h. After the reaction was completed, an aqueous solution of ammonium chloride was added to quench the reaction mixture. The mixture was then extracted with ethyl acetate and water, and the organic phase was dried and concentrated to obtain the crude product. The crude product was purified by rapid column chromatography to obtain 6.1 g of intermediate 2e, with a yield of 93%.

[0073] Step 220, Synthesis of intermediate 2f(1-(4'-hydroxy-2-fluoro-4-eicosyloxybiphenyl)ferrocene)

[0074] At room temperature, 6 g of intermediate 2e was dissolved in 50 mL of DMF, and 4 eq of potassium carbonate (8.24 g) and 1.2 eq of 1-bromodocosahexanes (7.5 g) were added. The mixture was stirred at 80 °C for 15 h. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction. The solution was dried and concentrated to obtain the crude product. The crude product was then slurried with methanol and filtered to obtain 9.17 g of intermediate 2f, with a yield of 96.5%.

[0075] 1 HNMR (400MHz, Chloroform-d) δ7.21 (dd, J=8.4, 5.8 Hz, 1H), 7.18-7.13 (m, 2H), 7.07-7.02 (m, 2H), 6.94-6.87 (m, 1H), 6.82-6.76 (m, 2H), 4.27 (s, 2H), 4.18 (s, 5H), 4.03 (d, J=16.4Hz, 2H), 3.92 (t, J=6.4 Hz, 2H), 1.76 (q, J=7.2Hz, 2H), 1.46-1.41 (m, 2H), 1.25 (s, 36H), 0.88 (t, J=6.8Hz, 3H).

[0076] Step 230, Synthesis of Compound B1:

[0077] 2g of intermediate 2f was added to chloroform, dissolved and clarified, and then 0.8mL of acetyl chloride solution was added dropwise. After the reaction was completed, the product was evaporated to dryness, and acetonitrile was added to precipitate a solid, thus obtaining compound B1.

[0078] Based on the above synthetic approach, compounds B2-B8 can be synthesized with simple modifications. Example 2

[0079] The polypeptide Fmoc-Tyr(tBu)-Phe-Ser(tBu)-Ala-Pro-Gly-OH was synthesized using compound B1 from Example 1, and the specific steps are as follows:

[0080] Step 410, synthesize intermediate 4a

[0081]

[0082] 4a

[0083] 2.3 g of Fmoc-Gly-OH (1.2 eq) and 2 mL of DIPEA (2 eq) were mixed and dissolved in a chloroform solution. Then, 3.9 g and 5 mmol of compound A1 were added, and the mixture was stirred thoroughly for 3 h. The mixture was monitored by TLC. 400 mL of methanol solution was added to the solution, and a solid precipitated. The solid was obtained by vacuum filtration and washed with 200 mL of acetonitrile solution. The solid was then obtained by vacuum filtration to give intermediate 4a.

[0084] 1 H-NMR (400MHz, Chloroform-d): δ7.82 (dd, J=7.6, 1.4Hz, 2H), 7.64 (dq, J=7.6, 0.8Hz, 2H), 7.46-7.35 (m, 5H), 7.28-7.14(m, 4H), 7.11-7.03(m, 1H), 6.92-6.84(m, 2H), 6.33(t, J=5.6Hz, 1H), 5.02-4.96(m, 1H), 4. 38(d, J=4.8Hz, 2H), δ4.21(s, 5H), 4.02(dt, J=12.8, 6.2Hz, 4H), 2.14-2.09(m, 2H), 1.89-1.84(m, 2H), 1.8 0-1.71 (m, 2H), 1.44 (dq, J=7.6, 7.0Hz, 2H), 1.35-1.26 (m, 38H), 1.26 (d, J=2.4Hz, 3H), 0.94-0.86 (m, 3H).

[0085] Step 420, synthesize intermediate 4b

[0086]

[0087] 4b

[0088] Intermediate 4a was added to a 20% DBU solution in chloroform and stirred at room temperature for 40 min. The reaction was monitored by TLC. After the reaction was complete, 200 mL of methanol solution was added, precipitating a solid. The solid was filtered under reduced pressure, washed with ACN solution, and filtered again under reduced pressure to obtain the solid. 2.2 g of Fmoc-Pro-OH (1.2 eq), 2 mL of DIC (2 eq), and 2 g of HOBT (1.2 eq) were added to the solid obtained by filtration under reduced pressure and dissolved in chloroform solution. The mixture was stirred thoroughly for 2 h, monitored by TLC, and 400 mL of methanol solution was added to the solution. A solid precipitated, was filtered under reduced pressure, washed with 200 mL of acetonitrile solution, and filtered again under reduced pressure to obtain intermediate 4b.

[0089] Step 430, synthesize intermediate 4c

[0090]

[0091] 4c

[0092] Intermediate 4b was added to a 20% DBU solution in chloroform and stirred at room temperature for 40 min. The reaction was monitored by TLC. After the reaction was complete, 200 mL of methanol solution was added, precipitating a solid. The solid was filtered under reduced pressure and washed with ACN solution. The mixture was then filtered again under reduced pressure to obtain the solid. 2.2 g of Fmoc-Ala-OH (1.2 eq), 2 mL of DIC (2 eq), 2 g of HOBT (1.2 eq), and the solid obtained from the reduced pressure filtration were added to the chloroform solution and dissolved. The mixture was stirred thoroughly for 2 h and monitored by TLC. 400 mL of methanol solution was added to the solution, precipitating a solid. The solid was then filtered under reduced pressure and washed with 200 mL of acetonitrile solution. The solid was then filtered again under reduced pressure to obtain the solid. Step 420 was repeated 12 times by replacing Fmoc-Pro-OH with different amino acid feedstocks to obtain intermediate 4c.

[0093] 1 H-NMR (400MHz, Chloroform-d): δ7.90 (dd, J=24.4, 8.6Hz, 2H), 7.82 (dd, J=7.6, 1.4Hz, 2H), 7.6 7-7.61(m, 3H), 7.46-7.35(m, 4H), 7.31-7.24(m, 6H), 7.24-7.17(m, 2H), 7.16-7.10(m, 2H), 6.8 5-6.76 (m, 3H), 6.73 (ddd, J=8.4, 2.2, 1.2Hz, 1H), 6.62 (t, J=2.4Hz, 1H), 6.16 (d, J=8.8Hz, 1H), 4.98-4.94(m, 1H), 4.51-4.28(m, 7H), δ4.21(s, 5H), 4.06-3.94(m, 4H), 3.85(dd, J=12.8, 4.1Hz , 1H), 3.68-3.55(m, 3H), 3.52(dddd, J=12.0, 4.7, 3.2, 1.4Hz, 1H), 3.04-2.99(m, 1H), 2.92(ddt , J=14.4, 6.3, 0.9Hz, 1H), 2.76 (ddt, J=14.4, 6.2, 0.8Hz, 1H), 2.67 (ddt, J=14.4, 6.3, 0.9Hz, 1H ), 2.28-2.23 (m, 2H), 2.08 (dddd, J=12.4, 7.1, 5.5, 3.7Hz, 1H), 1.98 (ddtd, J=12.8, 7.2, 5.4, 3. 6Hz, 1H), 1.92–1.71 (m, 6H), 1.44 (dq, J=7.6, 7.0Hz, 2H), 1.35-1.19 (m, 58H), 0.94-0.86 (m, 3H).

[0094] Figure 1 This is a photograph of the actual intermediate 4c. From... Figure 1 It can be seen that the intermediate 4c obtained by direct drying after vacuum filtration is in powder form, indicating that it is easy to filter.

[0095] Step 440: Synthesize the polypeptide Fmoc-Tyr(tBu)-Phe-Ser(tBu)-Ala-Pro-Gly-OH

[0096]

[0097] Intermediate 4c was added to a 0.5% TFA / TCM solution and stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the organic phase was separated using an aqueous solution, concentrated to dryness, and then acetonitrile solution was added. The mixture was filtered three times, and the filtrate was collected, concentrated, and purified by rapid column liquid chromatography to obtain the polypeptide Fmoc-Tyr(tBu)-Phe-Ser(tBu)-Ala-Pro-Gly-OH, with a yield of 83% and a crude product purity of 93.2%.

[0098] 1 H-NMR (400MHz, Chloroform-d): δ8.12 (t, J=6.8Hz, 1H), 7.95-7.86 (m, 2H), 7.8 6-7.79(m, 2H), 7.76(d, J=8.8Hz, 1H), 7.64(dq, J=7.2, 0.8Hz, 2H), 7.46-7.35(m , 4H), 7.26(pd, J=4.4, 1.9Hz, 5H), 7.16-7.10(m, 2H), 6.85-6.78(m, 2H), 6.16( d, J=8.8Hz, 1H), 4.99-4.93 (m, 1H), 4.47 (dt, J=8.8, 6.4Hz, 1H), 4.43-4.28 (m, 6 H), δ4.21(s, 5H), 3.94-3.81(m, 3H), 3.68–3.57(m, 2H), 3.56-3.48(m, 1H), 3.0 1(ddt, J=13.6, 6.2, 0.7Hz, 1H), 2.92 (ddt, J=13.6, 6.2, 0.8Hz, 1H), 2.76 (ddt, J =13.6, 6.2, 0.7Hz, 1H), 2.67 (ddt, J=13.6, 6.2, 0.8Hz, 1H), 2.14-2.04 (m, 1H), 1 .98(ddtd, J=12.4, 7.1, 5.5, 3.6Hz, 1H), 1.92-1.80(m, 2H), 1.26-1.19(m, 21H).

[0099] Figure 2 This is a photograph of the liquid-liquid mixture after reacting intermediate 4c with 0.5% TFA / TCM and separating the contents using an aqueous solution. Figure 2 As shown, no emulsification was observed in the organic phase, and the interface between the organic phase and the aqueous phase was clear, making it easy to separate or filter.

[0100] 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 compound for use as a support in the liquid-phase synthesis of peptides, the compound containing a ferrocene structure, the structural formula of which is: ； in: R1 is selected from C1 to C100 alkyl groups; R2 is selected from halogens; X is selected from halogens.

2. The compound according to claim 1, characterized in that: The structural formula of the compound is: 。 3. The compound according to claim 2, characterized in that: The compound is selected from the following structural formulas: 。 4. The use of the compound according to any one of claims 1-3 as a carrier in the liquid-phase synthesis of polypeptides.

5. The application as described in claim 4, characterized in that: The polypeptide is Fmoc-Tyr(tBu)-Phe-Ser(tBu)-Ala-Pro-Gly-OH.

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