WO2020155879A1 - Compound containing benzyl structure and use thereof - Google Patents

Abstract

The present invention discloses a compound containing a benzyl structure and a use thereof. The compound containing a benzyl structure of the present invention contains a hydroxyl, an amino group, a substituted amino group, and an active group, and can be used as an amino acid or a peptide C-terminal protection reagent. A peptide synthesis reaction using this protection carrier has a fast reaction speed and a high reagent utilization rate in a suitable solvent system; effective purification can be carried out when post-treatment is carried out by means of simple liquid-liquid extraction separation, and finally, a product with a high purity can be obtained; and during a synthesis process, the change in solubility is small and an operation process has a strong universality, and therefore a universal production method can be developed.

Description

A compound containing benzyl structure and its application Technical field

The present invention relates to the technical field of compound and polypeptide synthesis, in particular to a compound containing a benzyl structure and its application.

Background technique

The synthetic manufacturing methods of peptides can be roughly divided into three categories at present: solid-phase carrier synthesis, conventional liquid-phase synthesis and liquid-phase carrier synthesis.

The solid-phase carrier synthesis method can complete the separation and purification work through simple solid-liquid separation, and has the advantages of strong universality and short development cycle. However, due to the poor affinity between the solvent and the solid carrier and the spatial structure of the carrier, the solid-liquid two-phase reaction has serious mass transfer problems and the reaction speed is limited. In order to compensate for the low reactivity, under conventional reaction conditions, the reagents need to be greatly excessive. The intermediate is attached to a solid-phase carrier, which is difficult to perform routine analysis and purification, and the final product can only be purified by reverse-phase liquid chromatography.

The conventional liquid phase synthesis method is generally a homogeneous reaction with good reactivity. The intermediate can be purified by washing, crystallization and other means, and the final product has a higher purity. However, the properties of the products and impurities of each reaction are quite different, and no universal method can be found for separation and purification, the development cycle is long, and the manufacturing steps are complicated.

The liquid carrier synthesis method is a new peptide synthesis method developed in the past ten years to improve the above two methods. Among them, the more representative ones include JITSUBO's Molecular Hiving ^TM technology and Ajinomoto's Ajiphase technology.

JITSUBO’s Molecular Hiving ^TM technology uses long-chain alkoxy benzyl alcohols, such as 3,5-bis(docosyloxy)benzyl alcohol, 2,4-bis(docosyloxy) Benzyl alcohol, 3,4,5-tris(octadecyloxy)benzyl alcohol, etc. are used as liquid carrier. These carriers are used as C-terminal protective reagents for peptide synthesis. The reaction is carried out in a homogeneous phase. The product is precipitated by changing the solvent composition or temperature change, and separation and purification are achieved through the steps of precipitation-filtration-washing. However, this method has the following problems: ①The solubility of the carrier in solvents such as medium and low polarity acetate and toluene is not large, and the reaction concentration is low, which is not conducive to scale-up production; ②The solvent can be changed through quantitative distillation and other operations. The process of composition is complicated; ③The precipitation of the solvent system is generally amorphous solid, which is very difficult to filter and wash, and the effect of removing impurities is poor and time-consuming. Therefore, it cannot be said that this method is a universal peptide synthesis method with good repeatability.

Ajinomoto's Ajiphase technology has modified the former, using multi-branched alkyl groups instead of linear alkyl groups, which effectively improves the solubility of the carrier in solvents such as isopropyl acetate. The reaction can be carried out at a higher concentration. Water & organic polar solvent washing can achieve separation and purification. However, this technology still has the following problems: ①The reaction time is long. The patent publication No. CN107011132A uses isopropyl acetate or methylcyclopentyl ether as a solvent for condensation to react overnight, and deprotection requires 4-6 hours. Other publications The condensation reaction using chloroform as the solvent in the literature also takes more than 3 hours, and the long reaction time leads to an increase in by-product impurities; ②Due to the small difference in polarity between the two phases during liquid-liquid separation, the impurities are difficult to remove and the product purity is low; ③Use this In the process of peptide synthesis by the type carrier, the solubility decreases rapidly, and the gelation phenomenon occurs when the number of amino acids of the general peptide chain is greater than 4. Therefore, this method can hardly be said to be a universal peptide synthesis method with good repeatability.

Therefore, it is of great significance to synthesize a universal type of liquid phase synthesis protection carrier compound, and then obtain a universal peptide synthesis method with good reproducibility.

Summary of the invention

The purpose of the present invention is to provide a compound containing a benzyl structure and its application. Using this compound as a protective carrier for peptide liquid phase synthesis, in a homogeneous or heterogeneous solvent system, especially in a heterogeneous solvent system, it can increase the reaction speed and reagent utilization, simplify post-processing operations, and improve product purity. Improving the versatility of the operation process can be developed into a universal production method.

The technical scheme adopted by the present invention is:

One of the objectives of the present invention is to provide a compound containing a benzyl structure, the structure of which is shown in the general formula (1):

among them:

X is selected from OH, halogen, sulfonate, NHR _a ;

Wherein, R _a is selected from hydrogen, an alkyl group or an aromatic group;

Q is independently selected from O, NH, NHCO, CO, CONH, S, SO or SO ₂ ;

n is selected from an integer of 1 to 4;

R is independently selected from the group represented by the general formula (2):

Among them, * means connected with Q;

L is selected from C ₂ ～C ₁₅ organic chain groups containing O, N or S heteroatoms or C ₂ ～C ₁₅ organic chain groups without O, N or S heteroatoms, when L is selected from C ₂ ～C ₁₅ organic chain groups that do not contain O, N or When the C ₂ ～C ₁₅ organic chain group of S heteroatom, R ₂ ≠H;

R _{1 is} selected from a C ₁ ～C ₂₅ alkyl group or a group represented by the general formula (3):

Wherein, * means it is connected to the carbonyl group;

m1 represents an integer of 1 to 3;

R _{1a is} selected from C ₆ ～C ₂₅ alkyl groups, and the total carbon number of m1 R _1a is not less than 8;

k _{a is} selected from an integer of 0 to 3;

Ring B except that one R _1a O having m1 substituent groups, but may also contain selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen-containing atoms substituted with C ₁ ~ C ₅ alkoxy group, a halogen atom free of C ₁ ~ C ₅ alkoxy group substituent;

In the general formula (2), R _{2 is} selected from hydrogen, a C ₁ to C ₂₅ alkyl group or the group represented by the general formula (4):

In the general formula (4), * means connected with N;

m2 is selected from an integer of 0 to 3;

R _{2a is} selected from C ₆ ～C ₂₅ alkyl groups;

k _{b is} selected from an integer of 1 to 6;

In addition to an outer ring C m2 having a substituent group R _2a O, may also contain selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen-containing atoms substituted with C ₁ ~ C ₅ alkoxy group, a halogen atom free of C ₁ ~ C ₅ alkoxy group substituent;

When Q is selected from NH, R is selected from the group represented by the general formula (2'):

Wherein, R _{1 is} selected from the group represented by the general formula (3), and * means that it is connected to Q;

In addition to the ring A has n outer RQ substituents may further contain substituents selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen atom-containing The C ₁ -C ₅ alkoxy group or the substituent of the C ₁ -C ₅ alkoxy group without halogen atom substitution.

Preferably, the above-mentioned R is selected from the group represented by the general formula (5):

Among them, in the general formula (5), * means connected with Q;

k _{1 is} selected from an integer of 0 to 3, and when k ₁ =0, R ₂ ≠H; more preferably, k _{1 is} selected from an integer of 1 to 3.

Preferably, the above-mentioned R is selected from the group represented by the general formula (6):

Among them, in the general formula (6), * means connected with Q;

R _{4 is} selected from hydrogen, C ₁ ～C ₂₅ alkyl group or the group represented by general formula (4);

k _{2 is} selected from an integer of 1 to 4;

k _{3 is} selected from an integer of 1-4.

Preferably, the above R is selected from the group represented by the general formula (7):

Among them, in the general formula (7), * means connected with Q;

R _{6 is} selected from hydrogen, a C ₁ ～C ₂₅ alkyl group or a group represented by the general formula (4);

k _{4 is} selected from an integer from 0 to 3;

k _{5 is} selected from an integer from 0 to 3;

R _{5 is} selected from hydrogen, a side chain group of a natural amino acid, an alkyl group or a group represented by the general formula (8):

Wherein, k _{6 is} selected from an integer of 1 to 4;

R1' is selected from a C ₁ ～C ₂₅ alkyl group or a group represented by the general formula (3);

R2' is selected from hydrogen, a C ₁ to C ₂₅ alkyl group, or a group represented by the general formula (4).

Preferably, the aforementioned Q is selected from O or NH.

Preferably, the R _a is selected from hydrogen, methyl, ethyl, propyl, benzyl or methoxybenzyl.

Preferably, n is selected from an integer of 1 to 3; more preferably, n is selected from 1 or 2.

Preferably, the halogen in X in the general formula (1) is selected from Cl, Br or I.

Preferably, the sulfonic acid ester in X in the general formula (1) is selected from mesylate or p-toluenesulfonate.

Preferably, the above m1 is selected from 2 or 3, and the total carbon number of m1 R _1a is 8-60.

Preferably, the above-mentioned R _{1a is} selected from C ₈ to C ₂₂ alkyl groups.

More preferably, the total carbon number of the m1 R _1a is 24-60.

Preferably, m2 is selected from 2 or 3, and the total carbon number of m2 R _2a is 8-60.

Preferably, the above-mentioned R _{2a is} selected from C ₈ -C ₂₂ alkyl groups.

Preferably, the above k _{b is} selected from an integer of 1-3.

More preferably, the aforementioned R _{2 is} selected from hydrogen, methyl, ethyl, propyl, isopropyl, isooctyl, benzyl or 4-methoxybenzyl.

Preferably, the structural formula of the above compound is selected from the following:

Preferably, the C ₈ H ₁₇ alkyl group in the above structural formula is isooctyl, the C ₉ H ₁₉ alkyl group is isononyl, the C ₁₀ H ₂₁ alkyl group is isodecayl, and the C ₁₃ H ₂₇ alkyl group is iso Structure tridecyl, C ₂₀ H ₄₁ alkyl is 2,3-dihydrophytyl.

Preferably, the above-mentioned compound is easily soluble in at least one of hydrocarbon organic solvents, aromatic hydrocarbon organic solvents, ester organic solvents, ether organic solvents, and water-soluble aprotic polar organic solvents.

Preferably, the above-mentioned hydrocarbon organic solvent is selected from at least one of heptane, hexane, petroleum ether, cyclohexane, and methylcyclohexane.

Preferably, the above-mentioned aromatic hydrocarbon organic solvent is selected from at least one of toluene, ethylbenzene, and xylene.

Preferably, the above-mentioned ester organic solvent is selected from at least one of isopropyl acetate, tert-butyl acetate, and ethyl acetate.

Preferably, the above-mentioned ether organic solvent is selected from at least one of diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, and tetrahydrofuran.

Preferably, the water-soluble aprotic polar organic solvent is selected from the group consisting of N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methyl- Pyrrolidone, N-ethyl-pyrrolidone, dimethyl sulfoxide, sulfolane, 1,3-dimethylimidazolinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidine At least one of ketones.

Preferably, the solubility of the above compound in N,N-dimethylformamide is >1% at 25-30°C.

Preferably, the solubility of the above compound in N,N-dimethylformamide is >5% at 25-30°C.

Preferably, the solubility of the above compound in N,N-dimethylformamide is >10% at 25-30°C.

Preferably, the solubility of the above compound in N,N-dimethylformamide is >30% at 25-30°C.

Preferably, the solubility of the above compound in N,N-dimethylformamide is >50% at 25-30°C.

More preferably, the solubility of the above compound in N,N-dimethylformamide is >100% at 25-30°C.

Preferably, the solubility of the above compound in a hydrocarbon organic solvent is >5% at 25-30°C; more preferably, the solubility of the above compound in heptane is >5%.

Preferably, the solubility of the above-mentioned compound in a hydrocarbon organic solvent is> 10% at 25-30° C.; more preferably, the solubility of the above-mentioned compound in heptane is> 10%.

Preferably, the solubility of the above compound in a hydrocarbon organic solvent is >20% at 25-30°C; more preferably, the solubility of the above compound in heptane is >20%.

Preferably, the solubility of the above-mentioned compound in a hydrocarbon organic solvent is >30% at 25-30°C; more preferably, the solubility of the above-mentioned compound in heptane is >30%.

Preferably, the solubility of the above compound in a hydrocarbon organic solvent is >50% at 25-30°C; more preferably, the solubility of the above compound in heptane is >50%.

Preferably, the solubility of the above-mentioned compound in a hydrocarbon organic solvent is >70% at 25-30°C; more preferably, the solubility of the above-mentioned compound in heptane is >70%.

Preferably, the solubility of the above-mentioned compound in a hydrocarbon organic solvent is> 100% at 25-30° C.; more preferably, the solubility of the above-mentioned compound in heptane is> 100%.

Preferably, the solubility of the compound in the ester organic solvent is >30% at 25-30°C; more preferably, the solubility of the compound in the isopropyl acetate is >30%.

Preferably, the solubility of the above-mentioned compound in the ester organic solvent is >50% at 25-30°C; more preferably, the solubility of the above-mentioned compound in the isopropyl acetate is >50%.

Preferably, the solubility of the compound in the ester organic solvent is >70% at 25-30°C; more preferably, the solubility of the compound in the isopropyl acetate is >70%.

Preferably, the solubility of the compound in the ester organic solvent is> 100% at 25-30° C.; more preferably, the solubility of the compound in the isopropyl acetate is> 100%.

Preferably, the solubility of the above-mentioned compound in ether organic solvents is >30% at 25-30°C; more preferably, the solubility of the above-mentioned compound in methyl tert-butyl ether is >30%.

Preferably, the solubility of the above-mentioned compound in ether organic solvents is >50% at 25-30°C; more preferably, the solubility of the above-mentioned compound in methyl tert-butyl ether is >50%.

Preferably, the solubility of the above-mentioned compound in ether organic solvents is >70% at 25-30°C; more preferably, the solubility of the above-mentioned compound in methyl tert-butyl ether is >70%.

Preferably, the solubility of the above compound in ether organic solvents is> 100% at 25-30° C.; more preferably, the solubility of the above compound in methyl tert-butyl ether is> 100%.

The above-mentioned compounds of the present invention can be prepared by the following synthetic routes:

Aldehyde 1-1a goes through step 1-1 and step 1-2, or alcohol 1-5a goes through step 1-6 to synthesize X=OH compound.

Aldehyde 1-2a goes through step 1-3 or aldehyde 1-2a goes through step 1-4 and step 1-5, or protected phenolamine 1-6a goes through step 1-7 and step 1-8 to synthesize X=NHR _a compound, R _a represents a hydrogen atom, an alkyl group or an aralkyl group.

In addition, the OH in the compound with X=OH can be converted into compounds such as chlorine, bromine, iodine, methanesulfonate or p-toluenesulfonate through conventional reactions.

According to the above reaction route, R in general formulas (5), (6) and (7) can be synthesized.

Another object of the present invention is to provide a protective reagent for the C-terminus of an amino acid or peptide, the protective reagent comprising the above-mentioned compound containing a benzyl structure.

The invention also provides the application of the compound containing the benzyl structure in the synthesis of peptide reagents in a homogeneous or heterogeneous solvent system.

In addition, those skilled in the art can add other substances to the above reagents according to conventional selection and prepare the required compounds or complexes according to needs.

The present invention also provides a method for synthesizing peptides, which includes using the above-mentioned compound containing a benzyl structure.

Preferably, the above-mentioned peptide synthesis method includes the following steps:

1) Carrier access: The above-mentioned compound containing benzyl structure is used as a carrier to connect with N-protected amino acid or N-protected peptide compound through conventional reaction to obtain the N-protected amino acid or N-protected C-terminal of the carrier containing benzyl structure. -Protect peptide compounds;

2) N-terminal deprotection: dissolve the N-protected amino acid or N-protected peptide compound with the C-terminal protection of the benzyl structure carrier in the solvent, and add the N-terminal protection deprotection reagent solution to form a homogeneous or heterogeneous system. N-terminal deprotection, adding a highly polar solvent for extraction, to obtain N-deprotected amino acid or N-deprotected peptide compound solution containing benzyl structure carrier C-terminal protection;

3) Peptide chain extension: Add N-protected amino acid or N-protected peptide solution to the C-terminal protected N-deprotected amino acid or N-deprotected peptide compound solution of the benzyl structure carrier, and then add the condensation reagent solution to form Condensation reaction is carried out in homogeneous or heterogeneous system, and highly polar solvent is added for extraction to obtain N-protected amino acid or N-protected peptide compound solution containing benzyl structure carrier C-terminal protection;

4) Repeat step 2) and step 3) to insert the next amino acid until a complete peptide chain is obtained.

Preferably, the N-protected amino acid or N-protected peptide compound solution containing the C-terminal protection of the benzyl structure carrier in step 2) and the N-terminal protection deprotection reagent solution in step 2) form a heterogeneous system.

Preferably, the N-deprotected amino acid or N-deprotected peptide compound solution containing the C-terminal protection of the benzyl structure carrier in step 3) and the N-protected amino acid or N-protected peptide and condensation reagent solution in step 3) Into a heterogeneous system.

Preferably, in step 2) the solvent containing the C-terminal protected N-protected amino acid or N-protected peptide compound of the benzyl structure carrier and the N-deprotected amino acid containing the C-terminal protection of the benzyl structure carrier in step 3) Or the solvent in the N-deprotected peptide compound solution is independently selected from hydrocarbons or mixed solvents formed by hydrocarbons and at least one of esters, ethers, and halogenated hydrocarbons.

It should be noted that the content of hydrocarbons in the mixed solvent formed by at least one of hydrocarbons and esters, ethers, and halogenated hydrocarbons shall not affect the formation of a heterogeneous system.

Preferably, step 2) dissolve the solvent containing the N-protected amino acid or N-protected peptide compound protected by the C-terminal of the benzyl structure carrier and step 3) the N-deprotected amino acid or the C-terminal protected N-protected amino acid of the benzyl structure carrier. The solvent in the N-deprotected peptide compound solution is independently selected from hexane, heptane, cyclohexane, methylcyclohexane, petroleum ether or hexane, heptane, cyclohexane, methylcyclohexane, petroleum ether At least one of is formed with at least one of isopropyl acetate, ethyl acetate, tert-butyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, dichloromethane, and chloroform At least one of the mixed solvents.

Preferably, the solvent for dissolving the deprotection reagent for N-terminal protection in step 2), the solvent for dissolving the N-protected amino acid or N-protected peptide, and the condensation reagent in step 3) are independently selected from amide solvents.

Preferably, the aforementioned amide solvent is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, N-ethyl -At least one of pyrrolidone, 1,3-dimethylimidazolinone, and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.

Preferably, the high-polarity solvent in step 2) and step 3) is selected from at least one of water, alcohols, nitriles, amides, sulfoxides, sulfones, and water-soluble alcohol ethers.

Preferably, the highly polar solvent in the above step 2) and step 3) is selected from water, methanol, acetonitrile, N,N-dimethylformamide, N-methyl-pyrrolidone, dimethylsulfoxide, sulfolane, At least one of 1,3-dimethylimidazolinone and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.

It should be noted that in step 2), when the N-protected amino acid or N-protected peptide compound protected by the C-terminal of the benzyl structure carrier is dissolved in a solvent, the N-terminal protected deprotection reagent solution is added to form a homogeneous system. When the N-terminal is deprotected, the solvent containing the N-protected amino acid or N-protected peptide compound protected by the C-terminal of the benzyl structure carrier does not contain hydrocarbons or contains some hydrocarbons, but this part of the hydrocarbons does not affect the formation of a homogeneous system , The solvent for dissolving the deprotection reagent for N-terminal protection and the solvent for dissolving the N-protected amino acid or N-protected peptide compound protected by the C-terminal of the benzyl structure carrier can be ester solvents, ether solvents, halogenated hydrocarbons or At least one of amide solvents, preferably ethyl acetate, isopropionic acid acetate, tert-butyl acetate, isopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, dichloromethane, chloroform , N,N-dimethylformamide, N-methyl-pyrrolidone, 1,3-dimethylimidazolinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2- At least one of the pyrimidinones; in the same step 3), add the N-protected amino acid or N-protected peptide to the N-deprotected amino acid or N-deprotected peptide compound solution with the C-terminal protection of the benzyl structure carrier The solvent of the solution containing the N-deprotected amino acid or N-deprotected peptide compound protected by the C-terminal of the benzyl structure carrier does not contain hydrocarbons or contains part of the hydrocarbons. However, this part of the hydrocarbons does not affect the formation of a homogeneous system. The solvent for dissolving N-protected amino acids or N-protected peptides and condensation reagents and dissolving N-deprotected amino acids or N-deprotected C-terminal protection of the benzyl structure carrier The solvent phase of the peptide compound can be selected from at least one of ester solvents, ether solvents or amide solvents, preferably ethyl acetate, isopropyl acetate, tert-butyl acetate, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, N-methyl-pyrrolidone, 1,3-dimethylimidazolinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidine At least one of ketones.

In the peptide synthesis method of the present invention, the target product and impurities can be well separated only by adding a highly polar solvent, especially for a heterogeneous system, thereby greatly simplifying the post-processing operation steps.

Preferably, the amount of the above-mentioned N-protected amino acid or N-protected peptide is 0.8-3.0 equivalents of the compound containing the benzyl structure, and the amount of the condensation reagent is 0.8-3.0 equivalents of the compound containing the benzyl structure.

Preferably, the amount of the above-mentioned N-protected amino acid or N-protected peptide is 1.0 to 1.5 equivalents of the compound containing benzyl structure, and the amount of the condensation reagent is 1.0 to 1.5 equivalents of the compound containing benzyl structure

More preferably, the amount of the above-mentioned N-protected amino acid or N-protected peptide is 1-1.1 equivalents of the compound containing a benzyl structure, and the amount of the condensation reagent is 1-1.2 equivalents of the compound containing a benzyl structure.

In addition, in the peptide synthesis reaction, the compound of the present invention is introduced into an amino acid or peptide as a protecting group at the C terminal. In the process of introducing the compound of the present invention, the compound with X=OH can be converted into an equivalent active substance, such as a halide, a sulfonate, and then reacted with an amino acid or peptide, or it can be directly esterified or amidated. The compound introduced with X=NHR _a can be completed by reacting with amino acids or peptides by conventional condensation methods, and the operation steps can be the same as or different from step 3). The reaction can be carried out in homogeneous and heterogeneous solvent systems, wherein the carrier incorporation reaction of X=OH is preferably carried out in a homogeneous phase, and the carrier incorporation reaction of X=NHRa is preferably carried out in a heterogeneous solvent.

If necessary, those skilled in the art can perform subsequent C-terminal modification or N-terminal modification on the peptide chain according to conventional methods, or through selective side chain deprotection, and then perform reactions such as cyclization or introduction of other groups.

The beneficial effects of the present invention are:

1. The present invention provides a protective carrier that can be applied to the liquid phase synthesis of peptides. The peptide synthesis reaction using this protective carrier has fast reaction speed and high reagent utilization rate in a suitable solvent system; at the same time, simple liquid The liquid extraction separation can be effectively purified, and finally a product with higher purity can be obtained, so the post-processing operation is simple; and the solubility change during the synthesis process is small, the operation flow is strong, and it can be developed into a universal production method.

2. The benzyl structure-containing compound of the present invention contains hydroxyl, amino, substituted amino, and active groups, which can be used as amino acid or peptide C-terminal protection reagent; the compound of the present invention contains a non-polar and polar two-part structure, Soluble in both non-polar solvents and polar solvents, so it is suitable for use in a homogeneous or heterogeneous mixed solvent system composed of non-polar solvents and polar solvents, especially hydrocarbons, or hydrocarbons and ethers , A heterogeneous system composed of a mixed solvent of at least one solvent in esters and an amide polar solvent, which is used as a protective carrier for peptide synthesis reactions; and peptide synthesis reactions with such carriers: ① Fast reaction speed , Less by-products; ② high utilization of reagents, low reagent dosage, low cost, less three wastes; ③ good separation of impurities and products in post-processing extraction, high product purity; ④ solubility of intermediate compounds in the synthesis process The reaction rate changes little, the amino acid or peptide fragment has good repeatability, simple operation, strong universality, and it is suitable as a general production method.

detailed description

Examples are further listed below to illustrate the present invention in detail. It should also be understood that the following examples are only used to further illustrate the present invention, and cannot be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the principles set forth in the present invention belong to the present invention. The scope of protection. The specific process parameters in the following examples are only an example in the appropriate range, that is, those skilled in the art can make selections within the appropriate range through the description herein, and are not limited to the specific data illustrated below.

In this specification and in the following examples, the substances represented by the following abbreviations are:

DCM: Dichloromethane

DIPEA: N,N-Diisopropylethylamine

DMAP: 4-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

EA: ethyl acetate

EDCI: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride

HBTU: O-benzotriazole-tetramethylurea hexafluorophosphate

HOBt: 1-Hydroxybenzotriazole

HONB: N-hydroxy-5-norbornene-2,3-dicarboximide

PE: petroleum ether

TFA: Trifluoroacetic acid

TIS: Triisopropylsilane

Example 1

Synthesis of 2-(2-(2-(3,4,5-tris(isooctyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-001):

3,4,5-Trihydroxybenzoic acid methyl ester (18.4g, 0.1mol), isooctyl bromide (2-ethyl-hexyl bromide) (63.7g, 0.33mol), potassium carbonate (55.2g, 0.4mol) Mix with DMF (150mL) at room temperature, and heat to 110-120℃ to react for 12h. Cool to room temperature, pour into a mixture of petroleum ether (150 mL) and water (150 mL) while stirring. Separate the lower layer, wash the upper layer with petroleum ether solution with water (200mL*2), and concentrate to obtain the crude oily intermediate 1-2;

The crude intermediate 1-2 was dissolved in tetrahydrofuran (100mL), methanol (50mL) and 30% NaOH solution (67g) were added, and the reaction was stirred for 3h. Petroleum ether (100mL) and water (200mL) were added. After stirring for 10min, the mixture was separated. Lower layer; add 2N hydrochloric acid (100mL), stir for 10 minutes, and separate the lower layer; wash the upper layer to pH 6-7, and concentrate to obtain 48.0g of 3,4,5-tris(isooctyloxy)-benzoic acid (Intermediate 1- 2);

3,4,5-Tris(isooctyloxy)-benzoic acid (45.5g, 0.09mol), 2-(2-chloroethyl)oxy-ethylamine hydrochloride (16.0g, 0.1mol) and two Mix chloromethane (200mL), magnetically stir, and cool to 5-10℃; add HOBt (13.5g, 0.1mol) and EDCI (19.2, 0.1mol) in sequence; keep it at 5-10℃ for 10min, remove the cold bath, Warm to room temperature and react for 3h. Wash with water (100mL), saturated sodium bicarbonate (100mL*2), 1N hydrochloric acid (50mL) and saturated brine (50mL) successively, and concentrate to obtain 2-(2-(3,4,5-triisooctyloxy- Benzamido)-ethoxy)-ethyl chloride 55.1g (1-3);

2-(2-(3,4,5-Tris(isooctyloxy)-benzamide)-ethoxy)-ethyl chloride (55.1g, 0.09mmoL), 2-hydroxybenzaldehyde (12.2g , 0.1mol, 1-4), potassium carbonate (41.5g, 0.3moL), potassium iodide (0.1g) and DMF (120mL) were mixed, mechanically stirred, and heated to 80-90°C for 5h. Cool to room temperature, pour into a mixture of petroleum ether (150mL) and water (150mL) with stirring, separate the lower layer, wash the upper layer with water (200mL×2), and concentrate to obtain 2-(2-(2-(3,4, 5-Tris(isooctyloxy)-benzamide)-ethoxy)-ethoxy)-benzaldehyde crude product (1-5);

The above crude product was dissolved in ethanol (120 mL), cooled to 5-10°C, and sodium borohydride (0.4 g, 0.1 mol) was added in batches. After the addition, warm up to room temperature, continue the reaction for 2h, add 1N hydrochloric acid dropwise until no bubbles are formed, remove the ethanol under reduced pressure, add petroleum ether (150mL) for extraction; separate the lower layer, the petroleum ether layer sequentially water (100mL) and saturated brine ( 100mL) was washed, concentrated to obtain BM-001 crude product, column chromatography purification (100%PE→50%EA) to obtain 2-(2-(2-(3,4,5-tris(isooctyloxy)-benzyl) Amido)-ethoxy)-ethoxy)-benzyl alcohol (BM-001) 50.0g;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.85-1.00 (m, 18H), 1.30-1.80 (m, 27H), 3.60-4.20 (m, 14H), 4.50-4.60 (m, 2H), 6.90 -7.00 (m, 2H), 7.05-7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 700.5024.

Example 2

2-(2-(2-(3,4,5-Tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-002) and 2-(2 -(2-(3,4,5-Tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzylamine (BM-002A):

The synthesis method of BM-002 in Example 2 is the same as that in Example 1, except that: Example 2 uses isononyl bromide (3,5,5-trimethyl-hexyl bromide) instead of in Example 1 Isooctyl bromide;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.20 (m, 14H), 44.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.1.0-7.20 (m, 3H), 7.25-7.35 (m, 3H); HRMS TOF[M +1] ⁺ : 742.5674;

Synthesis of BM-002A:

Aldehyde intermediate 2-1 (7.5g, 0.01mol) was dissolved in tetrahydrofuran (20mL) and absolute ethanol (30mL), hydroxylamine hydrochloride (1.04g, 0.015mol) and triethylamine (1.4g, 0.014mol) were added to the mixture, Heat to 60-70℃ and react for 2h; add heptane (100mL) and water (100mL) to extract and separate; the heptane layer is concentrated to obtain the crude oxime 2-2;

Dissolve the crude oxime 2-2 in acetic acid (50mL), heat to 50-60℃, add zinc powder (2.0g, 0.03mol), incubate the reaction for 2h, cool to room temperature, filter to remove unreacted zinc powder, and remove under reduced pressure Acetic acid, the remainder was dissolved in heptane (100mL), washed with 1N NaOH solution (100mL); the heptane layer was washed with water until neutral, concentrated to obtain a crude product, purified by column chromatography to obtain 2-(2-(2-(3, 4,5-Tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzylamine (BM-002A) 3.0g;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.20 (m, 14H), 4.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.05-7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 741.5738, [2M+1] ⁺ : 1482.1443.

Example 3

Synthesis of 2-(2-(2-(3,4,5-tris(isodecyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-003):

The synthesis method of BM-003 in Example 3 is the same as that in Example 1, except that: isooctyl bromide (prepared by Exxal 10 bromination) is used instead of the isooctyl bromide in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 57H), 3.65-4.15 (m, 14), 4.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.05 -7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 784.6064.

Preparation of isodecyl bromide (preparation of bromide):

Exxal 10 (100 mL) and 37% HBr (300 mL) were mixed in a three-necked flask. Under mechanical stirring, concentrated sulfuric acid (30 mL) was slowly added, and the mixed reaction solution was heated to 115-120°C for reaction. The reaction was stopped after GC analysis of alcohol <0.5%. The temperature was lowered to below 50° C., petroleum ether (100 mL) was added for extraction, the petroleum ether layer was first neutralized with water, and the petroleum ether was removed under reduced pressure to obtain isodecyl bromide.

Example 4

2-(2-(2-(3,4,5-Tris(octa/dec/dodecyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-004) Synthesis:

The synthesis method of BM-004 in Example 4 is the same as that in Example 1, except that: n-octyl bromide, n-decyl bromide and n-dodecyl bromide (1:1:1) are used instead of the one in Example 1. Isooctyl bromide;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 57H), 3.65-4.15 (m, 14), 4.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.05 -7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 756.5749, 784.6059, 812.6378.

Example 5

Synthesis of 2-(2-(2-(3,4,5-tris(isotridecyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-005) :

The synthesis method of BM-005 in Example 5 is the same as that in Example 1, but the difference is that iso-tridecyl bromide (prepared by Exxal 13 according to the bromide preparation method in Example 3) is used instead of the isooctane in Example 1. Base bromide;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 75H), 3.65-4.15 (m, 14), 4.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.05 -7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF [M+1] ⁺ : 910.7491, [M-OH] ⁺ : 892.7371.

Example 6

2-(2-(2-(3,4,5-Tris(2,3-dihydrophytaalkoxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-006 ) Synthesis:

The synthesis method of BM-006 in Example 6 is the same as that in Example 1, except that 2,3-dihydrophytyl bromide (3,7,11,15-tetramethyl-hexadecyl bromide) is used instead Isooctyl bromide in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.70-1.90 (m, 167H), 3.65-4.15 (m, 14H), 4.50-4.60 (s, 2H), 6.90-7.00 (m, 2H), 7.05 -7.15 (m, 3H), 7.20-7.30 (m, 1H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 1205.0720.

Example 7

2-(2-(2-(N-benzyl-3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-007) Synthesis:

The synthesis method of BM-007 in Example 7 is the same as that in Example 1, except that isononyl bromide is used instead of isooctyl bromide, N-benzyl-2-(2-chloroethyl)oxy-ethylamine salt The acid salt replaces 2-(2-chloroethyl)oxy-ethylamine hydrochloride in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.50-2.00 (m, 9H), 3.40-4.20 (m, 14), 4.50-4.90 (m, 4H), 6.60 -6.70 (bs, 2H), 6.80-6.90 (m, 1H), 6.90-7.00 (m, 1H), 7.15-7.40 (m, 7H); HRMS TOF[M+1] ⁺ : 832.6031.

Preparation of N-benzyl-2-(2-chloroethyl)oxy-ethylamine hydrochloride

Diethylene glycolamine (21.0g, 0.2mol) was dissolved in absolute ethanol (100mL), benzaldehyde (21.2g, 0.2mol) was added, and reacted at room temperature for half an hour; the temperature was reduced to 5-10°C, and sodium borohydride (11.4g) was added , 0.3mol), warm to room temperature and react for 2h; cool to 5-10°C, adjust pH to 1 with concentrated hydrochloric acid, remove ethanol under reduced pressure; add water (200mL) to dissolve the remainder, extract with dichloromethane (50mL), discard the second The methyl chloride layer, the aqueous layer was adjusted to pH >14 with 10% NaOH solution; extracted with dichloromethane (100mL*2), combined the dichloromethane extracts, washed with water (50mL) and saturated brine (50mL), no Dry with sodium sulfate and concentrate to obtain crude N-benzyl-diethanolamine (23.4g);

Dissolve the crude N-benzyl-diethanolamine (23.4g, 0.12mol) in dichloromethane (150mL), cool to 0-5°C, add thionyl chloride (42.8g, 0.36mol) dropwise; after the addition is complete , Heating and refluxing for 3h, removing dichloromethane and unreacted thionyl chloride under reduced pressure; adding toluene (200mL) to make the remainder, and filtering and drying to obtain N-benzyl-2-(2-chloroethyl)oxy- Ethylamine hydrochloride (25.0g).

Example 8

2-(2-(2-(N-benzyl-3,4,5-tris(isotridecyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM -008) Synthesis:

The synthesis method of BM-008 in Example 8 is the same as that in Example 1, except that the isooctyl bromide in Example 1 is replaced by isotridecyl bromide, and N-benzyl-2-(2-chloroethyl Yl)oxy-ethylamine hydrochloride instead of 2-(2-chloroethyl)oxy-ethylamine hydrochloride in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 75H), 3.65-4.15 (m, 14), 4.50-4.90 (m, 4H), 6.90-7.00 (m, 2H), 7.05 -7.15 (m, 3H), 7.25-7.35 (m, 6H); HRMS TOF[M+1] ⁺ : 1000.7881.

Example 9

Synthesis of 3-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-009):

The synthesis method of BM-009 in Example 9 is the same as that in Example 2, except that 3-hydroxybenzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 2;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.40 -4.20 (m, 14), 4.50-4.90 (m, 4H), 6.60-6.70 (bs, 2H), 6.80-6.90 (m, 1H), 6.90-7.00 (m, 1H), 7.15-7.40 (m, 7H); HRMS TOF[M+1] ⁺ : 742.5574.

Example 10

Synthesis of 4-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-010):

The synthesis method of BM-010 in Example 10 is the same as that in Example 2, except that 4-hydroxybenzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 2;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.10 (m, 14H), 4.55 (s, 2H), 6.70-6.80 (d, 2H), 6.80-6.90 (m, 1H), 6.90-7.00 (s, 2H), 7.10-7.20 (d, 2H) ; HRMS TOF[M+1] ⁺ : 742.5574.

Example 11

4-methoxy-2-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-011 )Synthesis:

The synthesis method of BM-011 in Example 11 is the same as that in Example 2, except that 2-hydroxy-4-methoxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 2;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.20 (m, 17H), 4.55 (s, 2H), 6.40-6.50 (m, 2H), 6.90-6.95 (m, 1H), 7.10-7.11 (s, 2H), 7.30-7.40 (bs, 1H) ; HRMS TOF[M+1] ⁺ : 772.5600.

Example 12

5-chloro-2-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-012) synthesis:

The synthesis method of BM-012 in Example 12 is the same as that in Example 2, except that 2-hydroxy-5-chloro-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 2;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.20 (m, 14H), 4.55 (s, 2H), 6.80-6.90 (d, 1H), 7.10-7.11 (s, 2H), 7.12-7.25 (m, 3H); HRMS TOF[M+1] ⁺ : 776.5146.

Example 13

4-methoxy-2-(2-(2-(3,4,5-tris(isotridecyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol ( Synthesis of BM-013):

The synthesis method of BM-013 in Example 13 is the same as that in Example 5, except that: 2-hydroxy-4-methoxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 5;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 75H), 3.60-4.20 (m, 17H), 4.55 (s, 2H), 6.40-6.50 (m, 2H), 6.90-6.95 (m, 1H), 7.10-7.11 (s, 2H), 7.30-7.40 (bs, 1H); HRMS TOF[M+1] ⁺ : 940.7512.

Example 14

4-methoxy-2-(2-(N-benzyl-2-(3,4,5-tris(isotridecyloxy)-benzamide)-ethoxy)-ethoxy Synthesis of benzyl alcohol (BM-014):

The synthesis method of BM-014 in Example 14 is the same as that in Example 5, except that: 2-hydroxy-4-methoxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 5;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 75H), 3.60-4.20 (m, 17H), 4.50-4.90 (m, 4H), 6.40-6.50 (m, 2H), 6.90 -6.95 (m, 1H), 7.10-7.11 (s, 2H), 7.15-7.40 (m, 6H); HRMS TOF[M+1] ⁺ : 1030.8010.

Example 15

3-(2-(2-(N'-(3,4-bis(isotridecyloxy)-benzyl)-acetamido)-ethoxy)-ethoxy)-benzyl alcohol ( Synthesis of BM-015):

3,4-Dihydroxy-benzaldehyde (13.8g, 0.1mol, 15-1), isotridecyl bromide (63.1g, 0.24mol), potassium carbonate (41.4g, 0.3mol) and DMF (200mL) Mix, heat to 90-100℃ for 10h; pour into a reaction flask pre-placed with petroleum ether (200mL) and water (200mL) under stirring, separate the lower layer, and wash the upper layer with water (100mL) and saturated brine (100mL) , Concentrated to obtain crude intermediate 15-2;

The above crude product was dissolved in tetrahydrofuran (100mL) and ethanol (200mL), and 2-(2-chloroethyl)oxy-ethylamine hydrochloride (16.0g, 0.1mol) and triethylamine (10.0g, 0.1mol) were added , React at room temperature for 3h; cool to 0-5℃, add sodium borohydride (3.8g, 0.1mol), naturally warm to room temperature and react for 2h, add 1N hydrochloric acid until no bubbles are generated, pH 7-8; add petroleum ether (300mL ) And water (300mL), separate the lower layer, wash the upper layer with water (100mL*2) and saturated salt, and concentrate to obtain 15-3 crude intermediate;

Dissolve 15-3 crude product in ethyl acetate (300mL), add triethylamine (15.0g, 0.15mol) and acetic anhydride (10.3g, 0.1mol); react for half an hour at room temperature, add water and stir for 10min; divide and remove water The upper layer was washed with water (100mL*2) and concentrated to obtain the crude intermediate 15-4, which was purified by column chromatography to obtain 38.0 g;

Using the intermediate 15-4 and 3-hydroxybenzaldehyde as raw materials, 3-(2-(2-(N′-(3,4-bis(isotridecane) was obtained through a two-step reaction according to the method of Example 1 (Oxy)-benzyl)-acetamido)-ethoxy)-ethoxy)-benzyl alcohol (BM-015);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 50H), 2.10-2.20 (ss, 3H), 3.60-4.20 (m, 12H), 4.55 (s, 2H), 4.68 (s , 2H), 6.65 (s, 1H), 6.70-6.90 (m, 3H), 6.90-7.00 (m, 2H), 7.20-7.30 (m, 1H); HRMS TOF[M+1] ⁺ : 740.5864.

Example 16

3-(2-(2-(N′-(3,4-bis(isotridecyloxy)-benzyl)-isononamido)-ethoxy)-ethoxy)-benzyl alcohol (BM-016) and 3-(2-(2-(N'-(3,4-bis(isotridecyloxy)-benzyl)-isononamido)-ethoxy)-ethyl Synthesis of oxy)-benzylamine (BM-016A):

The preparation method of Example 16 is the same as that of Example 15, except that the acetic anhydride in Example 15 is replaced by isononanoyl chloride;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 65H), 2.10-2.40 (m, 2H), 3.60-4.20 (m, 12H), 4.50-4.60 (m, 2H), 4.68 (s, 2H), 6.65 (s, 1H), 6.70-6.90 (m, 3H), 6.90-7.00 (m, 2H), 7.20-7.30 (m, 1H); HRMS TOF[M+1] ⁺ : 838.6980 ；

Synthesis of BM-016A:

Substitute the oxyaldehyde 16-1 as an intermediate in the synthesis of BM-016 to synthesize 3-(2-(2-(N′-(3,4-bis(isotridecyloxy)- (Benzyl)-isononamido)-ethoxy)-ethoxy)-benzylamine (BM-016A);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 65H), 2.10-2.40 (m, 4H), 3.40-4.40 (m, 14H), 4.68 (s, 2H), 6.65 (m , 1H), 6.70-6.90 (m, 3H), 6.90-7.00 (m, 2H), 7.25-7.30 (m, 1H); HRMS TOF[M+1] ⁺ : 837.7020.

Example 17

3-(2-(2-(N'-(3,4-bis(isotridecyloxy)-benzyl)-(3,4,5-tris(isononyloxy)-benzamide Yl)-ethoxy)-ethoxy)-benzyl alcohol (BM-017) and 3-(2-(2-(N′-(3,4-bis(isotridecyloxy)-benzyl) Synthesis of (3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)-benzylamine (BM-017A):

Using 3,4,5-triisononyloxybenzoic acid as raw materials and intermediate 15-3 as raw materials to synthesize 3-(2-(2-(N′-(3,4-bis(isotridecyloxy) (Yl)-benzyl)-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)-benzyl alcohol (BM-017);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 101H), 3.40-4.20 (m, 18H), 4.50-4.80 (m, 4H), 6.60-6.80 (m, 3H), 6.80 -7.00 (m, 5H), 7.20-7.30 (m, 1H); HRMS TOF[M+1] ⁺ : 1229.0012;

Synthesis of BM-017A:

Using the intermediate substituted oxyaldehyde 17-1 in the synthesis of BM-017 as the raw material, 3-(2-(2-(N′-(3,4-bis(isotridecyloxy) was synthesized according to the method of Example 2. )-Benzyl)-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)-benzylamine (BM-017A);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 101H), 2.30-2.40 (bs, 2H), 3.40-4.20 (m, 20H), 4.50-4.80 (m, 2H), 6.60 -6.80 (m, 3H), 6.80-7.00 (m, 5H), 7.20-7.30 (m, 1H); HRMS TOF[M+1] ⁺ : 1228.0200.

Example 18

3-(2-(2-(3,5-bis(2,3-dihydrophytanoxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-018) synthesis:

The synthesis method of BM-018 in Example 18 is the same as that in Example 6, except that: methyl 3,5-dihydroxybenzoate is used instead of methyl 3,4,5-trihydroxybenzoate in Example 6;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 78H), 3.60-4.20 (m, 12H), 4.55 (s, 2H), 6.60-6.70 (s, 2H), 6.80-6.85 (m, 1H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 908.7740.

Example 19

Synthesis of 3-(2-(2-(3,4-bis(isotridecyloxy)-phenylacetamido)-ethoxy)-ethoxy)benzyl alcohol (BM-019):

The synthesis method of BM-019 in Example 19 is the same as that in Example 2, except that methyl 3,4-dihydroxyphenylacetate is used instead of methyl 3,4,5-trihydroxybenzoate in Example 2;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.70-1.90 (m, 50H), 3.40-4.10 (m, 14H), 4.55 (s, 2H), 6.70-6.90 (m, 4H), 6.90-7.05 (m, 2H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 726.5620.

Example 20

Synthesis of 3-(2-(N-methyl-3,4,5-tris(isotridecyloxy)-benzamide)-ethoxy)benzyl alcohol (BM-020):

The synthesis method of BM-020 in Example 20 is the same as that in Example 5, except that N-methyl-2-chloroethylamine hydrochloride is used instead of 2-(2-chloroethyl)oxy in Example 5. -Ethylamine hydrochloride;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.70-1.90 (m, 75H), 2.90-3.05 (m, 3H), 3.65-4.15 (m, 10H), 4.55 (s, 2H), 6.70-6.90 (m, 4H), 6.90-7.05 (m, 2H), 7.25-7.40 (m, 6H); HRMS TOF[M+1] ⁺ : 880.7352.

Example 21

Synthesis of 3,4-bis(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-021) :

The synthesis method of BM-021 in Example 21 is the same as that in Example 1, except that 3,4-dihydroxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 72H), 1.05-1.20 (m, 6H), 1.25-1.35 (m, 6H), 1.50-2.00 (m, 18H), 3.40 -4.10 (m, 28H), 4.55 (s, 2H), 6.75-6.85 (m, 4H), 7.10 (s, 4H), 7.30-7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 1376.0520 .

Example 22

Synthesis of 2,4-bis(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-022) :

The synthesis method of BM-022 in Example 22 is the same as that in Example 1, except that: 2,4-dihydroxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 1;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 72H), 1.05-1.20 (m, 6H), 1.25-1.35 (m, 6H), 1.50-2.00 (m, 18H), 3.40 -4.10 (m, 28H), 4.55 (s, 2H), 6.40-6.50 (m, 2H), 6.60-6.65 (m, 1H), 7.00-7.10 (m, 3H), 7.15 (s, 2H), 7.30 -7.40 (m, 1H); HRMS TOF[M+1] ⁺ : 1376.0520.

Example 23

Synthesis of 3,5-bis(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzyl alcohol (BM-023) :

The synthesis method of BM-023 in Example 23 is the same as that in Example 1, except that: 3,5-dihydroxy-benzaldehyde is used instead of 2-hydroxybenzaldehyde in Example 1, and isononyl bromide is used instead of Example 1. Isooctyl bromide in;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 72H), 1.05-1.20 (m, 6H), 1.25-1.35 (m, 6H), 1.50-2.00 (m, 18H), 3.40 -4.10 (m, 28H), 4.55 (s, 2H), 6.30-6.50 (m, 3H), 6.60-6.65 (m, 2H), 7.10 (s, 4H); HRMS TOF[M+1] ⁺ : 1376.0520 .

Example 24

Synthesis of 2,4-bis(2-(N-benzyl-2-isononamido-ethoxy)-ethoxy)benzyl alcohol (BM-024):

The synthesis method of BM-024 in Example 24 is the same as that in Example 1, except that the intermediate 1-2 in Example 1 is replaced by isononanoic acid, and N-benzyl-2-(2-chloroethyl) is used. Oxy-ethylamine hydrochloride replaces 2-(2-chloroethyl)oxy-ethylamine hydrochloride in Example 1, and 3,4-dihydroxy-benzaldehyde replaces 2- in Example 1. Hydroxybenzaldehyde

¹ H-NMR (400MHz, CDC ₁₃ ): δ 0.8-1.90 (m, 30H), 2.10-2.35 (m, 4H) 3.40-3.80 (m, 12H), 4.10-4.20 (m, 4H) 4.55-4.70 (ss, 6H), 6.85-7.05 (m, 3H), 7.10-7.40 (m, 10H); HRMS TOF[M+1] ⁺ : 775.5250.

Example 25

Synthesis of 4-(2-(N-benzyl-2-isostearamido-ethoxy)-ethoxy)benzyl alcohol (BM-025):

The synthesis method of BM-025 in Example 25 is the same as that in Example 1, except that isostearic acid is used instead of Intermediate 1-2 in Example 1, and 4-hydroxy-benzaldehyde is used instead of 2 in Example 1. -Hydroxybenzaldehyde, N-benzyl-2-(2-chloroethyl)oxy-ethylamine hydrochloride is used instead of 2-(2-chloroethyl)oxy-ethylamine hydrochloride in Example 1 salt;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.8-1.90 (m, 33H), 2.30-2.50 (m, 1H) 3.40-4.10 (m, 8H), 4.55 (s, 2H), 4.60-4.80 ( m, 2H), 6.80-6.90 (m, 2H), 7.15-7.30 (m, 7H); HRMS TOF[M+1] ⁺ : 568.4320.

Example 26

3-((5-(3,4,5-Tris(isononyloxy)-benzamide)-2-one-3-aza-hexyl)oxy)-benzyl alcohol (BM-026) synthesis:

Acid (26-1) (27.4g, 0.05mol), HONB (10.8g, 0.06mol) were dissolved in DCM (150mL), EDCI (11.5g, 0.06mol) was added to react at room temperature for 1h, the reaction solution was water (100mL) in turn, Saturated sodium bicarbonate aqueous solution (100mL), 1N hydrochloric acid (100mL) and saturated brine were washed sequentially, and the dichloromethane solution of Intermediate 26-2 was directly used in the next reaction;

1,3-propanediamine (11.1g, 0.15mol) was dissolved in DCM (20mL), the dichloromethane solution obtained in the previous step was added dropwise at room temperature, after the addition, reacted at room temperature for half an hour, washed with water (100mL*2) in turn, The dichloromethane solution of Intermediate 26-3 is directly used in the next reaction;

The dichloromethane solution obtained in the previous step was cooled to 0-5°C, and triethylamine (10g, 0.1mol) was added; the temperature was kept at 0-5°C, and 2-chloroacetyl chloride (5.6g, 0.05mol) was added dropwise; Reacted at -5°C for 0.5h, washed with 1N hydrochloric acid (100mL), water (100mL), saturated brine (50mL), and concentrated to obtain the crude intermediate 26-4.

Intermediate 26-4 and 3-hydroxybenzaldehyde undergo two conventional reactions (such as Example 1) to sequentially obtain 26-5 and BM-026;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.50-2.00 (m, 11H), 3.40-3.50 (m, 4H), 4.00-4.10 (m, 6H), 4.45 -4.55 (m, 4H), 6.80-6.85 (m, 1H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 769.5786.

Example 27

3-(2-(N′-benzyl-(3-(N″-benzyl-3,4,5-triisononyloxy-benzamide)-propylamino)-2-one-ethoxy Synthesis of benzyl alcohol (BM-027):

The synthesis method of BM-027 in embodiment 27 is the same as that in embodiment 26, except that: N,N'-dibenzyl-1,3-propanediamine is used instead of 1,3-propanediamine in embodiment 26;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.50-2.00 (m, 11H), 3.40-3.50 (m, 4H), 4.00-4.10 (m, 6H), 4.45 -4.55(m, 4H), 4.7-4.9(m, 4H), 6.80-6.85(m, 1H), 6.90-7.05(m, 4H), 7.25-7.40(m, 11H); HRMS TOF[M+1 ] ⁺ : 949.6602.

Example 28

3-(2-(2-Methyl-2-(3,4,5-tris(isononyloxy)-benzamide)-acetamido)-ethoxy)-ethoxy)-benzene Synthesis of methanol (BM-028):

Boc-Ala-OH (18.9g, 0.1mol, 28-1), 2-(2-chloroethyl)oxy-ethylamine hydrochloride (16.0g, 0.1mol), HOBt (14.9, 0.11mol) and Triethylamine (15.1g, 0.15mol) was mixed with DMF (150mL) and cooled to 5-10°C; EDCI (21.1g, 0.11mol) was added, and the reaction was kept at 5-10°C for 0.5h, and naturally warmed to room temperature for 1h; Wash with water (100mL), saturated sodium bicarbonate (100mL), 1N hydrochloric acid (100mL) and saturated brine (50mL) successively; concentrate to obtain the crude intermediate 28-2;

Dissolve the above crude product with ether (200mL), add 4N HCl/ether solution (200mL) dropwise, stir at room temperature for 5h, filter and collect the solid as Intermediate 28-3;

Intermediate 28-3 and acid 28-4 were used to synthesize 3-(2-(2-methyl-2-(3,4,5-tris(isononyloxy)-benzamide) according to the reaction steps of Experimental Example 1. )-Acetamido)-ethoxy)-ethoxy)-benzyl alcohol (BM-028);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.40-1.50 (d, 3H), 1.50-2.00 (m, 9H), 3.45-4.15 (m, 14), 4.55 (s, 2H), 4.60-4.70 (m, 1H), 6.80-6.85 (m, 1H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 813.5902.

Example 29

3-(2-(2-(N″-Methyl 3,4,5-Tris(isononyloxy)-benzamide)-acetamido)-ethoxy)-ethoxy)benzyl alcohol Synthesis of (BM-029):

The synthesis method of BM-029 in embodiment 29 is the same as that in embodiment 28, except that N-Boc-sarcosine is used instead of N-Boc-alanine in embodiment 28;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.50-2.00 (m, 9H), 2.90-3.00 (m, 3H), 3.45-4.15 (m, 14), 4.50 -4.60 (ss, 4H), 6.80-6.85 (m, 1H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 813.5902.

Example 30

3-(2-(2-((2,6-bis(3,4,5-tris(isononyloxy)-benzamide)-hexanamido)-ethoxy)-ethoxy Synthesis of )-Benzyl Alcohol (BM-030):

Lysine (7.3g, 0.05mol) was dissolved in tetrahydrofuran (100mL) and water (50mL), LiOH (1.2g, 0.05mol) was added and heated to 70°C; the active ester 30-1 (62.9, 0.11mol) was dissolved in Tetrahydrofuran (150mL) was slowly added dropwise to the reaction solution. After the dripping, the reaction was kept for half an hour. After cooling to room temperature, 50mL 1N hydrochloric acid was added and extracted with petroleum ether (200mL). The upper layer was successively water (100mL) and saturated brine (100mL). ) Wash and concentrate to obtain the crude intermediate 30-2;

Dissolve the above crude product in dichloromethane (300mL), cool to 0-5°C; add triethylamine (5.5g, 0.06mol), HOBt (8.5g, 0.06mol), EDCI (11.5g, 0.06mol), keep warm React at 0-5°C for half an hour; wash sequentially with water (200mL), saturated aqueous sodium bicarbonate (100mL×2), 1N hydrochloric acid and (50mL) and saturated brine (50mL), concentrate, and purify by column chromatography to obtain 49.0g middle Body 30-3;

Intermediate 30-3 and 3-hydroxybenzaldehyde undergo a two-step conventional reaction (as in Example 1) to synthesize 3-(2-(2-((2,6-bis(3,4,5-tris(isononane)) (Oxy)-benzamide)-hexanamido)-ethoxy)-ethoxy)-benzyl alcohol (BM-030);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 84H) 1.50-2.00 (m, 22H), 3.65-4.15 (m, 22), 4.50-4.60 (m, 3H), 6.30- 6.35 (m, 1H), 6.40-6.45 (m, 1H), 6.80-6.85 (m, 2H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 1H); HRMS TOF[M+1] ⁺ : 1401.0940.

Example 31

3-(2-(2-(4-(3,4,5-tris(isotridecyloxy)-benzamide)-butyramido)-ethoxy)-ethoxy)- Synthesis of benzyl alcohol (BM-031):

The synthesis method of BM-031 in embodiment 31 is the same as that in embodiment 30, except that 4-amino-butyric acid is used instead of lysine in embodiment 30;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 77H), 2.25-2.35 (m, 2H), 3.40-3.50 (m, 4H), 3.55-4.10 (m, 12H), 4.55 (s, 2H), 6.15-6.25 (m, 1H),, 6.80-6.85 (m, 1H), 6.90-7.05 (m, 4H), 7.25-7.26 (m, 2H); HRMS TOF[M+1] ⁺ : 995.8015.

Example 32

Synthesis of 4-(2-(2-(2,6-Diisostearylamido-hexanamido)-ethoxy)-ethoxy)-benzyl alcohol (BM-032):

Lysine (14.6.3g, 0.1mol) was dissolved in tetrahydrofuran (150mL) and water (100mL), NaOH (4.0g, 0.1mol) was added and cooled to 0-5°C; under vigorous stirring, isostearoyl chloride (2 , 2,4,8,10,10-hexamethylundecane-5-acid chloride) (66.6g, 0.22mol) and 20% NaOH (44g) were added dropwise to the reaction solution at the same time, and the dropping rate was controlled to maintain the reaction temperature After dripping at 0-5℃, keep the temperature at 0-5℃ and react for half an hour, adjust the pH to 1 with 1N hydrochloric acid, and extract with petroleum ether (300mL); petroleum ether solution is water (100mL) and saturated brine (100mL) successively Wash, concentrate, and purify by column chromatography to obtain 50.5g of intermediate diisostearoyllysine;

Synthesize 4-(2-(2-(2,6-Diisostearyl amide-hexanamido)-ethoxy)-ethoxy by using diisostearyl lysine as the raw material according to the steps of Example 30 Base)-Benzyl alcohol (BM-032);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 74H), 2.30-2.50 (m, 2H), 3.55-4.20 (m, 10H), 4.30-4.40 (m, 1H), 4.55 (s, 2H), 6.10-6.20 (m, 1H), 6.80-6.90 (m, 2H), 6.90-7.00 (m, 1H), 7.10-7.20 (m, 3H); HRMS TOF[M+1] ⁺ : 872.7424.

Example 33

Synthesis of 4-(3,4,5-tris(isononyloxy)-benzamide)-benzyl alcohol (BM-033):

Active ester 33-1 (7.1g, 0.01mol) and 4-aminobenzyl alcohol (1.2g, 0.01mol) were dissolved in tetrahydrofuran (30mL), heated and refluxed for 5h; concentrated under reduced pressure and purified by column chromatography (PE→EA) Obtain 5-(3,4,5-tris(isononyloxy)-benzamide)-benzyl alcohol (BM-033) 5g;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.40 (m, 42H), 1.50-2.00 (m, 9H), 4.00-4.10 (m, 6H), 4.65-4.70 (s, 2H), 7.05 -7.10 (s, 2H), 7.30-7.40 (d, 2H), 7.60-7.65 (d, 2H), 7.85 (s, 1H); HRMS TOF[M+1] ⁺ : 654.5082.

Example 34

Synthesis of 4-(3,4-bis(isotridecyloxy)-phenylacetamido)-benzyl alcohol (BM-034):

Using 3,4-dihydroxyphenylacetic acid and isotridecyl bromide as raw materials, 3,4-bis(isotridecyloxy)-phenylacetic acid was synthesized according to the method in Example 1. Using this as raw materials, the implementation Synthesize active ester according to the method of Example 26, and then synthesize 4-(3,4-bis(isotridecyloxy)-benzamide)-benzyl alcohol (BM-034) according to the method of Example 33;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-2.00 (m, 50H), 3.60-3.70 (s, 2H), 4.00-4.10 (m, 4H), 4.65-4.70 (s, 2H), 6.80 -6.90 (m, 3H), 7.20-7.30 (m, 2H), 7.35-7.45 (m, 3H); HRMS TOF[M+1]+: 638.5102.

Example 35

N-benzyl-4-methoxy-2-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzene Synthesis of methylamine (BM-035):

Aldehyde 35-1 (Intermediate of Example 11) (15.4g, 0.02mol) was dissolved in tetrahydrofuran (50mL) and absolute ethanol (50mL), benzylamine (4.3g, 0.04mol) was added, stirred at room temperature for half an hour, and Na (CN) BH ₃ (2.5g, 0.04mL), continue the reaction for 2h, add water (100mL), remove tetrahydrofuran and ethanol under reduced pressure, and add heptane (200mL) to extract the remainder. Concentrate the heptane solution to obtain a crude product. Column layer Analytical purification to obtain N-benzyl-4-methoxy-2-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy Benzylamine (BM-035) 15.0g;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 3.60 -4.20 (m, 21H), 6.40-6.50 (m, 2H), 7.00-7.05 (m, 1H), 7.10-7.11 (s, 2H), 7.30-7.50 (m, 6H); HRMS TOF[M+1 ] ⁺ : 861.6324.

Example 36

N-methyl-4-(2-(2-(3,4,5-tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzylamine (BM-036 )Synthesis:

Add aldehyde 36-1 (intermediate of Example 10) (15.4g, 0.02mol) and methylamine aqueous solution as raw materials to synthesize N-methyl-4-(2-(2-(3,4,5) according to the method of Example 35 -Tris(isononyloxy)-benzamide)-ethoxy)-ethoxy)benzylamine (BM-036);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.80-1.05 (m, 36H), 1.05-1.20 (m, 3H), 1.25-1.35 (m, 3H), 1.50-2.00 (m, 9H), 2.45 (s, 3H), 2.70 (bs, 1H), 3.60-4.20 (m, 16H), 6.70-6.85 (d, 2H), 6.85-6.90 (m, 1H), 7.10-7.11 (s, 2H), 7.20 -7.25(d, 2H); HRMS TOF[M+1] ⁺ : 755.5934.

Example 37

The heterogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH using BM-002 carrier includes the following steps:

1) Dissolve BM-002 in DMF to form a carrier solution, add Fmoc-Ser(t-Bu)-OH solution (the amount of Fmoc-Ser(t-Bu)-OH is 1～1.5 equivalent of BM-002) and DMAP, stir and cool to 0-10℃; add EDCI (the amount of EDCI is 1～1.5 equivalent of BM-002), keep 0-10℃ for reaction;

After the reaction is complete, add heptane and water (the volume ratio of heptane to water is (1-15):1), stir for 10 minutes, and let stand for layering; divide the lower layer, add DMF: water (the volume ratio of DMF and water is (1～10):1), stir for 5min, stand still for layering; separate the lower layer, and use the upper layer directly for the next step to remove Fmoc;

2) The upper layer solution obtained in the previous step is heated to 40-50°C, and a mixture of mercaptopropionic acid, diethylenetriamine and DMF is added (the amount of mercaptopropionic acid and diethylenetriamine is 3 to 5 equivalents of BM-002), Incubate at 40-50°C for reaction. After the reaction is complete, add DMF: water (the volume ratio of DMF and water is (1～5): (5～1)), stir for 5 min, and let stand for layering; divide the lower layer, add DMF: water (DMF to water) The volume ratio is (1-8):1), stir for 5min, stand still for layering; divide the lower layer, repeat the above washing steps for the upper layer until the eluate is neutral, and use the upper layer directly for the next amino acid condensation;

3) Fmoc-Lys(Boc)-OH, HOBt (the dosage of Fmoc-Lys(Boc)-OH and HOBt is 1～1.5 equivalent of BM-002 respectively) and DIPEA (the dosage of DIPEA is 2～3 of BM-002) Equivalent) dissolved in DMF, added to the heptane reaction solution processed after step 2, stirred and cooled to 15-20°C; added HBTU/DMF solution (HBTU dosage is 1 to 1.5 equivalents of BM-002), and kept for 15-20 ℃ reaction. After the reaction is complete, add water, stir for 5 minutes, stand for layering; divide the lower layer, add DMF: water to the upper layer (the volume ratio of DMF to water is (1-8): 1), stir for 5 minutes, stand for layering; divide Remove the lower layer, and the upper layer is directly used for the Fmoc removal reaction;

4) Repeat steps 2) and 3), connect Fmoc-Thr(t-Bu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Arg(Pbf)-OH, and remove Fmoc to obtain H- Arg(Pbf)-Lys(Boc)-Thr(t-Bu)-Lys(Boc)-Ser(t-Bu)-(BM-002) heptane solution, concentrated to obtain a solid;

5) Dissolve the above solid in TFA:TIS:water (94:3:3, lysate, 5-10 times the weight of the solid), and stir for 2h at room temperature. Slowly add methyl tert-butyl ether at 0-10℃ (the weight of methyl tert-butyl ether is 2-20 times of the lysate), keep it at 0-10℃ and stir for half an hour; filter, filter cake with methyl tertiary The butyl ether was washed until the eluate was neutral, and dried to obtain a crude H-Arg-Lys-Thr-Lys-Ser-OH, with an HPLC purity of 97.5% and HRMS TOF[M+1] ⁺ : 619.3888.

Example 38

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-003 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-003, and the HPLC purity is 97.0%.

Example 39

Heterogeneous Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with BM-005 Carrier

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-005, and the HPLC purity is 98.2%.

Example 40

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-006 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-006, and the HPLC purity is 92.5%.

Example 41

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-008 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-008, and the HPLC purity is 98.5%.

Example 42

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-009 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-009, and the HPLC purity is 97.5%.

Example 43

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with BM-010 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that: the carrier of embodiment 37 is replaced with BM-010, and the HPLC purity is 96.2%.

Example 44

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-014 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-014, and the HPLC purity is 98.5%.

Example 45

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-016 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-016, and the HPLC purity is 98.8%.

Example 46

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-022 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-022, and the HPLC purity is 94.5%.

Example 47

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-024 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-024, and the HPLC purity is 93.7%.

Example 48

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-026 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-026, and the HPLC purity is 91.7%.

Example 49

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-028 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-028, and the HPLC purity is 94.5%.

Example 50

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-030 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-030, and the HPLC purity is 95.5%.

Example 51

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-033 carrier heterogeneous method

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with BM-033, and the HPLC purity is 90.8%.

Example 52

Heterogeneous synthesis of H-β-Ala-Pro-Dab-NHBn with BM-035 carrier includes the following steps:

1) The BM-035 carrier is dissolved in heptane, replace the heptane solution in step 3 of Example 37 with the heptane solution of BM-035, repeat steps 3 and 2, and then reconnect Fmoc-Dab(Boc)-OH in sequence , Fmoc-Pro-OH and Boc-β-Ala-OH to obtain Boc-β-Ala-Pro-Dab(Boc)- (BM-035), each amino acid access condensation reaction is about 0.5h, and the de-Fmoc reaction is about 0.5h, the post-treatment time for each step of the reaction is 30-40min;

2) Boc-β-Ala-Pro-Dab(Boc)-(BM-035) was dissolved in TFA:TIS:water (50mL, 94:3:3), and stirred at room temperature for 2h. Slowly add methyl tert-butyl ether at 0-10°C, keep it at 0-10°C and stir for half an hour; filter, wash the filter cake with methyl tert-butyl ether until the eluate is neutral, and dry to obtain H-β-Ala -Pro-Dab-NHBn, HPLC purity 90.5%, HRMS TOF[M+1] ⁺ : 376.2386.

Example 53

The homogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with BM-002 carrier

A) Dissolve BM-002 (7.4g, 10.0mmol) in isopropyl acetate (100ml), add Fmoc-Ser(t-Bu)-OH (5.76g, 15.0mmol) and DMAP (0.06g, 0.5mmol) , Stir and cool to 0-10℃; add EDCI (3.84g, 20.0mmol), keep 0-10℃ and react for half an hour, warm to room temperature and react to completion; after the reaction is complete, add acetonitrile/water (9:1) to wash (according to Need to add isopropyl acetate), the isopropyl acetate solution is used in the next step of the Fmoc removal reaction.

B) The isopropyl acetate solution obtained in step 1), add diethylenetriamine (6.2g, 60mmol) and mercaptopropionic acid (4.3g, 40mmol), heat to 40-50℃ to react, TLC analysis after the reaction is complete, use acetonitrile /Water (9:1) washing (add isopropyl acetate as needed) to remove by-products, and isopropyl acetate solution for the next amino acid condensation.

C) Step 2) Add Fmoc-Lys(Boc)-OH (5.63g, 12.0mmol), HOBt (2.0g, 15mmol), and DIPEA (3.24g, 25.0mmol) to the isopropyl acetate solution obtained from the de-Fmoc reaction. Stir and cool down to 5-10°C, add HBTU (5.62g, 15mmol) for reaction; after the reaction is complete, add acetonitrile/water (9:1) to wash (add isopropyl acetate as needed), isopropyl acetate solution is used The next step is the Fmoc reaction.

D) Repeat the above steps 2) and 3) to connect to Fmoc-Thr(t-Bu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Arg(Pbf)-OH, and remove Fmoc to obtain H -Arg(Pbf)-Lys(Boc)-Thr(t-Bu)-Lys(Boc)-Ser(t-Bu)-(BM-002) isopropyl acetate solution, concentrated to obtain a solid;

E) According to the method of Example 37, H-Arg-Lys-Thr-Lys-Ser-OH was obtained by cleavage, with an HPLC purity of 82.0%.

Example 54

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by BM-014 carrier homogeneous method

The synthesis method of this embodiment is the same as that of embodiment 53, except that the carrier of embodiment 53 is replaced with BM-014, and the HPLC purity is 81.6%.

Example 55

The homogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with BM-026 carrier

The synthesis method of this embodiment is the same as that of embodiment 53, except that the carrier of embodiment 53 is replaced with BM-026, and the HPLC purity is 80.8%.

Example 56

The homogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with BM-030 carrier

The synthesis method of this embodiment is the same as that of embodiment 53, except that the carrier of embodiment 53 is replaced with BM-030, and the HPLC purity is 81.0%.

Comparative example 1

Synthesis of 3,4,5--tris(dihydrophytoxy)-benzyl alcohol (REF-001):

The 3,4,5-tris(2,3-dihydrophytalkoxy)-benzoic acid methyl ester (28.0g, 0.05mol, R1-1) synthesized in Example 6 was dissolved in anhydrous tetrahydrofuran (200mL), Cool down to 5-10°C; add lithium aluminum tetrahydrogen (1.8g, 0.05mol) in batches, after the addition, naturally rise to room temperature and react for 2h; reduce the temperature to 5-10°C again, and add saturated sodium sulfate solution dropwise until there are no bubbles Emerging; filter to remove solids, and concentrate the filtrate to obtain REF-001 (21.5g);

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.8-2.0 (m, 118H), 3.95-4.10 (m, 6H), 4.60-4.65 (m, 2H), 6.70 (s, 2H),; HRMS TOF [M-17] ⁺ : 979.9700.

Comparative example 2

Synthesis of 3,4-bis(2,3-dihydrophytaalkoxy)-benzyl alcohol (REF-002):

3,4-Dihydroxybenzaldehyde R2-1 (13.8g, 0.1mol), 2,3-dihydrophytyl bromide (79.2g, 0.22mol), potassium carbonate (41.4g, 0.3mol) and KI (0.83 g, 0.005mol) was mixed with DMF (250mL) and heated to 80-90℃ for 5h. Cool to room temperature, filter to remove solids, add heptane (200 mL) and water (200 mL) to the filtrate; separate the lower layer, wash the upper layer with water (200 mL), and concentrate to obtain crude oil R2-2.

Dissolve the crude R2-2 in absolute ethanol (300mL), cool to 5-10℃, add NaBH ₄ (3.8g, 0.1mol); stir and react at room temperature for 2h, then cool to 5-10℃ again, add 1N hydrochloric acid until nothing Bubble generation, pH 6-7; add heptane (200mL) and water (200mL) for extraction, separate the lower layer, concentrate the upper layer to obtain a crude product; column chromatography purification (PE→30%EA/PE) to obtain 3,4-bis( 2,3-Dihydrophytaalkoxy)-benzyl alcohol (REF-002) 65g;

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.8-2.0 (m, 78H), 2.15-2.20 (m, 1H), 4.00-4.10 (m, 4H), 4.60-4.65 (m, 2H), 6.85 (m, 2H), 6.95 (s, 1H); HRMS TOF[M-17] ⁺ : 683.6780.

Comparative example 3

Synthesis of 2,4-bis(3,4-bis(2,3-dihydrophytalkoxy)-benzyl)-benzyl alcohol (REF-003):

REF-002 (27.0g, 0.04mol) was dissolved in dichloromethane (100mL), cooled to 0-5°C, SOCl ₂ (6.0g, 0.05mol) was added dropwise; after dripping, warm to room temperature and react for 2h, then remove under reduced pressure Dichloromethane and unreacted SOCl ₂ ; the remainder was dissolved in 50 mL of dichloromethane, and then concentrated to remove the residual acidic impurities to obtain crude R3-1 for the next reaction;

R3-1 crude product, 2,4-dihydroxy-dibenzaldehyde (2.5g, 0.018) and K ₂ CO _{3 were} mixed in DMF (150 mL), heated to 60-70°C and reacted for 2 hours; filtered to remove solids, added heptane ( 200mL) and water (200mL), separate the water layer, wash the heptane layer with water (200mL), and concentrate to obtain the crude aldehyde;

The above crude product was reduced with sodium borohydride according to the REF-002 method to obtain 2,4-bis(3,4-bis(2,3-dihydrophytalkoxy)-benzyl)-benzyl alcohol (REF-003) ；

¹ H-NMR (400MHz, CDCl ₃ ): δ 0.8-2.0 (m, 156H), 2.25-2.30 (m, 1H), 4.00-4.10 (m, 8H), 4.65-4.70 (m, 2H), 4.95 -5.05 (ss, 4H), 6.60 (d, 1H), 6.70 (s, 1H), 6.90-7.05 (m, 6H), 7.20 (d, 1H); HRMS TOF[M-17] ⁺ : 1482.3679.

Comparative example 4

Heterogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH with REF-001 carrier:

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with REF-001, and the HPLC purity is 85.5%.

Comparative example 5

REF-002 carrier heterogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH:

The synthesis method of this embodiment is the same as that of embodiment 37, except that: the carrier of embodiment 37 is replaced with REF-002, and the HPLC purity is 86.9%.

Comparative example 6

REF-003 carrier heterogeneous synthesis of H-Arg-Lys-Thr-Lys-Ser-OH:

The synthesis method of this embodiment is the same as that of embodiment 37, except that the carrier of embodiment 37 is replaced with REF-003, and the HPLC purity is 80.0%.

Comparative example 7

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by REF-001 carrier homogeneous method

The synthesis method of this embodiment is the same as that of embodiment 53, except that the carrier of embodiment 53 is replaced with REF-001, and the HPLC purity is 62.0%.

Comparative example 8

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by REF-002 carrier homogeneous method

The synthesis method of this example is the same as that of Example 53, except that the carrier of Example 53 is replaced with REF-002, and the HPLC purity is 65.5%.

Comparative example 9

Synthesis of H-Arg-Lys-Thr-Lys-Ser-OH by REF-003 carrier homogeneous method

The synthesis method of this embodiment is the same as that of embodiment 53, except that the carrier of embodiment 53 is replaced with REF-003, and the HPLC purity is 60.0%.

Test case 1:

The compounds synthesized in Examples 1 to 36 of the present invention and the compounds synthesized in Comparative Examples 1 to 3 were investigated for their solubility in common solvents at room temperature (25-30°C). The results are shown in Table 1:

Table 1

Carrier	Heptane (%)	i-PrOAc(%)	MTBE(%)	DMF(%)	MeOH(%)	DMSO(%)
BM-001	>10	>50	>50	>100	<1	<1
BM-002	>30	>50	>50	>100	<1	<1
BM-002A	>10	>30	>30	>100	<1	<1
BM-003	>100	>100	>100	>100	<1	<1
BM-004	>30	>50	>50	>100	<1	<1
BM-005	>100	>100	>100	>100	<1	<1
BM-006	>100	>100	>100	>30	<1	<1
BM-007	>100	>100	>100	>100	<1	<1
BM-008	>100	>100	>100	>100	<1	<1
BM-009	>30	>50	>50	>100	<1	<1
BM-010	>30	>50	>50	>100	<1	<1
BM-011	>30	>50	>50	>100	<1	<1
BM-012	>70	>70	>70	>100	<1	<1

BM-013	>100	>100	>100	>100	<1	<1
BM-014	>100	>100	>100	>100	<1	<1
BM-015	>100	>100	>100	>100	<1	<1
BM-016	>100	>100	>100	>100	<10	<20
BM-016A	>20	>50	>50	>100	<10	<20
BM-017	>100	>100	>100	>100	<1	<1
BM-017A	>50	>100	>100	>100	<1	<1
BM-018	>30	>100	>50	>100	<1	<1
BM-019	>30	>70	>50	>100	<1	<1
BM-020	>100	>100	>100	>100	<1	<1
BM-021	>50	>100	>100	>100	<1	<1
BM-022	>100	>100	>100	>100	<1	<1
BM-023	>100	>100	>100	>100	<1	<1
BM-024	>30	>50	>50	>100	<15	<50
BM-025	>30	>50	>50	>100	<10	<50
BM-026	>30	>70	>50	>100	<1	<1
BM-027	>100	>100	>100	>100	<1	<1
BM-028	>30	>50	>50	>100	<5	<10
BM-029	>30	>70	>50	>100	<5	<10
BM-030	>50	>100	>100	>100	<1	<1
BM-031	>30	>50	>50	>100	<1	<1
BM-032	>30	>70	>70	>100	<30	<30
BM-033	>100	>100	>100	>100	<1	<1
BM-034	>50	>100	>100	>100	<10	<80
BM-035	>100	>100	>100	>100	<10	<80
BM-036	>50	>50	>50	>100	<1	<1
REF-001	>100	>100	>100	<5	<1	<1
REF-002	>100	>100	>100	<10	<1	<1
REF-003	>100	>100	>100	<1	<1	<1

It can be seen from Table 1 that the compound of the present invention has better properties in heptane, isopropyl acetate (i-PrOAc), methyl tert-butyl ether (MTBE), and N,N-dimethylformamide (DMF). The solubility, especially the solubility in DMF is much higher than the comparative example.

Test case 2:

Using the compound of the present invention as a carrier, H-Arg-Lys-Thr-Lys-Ser-OH pentapeptide was synthesized by the heterogeneous method and the homogeneous method (Example 37-51 of the heterogeneous method, Example 53-51 of the homogeneous method) 56), synthesis of H-β-Ala-Pro-Dab-NHBn tripeptide (Example 52) and the compounds of Comparative Examples 1-3 were used as carriers to synthesize H-Arg-Lys-Thr- by the heterogeneous method and the homogeneous method The reaction time, post-processing time, and purity of Lys-Ser-OH pentapeptide (Comparative Examples 4-6 for Heterogeneous Method and Comparative Examples 7-9 for Homogeneous Method) were counted. The results are shown in Table 2. Among them, AA ₁ Is the first amino acid, AA ₂ is the second amino acid, AA ₃ is the third amino acid, AA ₄ is the fourth amino acid, AA ₅ is the fifth amino acid, t _R is the condensation reaction time, t _W is the condensation reaction Post-treatment time, t _D is the deprotection reaction time, t _Dw is the post-treatment time of the deprotection reaction, unit: hour;

Table 2

* Indicates a homogeneous reaction, the rest are heterogeneous reactions.

It can be seen from Table 2 that the compound of the present invention is used as a carrier for the synthesis of pentapeptide. Compared with the comparative examples REF-001～003, in the heterogeneous reaction system, the condensation reaction time, post-condensation treatment time, deprotection reaction time, and The treatment time after the protection reaction is significantly shortened; among them, the condensation reaction time of the comparative examples REF-001～003 is more than 2 hours, the post-condensation treatment time is more than 1 hour, the deprotection reaction time is more than 2.5 hours, and the post-deprotection treatment time is more than 2 Hours; and the condensation reaction time of the compound of the present invention is 0.5 to 1.5 hours, the post-condensation treatment time is 0.5 to 1.0 hours, the deprotection reaction time is 0.5 to 1.0 hours, and the deprotection reaction post treatment time is 0.5 to 1.0 hours. In the peptide chain elongation stage (AA ₂ -AA ₅ ), the condensation reaction time for each amino acid fragment is 0.5 to 1.0 hours, the post-condensation treatment time is 0.5 to 1.0 hours, and the deprotection reaction time is about 0.5 to 1.0 Hours, the processing time after deprotection reaction is 0.5-1.0 hours, the time required for each amino acid fragment access step is very small, and the repeatability is good; and the comparative example REF-001～003 requires time for each amino acid fragment access step A big difference.

In addition, the solubility of Comparative Examples REF-001～003 decreased rapidly during the process of peptide synthesis, and the solvent needed to be continuously added in the post-treatment process to maintain the solution state. The gelation phenomenon began to appear from AA ₄ , while the compound of the present invention In polypeptide synthesis, the solubility is basically unchanged; the compound of the present invention is used as a carrier to synthesize peptides in a heterogeneous system with a product purity greater than 90%, most of which are greater than 95%, while the product purity of the comparative examples REF-001～003 is not higher than 87%.

In addition, when the benzyl structure-containing compounds of the present invention are BM-005, BM-008, BM-014 and BM-016, the condensation reaction time and post-condensation treatment time for the synthesis of peptides in a heterogeneous system as a carrier , Deprotection reaction time, shorter processing time after deprotection reaction, higher product purity.

In the example of using a homogeneous system to synthesize H-Arg-Lys-Gly-Thr-Lys-Ser-OH, the compound of the present invention compared with the comparative examples REF-001～003, the condensation reaction time, the post-condensation treatment time, and The treatment time after the protection reaction is also significantly shortened, and the purity of the product using the compound of the present invention as a carrier is also significantly higher.

In summary, the use of the compound of the present invention as a carrier is suitable for both homogeneous and heterogeneous systems, and has better effects than the compounds in the comparative example. At the same time, the compound of the present invention is more effective than the compounds in the heterogeneous system. It has better effect in homogeneous system, especially in two-phase system (heterogeneous system) formed by medium and low polar solvents and amide solvents. For peptide synthesis, it can significantly shorten the condensation reaction time and post-condensation treatment Time, deprotection reaction time, and post-treatment time of deprotection reaction, and finally a product with higher purity is obtained.

Claims (17)

1. A compound containing a benzyl structure, characterized in that the structure of the compound is as shown in the general formula (1):

   

   among them:

   X is selected from OH, halogen, sulfonate, NHR _a ;

   Wherein, R _a is selected from hydrogen, an alkyl group or an aromatic group;

   Q is independently selected from O, NH, NHCO, CO, CONH, S, SO or SO ₂ ;

   n is selected from an integer of 1 to 4;

   R is independently selected from the group represented by the general formula (2):

   

   Among them, * means connected with Q;

   L is selected from C ₂ ～C ₁₅ organic chain groups containing O, N or S heteroatoms or C ₂ ～C ₁₅ organic chain groups without O, N or S heteroatoms, when L is selected from C ₂ ～C ₁₅ organic chain groups that do not contain O, N or When the C ₂ ～C ₁₅ organic chain group of S heteroatom, R ₂ ≠H;

   R _{1 is} selected from a C ₁ ～C ₂₅ alkyl group or a group represented by the general formula (3):

   

   Wherein, * means it is connected to the carbonyl group;

   m1 represents an integer of 1 to 3;

   R _{1a is} selected from C ₆ ～C ₂₅ alkyl groups, and the total carbon number of m1 R _1a is not less than 8;

   k _{a is} selected from an integer of 0 to 3;

   Ring B except that one R _1a O having m1 substituent groups, but may also contain selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen-containing atoms substituted with C ₁ ~ C ₅ alkoxy group, a halogen atom free of C ₁ ~ C ₅ alkoxy group substituent;

   In the general formula (2), R _{2 is} selected from hydrogen, a C ₁ to C ₂₅ alkyl group or the group represented by the general formula (4):

   

   In the general formula (4), * means connected with N;

   m2 is selected from an integer of 0 to 3;

   R _{2a is} selected from C ₆ ～C ₂₅ alkyl groups;

   k _{b is} selected from an integer of 1 to 6;

   In addition to an outer ring C m2 having a substituent group R _2a O, may also contain selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen-containing atoms substituted with C ₁ ~ C ₅ alkoxy group, a halogen atom free of C ₁ ~ C ₅ alkoxy group substituent;

   When Q is selected from NH, R is selected from the group represented by the general formula (2'):

   

   Wherein, R _{1 is} selected from the group represented by the general formula (3), and * means that it is connected to Q;

   In addition to the ring A has n outer RQ substituents may further contain substituents selected from halogen atoms, substituted with a halogen atom-containing C ₁ ~ C ₅ alkyl group, a halogen atom free of C ₁ ~ C ₅ alkyl group, a halogen atom-containing The C ₁ -C ₅ alkoxy group or the substituent of the C ₁ -C ₅ alkoxy group without halogen atom substitution.
2. The compound containing a benzyl structure according to claim 1, wherein the R is selected from the group represented by the general formula (5):

   

   Among them, in the general formula (5), * means connected with Q;

   k _{1 is} selected from an integer of 0 to 3, and when k ₁ =0, R ₂ ≠H.
3. The compound containing a benzyl structure according to claim 1, wherein the R is selected from the group represented by the general formula (6):

   

   Among them, in the general formula (6), * means connected with Q;

   R _{4 is} selected from hydrogen, C ₁ to C ₂₅ alkyl group or the group represented by general formula (4) in claim 1;

   k _{2 is} selected from an integer of 1 to 4;

   k _{3 is} selected from an integer of 1-4.
4. The compound containing a benzyl structure according to claim 1, wherein the R is selected from the group represented by the general formula (7):

   

   Among them, in the general formula (7), * means connected with Q;

   R _{6 is} selected from hydrogen, C ₁ -C ₂₅ alkyl group or the group represented by the general formula (4) in claim 1;

   k _{4 is} selected from an integer from 0 to 3;

   k _{5 is} selected from an integer from 0 to 3;

   R _{5 is} selected from hydrogen, a side chain group of a natural amino acid, an alkyl group or a group represented by the general formula (8):

   

   Wherein, k _{6 is} selected from an integer of 1 to 4;

   R ₁ ′ is selected from C ₁ ～C ₂₅ alkyl group or the group represented by general formula (3) in claim 1;

   R ₂ ′ is selected from hydrogen, a C ₁ -C ₂₅ alkyl group, or the group represented by the general formula (4) in claim 1.
5. The compound having a benzyl group of the structure of any one of claims 1 to 4, wherein: said Q is selected from O or NH; preferably, the R _a is selected from hydrogen, methyl, ethyl, Propyl, benzyl or methoxybenzyl; preferably, the n is selected from an integer of 1-3.
6. The compound containing a benzyl structure according to any one of claims 1 to 4, wherein the m1 is selected from 2 or 3, and the total carbon number of m1 R _1a is 8 to 60; preferably, The R _{1a is} selected from C ₈ to C ₂₂ alkyl groups.
7. The compound containing a benzyl structure according to any one of claims 1 to 4, wherein the m2 is selected from 2 or 3, and the total carbon number of m2 R _2a is 8-60; preferably, The R _{2a is} selected from C ₈ -C ₂₂ alkyl groups.
8. The compound containing a benzyl structure according to any one of claims 1 to 4, wherein the R _{2 is} selected from hydrogen, methyl, ethyl, propyl, isopropyl, isooctyl, benzyl Or 4-methoxybenzyl.
9. The compound containing a benzyl structure according to any one of claims 1 to 4, wherein the structural formula of the compound is selected from the following:

   

   

   
10. The benzyl structure-containing compound according to any one of claims 1 to 4, wherein the benzyl structure-containing compound is easily soluble in hydrocarbon organic solvents, aromatic hydrocarbon organic solvents, and ester organic solvents. At least one of solvents, ether organic solvents, and water-soluble aprotic polar organic solvents; preferably, the hydrocarbon organic solvent is selected from heptane, hexane, petroleum ether, cyclohexane, and methylcyclohexane Preferably, the aromatic hydrocarbon organic solvent is selected from at least one of toluene, ethylbenzene, and xylene; preferably, the ester organic solvent is selected from isopropyl acetate, tertiary acetic acid At least one of butyl ester and ethyl acetate; preferably, the ether organic solvent is selected from at least one of diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, and tetrahydrofuran; Preferably, the water-soluble aprotic polar organic solvent is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methyl -Pyrrolidone, N-ethyl-pyrrolidone, dimethyl sulfoxide, sulfolane, 1,3-dimethylimidazolinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2- At least one of pyrimidinones.
11. The compound containing a benzyl structure according to claim 10, wherein the solubility of the compound in N,N-dimethylformamide is >1% at 25-30°C.
12. An amino acid or peptide C-terminal protective reagent, characterized in that the protective reagent comprises the benzyl structure-containing compound according to any one of claims 1-11.
13. The use of the compound containing a benzyl structure according to any one of claims 1 to 11 in the synthesis of peptide reagents in a homogeneous or heterogeneous solvent system.
14. A method for synthesizing peptides, characterized in that: the compound containing a benzyl structure according to any one of claims 1 to 11 is used; preferably, it comprises the following steps:

    1) Carrier access: The benzyl structure-containing compound described in any one of claims 1 to 11 is used as a carrier and the N-protected amino acid or N-protected peptide compound is connected through a conventional reaction to obtain a benzyl structure-containing carrier C-terminal protected N-protected amino acid or N-protected peptide compound;

    2) N-terminal deprotection: dissolve the N-protected amino acid or N-protected peptide compound with the C-terminal protection of the benzyl structure carrier in the solvent, and add the N-terminal protection deprotection reagent solution to form a homogeneous or heterogeneous system. N-terminal deprotection, adding a highly polar solvent for extraction, to obtain N-deprotected amino acid or N-deprotected peptide compound solution containing benzyl structure carrier C-terminal protection;

    3) Peptide chain extension: Add N-protected amino acid or N-protected peptide solution to the C-terminal protected N-deprotected amino acid or N-deprotected peptide compound solution of the benzyl structure carrier, and then add the condensation reagent solution to form Condensation reaction is carried out in homogeneous or heterogeneous system, and highly polar solvent is added for extraction to obtain N-protected amino acid or N-protected peptide compound solution containing benzyl structure carrier C-terminal protection;

    4) Repeat step 2) and step 3) to insert the next amino acid until a complete peptide chain is obtained.
15. The method of synthesis according to claim 14, characterized in that: the N-protected amino acid or N-protected peptide compound solution containing the C-terminal protection of the benzyl structure carrier in step 2) and the N-terminal protection in step 2) The deprotection reagent solution becomes a heterogeneous system; the N-deprotected amino acid or N-deprotected peptide compound solution containing the benzyl structure carrier C-terminal protection in step 3) and the N-protected amino acid or N in step 3) -The protective peptide and the condensation reagent solution form a heterogeneous system; preferably, in step 2), the solvent containing the N-protected amino acid or N-protected peptide compound protected by the C-terminal of the benzyl structure carrier is dissolved and the step 3) contains benzene The solvent in the N-deprotected amino acid or N-deprotected peptide compound solution protected by the C-terminal of the methyl structure carrier is independently selected from hydrocarbons or a mixture of hydrocarbons and at least one of esters, ethers, and halogenated hydrocarbons Solvent; preferably, step 2) dissolve the N-protected amino acid or N-protected peptide compound containing the C-terminal protection of the benzyl structure carrier and step 3) the N-deprotection of the C-terminal protection of the benzyl structure carrier The solvent in the amino acid or N-deprotected peptide compound solution is independently selected from hexane, heptane, cyclohexane, methylcyclohexane, petroleum ether or hexane, heptane, cyclohexane, methylcyclohexane, petroleum At least one of the ethers is formed with at least one of isopropyl acetate, tert-butyl acetate, ethyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, dichloromethane, and chloroform Preferably, the solvent for dissolving the N-terminal protected deprotection reagent in step 2), the solvent for dissolving the N-protected amino acid or N-protected peptide, and the condensation reagent in step 3) are independently selected from amides Solvent, preferably, the amide solvent is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, At least one of N-ethyl-pyrrolidone, 1,3-dimethylimidazolinone, and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone.
16. The synthesis method according to claim 14, characterized in that: the highly polar solvents in step 2) and step 3) are selected from water, alcohols, nitriles, amides, sulfoxides, sulfones, water-soluble At least one of alcohol ethers; preferably, the highly polar solvent described in step 2) and step 3) is selected from water, methanol, acetonitrile, N,N-dimethylformamide, and N-methyl-pyrrolidone , Dimethyl sulfoxide, sulfolane, dimethyl sulfoxide, sulfolane, 1,3-dimethylimidazolinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidine At least one of ketones.
17. The synthesis method according to any one of claims 14-16, wherein the amount of the N-protected amino acid or N-protected peptide is 0.8-3.0 equivalents of the compound containing the benzyl structure, and the The amount of the condensation reagent is 0.8 to 3.0 equivalents of the compound containing benzyl structure; preferably, the amount of the N-protected amino acid or N-protected peptide is 1 to 1.5 of the compound containing benzyl structure Equivalent, the amount of the condensation reagent is 1 to 1.5 equivalents of the compound containing the benzyl structure.