Compound containing 2-phenyl-2-trimethylsilyl ethanol structure as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of polypeptide synthesis, and relates to a compound containing a 2-phenyl-2-trimethylsilyl ethanol structure as well as a preparation method and application thereof. The structural formula of the compound containing the 2-phenyl-2-trimethylsilylethanol structure is shown as a formula I. The carrier compound containing the 2-phenyl-2-trimethylsilylethanol structure is used as a protective carrier of amino acid or polypeptide C terminal; the amino acid or polypeptide protected by the carrier compound containing the 2-phenyl-2-trimethylsilyl ethanol structure can be dissolved in a proper solvent, so that the peptide grafting reaction is carried out in a homogeneous system, the reaction condition is mild, the energy consumption is low, the reaction is rapid and efficient, the reaction speed is high, the reagent utilization rate is high, and the reaction process can be quantitatively monitored in real time; after the reaction, rapid separation and purification are realized through sedimentation or extraction separation, the operation process is simple and efficient, and the universality is high.

Description

Technical Field

[0001] This invention belongs to the field of polypeptide synthesis technology, and relates to a compound containing a 2-phenyl-2-trimethylsilylethanol structure, its preparation method and application. Background Technology

[0002] The chemical synthesis of peptides can be broadly classified into two categories: solid-phase synthesis and liquid-phase synthesis. Solid-phase synthesis allows for the direct synthesis of compounds on a solid support during the reaction process, eliminating the need to separate and purify intermediates. This significantly simplifies the operation and improves reaction efficiency, making it ideal for the synthesis of peptide molecules that require the stepwise addition of amino acid monomers. However, solid-phase synthesis has inherent drawbacks: due to its heterogeneous nature, excessive amounts of reagents are typically required to compensate for its low reactivity and ensure complete reaction on the solid phase; large amounts of solvent are needed to wash the resin after each step to avoid excessive impurities, resulting in significant solvent waste; furthermore, there is a lack of effective means to monitor the progress of the reaction on the solid support. Liquid-phase synthesis avoids the use of excessive reagents, offers good atom economy, and facilitates monitoring of the reaction process. Intermediates at each step can be separated and purified using methods such as extraction, distillation, recrystallization, and column chromatography. However, liquid-phase operations are complex, time-consuming, and inefficient.

[0003] To address these issues, peptide chemists have recently developed soluble supports to replace resin supports in solid-phase synthesis for liquid-phase peptide synthesis. Bayer and Mutter et al. first combined the advantages of solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS) by using soluble polymers (PEG) instead of solid resin supports for peptide synthesis in solution. However, these soluble polymer supports still inevitably exhibit low loading values. To solve this problem, soluble supports based on small molecules have been developed. Chiba's group designed a soluble support based on the simple hydrophobic group benzyl alcohol for peptide synthesis via a sedimentation post-treatment method; Takahashi's group developed a branched-chain alkane soluble support that enables peptide synthesis via a water-washing extraction post-treatment method, which is simpler and more convenient than sedimentation. The problems with these all-carbon chain support methods are: 1) The soluble supports have low solubility in common green solvents (such as ethyl acetate), and the reactions are usually carried out in halogenated solvents (such as chloroform, dichloromethane, etc.) which are highly harmful to the environment; 2) Under normal circumstances, the precipitation and crystallization efficiency is low, resulting in significant product loss; 3) As the peptide sequence lengthens, the solubility decreases, and the reaction often cannot proceed due to difficulty in dissolving the peptide. Therefore, these methods are generally only applicable to the synthesis of short peptides with specific sequences and can hardly be considered universal peptide synthesis methods. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to address the shortcomings of the prior art by introducing a hydrophobic silane group to prepare a novel soluble carrier, which has good solubility in conventional green organic solvents (such as ethyl acetate), and enables the peptide insemination reaction to proceed efficiently, rapidly and smoothly in non-halogen-containing green organic solvents. The post-processing is carried out by liquid-liquid extraction to remove impurities, which is simple, convenient and universal, and can be used for the synthesis of various peptide sequences and is suitable for industrial production.

[0005] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0006] This invention discloses a compound containing a 2-phenyl-2-trimethylsilanediol structure, the structure of which is shown in Formula I below:

[0007]

[0008] in,

[0009] n is an integer selected from 1 to 5;

[0010] R is independently selected from R1, -OR2, or

[0011] R1 is selected from substituted or unsubstituted C1-C22 alkyl groups;

[0012] R2 is selected from substituted or unsubstituted C1-C30 alkyl groups;

[0013] R3, R4, and R5 are independently selected from substituted or unsubstituted C1-C22 alkyl groups or substituted or unsubstituted aromatic groups;

[0014] Wherein, the substitution is selected from C1-C6 alkyl substitution;

[0015] The compound containing the 2-phenyl-2-trimethylsilylethanol structure is not a compound from the following group:

[0016]

[0017] Among them, the C1-C22 alkyl and C1-C30 alkyl mentioned above include straight-chain alkyl or branched alkyl.

[0018] In some embodiments, n is selected from an integer from 1 to 3; R1 is selected from substituted or unsubstituted C4-C20 alkyl groups; R2 is selected from substituted or unsubstituted C1-C22 alkyl groups; R3, R4, and R5 are independently selected from substituted or unsubstituted C1-C20 alkyl groups or substituted or unsubstituted aromatic groups.

[0019] In some embodiments, preferably, n = 1, 2, or 3; when R is selected from R1, R1 is selected from substituted or unsubstituted C4 alkyl, C8 alkyl, C10 alkyl, C14 alkyl, or C20 alkyl; when R is selected from -OR2, R2 is selected from substituted or unsubstituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, C20 alkyl, or C22 alkyl; R is selected from... In this case, R3, R4, and R5 are independently selected from substituted or unsubstituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C6 alkyl, C8 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, or C20 alkyl, or substituted or unsubstituted aromatic groups.

[0020] In some embodiments, more preferably, n = 1, 2, or 3; when n = 1, R is selected from R1, where R1 is selected from unsubstituted n-butyl, n-octyl, n-decyl, n-tetradecyl, or n-eicosyl; when n = 1, R is selected from -OR2, where R2 is selected from unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, or n-docodialkyl; when n = 2, R is selected from -OR2, where R2 is selected from unsubstituted n-butyl, n-octyl, or n-dodecyl; when n = 3, R is selected from -OR2, where R2 is selected from unsubstituted n-octyl; when n = 1, R is selected from... When n=2, R3=R5, R3 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, or phenyl; R4 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, or phenyl; when n=2, R is selected from... When n=3, R3=R5, R3 is selected from methyl; R4 is selected from methyl; when n=3, R is selected from methyl. When R3 = R5, R3 is selected from methyl; R4 is selected from methyl.

[0021] In some embodiments, more preferably, n = 1, 2, or 3; when n = 1, R is selected from R1, where R1 is selected from unsubstituted n-butyl, n-octyl, n-octyl, n-decyl, n-tetradecyl, or n-eicosyl; R1 is ortho-, meta-, or para-substituted relative to the parent nucleus structure; when n = 1, R is selected from -OR2, where R2 is selected from unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, or n-docodialkyl, and -OR2 is ortho-, meta-, or para-substituted relative to the parent nucleus structure. Or para substitution; when n=2, R is selected from -OR2, and R2 is selected from unsubstituted n-butyl, the two -OR2 groups are ortho-substituted and para-substituted relative to the parent nucleus structure, respectively; when R2 is selected from n-octyl, the two -OR2 groups are meta-substituted and the other meta-substituted relative to the parent nucleus structure, respectively; when R2 is selected from n-dodecyl, the two -OR2 groups are meta-substituted and para-substituted relative to the parent nucleus structure, respectively; when n=3, R is selected from -OR2, and R2 is selected from unsubstituted n-octyl, the three -OR2 groups are meta-substituted, para-substituted, and the other meta-substituted relative to the parent nucleus structure, respectively; when n=1, R is selected from... When R3 = R5, R3 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, or phenyl; R4 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, or phenyl. The group represents para-substitution relative to the parent nucleus structure; when n=2, R is selected. When R3 = R5, R3 is selected from methyl; R4 is selected from methyl; both The groups are respectively meta-substituted and another meta-substituted relative to the parent nucleus structure; when n=3, R is selected. When R3 = R5, R3 is selected from methyl; R4 is selected from methyl; all three The groups are respectively meta-substituted, para-substituted, and another meta-substituted relative to the parent nucleus structure.

[0022] In some embodiments, most preferably, the compound containing the 2-phenyl-2-trimethylsilylethanol structure is selected from any of the following compounds:

[0023]

[0024]

[0025] Among them, the -C2H5, -C3H7, -C4H9, and -C5H components in the structure of the compound 11 -C6H 13 -C7H 15 -C8H17 -C9H 19 -C 10 H 21 -C 12 H 25 -C 14 H 29 -C 16 H 33 -C 18 H 37 -C 20 H 41 -C 22 H 45 Unless otherwise specified, all are straight-chain saturated alkyl groups.

[0026] Furthermore, the present invention provides a method for preparing the above-mentioned compound containing the 2-phenyl-2-trimethylsilaneethanol structure, wherein the halophenyl compound a undergoes a substitution reaction in the presence of a lithium reagent, and then continues to undergo a ring-opening reaction with compound b in the presence of an additive, thereby obtaining compound I containing the 2-phenyl-2-trimethylsilaneethanol structure;

[0027]

[0028] in,

[0029] X is selected from Br or Cl;

[0030] n is an integer selected from 1 to 5;

[0031] R is independently selected from R1, -OR2, or

[0032] R1 is selected from substituted or unsubstituted C1-C22 alkyl groups;

[0033] R2 is selected from substituted or unsubstituted C1-C30 alkyl groups;

[0034] R3, R4, and R5 are independently selected from substituted or unsubstituted C1-C22 alkyl groups or substituted or unsubstituted aromatic groups;

[0035] Wherein, the substitution is selected from C1-C6 alkyl substitution;

[0036] The compound containing the 2-phenyl-2-trimethylsilylethanol structure is not a compound from the following group:

[0037]

[0038] In some embodiments, the lithium reagent is n-butyllithium; the additive is cuprous iodide; the molar ratio of the halophenyl compound a, the lithium reagent, compound b, and the additive is 2.0–8.0: 2.0–8.0: 1.0: 1.0–4.0, preferably 3.0–5.0: 3.0–5.0: 1.0: 1.0–3.0, more preferably 3.5–4.0: 3.5–4.0: 1.0: 2.0; the substitution reaction is carried out at a temperature of -40°C to 12°C; the ring-opening reaction is carried out at a temperature of -40°C to 0°C, and the reaction is carried out under an inert gas atmosphere.

[0039] The solvent used in the substitution reaction is preferably anhydrous methyl ether. There are no special requirements for the amount of solvent used; it is sufficient to dissolve the raw material and achieve a suitable viscosity.

[0040] In the ring-opening reaction, the inert gas is preferably nitrogen, and the solvent is preferably anhydrous methyl ether. There are no special requirements for the amount of solvent used; it is sufficient to dissolve the raw material and achieve a suitable viscosity.

[0041] Furthermore, the present invention provides a protective agent for the C-terminus of an amino acid or peptide, the protective agent comprising the above-mentioned compound containing the 2-phenyl-2-trimethylsilylethanol structure.

[0042] The application of the compounds containing the 2-phenyl-2-trimethylsilylethanol structure or the above-mentioned amino acid or peptide C-terminal protecting agents in the synthesis of polypeptides in homogeneous solvent systems is also within the scope of protection of this invention.

[0043] The polypeptides mentioned herein include, but are not limited to, pharmaceutical polypeptides and cosmetic polypeptides.

[0044] The pharmaceutical polypeptides mentioned include, but are not limited to, bivalirudin, linaclotide, cell adhesion peptide, atebande, etc.; the cosmetic polypeptides include, but are not limited to, palmitoyl pentapeptide-3 (palmitoyl pentapeptide), palmitoyl hexapeptide, palmitoyl tripeptide-5, myristoyl pentapeptide-11, hexapeptide-9, etc.

[0045] Furthermore, the present invention provides a method for synthesizing polypeptides, using the above-mentioned compound containing the 2-phenyl-2-trimethylsilylethanol structure as a carrier to synthesize polypeptides in a homogeneous phase; comprising the following steps:

[0046] (1) Carrier incorporation: The above-mentioned compound containing the 2-phenyl-2-trimethylsilane ethanol structure is used as a carrier and linked with an N-protected amino acid or N-protected peptide compound through a conventional condensation reaction to obtain an N-protected amino acid or N-protected peptide compound with the C-terminus protected by the carrier containing the 2-phenyl-2-trimethylsilane ethanol structure.

[0047] (2) N-terminal deprotection: The N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structural carrier is mixed with the N-terminal deprotection reagent and solvent, and the N-terminal deprotection is carried out in an organic homogeneous system to obtain a solution of the N-deprotected amino acid or N-deprotected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structural carrier.

[0048] (3) Peptide chain elongation: In a solution of N-deprotected amino acids or N-deprotected peptide compounds protected at the C-terminus of a 2-phenyl-2-trimethylsilylethanol structural carrier, N-protected amino acids or N-protected peptide compounds are added, followed by the addition of a condensation reagent to carry out a coupling condensation reaction in a homogeneous system, and then extraction is performed to remove impurities, thereby obtaining a solution of N-protected amino acids or N-protected peptide compounds protected at the C-terminus of a 2-phenyl-2-trimethylsilylethanol structural carrier.

[0049] (4) Repeat steps (2) and (3) to add the next amino acid until a complete peptide chain is obtained;

[0050] (5) Carrier removal and sedimentation: After the N-terminus of the intact N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structure carrier is deprotected, the C-terminus carrier is removed using a removal reagent, and the mixture is added to a sedimentation solution for sedimentation to obtain the polypeptide.

[0051] In some embodiments, in step (5), when the N-terminus of the complete N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structural carrier needs to be amidated, the N-terminus is deprotected and then amidated, and the C-terminal carrier is removed using a removal reagent after amidation.

[0052] In some embodiments, in step (5), when the complete N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structural carrier contains a side-chain protecting group, the C-terminal carrier is removed and then the cleavage reaction is carried out in the cleavage solution. After the cleavage is completed, a sedimentation solution is added for sedimentation to obtain the polypeptide.

[0053] In some embodiments, in step (1), the conventional condensation reaction uses any one or a combination of several of the condensation reagents DCC, DIC, EDC·HCl, DMAP, HOBt, HATU, and HBTU; the molar ratio of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure to the N-protected amino acid is 1:1 to 2, preferably 1:1.2 to 2; the molar ratio of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure to the N-protected peptide compound is 1:1 to 2, preferably 1:1.2. ~2; the molar ratio of the compound containing the 2-phenyl-2-trimethylsilylethanol structure to the condensing reagent is 2:2.5~4.5; the solvent used in the conventional condensation reaction is any one or a combination of several of dichloromethane, dimethylformamide, dimethyl sulfoxide and ethyl acetate, preferably ethyl acetate; the amount of solvent is not particularly limited, as long as it dissolves the raw material and has a suitable viscosity; the conventional condensation reaction is carried out at 25℃~40℃; after the conventional condensation reaction is completed, the reaction solution is washed with 5wt% K2CO3 and extracted to remove impurities.

[0054] In some embodiments, in step (2), when the N-terminal protecting group is CBz, the deprotecting reagent used is Pd / C and hydrogen, and the solvent used is any one or a combination of several of dichloromethane, ammonium formate, tetrahydrofuran, formic acid, hydrochloric acid, ethyl acetate and methanol, preferably a mixed solvent of ethyl acetate and methanol in any proportion, and more preferably a mixed solvent of ethyl acetate and methanol in a volume ratio of 1:1. The amount of solvent used is not particularly limited, as long as it dissolves the raw material and the viscosity is appropriate; the amount of Pd in ​​Pd / C is preferably 0.03 to 0.08 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure, preferably 0.05 molar equivalents; the pressure of the hydrogen is 1 standard atmosphere; the N-terminal deprotection is carried out at 25°C to 40°C; after the N-terminal deprotection is completed, the reaction solution is washed with 5wt% K2CO3 and extracted to remove impurities.

[0055] In some embodiments, in step (2), when the N-terminal protecting group is Fmoc-, the deprotecting agent used is any one or a combination of piperidine, pyrrolidine, and palladium on carbon, preferably pyrrolidine. The amount of the deprotecting agent is 8 to 10 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure. The solvent used is any one or a combination of dichloromethane, tetrahydrofuran, methanol, acetonitrile, and ethyl acetate, preferably ethyl acetate. The amount of solvent is not particularly limited, as long as it dissolves the raw material and has a suitable viscosity. The N-terminal deprotection is carried out at 25°C to 40°C. After the N-terminal deprotection is completed, the reaction solution is washed with 5% hydrochloric acid aqueous solution and then washed with 5wt% K2CO3 to remove impurities.

[0056] In some embodiments, in step (3), the condensing agent is DCC, DIC, EDC·HCl, or DMAP. The combination of any one or more of HOBt, HATU, and HBTU is preferred, preferably a mixture of EDC·HCl and HOBt in any molar ratio, and more preferably a mixture of EDC·HCl and HOBt in a 1:1 molar ratio; the amount of the condensing reagent used is 2 to 3 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure; the amount of the N-protected amino acid used is 1 to 2 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure; the amount of the N-protected peptide compound used is 1 to 2 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure; the solvent used in the coupling condensation reaction is any one or more of dichloromethane, dimethylformamide, dimethyl sulfoxide, and ethyl acetate, preferably ethyl acetate, and the amount of solvent is not particularly limited, as long as it dissolves the raw materials and has a suitable viscosity; the coupling condensation reaction is carried out at 25℃ to 40℃; after the coupling condensation reaction is completed, the reaction solution is washed with 5wt% K2CO3 and extracted to remove impurities.

[0057] In some embodiments, in step (5), the removal reagent is any one or a combination of two of trifluoroacetic acid and tetrabutylammonium fluoride trihydrate, preferably tetrabutylammonium fluoride trihydrate; the amount of the removal reagent is 2.5 to 3.5 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilylethanol structure; the solvent used in the removal of the C-terminal carrier is any one or a combination of two of dichloromethane, dimethylformamide, dimethyl sulfoxide and ethyl acetate, preferably dichloromethane, and the amount of solvent is not particularly limited, as long as it dissolves the raw material and has a suitable viscosity; the removal of the C-terminal carrier is carried out at room temperature.

[0058] In some embodiments, in step (5), the settling liquid is a mixture of methyl tert-butyl ether and n-hexane, wherein the preferred volume ratio of the two is: V 甲基叔丁基醚 V 正己烷 =1:1.

[0059] In some embodiments, in step (5), when the N-terminus of the complete N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structure carrier needs to be amidated, amidation is performed after deprotection of the N-terminus, and the C-terminal carrier is removed using a removal reagent after amidation; wherein, during amidation, the amidation condensation reagent used is any one or a combination of several of DCC, DIC, EDC·HCl, HOBt, HATU and HBTU, preferably a mixture of EDC·HCl and HOBt in any molar ratio, and more preferably a mixture of EDC·HCl and HOBt in a 1:1 molar ratio; the amidation The amount of condensing reagent used is 2 to 3 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure; the amount of the substrate providing the carboxyl group used in the amidation process is 1 to 2 molar equivalents of the compound containing the 2-phenyl-2-trimethylsilaneethanol structure; the solvent used in the amidation is any one or a combination of several of dichloromethane, dimethylformamide, dimethyl sulfoxide, and ethyl acetate, preferably ethyl acetate, and the amount of solvent is not particularly limited, as long as it dissolves the raw material and has a suitable viscosity; the amidation is carried out at 25°C to 40°C; after the amidation reaction is completed, the reaction solution is washed with 5 wt% K2CO3 and extracted to remove impurities.

[0060] In some embodiments, in step (5), when the intact N-protected amino acid or N-protected peptide compound containing the C-terminus of the 2-phenyl-2-trimethylsilylethanol structural carrier contains a side-chain protecting group, the C-terminal carrier is removed before cleavage in the cleavage solution. After cleavage, a settling solution is added for sedimentation to obtain the polypeptide. The cleavage solution is a mixture of TFA, DODT, TIS, and pure water, with the preferred volume ratio being: V / V. TFA :V DODT :V TIS :V 纯水 = 92.5:2.5:2.5:2.5; The amount of the cutting fluid used is 10 to 15 times the volume of the complete N-protected amino acid or N-protected peptide compound containing the C-terminus protected by the 2-phenyl-2-trimethylsilylethanol structural carrier.

[0061] Beneficial effects:

[0062] (1) The soluble carrier provided by the present invention is simple and efficient to synthesize, and the raw materials are cheap and readily available; the soluble carrier has good solubility and stability in green solvents (such as ethyl acetate).

[0063] (2) In this invention, a carrier compound containing a 2-phenyl-2-trimethylsilylethanol structure is used as a protective carrier for the C-terminus of amino acids or peptides. Amino acids or peptides protected by this carrier compound can dissolve in a suitable solvent, allowing the peptide initiation reaction to proceed in a homogeneous system. The reaction conditions are mild, energy consumption is low, and the reaction is rapid and efficient. The reaction rate is fast, reagent utilization is high, and the reaction process can be quantitatively monitored in real time. Impurities are removed after each reaction step through continuous washing and extraction, simplifying the process and significantly reducing the consumption of organic solvents and the emission of waste, making it green and safe. Rapid separation and purification are achieved after the reaction through sedimentation or extraction, resulting in a simple, efficient, and versatile operation. Compared to existing peptide synthesis routes, the peptide synthesis route provided by this invention is easier to industrialize, offering a new solution for large-scale, green, and efficient peptide synthesis. Attached Figure Description

[0064] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0065] Figure 1 This is the NMR spectrum of compound b.

[0066] Figure 2 This is the NMR spectrum of compound a-10.

[0067] Figure 3 This is the NMR spectrum of compound 10.

[0068] Figure 4 This is the 1H NMR spectrum of compound 14.

[0069] Figure 5 This is the mass spectrum of Pal-Lys-Thr-Thr-Lys-Ser-OH.

[0070] Figure 6 This is the mass spectrum of NH2-Gly-Arg-Gly-Asp-Ser-Pro-Cys-OH.

[0071] Figure 7 This is the mass spectrum of Pal-Val-Gly-Val-Ala-Pro-Gly-OH.

[0072] Figure 8 This is the mass spectrum of bivalirudin. Detailed Implementation

[0073] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0074] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0075] All chemical structural formulas in this invention were drawn using KingDraw software.

[0076] 1. The main method for synthesizing compound I in this invention is as follows: a halophenyl compound a undergoes a substitution reaction under the action of a lithium reagent, and then continues to undergo a ring-opening reaction with compound b under the action of an additive, thereby obtaining compound I containing the 2-phenyl-2-trimethylsilylethanol structure;

[0077]

[0078] in,

[0079] X is selected from Br or Cl;

[0080] n is an integer selected from 1 to 5;

[0081] R is independently selected from R1, -OR2, or

[0082] R1 is selected from substituted or unsubstituted C1-C22 alkyl groups;

[0083] R2 is selected from substituted or unsubstituted C1-C30 alkyl groups;

[0084] R3, R4, and R5 are independently selected from substituted or unsubstituted C1-C22 alkyl groups or substituted or unsubstituted aromatic groups;

[0085] The substitution is selected from C1-C6 alkyl substitutions.

[0086] The preparation method described above can be found in existing technology (Wagner, Michael, Kunz, Horst, et al. The (2-phenyl-2-trimethylsilyl)ethyl(PTMSE)ester-a carboxy protecting group cleavable under neutral conditions. Chemical Sciences (2002), 57(8), 928-936):

[0087]

[0088] 2. The preparation method of compound b is described in the prior art (Reddel, JCT., Wang, WW., Koukounas, K., et al. Triflimide-catalyzed allylsilane annulations of benzylic alcohols for the diversified synthesis of indanes and tetralins, CHEMICAL SCIENCE, Volume 8 Issue 3 Page 2156-2160.). Vinyltrimethylsilane undergoes an epoxidation reaction under the conditions of m-chloroperoxybenzoic acid to produce trimethylsilyl ethylene oxide, i.e., compound b;

[0089]

[0090] 3. The substitution reaction of the aforementioned halophenyl compound a under the action of lithium reagent can be referenced from existing techniques:

[0091] When R is selected from R1, and R1 is selected from substituted or unsubstituted C1-C22 alkyl groups, halophenyl compound a undergoes a direct substitution reaction under the action of lithium reagent, and then continues to undergo a ring-opening reaction with compound b under the action of additives, thus obtaining compound I-1 containing the 2-phenyl-2-trimethylsilylethanol structure.

[0092]

[0093] When R is selected from -OR2 and R2 is selected from substituted or unsubstituted C1-C30 alkyl groups, the halophenol undergoes a substitution reaction with the haloalkane compound under the action of a base to generate halophenyl compounds; the halophenyl compound undergoes a substitution reaction under the action of a lithium reagent, and then continues to undergo a ring-opening reaction with compound b under the action of an additive to obtain compound I-2 containing the 2-phenyl-2-trimethylsilylethanol structure.

[0094]

[0095] R is selected from When R3, R4, and R5 are independently selected from substituted or unsubstituted C1-C22 alkyl groups or substituted or unsubstituted aromatic groups, halophenols undergo a substitution reaction with trisubstituted halosilanes under the action of a base to generate halophenyl compounds. These halophenyl compounds then undergo a substitution reaction under the action of a lithium reagent, followed by a ring-opening reaction with compound b under the action of an additive, yielding compound I-3 containing the 2-phenyl-2-trimethylsilylethanol structure.

[0096]

[0097] Example 1: Synthesis of compound b

[0098] Compound b can be synthesized using existing techniques, or it can be prepared using the following method:

[0099] Weigh out 75 mmol (15 g, 85% purity) of m-chloroperoxybenzoic acid and dissolve it in chloroform (135 mL). Stir until the solution becomes clear. At 0 °C, add vinyltrimethylsilane (50 mmol, 7.3 mL) using a syringe and react at 0 °C with stirring for 48 h. After the reaction is complete, filter out the white solid. Wash the organic phase with saturated NaHCO3 solution until no color is observed on thin-layer chromatography (TLC). The washing is then complete. Dry with anhydrous MgSO4 for 2-3 h and remove MgSO4 by vacuum filtration. Set up a distillation apparatus and remove the solvent by distillation. When the temperature reaches 80 °C, the solvent chloroform can be removed. Heating to 120 °C yields compound b. Compound b is a colorless oily liquid with a yield of 78.8%.

[0100] The NMR spectrum of compound b is shown in [reference needed]. Figure 1 The specific NMR data are as follows: 1 H NMR (400MHz, Chloroform-d) δ2.84 (td, J=5.8, 1.9Hz, 1H), 2.49 (q, J=4.2, 3.3Hz, 1H), 2.17–2.09 (m, 1H), -0.00 (d, J=2.0Hz, 9H).

[0101] Example 2: Synthesis of Compound 1

[0102]

[0103] Weigh out p-n-butylbromobenzene (12 mmol, 2.56 g, Mw = 213.1 g / mol) and dissolve it in anhydrous methyl ether (15 mL). Add n-butyllithium (12 mmol, 4.8 mL) dropwise at -40 °C and stir the reaction at -40 °C for 30 min. Then raise the temperature to 10 °C and stir the reaction for 1.5 h to obtain a reaction solution containing p-n-butylphenyllithium. Store the solution at 10 °C for later use.

[0104] Cuprous iodide (6 mmol, 1.2 g, Mw = 190.5 g / mol) was weighed and placed in a 100 mL three-necked flask. The flask was vented and protected with nitrogen to ensure an anhydrous and oxygen-free environment. Anhydrous methyl ether (4 mL) was added using a syringe at 0 °C, followed by a reaction solution containing p-n-butylphenyllithium. The reaction was stirred at 0 °C for 1 h. The temperature was then lowered to -40 °C, and compound b (3 mmol, 0.4 mL) was added to the flask. The reaction was stirred at -40 °C for 5 h, then raised to -20 °C and stirred overnight. After the reaction was complete, the reaction was quenched with saturated NH4Cl, followed by washing with ethyl acetate and saturated NH4Cl solution. Finally, the mixture was dried over anhydrous MgSO4 for 2-3 h, and MgSO4 was removed by vacuum filtration. The solution was concentrated under reduced pressure to obtain a colorless oily liquid, which was then purified by column chromatography (EA:PE = 1:10) to give compound 1 in 88.6% yield.

[0105] The NMR data for compound 1 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.10–6.99(m,2H),6.92–6.84(m,2H),4.77(s,1H),4.11(t,J=11.4Hz,1H),3.92(d,J=6.5Hz,1H),2.59–2.54(dd ,J=11.5,4.5Hz,2H),2.41(dd,J=11.5,4.5Hz,1H),1.60–1.56(m,2H),1.40–1.36(dd,J=7.4,1.6Hz,2H),0.96(t,J=3.7Hz,3H),-0.00(s,9H).

[0106] Example 3:

[0107] (1) Preparation of compound 2:

[0108]

[0109] The preparation method is the same as that of compound 1 in Example 2, except that p-n-butylbromobenzene is replaced with p-n-octylbromobenzene, and the generated p-n-octylphenyllithium intermediate is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 2.

[0110] The 1H NMR spectrum data of compound 2 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.12–6.89(dd,4H),4.32(t,J=11.4Hz,1H),3.81(d,J=6.5Hz,1H),3.56(d,J=6.5Hz,1H),2.98(m,J=11.5,4.5Hz ,2H),2.45(dd,J=11.5,4.5Hz,1H),1.66–1.63(dd,J=7.4,1.6Hz,2H),1.28–1.23(dd,J=7.4,1.6Hz,10H),0.97(t,J=3.7Hz,3H),-0.00(s,9H).

[0111] (2) Preparation of compound 3:

[0112]

[0113] The preparation method is the same as that of compound 1 in Example 2, except that p-n-butylbromobenzene is replaced with p-n-tetradecylbromobenzene, and the generated p-n-tetradecylphenyllithium intermediate is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 3.

[0114] The 1H NMR spectrum data of compound 3 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.21–7.15(m,4H),4.44(t,J=11.4Hz,1H),3.95(d,J=6.5Hz,1H),3.68(d,J=6.5Hz,1H),2.58(dd,J=11.5,4.5Hz ,2H),2.43(m,J=11.5,4.5Hz,1H),1.89–1.86(dd,J=7.4,1.6Hz,2H),1.66–1.63(dd,J=7.4,1.6Hz,22H),0.97(t,J=3.7Hz,3H),-0.00(s,9H).

[0115] (3) Preparation of compound 4:

[0116]

[0117] The preparation method is the same as that of compound 1 in Example 2, except that p-n-butylbromobenzene is replaced with...

[0118] p-eicosylbromobenzene, the resulting p-eicosylphenyllithium intermediate is immediately reacted with compound b in the presence of cuprous iodide to synthesize compound 4.

[0119] The 1H NMR spectrum data of compound 4 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.12–7.08(m,2H),6.89–6.86(m,2H),4.73(s,1H),4.01(t,J=11.4Hz,1H),3.72(d,J=6.5Hz,1H),2.53–2.49(dd ,J=11.5,4.5Hz,2H),2.45(dd,J=11.5,4.5Hz,1H),1.66–1.63(m,2H),1.28–1.23(dd,J=7.4,1.6Hz,34H),0.87(t,J=3.7Hz,3H),-0.00(s,9H).

[0120] (4) Preparation of compound 5:

[0121]

[0122] The preparation method is the same as that of compound 1 in Example 2, except that p-n-butylbromobenzene is replaced with m-n-octylbromobenzene, and the generated m-n-octylphenyllithium intermediate is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 5.

[0123] The 1H NMR spectrum data of compound 5 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.59(m,1H),7.15–7.10(m,3H),4.61(s,1H),3.93(t,J=11.4Hz,1H),3.77(d,J=6.5Hz,1H),2.51(dd,J=11.5,4.5H z,2H),2.49(dd,J=11.5,4.5Hz,1H),1.78-1.74(t,J=11.5,4.5Hz,2H),1.28–1.23(dd,J=7.4,1.6Hz,10H),0.87(t,J=3.7Hz,3H),-0.00(s,9H).

[0124] (5) Preparation of compound 6:

[0125]

[0126] The preparation method is the same as that of compound 1 in Example 2, except that p-n-butylbromobenzene is replaced with o-n-decylbromobenzene, and the generated o-n-decylphenyl lithium intermediate is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 6.

[0127] The 1H NMR spectrum data of compound 6 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.18–7.15(t,4H),4.63(s,1H),3.91(t,J=11.4Hz,1H),3.87(d,J=6.5Hz,1H),2.71(dd,J=11.5,4 .5Hz,3H),1.67(dd,J=11.5,4.5Hz,2H),1.28–1.25(dd,J=11.5,4.5Hz,14H),0.97–0.94(dd,J=11.5,4.5Hz,3H),-0.00(s,9H).

[0128] Example 4: Preparation of Compound 10

[0129]

[0130] Synthesis of compound a-10: p-Bromophenol (12 mmol, 2.08 g, Mw = 173.0 g / mol) and cesium carbonate (24 mmol, 7.82 g, Mw = 325.8 g / mol) were dissolved in DMF (15 mL). Bromobutane (15.6 mmol, 2.71 mL, Mw = 137.0 g / mol) was added with stirring. The mixture was heated to 65 °C and stirred at this temperature for 24 h. After the reaction was complete, the mixture was washed with DCM and saturated NaCl solution. The organic phase remained in the lower layer. The mixture was dried over anhydrous MgSO4 for 2-3 h, and the MgSO4 was removed by vacuum filtration. The solution was concentrated under reduced pressure to obtain a colorless oily liquid. Finally, the solution was purified by column chromatography (100% PE) to obtain compound a-10 in 99.5% yield.

[0131] The NMR spectrum of compound a-10 is shown in [reference needed]. Figure 2 The specific NMR data are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.46–7.31(m,2H),6.88–6.71(m,2H),3.95(t,J=6.5Hz,2H),1.85–1.70(m,2H),1.51(h,J=7.5Hz,2H),1.00(t,J=7.4Hz,3H).

[0132] Synthesis of compound 10:

[0133] Anhydrous methyl ether (15 mL) was added to compound a-10 above, and n-butyllithium (12 mmol, 4.8 mL) was added dropwise at -40 °C. The reaction was stirred at -40 °C for 30 min, and then heated to 10 °C and stirred for 1.5 h to obtain a reaction solution containing p-n-butyloxyphenyllithium intermediate. The solution was stored at 10 °C for later use.

[0134] Cuprous iodide (6 mmol, 1.2 g) was weighed and placed in a 100 mL three-necked flask. The flask was vented and protected with nitrogen to ensure an anhydrous and oxygen-free environment. Anhydrous tert-methyl ether (4 mL) was added using a syringe at 0 °C, followed by the reaction solution containing the previously generated p-n-butyloxyphenyl lithium intermediate. The reaction was stirred at 0 °C for 1 h. The temperature was lowered to -40 °C, and compound b (3 mmol, 0.4 mL) was added to the three-necked flask. The reaction was stirred at -40 °C for 5 h, then the temperature was raised to -20 °C and stirred overnight. After the reaction was complete, the reaction was quenched with saturated NH4Cl, followed by washing with ethyl acetate and saturated NH4Cl solution. Finally, the mixture was dried over anhydrous MgSO4 for 2-3 h, and MgSO4 was removed by vacuum filtration. The solution was concentrated under reduced pressure to obtain a colorless oily liquid, which was then purified by column chromatography (EA:PE = 1:10) to give compound 10 in 86.7% yield.

[0135] The NMR spectrum of compound 10 is as follows: Figure 3 The specific NMR data are as shown: 1 H NMR(400MHz,Chloroform-d)δ7.10–6.99(m,2H),6.92–6.84(m,2H),4.77(s,1H),4.11(t,J=11.4Hz,1H),3.98(d,J=6.5Hz,2H),3.92 (d,J=6.5Hz,1H),2.41(dd,J=11.5,4.5Hz,1H),1.80–1.76(m,2H),1.53(dd,J=7.4,1.6Hz,2H),1.01(t,J=3.7Hz,3H),-0.00(s,9H).

[0136] Example 5:

[0137] (1) Preparation of compound 7:

[0138]

[0139] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with bromomethane to generate 1-bromo-4-methoxybenzene; 4-(methoxy)phenyllithium generated by 1-bromo-4-methoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 7.

[0140] The 1H NMR spectrum data of compound 7 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.23–7.21(m,2H),7.11–7.08(m,2H),4.76(s,1H),4.12(dd,J=6.5 Hz,1H),3.90(s,J=6.5Hz,3H),3.81(d,J=6.5Hz,1H),2.52(dd,J=11.5,4.5Hz,1H),-0.00(s,9H).

[0141] (2) Preparation of compound 8:

[0142]

[0143] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with bromoethane to generate 1-bromo-4-ethoxybenzene; 4-(ethoxy)phenyllithium generated by 1-bromo-4-ethoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 8.

[0144] The 1H NMR spectrum data of compound 8 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.25–7.22(m,2H),7.15–7.12(m,2H),4.78(s,1H),4.12(dd,J=6.5Hz,2H),4.0 8(dd,J=6.5Hz,1H),3.90(s,J=6.5Hz,1H),2.52(dd,J=11.5,4.5Hz,1H),1.31(t,J=3.7Hz,3H),-0.00(s,9H).

[0145] (3) Preparation of compound 9:

[0146]

[0147] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-propane to generate 1-bromo-4-propoxybenzene; 4-(propoxy)phenyllithium generated by 1-bromo-4-propoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 9.

[0148] The 1H NMR spectrum data of compound 9 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.22–7.20(m,2H),7.14–7.11(m,2H),4.68(s,1H),4.02(dd,J=6.5Hz,2H),3.96(dd,J=6.5 Hz,1H),3.90(s,J=6.5Hz,1H),2.42(dd,J=11.5,4.5Hz,1H),1.71(t,J=3.7Hz,2H),1.31(t,J=3.7Hz,3H),-0.00(s,9H).

[0149] (4) Preparation of compound 11:

[0150]

[0151] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-pentane to generate 1-bromo-4-n-pentoxybenzene; 4-(n-pentoxy)phenyllithium generated by 1-bromo-4-n-pentoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 11.

[0152] The 1H NMR spectrum data of compound 11 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.18–7.15(m,2H),7.13–7.10(m,2H),4.69(s,1H),4.12(dd,J=6.5Hz,2H),4.01(dd,J=6.5Hz,1H),3. 92(s,J=6.5Hz,1H),2.72(dd,J=11.5,4.5Hz,1H),1.71(t,J=3.7Hz,2H),1.31(t,J=3.7Hz,4H),1.01(t,J=3.7Hz,3H),-0.00(s,9H).

[0153] (5) Preparation of compound 12:

[0154]

[0155] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromohexane to generate 1-bromo-4-hexyloxybenzene; 4-(hexyloxy)phenyllithium generated by 1-bromo-4-hexyloxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 12.

[0156] The 1H NMR spectrum data of compound 12 are as follows: 1H NMR (400MHz, Chloroform-d) δ7.28–7.25(m,2H),7.18–7.15(m,2H),4.79(s,1H),4.19(dd,J=6.5Hz,2H),4.21(dd,J=6.5Hz,1H),3.99( s,J=6.5Hz,1H),2.82(dd,J=11.5,4.5Hz,1H),1.71(t,J=3.7Hz,2H),1.31-1.21(t,J=3.7Hz,6H),1.01(t,J=3.7Hz,3H),-0.00(s,9H).

[0157] (6) Preparation of compound 13:

[0158]

[0159] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-heptane to generate 1-bromo-4-n-heptoxybenzene; 4-(n-heptoxy)phenyllithium generated by 1-bromo-4-n-heptoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 13.

[0160] The 1H NMR spectrum data of compound 13 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.24–7.22(m,2H),7.17–7.15(m,2H),4.62(s,1H),4.29(dd,J=6.5Hz,2H),4.11(dd,J=6.5Hz,1H),3.99(s,J=6.5 Hz,1H),2.42(dd,J=11.5,4.5Hz,1H),1.71(t,J=3.7Hz,2H),1.41(t,J=3.7Hz,2H),1.36(t,J=3.7Hz,6H),1.01(t,J=3.7Hz,3H),-0.00(s,9H).

[0161] (7) Preparation of compound 14:

[0162]

[0163] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-octane to generate 1-bromo-4-n-octyloxybenzene; 4-(n-octyloxy)phenyllithium generated by 1-bromo-4-n-octyloxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 14.

[0164] The 1H NMR spectrum of compound 14 is shown below.Figure 4 The specific 1H NMR data are shown below: 1 H NMR(400MHz,Chloroform-d)δ7.04(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),4.12(t,J=11.4Hz,1H),3.97(d,J=6.6Hz,2H),3.94(s,1H), 3.91(s,1H),2.41(dd,J=11.6,4.5Hz,1H),1.80(d,J=2.6Hz,2H),1.50–1.48(m,2H),1.35(d,J=4.3Hz,8H),0.90(s,3H),-0.00(s,9H).

[0165] (8) Preparation of compound 15:

[0166]

[0167] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-nonane to generate 1-bromo-4-n-nonoxybenzene; 4-(n-nonoxy)phenyllithium generated by 1-bromo-4-n-nonoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 15.

[0168] The 1H NMR spectrum data of compound 15 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.25–7.23(m,2H),7.11–7.09(m,2H),4.87(s,1 H),4.04(dd,J=6.5Hz,2H),3.95(d,J=6.5Hz,1H),3.62(d,J=6.5Hz,1H),2.82 (dd,J=11.5,4.5Hz,1H),1.74(dd,J=7.4,1.6Hz,2H),1.43(dd,J=7.4,1.6Hz, 2H), 1.34-1.28 (dd, J=7.4, 1.6Hz, 10H), 0.98 (t, J=3.7Hz, 3H), -0.00 (s, 9H).

[0169] (9) Preparation of compound 16:

[0170]

[0171] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-decane to generate 1-bromo-4-n-decoxybenzene; 4-(n-decoxy)phenyllithium generated by 1-bromo-4-n-decoxybenzene under the action of n-butyllithium immediately reacts with compound b under the action of cuprous iodide to synthesize compound 16.

[0172] The 1H NMR spectrum data of compound 16 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.22–7.20(m,2H),7.13–7.11(m,2H),4.77(s,1 H),4.14(dd,J=6.5Hz,2H),3.85(d,J=6.5Hz,1H),3.52(d,J=6.5Hz,1H),2.77 (dd,J=11.5,4.5Hz,1H),1.79(dd,J=7.4,1.6Hz,2H),1.63(dd,J=7.4,1.6Hz, 2H), 1.31-1.28 (dd, J=7.4, 1.6Hz, 12H), 0.98 (t, J=3.7Hz, 3H), -0.00 (s, 9H).

[0173] (10) Preparation of compound 17:

[0174]

[0175] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-dodecane to generate 1-bromo-4-n-dodecyloxybenzene; 4-(n-dodecyloxy)phenyllithium generated by 1-bromo-4-n-dodecyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 17.

[0176] The 1H NMR spectrum data of compound 17 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.27–7.25(m,2H),7.18–7.16(m,2H),4.74(s,1 H),4.07(dd,J=6.5Hz,2H),3.75(d,J=6.5Hz,1H),3.53(d,J=6.5Hz,1H),2.97 (dd,J=11.5,4.5Hz,1H),1.69(dd,J=7.4,1.6Hz,2H),1.53(dd,J=7.4,1.6Hz, 2H), 1.31-1.28 (dd, J=7.4, 1.6Hz, 16H), 0.88 (t, J=3.7Hz, 3H), -0.00 (s, 9H).

[0177] (11) Preparation of compound 18:

[0178]

[0179] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromotetradecane to generate 1-bromo-4-tetradecyloxybenzene; 4-(tetradecyloxy)phenyllithium generated by 1-bromo-4-tetradecyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 18.

[0180] The 1H NMR spectrum data of compound 18 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.26–7.24(m,2H),7.17–7.15(m,2H),4.78(s,1 H),4.09(dd,J=6.5Hz,2H),3.79(d,J=6.5Hz,1H),3.58(d,J=6.5Hz,1H),2.96 (dd,J=11.5,4.5Hz,1H),1.68(dd,J=7.4,1.6Hz,2H),1.63(dd,J=7.4,1.6Hz, 2H), 1.37-1.33 (dd, J=7.4, 1.6Hz, 20H), 0.86 (t, J=3.7Hz, 3H), -0.00 (s, 9H).

[0181] (12) Preparation of compound 19:

[0182]

[0183] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-hexadecane to generate 1-bromo-4-n-hexadecyloxybenzene; 4-(n-hexadecyloxy)phenyllithium generated by 1-bromo-4-n-hexadecyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 19.

[0184] The 1H NMR spectrum data of compound 19 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.25–7.24(m,2H),7.18–7.15(m,2H),4.88(s,1 H),4.19(dd,J=6.5Hz,2H),3.69(d,J=6.5Hz,1H),3.56(d,J=6.5Hz,1H),2.86 (dd,J=11.5,4.5Hz,1H),1.78(dd,J=7.4,1.6Hz,2H),1.63(dd,J=7.4,1.6Hz, 2H), 1.27-1.23 (dd, J=7.4, 1.6Hz, 24H), 0.87 (t, J=3.7Hz, 3H), -0.00 (s, 9H).

[0185] (13) Preparation of compound 20:

[0186]

[0187] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-octadecane to generate 1-bromo-4-n-octadecyloxybenzene; 4-(n-octadecyloxy)phenyllithium generated by 1-bromo-4-n-octadecyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 20.

[0188] The 1H NMR spectrum data of compound 20 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.15–7.14(m,2H),7.08–7.05(m,2H),4.68(s,1 H),4.29(dd,J=6.5Hz,2H),3.59(d,J=6.5Hz,1H),3.43(d,J=6.5Hz,1H),2.78 (dd,J=11.5,4.5Hz,1H),1.64(dd,J=7.4,1.6Hz,2H),1.51(dd,J=7.4,1.6Hz, 2H), 1.26-1.22 (dd, J=7.4, 1.6Hz, 28H), 0.97 (t, J=3.7Hz, 3H), -0.01 (s, 9H).

[0189] (14) Preparation of compound 21:

[0190]

[0191] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromoeicosane to generate 1-bromo-4-eicosyloxybenzene; 4-(eicosyloxy)phenyllithium generated by 1-bromo-4-eicosyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 21.

[0192] The 1H NMR spectrum data of compound 21 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.33–7.30(m,2H),7.10–7.06(m,2H),4.77(s,1H ),4.27(d,J=6.5Hz,2H),4.03(d,J=6.5Hz,1H),3.92(d,J=6.5Hz,1H),2.65(dd, J=11.5,4.5Hz,1H),1.95–1.94(m,J=7.4,1.6Hz,2H),1.56–1.54(m,J=7.4,1.6H z,2H),1.34-1.28(dd,J=7.4,1.6Hz,32H),1.11(t,J=3.7Hz,3H),-0.00(s,9H).

[0193] (15) Preparation of compound 22:

[0194]

[0195] The preparation method is the same as that of compound 10 in Example 4, except that bromobutane is replaced with 1-bromo-n-docosane to generate 1-bromo-4-n-docosoxybenzene; 4-(n-docosoxy)phenyllithium generated by 1-bromo-4-n-docosoxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 22.

[0196] The 1H NMR spectrum data of compound 22 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.36–7.34(m,2H),7.18–7.16(m,2H),4.87(s,1H ),4.37(d,J=6.5Hz,2H),4.13(d,J=6.5Hz,1H),3.82(d,J=6.5Hz,1H),2.63(dd, J=11.5,4.5Hz,1H),1.99–1.98(m,J=7.4,1.6Hz,2H),1.76–1.74(m,J=7.4,1.6H z,2H),1.34-1.28(dd,J=7.4,1.6Hz,36H),1.01(t,J=3.7Hz,3H),-0.00(s,9H).

[0197] (16) Preparation of compound 23:

[0198]

[0199] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with m-bromophenol and bromobutane is replaced with 1-bromo-n-octane to generate 1-bromo-4-n-octyloxybenzene; 4-(n-octyloxy)phenyllithium generated by 1-bromo-4-n-octyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 23.

[0200] The NMR data for compound 23 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J=8.6Hz,1H),6.87(d,J=8.6Hz,2H),6.78( d,J=8.6Hz,1H),4.67(t,J=11.4Hz,1H),4.12(t,J=11.4Hz,2H),3.97(d,J=6.6Hz, 1H),3.65(d,J=6.6Hz,1H),2.41(dd,J=11.6,4.5Hz,1H),1.80(d,J=2.6Hz,2H),1. 50–1.48(d,J=2.6Hz,2H),1.35-1.30(d,J=4.3Hz,8H),0.90(s,3H),-0.00(s,9H).

[0201] (17) Preparation of compound 24:

[0202]

[0203] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with m-bromophenol and bromobutane is replaced with 1-bromo-n-dodecane to generate 1-bromo-4-n-dodecyloxybenzene; 4-(n-dodecyloxy)phenyllithium generated by 1-bromo-4-n-dodecyloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 24.

[0204] The 1H NMR spectrum data of compound 24 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.26(d,J=8.6Hz,1H),6.87-6.86(d,J=8.6Hz,2H),6 .76(d,J=8.6Hz,1H),4.62(t,J=11.4Hz,1H),4.06(t,J=11.4Hz,2H),3.87(d,J=6. 6Hz,1H),3.55(d,J=6.6Hz,1H),2.51(dd,J=11.6,4.5Hz,1H),1.76(d,J=2.6Hz,2H ),1.48(d,J=2.6Hz,2H),1.35-1.30(d,J=4.3Hz,16H),0.90(s,3H),-0.00(s,9H).

[0205] (18) Preparation of compound 25:

[0206]

[0207] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with o-bromophenol to generate 1-bromo-4-n-butoxybenzene; 4-(n-butoxy)phenyllithium generated by 1-bromo-4-n-butoxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 25.

[0208] The 1H NMR spectrum data of compound 25 are as follows: NMR(400MHz,Chloroform-d)δ7.31–7.28(d,J=8.6Hz,1H),7.02–6.98(d,J=8.6Hz ,1H),6.87-6.85(d,J=8.6Hz,2H),4.67(s,1H),4.14(d,J=6.5Hz,2H),4.03(d,J= 6.5Hz,1H),3.67(d,J=6.5Hz,1H),2.58(dd,J=11.5,4.5Hz,1H),1.95(m,J=7.4,1 .6Hz, 2H), 1.70 (dd, J=7.4, 1.6Hz, 2H), 1.21 (m, J=7.4, 1.6Hz, 3H), -0.00 (s, 9H).

[0209] (19) Preparation of compound 26:

[0210]

[0211] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with 5-bromoresorcinol, bromobutane is replaced with 1-bromo-n-octane, and the amount of 1-bromo-n-octane is twice that of bromobutane, to generate 1-bromo-3,5-di(n-octyloxy)benzene; 3,5-di(n-octyloxy)phenyllithium generated by 1-bromo-3,5-di(n-octyloxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 26.

[0212] The 1H NMR data of compound 26 are as follows: 1H NMR (400MHz, Chloroform-d) δ 6.67 (m, 2H), 6.29 (d, J = 8.6Hz, 1H), 4.63 (s, 1H), 4.11 (d, J = 6.5Hz, 4H), 4.03 (d, J = 6.5Hz, 1H), 3.74 (d, J = 6.5Hz, 1H), 2.55 (dd, J = 11.5, 4.5Hz, 1H), 1.78 (m, J = 7.4, 1.6Hz, 4H), 1.38 (dd, J = 7.4, 1.6Hz, 4H), 1.35-1.32 (dd, J = 7.4, 1.6Hz, 16H), 1.10 (m, J = 7.4, 1.6Hz, 6H), -0.00 (s, 9H).

[0213] (20) Preparation of compound 27:

[0214]

[0215] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with 4-bromocatechol, bromobutane is replaced with 1-bromo-n-dodecane, and the amount of 1-bromo-n-dodecane is twice that of bromobutane, to generate 1-bromo-3,4-di(n-dodecyloxy)benzene; 3,4-di(n-dodecyloxy)phenyllithium generated by 1-bromo-3,4-di(n-dodecyloxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 27.

[0216] The 1H NMR data of compound 27 are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.25–7.23 (d, J = 8.6 Hz, 3H), 4.57 (s, 1H), 4.08 (d, J = 6.5 Hz, 4H), 4.01 (d, J = 6.5 Hz, 1H), 3.54 (d, J = 6.5 Hz, 1H), 2.58 (dd, J = 11.5, 4.5 Hz, 1H), 1.72 (dd, J = 7.4, 1.6 Hz, 4H), 1.48 (dd, J = 7.4, 1.6 Hz, 4H), 1.38–1.34 (t, J = 7.4, 1.6 Hz, 32H), 1.02 (dd, J = 7.4, 1.6 Hz, 6H), -0.00 (s, 9H).

[0217] (21) Preparation of compound 28:

[0218]

[0219] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with 4-bromoresorcinol, and the amount of bromobutane used is twice that in Example 4, to generate 1-bromo-2,4-di(n-butoxy)benzene; 2,4-di(n-butoxy)phenyllithium generated by 1-bromo-2,4-di(n-butoxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 28.

[0220] The 1H NMR data of compound 28 are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.28–7.25 (m, 1H), 7.06–7.02 (d, J = 8.6 Hz, 2H), 4.59 (s, 1H), 4.04–4.01 (t, J = 6.5 Hz, 4H), 3.78 (d, J = 6.5 Hz, 1H), 3.47 (d, J = 6.5 Hz, 1H), 2.51 (dd, J = 11.5, 4.5 Hz, 1H), 1.72 (m, J = 7.4, 1.6 Hz, 4H), 1.48 (m, J = 7.4, 1.6 Hz, 4H), 0.99 (dd, J = 7.4, 1.6 Hz, 6H), -0.00 (s, 9H).

[0221] (22) Preparation of compound 29:

[0222]

[0223] The preparation method is the same as that of compound 10 in Example 4, except that p-bromophenol is replaced with 5-bromo-1,2,3-benzenepyrogallol, and bromobutane is replaced with 1-bromo-n-octane. The amount of 1-bromo-n-octane is three times that of bromobutane, generating 1-bromo-3,4,5-tris(n-octyloxy)benzene. The 3,4,5-tris(n-octyloxy)phenyllithium generated by 1-bromo-3,4,5-tris(n-octyloxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 29.

[0224] The 1H NMR data of compound 29 are as follows: 1H NMR (400MHz, Chloroform-d) δ 7.25 (s, 2H), 4.59 (s, 1H), 4.14 (t, J = 6.5Hz, 6H), 3.98 (d, J = 6.5Hz, 1H), 3.47 (d, J = 6.5Hz, 1H), 2.51 (dd, J = 11.5, 4.5Hz, 1H), 1.72 (t, J = 7.4, 1.6Hz, 6H), 1.48 (t, J = 7.4, 1.6Hz, 6H), 1.20–1.16 (t, J = 7.4, 1.6Hz, 24H), 0.88 (dd, J = 7.4, 1.6Hz, 9H), -0.00 (s, 9H).

[0225] Example 6: Preparation of compound 43

[0226]

[0227] Synthesis of compound a-43: p-Bromophenol (12 mmol, 2.08 g), triisopropylchlorosilane (compound e-43, 30 mmol, 5.78 g), and imidazole (72 mmol, 4.92 g) were weighed and dissolved in DCM (40 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was washed with ethyl acetate and 5% K₂CO₃ solution, and finally dried over anhydrous MgSO₄ for 2-3 h. MgSO₄ was removed by vacuum filtration, and the solution was concentrated under reduced pressure to obtain a colorless oily liquid. Finally, the solution was purified by column chromatography (EA:PE = 1:6) to give compound a-43 in 95.1% yield.

[0228] The NMR data for compound a-43 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.31–7.28(m,2H),6.81–6.77(m,2H),1.25(dd,J=7.4,1.6Hz,3H),0.86(s,18H).

[0229] Synthesis of compound 43:

[0230] Anhydrous methyl ether (15 mL) was added to compound a-43 above, and n-butyllithium (12 mmol, 4.8 mL) was added dropwise at -40 °C. The reaction was stirred at -40 °C for 30 min, and then heated to 10 °C and stirred for 1.5 h to obtain a reaction solution containing 4-(triisopropylsilyl)oxyphenyllithium intermediate, which was stored at 10 °C for later use.

[0231] Cuprous iodide (6 mmol, 1.2 g) was weighed and placed in a 100 mL three-necked flask. The flask was vented and protected with nitrogen to ensure an anhydrous and oxygen-free environment. At 0 °C, anhydrous tert-methyl ether (4 mL) was added using a syringe, followed by the reaction solution containing the previously generated 4-(triisopropylsilyl)oxyphenyl lithium intermediate. The reaction was stirred at 0 °C for 1 h. The temperature was lowered to -40 °C, and compound b (3 mmol, 0.4 mL) was added to the three-necked flask. The reaction was stirred at -40 °C for 5 h, then the temperature was raised to -20 °C, and the reaction was stirred overnight. After the reaction was complete, the reaction was quenched with saturated NH4Cl, followed by washing with ethyl acetate and saturated NH4Cl solution. Finally, the mixture was dried over anhydrous MgSO4 for 2-3 h, and MgSO4 was removed by vacuum filtration. The solution was concentrated under reduced pressure to obtain a colorless oily liquid, which was then purified by column chromatography (EA:PE = 1:10) to give compound 43 in 82.3% yield.

[0232] The NMR data for compound 43 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.25–7.22(m,2H),6.85–6.81(m,2H),4.63(s,1H),4.15(t,J=11.4Hz,1H),3. 87(d,J=6.5Hz,1H),2.49(dd,J=11.5,4.5Hz,1H),1.41(dd,J=7.4,1.6Hz,3H),0.83(s,18H),-0.00(s,9H).

[0233] Example 7:

[0234] (1) Preparation of compound 30:

[0235]

[0236] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with trimethylchlorosilane to generate 1-bromo-4-trimethylsiloxybenzene; the 4-trimethylsiloxyphenyl lithium intermediate generated by 1-bromo-4-trimethylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 30.

[0237] The 1H NMR spectrum data of compound 30 are as follows:1 H NMR(400MHz,Chloroform-d)δ7.24–7.22(m,2H),7.02–6.97(m,2H),4.79(t,J=11.4Hz,1H) ,4.12(d,J=6.5Hz,1H),3.82(d,J=6.5Hz,1H),2.83(dd,J=11.5,4.5Hz,1H),-0.00(s,18H).

[0238] (2) Preparation of compound 31:

[0239]

[0240] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl tert-butylchlorosilane to generate 1-bromo-4-dimethyltert-butylsiloxybenzene; the 4-dimethyltert-butylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyltert-butylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 31.

[0241] The 1H NMR spectrum data of compound 31 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.21–7.18(m,2H),7.12–7.09(m,2H),4.89(t,J=11.4Hz,1H),4.08( d,J=6.5Hz,1H),3.62(d,J=6.5Hz,1H),2.63(dd,J=11.5,4.5Hz,1H),0.83(s,9H),-0.00(s,15H).

[0242] (3) Preparation of compound 32:

[0243]

[0244] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl-n-butylchlorosilane to generate 1-bromo-4-dimethyl-n-butylsiloxybenzene; the 4-dimethyl-n-butylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl-n-butylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 32.

[0245] The 1H NMR spectrum data of compound 32 are as follows: 1H NMR (400MHz, Chloroform-d) δ7.24–7.22(m,2H),7.16–7.13(m,2H),4.79(t,J=11.4Hz,1H),4.03(d,J=6.5Hz,1H),3.72(d,J=6.5Hz,1H) ,2.73(dd,J=11.5,4.5Hz,1H),1.73-1.67(t,J=11.5,4.5Hz,4H),0.83(dd,J=7.4,1.6Hz,3H),0.61(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0246] (4) Preparation of compound 33:

[0247]

[0248] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl n-hexylchlorosilane to generate 1-bromo-4-dimethyln-hexylsiloxybenzene; the 4-dimethyln-hexylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyln-hexylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 33.

[0249] The 1H NMR spectrum data of compound 33 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.22–7.20(m,2H),7.13–7.10(m,2H),4.59(t,J=11.4Hz,1H),4.01(d,J=6.5Hz,1H),3.62(d,J=6.5Hz,1H) ,2.63(dd,J=11.5,4.5Hz,1H),1.78-1.74(t,J=11.5,4.5Hz,8H),0.93(dd,J=7.4,1.6Hz,3H),0.81(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0250] (5) Preparation of compound 34:

[0251]

[0252] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl-n-octylchlorosilane to generate 1-bromo-4-dimethyl-n-octylsiloxybenzene; the 4-dimethyl-n-octylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl-n-octylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 34.

[0253] The 1H NMR spectrum data of compound 34 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.32–7.30(m,2H),7.25–7.22(m,2H),4.49(t,J=11.4Hz,1H),4.21(d,J=6.5Hz,1H),3.87(d,J=6.5Hz,1H), 2.59(dd,J=11.5,4.5Hz,1H),1.81-1.76(t,J=11.5,4.5Hz,12H),0.97(dd,J=7.4,1.6Hz,3H),0.61(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0254] (6) Preparation of compound 35:

[0255]

[0256] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl-n-decylchlorosilane to generate 1-bromo-4-dimethyl-n-decylsiloxybenzene; the 4-dimethyl-n-decylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl-n-decylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 35.

[0257] The 1H NMR spectrum data of compound 35 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.22–7.20(m,2H),7.05–7.02(m,2H),4.43(t,J=11.4Hz,1H),4.11(d,J=6.5Hz,1H),3.67(d,J=6.5Hz,1H), 2.53(dd,J=11.5,4.5Hz,1H),1.93-1.91(t,J=11.5,4.5Hz,16H),0.96(dd,J=7.4,1.6Hz,3H),0.81(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0258] (7) Preparation of compound 36:

[0259]

[0260] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl n-dodecylchlorosilane to generate 1-bromo-4-dimethyl n-dodecylsiloxybenzene; the 4-dimethyl n-dodecylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl n-dodecylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 36.

[0261] The 1H NMR spectrum data of compound 36 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.25–7.23(m,2H),7.06–7.04(m,2H),4.53(t,J=11.4Hz,1H),4.21(d,J=6.5Hz,1H),3.87(d,J=6.5Hz,1H), 2.73(dd,J=11.5,4.5Hz,1H),1.83-1.80(t,J=11.5,4.5Hz,20H),0.99(dd,J=7.4,1.6Hz,3H),0.83(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0262] (8) Preparation of compound 37:

[0263]

[0264] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl n-tetradecylchlorosilane to generate 1-bromo-4-dimethyl n-tetradecylsiloxybenzene; the 4-dimethyl n-tetradecylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl n-tetradecylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 37.

[0265] The 1H NMR spectrum data of compound 37 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.28–7.26(m,2H),7.16–7.14(m,2H),4.33(t,J=11.4Hz,1H),4.01(d,J=6.5Hz,1H),3.87(d,J=6.5Hz,1H), 2.65(dd,J=11.5,4.5Hz,1H),1.67-1.62(t,J=11.5,4.5Hz,24H),0.92(dd,J=7.4,1.6Hz,3H),0.83(m,J=7.4,1.6Hz,2H),-0.01(s,15H).

[0266] (9) Preparation of compound 38:

[0267]

[0268] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl n-hexadecylchlorosilane to generate 1-bromo-4-dimethyl n-hexadecylsiloxybenzene; the 4-dimethyl n-hexadecylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl n-hexadecylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 38.

[0269] The 1H NMR spectrum data of compound 38 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.23–7.20(m,2H),7.15–7.14(m,2H),4.43(t,J=11.4Hz,1H),4.07(d,J=6.5Hz,1H),3.77(d,J=6.5Hz,1H), 2.53(dd,J=11.5,4.5Hz,1H),1.87-1.83(t,J=11.5,4.5Hz,28H),0.84(dd,J=7.4,1.6Hz,3H),0.76(m,J=7.4,1.6Hz,2H),-0.01(s,15H).

[0270] (10) Preparation of compound 39:

[0271]

[0272] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyl-n-octadecylchlorosilane to generate 1-bromo-4-dimethyl-n-octadecylsiloxybenzene; the 4-dimethyl-n-octadecylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyl-n-octadecylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 39.

[0273] The 1H NMR spectrum data of compound 39 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.24–7.23(m,2H),7.18–7.16(m,2H),4.67(t,J=11.4Hz,1H),4.32(d,J=6.5Hz,1H),3.98(d,J=6.5Hz,1H), 2.78(dd,J=11.5,4.5Hz,1H),1.76-1.72(t,J=11.5,4.5Hz,32H),0.94(dd,J=7.4,1.6Hz,3H),0.66(m,J=7.4,1.6Hz,2H),-0.01(s,15H).

[0274] (11) Preparation of compound 40:

[0275]

[0276] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with dimethyleicosylchlorosilane to generate 1-bromo-4-dimethyleicosylsiloxybenzene; the 4-dimethyleicosylsiloxyphenyl lithium intermediate generated by 1-bromo-4-dimethyleicosylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 40.

[0277] The 1H NMR spectrum data of compound 40 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.26–7.25(m,2H),7.19–7.18(m,2H),4.62(t,J=11.4Hz,1H),4.22(d,J=6.5Hz,1H),3.91(d,J=6.5Hz,1H), 2.58(dd,J=11.5,4.5Hz,1H),1.66-1.62(t,J=11.5,4.5Hz,36H),0.84(dd,J=7.4,1.6Hz,3H),0.64(m,J=7.4,1.6Hz,2H),-0.00(s,15H).

[0278] (12) Preparation of compound 41:

[0279]

[0280] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with triethylchlorosilane to generate 1-bromo-4-triethylsiloxybenzene; the 4-triethylsiloxylithium intermediate generated by 1-bromo-4-triethylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 41.

[0281] The 1H NMR spectrum data of compound 41 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.13(m,2H),7.03(m,2H),4.59(t,J=11.4Hz,1H),4.15(d,J=6.5Hz,1H),3.62(d,J=6 .5Hz,1H),2.58(dd,J=11.5,4.5Hz,1H),1.01(dd,J=11.5,4.5Hz,9H),0.67(dd,J=11.5,4.5Hz,6H),-0.00(s,9H).

[0282] (13) Preparation of compound 42:

[0283]

[0284] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with tri-n-propylchlorosilane to generate 1-bromo-4-tri-n-propylsiloxybenzene; the 4-tri-n-propylsiloxylithium intermediate generated by 1-bromo-4-tri-n-propylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 42.

[0285] The 1H NMR spectrum data of compound 42 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.25–7.23(m,2H),7.12–7.07(m,2H),4.69(t,J=11.4Hz,1H),4.05(d,J=6.5Hz,1H),3.72(d,J=6.5Hz,1H ), 2.68(dd,J=11.5,4.5Hz,1H), 1.83(dd,J=11.5,4.5Hz,6H), 1.33(dd,J=11.5,4.5Hz,9H), 1.01(dd,J=11.5,4.5Hz,6H), -0.00(s,9H).

[0286] (14) Preparation of compound 44:

[0287]

[0288] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with tritert-butylchlorosilane to generate 1-bromo-4-(tritert-butyl)siloxybenzene; the 4-(tritert-butyl)siloxylithium intermediate generated by 1-bromo-4-(tritert-butyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 44.

[0289] The 1H NMR spectrum data of compound 44 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.29–7.26(m,2H),7.16–7.13(m,2H),4.72(t,J=11.4Hz,1H),4.11( d,J=6.5Hz,1H),3.92(d,J=6.5Hz,1H),2.77(dd,J=11.5,4.5Hz,1H),1.01(s,27H),-0.00(s,9H).

[0290] (15) Preparation of compound 45:

[0291]

[0292] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with di-tert-butylphenylchlorosilane to generate 1-bromo-4-(di-tert-butylphenyl)siloxybenzene; the 4-(di-tert-butylphenyl)siloxybenzene intermediate generated by 1-bromo-4-(di-tert-butylphenyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 45.

[0293] The 1H NMR spectrum data of compound 45 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.29–7.27(t,3H),7.24–7.22(t,2H),δ7.17–7.14(m,2H),6.99–6.96(m,2H),4.71(t,J =11.4Hz,1H),4.01(d,J=6.5Hz,1H),3.82(d,J=6.5Hz,1H),2.73(dd,J=11.5,4.5Hz,1H),1.04(s,18H),-0.00(s,9H).

[0294] (16) Preparation of compound 46:

[0295]

[0296] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with methyldiphenylchlorosilane to generate 1-bromo-4-(methyldiphenyl)siloxybenzene; the 4-(methyldiphenyl)siloxyphenyl lithium intermediate generated by 1-bromo-4-(methyldiphenyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 46.

[0297] The 1H NMR spectrum data of compound 46 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.59–7.55(m,4H),7.37(t,6H),6.96–6.95(m,2H),6.81–6.79(m,2H),4.59(s, 1H), 4.44 (t, J = 11.4Hz, 1H), 4.22 (d, J = 6.5Hz, 1H), 2.63 (dd, J = 11.5, 4.5Hz, 1H), 0.98 (s, 3H), -0.00 (s, 9H).

[0298] (17) Preparation of compound 47:

[0299]

[0300] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with tert-butyldiphenylchlorosilane to generate 1-bromo-4-(tert-butyldiphenyl)siloxybenzene; the 4-(tert-butyldiphenyl)siloxybenzene intermediate generated by 1-bromo-4-(tert-butyldiphenyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 47.

[0301] The 1H NMR spectrum data of compound 47 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.69–7.65(m,4H),7.57–7.50(m,6H),6.97–6.96(m,2H),6.89–6.86(m,2H),4.67 (s,1H),4.34(t,J=11.4Hz,1H),4.21(d,J=6.5Hz,1H),2.83(dd,J=11.5,4.5Hz,1H),0.98(s,9H),-0.00(s,9H).

[0302] (18) Preparation of compound 48:

[0303]

[0304] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with triphenylchlorosilane to generate 1-bromo-4-triphenylsiloxybenzene; the 4-triphenylsiloxyphenyl lithium intermediate generated by 1-bromo-4-triphenylsiloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 48.

[0305] The 1H NMR spectrum data of compound 48 are as follows: 1H NMR(400MHz,Chloroform-d)δ7.54–7.52(t,6H),7.48–7.46(t,9H),δ7.18–7.16(m,2H),7.05–7.02(m,2H),4. 78(t,J=11.4Hz,1H),4.11(d,J=6.5Hz,1H),3.75(d,J=6.5Hz,1H),2.64(dd,J=11.5,4.5Hz,1H),-0.00(s,9H).

[0306] (19) Preparation of compound 49:

[0307]

[0308] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with n-butyldiphenylchlorosilane to generate 1-bromo-4-(n-butyldiphenyl)siloxybenzene; the 4-(n-butyldiphenyl)siloxybenzene intermediate generated by 1-bromo-4-(n-butyldiphenyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 49.

[0309] The 1H NMR spectrum data of compound 49 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.59–7.58(t,4H),7.46–7.45(t,6H),δ7.08–7. 06(m,2H),7.01–6.98(m,2H),4.68(t,J=11.4Hz,1H),4.21(d,J=6.5Hz,1H),3. 65(d,J=6.5Hz,1H),2.54(dd,J=11.5,4.5Hz,1H),1.58(dd,J=7.4,1.6Hz,2H) ,1.26-1.23(dd,J=7.4,1.6Hz,4H),0.88(dd,J=7.4,1.6Hz,3H),-0.00(s,9H).

[0310] (20) Preparation of compound 50:

[0311]

[0312] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with n-octyldiisopropylchlorosilane to generate 1-bromo-4-(n-octyldiisopropyl)siloxybenzene; the 4-(n-octyldiisopropyl)siloxybenzene intermediate generated by 1-bromo-4-(n-octyldiisopropyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 50.

[0313] The 1H NMR spectrum data of compound 50 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.23–7.20(m,2H),6.87–6.85(m,2H),4.66(s,1H),4.05(t,J=11.4Hz,1H),3.82(d, J=6.5Hz,1H),2.41(dd,J=11.5,4.5Hz,1H),1.58(dd,J=7.4,1.6Hz,2H),1.26-1.23(dd,J=7.4,1.6Hz,12H),1.02 -0.99(dd,J=7.4,1.6Hz,12H),0.88(dd,J=7.4,1.6Hz,3H),0.64(dd,J=7.4,1.6Hz,2H),-0.00(s,9H).

[0314] (21) Preparation of compound 51:

[0315]

[0316] The preparation method is the same as that of compound 43 in Example 6, except that triisopropylchlorosilane is replaced with n-octadecyldiisopropylchlorosilane to generate 1-bromo-4-(n-octadecyldiisopropyl)siloxybenzene; the 4-(n-octadecyldiisopropyl)siloxyphenyl lithium intermediate generated by 1-bromo-4-(n-octadecyldiisopropyl)siloxybenzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 51.

[0317] The 1H NMR spectrum data of compound 51 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.13–7.10(m,2H),6.89–6.87(m,2H),4.76(s,1H) ,4.15(t,J=11.4Hz,1H),3.72(d,J=6.5Hz,1H),2.51(dd,J=11.5,4.5Hz,1H),1.4 5(dd,J=7.4,1.6Hz,2H),1.29-1.26(dd,J=7.4,1.6Hz,32H),0.98(dd,J=7.4,1.6 Hz, 12H), 0.74 (dd, J=7.4, 1.6Hz, 3H), 0.64 (dd, J=7.4, 1.6Hz, 2H), -0.00 (s, 9H).

[0318] (22) Preparation of compound 52:

[0319]

[0320] The preparation method is the same as that of compound 43 in Example 6, except that p-bromophenol is replaced with 5-bromoresorcinol, and triisopropylchlorosilane is replaced with trimethylchlorosilane. The amount of trimethylchlorosilane used is twice that of triisopropylchlorosilane. Trimethylchlorosilane reacts with 5-bromoresorcinol to generate 1-bromo-3,5-di(trimethylsiloxy)benzene. The 3,5-di(trimethylsiloxy)phenyl lithium intermediate generated by 1-bromo-3,5-di(trimethylsiloxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 52.

[0321] The 1H NMR spectrum data of compound 52 are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.20-7.16(m,2H),6.87–6.85(t,1H),4.66(s,1H),4.05 (t,J=11.4Hz,1H),3.82(d,J=6.5Hz,1H),2.41(dd,J=11.5,4.5Hz,1H),-0.00(s,27H).

[0322] (23) Preparation of compound 53:

[0323]

[0324] The preparation method is the same as that of compound 43 in Example 6, except that p-bromophenol is replaced with 5-bromo-1,2,3-phenylpyrogallol, and triisopropylchlorosilane is replaced with trimethylchlorosilane. The amount of trimethylchlorosilane used is 3 times that of triisopropylchlorosilane. Trimethylchlorosilane reacts with 5-bromo-1,2,3-phenylpyrogallol to generate 1-bromo-3,4,5-tris(trimethylsiloxy)benzene. The 3,4,5-tris(trimethylsiloxy)phenyl lithium intermediate generated by 1-bromo-3,4,5-tris(trimethylsiloxy)benzene under the action of n-butyllithium is immediately reacted with compound b under the action of cuprous iodide to synthesize compound 53.

[0325] The 1H NMR spectrum data of compound 53 are as follows: 1 H NMR (400MHz, Chloroform-d) δ7.20-7.16(m,2H),4.64(s,1H),4.15(t,J=11.4Hz,1H),3.72(d,J=6.5Hz,1H),2.31(dd,J=11.5,4.5Hz,1H),-0.00(s,36H).

[0326] Example 8: Homogeneous synthesis of palmitoyl pentapeptide using compound 2 as a carrier

[0327] The amino acid sequence of palmitoyl pentapeptide is: Pal-Lys-Thr-Thr-Lys-Ser-OH

[0328] (1) Synthesis of Cbz-Ser(tBu)-Tag2

[0329] Compound 2 (2 mmol, 0.61 g, Mw = 306.6 g / mol) (prepared in Example 3), Cbz-Ser(tBu)-OH (4 mmol, 1.18 g, Mw = 295.3 g / mol), DMAP (0.12 mmol, 0.015 g, Mw = 122.2 g / mol), and HOBt (4 mmol, 0.54 g, Mw = 135.1 g / mol) were weighed and added to 20 mL of ethyl acetate. The reaction was carried out at rt~40 °C for 1 h. After the reaction was completed, a Cbz-Ser(tBu)-Tag2 reaction solution with amino acid linked to compound 2 was obtained. The reaction solution was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The solvent was evaporated and purified by silica gel column chromatography (PE:EA = 10:1) to obtain 1.11 g of Cbz-Ser(tBu)-Tag2, with a yield of 95% (based on compound 2).

[0330] (2) De-Cbz protection

[0331] The Cbz-Ser(tBu)-Tag2 (1.9 mmol, 1.11 g, Mw = 583.9 g / mol) obtained in step (1) was dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1) with 5 wt% Pd / C (the palladium content in palladium on carbon is 0.05 equivalent of the support compound 2). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask, 1 standard atmosphere). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, and 40 mL of ethyl acetate was added to obtain a reaction solution containing NH2-Ser(tBu)-Tag2 (this step does not require washing and can be directly carried out in the next coupling reaction).

[0332] (3) Coupling of Cbz-Lys(Boc)-OH

[0333] Add Cbz-Lys(Boc)-OH (1.2 equivalents of carrier compound 2), EDC·HCl (1.2 equivalents of carrier compound 2), and HOBt (1.2 equivalents of carrier compound 2) to the reaction solution containing NH2-Ser(tBu)-Tag2 obtained in step (2), and maintain the temperature at rt~40℃ for 1 h. After the reaction is completed, wash the reaction solution three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents, and take the upper organic phase solution to obtain the washing solution containing Cbz-Lys(Boc)-Ser(tBu)-Tag2.

[0334] (4) De-Cbz protection

[0335] The washing solution containing Cbz-Lys(Boc)-Ser(tBu)-Tag2 obtained in step (3) was mixed with 5wt% Pd / C (the amount of palladium was 0.05 equivalents of the carrier compound 2) and dissolved in 20mL of ethyl acetate / methanol solvent (volume ratio 1:1). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask, 1 standard atmosphere). The reaction was stirred for 30min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40mL of ethyl acetate was added, and the mixture was washed three times with 40mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was taken to obtain the washing solution containing NH2-Lys(Boc)-Ser(tBu)-Tag2.

[0336] (5) Following the steps (3) and (4) above, amino acids Cbz-Thr(tBu)-OH·DCHA, Cbz-Thr(tBu)-OH·DCHA, and Cbz-Lys(Boc)-OH were sequentially added, and the Cbz protecting group was removed. The Cbz protecting group removal reaction was carried out for 30 min. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40 mL of ethyl acetate was added, and the mixture was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was taken to obtain a washing solution containing NH2-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-Tag2.

[0337] (6) Coupling palmitic acid

[0338] Palmitic acid (1.2 equivalents of carrier compound 2), EDC·HCl (1.2 equivalents of carrier compound 2), and HOBt (1.2 equivalents of carrier compound 2) were added to the washing solution containing NH2-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-Tag2 obtained in step (5), and the reaction was carried out at rt~40℃ for 1h. After the reaction was completed, the reaction solution was washed three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was taken to obtain a washing solution containing Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-Tag2. The solvent was removed by rotary evaporation to obtain the solid Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-Tag2.

[0339] (7) Pyrolysis

[0340] The washing solution containing Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-Tag2 obtained in step (6) was dissolved in 25 mL of DCM. TBAF·3H2O (tetrabutylammonium fluoride trihydrate, the amount of which was 3 equivalents of carrier compound 2) was weighed out and stirred at room temperature for 10 min. Tag2 was completely removed. The solution was washed three times with saturated NaCl solution to remove the solvent and obtain a washing solution containing Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-OH. The solvent was removed by rotary evaporation to obtain crude oily liquid Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-OH.

[0341] The crude Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-OH was dissolved in 10-15 times its volume of cutting fluid: TFA:DODT:TIS:pure water (V TFA :V DODT :V TIS :V 纯水 =92.5:2.5:2.5:2.5) and crude oily liquid Pal-Lys(Boc)-Thr(tBu)-Thr(tBu)-Lys(Boc)-Ser(tBu)-OH were mixed and cut in a shaker at rt~60℃ for 1.5h. After cutting, 10~15 times the volume of settling liquid (V) of cutting fluid was added. 甲基叔丁基醚 V正己烷 =1:1) Centrifuge at 3000 r / min in a centrifuge and repeat three times. Each time, discard the liquid and keep the solid at the bottom. Centrifuge for three minutes after each addition of sediment to obtain naked peptide Pal-Lys-Thr-Thr-Lys-Ser-OH. Repeat the experiment multiple times. The product yield is 91% to 95% (based on compound 2) and the HPLC purity is 92% to 96%.

[0342] The mass spectrum of Pal-Lys-Thr-Thr-Lys-Ser-OH is as follows: Figure 5 As shown, HRMS calcd for C 39 H 76 N7O 10 [M+H] + : 802.5649, found 802.5596.

[0343] Example 9: Homogeneous synthesis of cell adhesion peptides using compound 14 as a carrier

[0344] The cell adhesion peptide sequence is: H-Gly-Arg-Gly-Asp-Ser-Pro-Cys-OH

[0345] (1) Synthesis of Fmoc-Cys(Trt)-Tag14

[0346] Compound 14 (2 mmol, 0.65 g, Mw = 322.5 g / mol) (prepared in Example 5), Fmoc-Cys(Trt)-OH (2.4 mmol, 1.41 g, Mw = 585.7 g / mol), DMAP (0.12 mmol, 0.015 g, Mw = 122.2 g / mol), and HOBt (2.4 mmol, 0.33 g, Mw = 135.1 g / mol) were weighed and added to 20 mL of ethyl acetate. The reaction was carried out at rt~40 °C for 1 h. After the reaction was completed, Fmoc-Cys(Trt)-Tag14 reaction solution with amino acid linked to compound 14 was obtained. The reaction solution was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The solvent was evaporated and purified by silica gel column chromatography (PE:EA = 10:1) to obtain 1.69 g of Fmoc-Cys(Trt)-Tag14, with a yield of 95% (based on compound 14).

[0347] (2) De-Fmoc protection

[0348] The Fmoc-Cys(Trt)-Tag14 (1.9 mmol, 1.69 g, Mw = 890.3 g / mol) obtained in step (1) and pyrrolidine (16 mmol, 1.14 g, Mw = 71.121 g / mol) were dissolved in 40 mL of ethyl acetate. The reaction was stirred at rt~40℃ for 1 h to remove protection. After the reaction was completed, the mixture was extracted and washed three times with an equal volume of 40 mL of 5% hydrochloric acid aqueous solution. Then, the reaction solution was washed three times with 40 mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain a washing solution containing NH2-Cys(Trt)-Tag14.

[0349] (3) Coupling of Fmoc-Pro-OH

[0350] Add Fmoc-Pro-OH (1.2 equivalents of carrier compound 14), EDC·HCl (1.2 equivalents of carrier compound 14), and HOBt (1.2 equivalents of carrier compound 14) to the washing solution containing NH2-Cys(Trt)-Tag14 obtained in step (2), and maintain the temperature at rt~40℃ for 1 h. After the reaction is complete, extract the washing reaction solution three times with 40 mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents, and take the upper organic phase to obtain the washing solution containing Fmoc-Pro-Cys(Trt)-Tag14.

[0351] (4) Fmoc deprotection

[0352] Add pyrrolidine (the amount of pyrrolidine is 8 to 10 equivalents of the carrier compound 14) and 40 mL of ethyl acetate to the washing solution containing Fmoc-Pro-Cys(Trt)-Tag14 obtained in step (3). Stir the reaction at rt~40℃ for 1 h. After the reaction is completed, use 40 mL of 5% hydrochloric acid aqueous solution to extract and wash three times, and then use 40 mL of 5wt% K2CO3 washing solution three times to remove excess amino acids and coupling reagents. Take the upper organic phase solution to obtain the washing solution containing NH2-Pro-Cys(Trt)-Tag14.

[0353] (5) Following the steps (3) and (4) above, Fmoc-Ser(tBu)-OH, Fmoc-Asp(OtBu)-OH, and Fmoc-Gly-OH were sequentially added and Fmoc was removed. After the removal reaction was completed, the solution was extracted and washed three times with 40 mL of 5% hydrochloric acid aqueous solution, and then washed three times with 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain a washing solution containing NH2-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14.

[0354] (6) Coupling of Fmoc-Arg(Pbf)-OH

[0355] Weigh out Fmoc-Arg(Pbf)-OH·CHA (1.2 equivalents of carrier compound 14) and dissolve it in 20 mL of ethyl acetate. Wash it twice with 3 wt% hydrochloric acid aqueous solution (20 mL × 2). Then add it to the washing solution containing NH2-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14 obtained in step (5). Add EDC·HCl (1.2 equivalents of carrier compound 14) and HOBt (1.2 equivalents of carrier compound 14). Keep the temperature at rt~40℃ and react for 1 h. After the reaction was completed, the reaction solution was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain a washing solution containing Fmoc-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14.

[0356] (7) Remove the Fmoc protecting group according to the method in step (4) above, then inoculate Fmoc-Gly-OH according to the methods in steps (3) and (4) and remove Fmoc. After the removal of the protecting group, use 40 mL of 5% hydrochloric acid aqueous solution to extract and wash three times, and then use 5wt% K2CO3 to wash the reaction solution three times to remove excess amino acids and coupling reagents. Take the upper organic phase solution to obtain the washing solution of NH2-Gly-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14. Vacuum evaporate the solvent, and separate and purify by column chromatography (DCM:MeOH=20:1) to obtain NH2-Gly-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14 with an HPLC purity of over 99%.

[0357] (8) Pyrolysis

[0358] Dissolve the NH2-Gly-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-Tag14 obtained in step (7) in 25 mL of DCM, weigh TBAF·3H2O (the amount used is 3 equivalents of the carrier compound 14), stir the reaction at room temperature for 10 min, completely remove Tag14, wash three times with saturated NaCl solution to remove the solvent and obtain oily NH2-Gly-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-OH.

[0359] Dissolve the oily liquid NH2-Gly-Arg(Pbf)-Gly-Asp(OtBu)-Ser(tBu)-Pro-Cys(Trt)-OH in 10-15 times its volume of cutting fluid TFA: DODT: TIS: pure water (V TFA :V DODT :V TIS :V 纯水 = 92.5:2.5:2.5:2.5), and cut at rt~60℃ for 1.5h in a shaker. After cutting, add 10~15 times the volume of settling liquid (V) of cutting fluid. 甲基叔丁基醚 V 正己烷 The mixture was centrifuged at 3000 rpm for 1:1 ratio to allow sedimentation. This process was repeated three times, discarding the liquid each time and retaining the solid at the bottom. Centrifugation for three minutes was required after each addition of sediment to obtain naked peptide (NH2-Gly-Arg-Gly-Asp-Ser-Pro-Cys-OH) with a yield of 92%–96% (based on compound 14) and an HPLC purity of 91%–95%.

[0360] The mass spectra of NH2-Gly-Arg-Gly-Asp-Ser-Pro-Cys-OH are as follows: Figure 6 As shown, HRMS calcd for C 25 H 43 N 10 O 11 S[M+H] + : 691.2828, found 691.2823.

[0361] Example 10: Homogeneous synthesis of palmitoyl hexapeptide from compound 43

[0362] The sequence of palmitoyl hexapeptide is Pal-Val-Gly-Val-Ala-Pro-Gly-OH

[0363] (1) Synthesis of Cbz-Gly-Tag43

[0364] Compound 43 (2 mmol, 0.73 g, Mw = 366.7 g / mol) (prepared in Example 6), Cbz-Gly-OH (4 mmol, 0.84 g, Mw = 209.2 g / mol), DMAP (0.12 mmol, 0.015 g, Mw = 122.2 g / mol), and HOBt (4 mmol, 0.54 g, Mw = 135.1 g / mol) were weighed and added to 20 mL of ethyl acetate. The reaction was carried out at rt–40 °C for 1 h. After the reaction was completed, a Cbz-Gly-Tag43 reaction solution with amino acid linked to compound 43 was obtained. The reaction solution was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The solvent was evaporated, and the solution was purified by silica gel column chromatography (PE:EA = 10:1) to obtain 1.06 g of Cbz-Gly-Tag43, with a yield of 95% (based on compound 43).

[0365] (2) De-Cbz protection

[0366] The Cbz-Gly-Tag43 (1.9 mmol, 1.06 g, Mw = 557.9 g / mol) obtained in step (1) was dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1) with 5 wt% Pd / C (the palladium content on carbon is 0.05 equivalent of the support compound 43). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask, 1 standard atmosphere). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, and 40 mL of ethyl acetate was added to obtain a reaction solution containing NH2-Gly-Tag43 (this step does not require washing and can be directly carried out in the next coupling reaction).

[0367] (3) Coupling of Cbz-Pro-OH

[0368] Add Cbz-Pro-OH (1.2 equivalents of carrier compound 43), EDC·HCl (1.2 equivalents of carrier compound 43), and HOBt (1.2 equivalents of carrier compound 43) to the reaction solution containing NH2-Gly-Tag43 obtained in step (2), and maintain the temperature at rt~40℃ for 1 h. After the reaction is complete, wash the reaction solution three times with 40 mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents, and take the upper organic phase solution to obtain the washing solution containing Cbz-Pro-Gly-Tag43.

[0369] (4) De-Cbz protection

[0370] The washing solution containing Cbz-Pro-Gly-Tag43 obtained in step (3) was mixed with 5wt% Pd / C (the amount of palladium was 0.05 equivalents of the carrier compound 43) and dissolved in 20mL of ethyl acetate / methanol solvent (volume ratio 1:1). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask, 1 standard atmosphere). The reaction was stirred for 30min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40mL of ethyl acetate was added, and the mixture was washed three times with 40mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain the washing solution containing NH2-Pro-Gly-Tag43.

[0371] (5) Following the steps (3) and (4) above, Cbz-Ala-OH, Cbz-Val-OH, Cbz-Gly-OH, and Cbz-Val-OH were added sequentially, and the Cbz protecting group was removed. After the removal reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40 mL of ethyl acetate was added, and the mixture was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain a reaction solution containing NH2-Val-Gly-Val-Ala-Pro-Gly-Tag43.

[0372] (6) Coupling palmitic acid

[0373] Palmitic acid (1.2 equivalents of carrier compound 43), EDC·HCl (1.2 equivalents of carrier compound 43), and HOBt (1.2 equivalents of carrier compound 43) were added to the reaction solution containing NH2-Val-Gly-Val-Ala-Pro-Gly-Tag43 obtained in step (5). The reaction was carried out at rt~40℃ for 1 h. After the reaction was completed, the reaction solution was washed three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was taken to obtain a washing solution containing Pal-Val-Gly-Val-Ala-Pro-Gly-Tag43. The solution was evaporated to dryness and the solvent was removed to obtain solid Pal-Val-Gly-Val-Ala-Pro-Gly-Tag43.

[0374] (7) Pyrolysis

[0375] The solid Pal-Val-Gly-Val-Ala-Pro-Gly-Tag43 obtained in step (6) was dissolved in 25 mL of DCM. TBAF·3H2O was weighed (the amount used was 3 equivalents of carrier compound 43). The reaction was stirred at room temperature for 10 min until Tag43 was completely removed. The mixture was washed three times with saturated NaCl solution to remove the solvent and obtain the crude peptide (Pal-Val-Gly-Val-Ala-Pro-Gly-OH). A sedimentation solution of 10–15 times the volume of the crude peptide was prepared (V... 甲基叔丁基醚 V 正己烷 =1:1) Centrifuge at 3000 r / min in a centrifuge and repeat three times. Each time, discard the liquid and keep the solid at the bottom. Centrifuge for three minutes after each addition of sediment to obtain naked peptide (Pal-Val-Gly-Val-Ala-Pro-Gly-OH). Repeat the experiment multiple times. The product yield is 91% to 95% (based on compound 43) and the HPLC purity is 92% to 94%.

[0376] The mass spectrum of Pal-Val-Gly-Val-Ala-Pro-Gly-OH is as follows: Figure 7 As shown, HRMS calcd for C 38 H 69 N6O8[M+H] + : 737.5172, found 737.5112.

[0377] Example 11: Homogeneous synthesis of bivalirudin from compound 31

[0378] The sequence of bivalirudin is shown below:

[0379] HD-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH

[0380] (1) Synthesis of Cbz-Leu-Tag31

[0381] Compound 31 (2 mmol, 0.65 g, Mw = 324.611 g / mol) (prepared in Example 7), Cbz-Leu-OH·DCHA (4 mmol, 1.79 g, Mw = 446.6 g / mol), HOBt (4 mmol, 0.54 g, Mw = 135.1 g / mol), and DMAP (0.12 mmol, 0.012 g, Mw = 122.2 g / mol) were added to 20 mL of ethyl acetate, and the reaction was carried out at rt~40 °C for 1 h. After the reaction was completed, a Cbz-Leu–Tag31 reaction solution with amino acid linked to compound 31 was obtained. The reaction solution was washed three times with 40 mL of 5 wt% K2CO3 to remove excess amino acids and coupling reagents. The solvent was evaporated and purified by silica gel column chromatography (PE:EA = 10:1) to obtain 1.06 g of Cbz-Leu–Tag31, with a yield of 93% (based on compound 31).

[0382] (2) De-Cbz protection

[0383] The Cbz-Leu–Tag31 (1.86 mmol, 1.06 g, Mw = 571.905 g / mol) obtained in step (1) was dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1) with 5% Pd / C (the palladium content on carbon is 0.05 equivalent of the support compound 31). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, and 40 mL of ethyl acetate was added to obtain a reaction solution containing NH2-Leu–Tag31 (this step does not require washing and can be directly carried out in the next coupling reaction).

[0384] (3) Coupling of Cbz-Tyr(tBu)-OH·DCHA

[0385] Add Cbz-Tyr(tBu)-OH·DCHA (1.2 equivalents of carrier compound 31), EDC·HCl (1.2 equivalents of carrier compound 31), and HOBt (1.2 equivalents of carrier compound 31) to the reaction solution containing NH2-Leu–Tag31 obtained in step (2), and maintain the temperature at rt~40℃ for 1 h. After the reaction is completed, wash the reaction solution three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents, and take the upper organic phase solution to obtain the washing solution containing Cbz-Tyr(tBu)-Leu-Tag31.

[0386] (4) Deprotection

[0387] The washing solution containing Cbz-Tyr(tBu)-Leu-Tag31 obtained in step (3) was mixed with 5% Pd / C (the amount of palladium was 0.05 equivalent of the carrier compound 31) and dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40 mL of ethyl acetate was added, and the mixture was washed three times with 40 mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was taken to obtain the washing solution containing NH2-Tyr(tBu)-Leu-Tag31.

[0388] (5) Following the methods in steps (3) and (4) above, sequentially add amino acids Cbz-Glu(OtBu)-OH, Cbz-Glu(OtBu)-OH, Cbz-Pro-OH, Cbz-Ile-OH·DCHA, Cbz-Glu(OtBu)-OH, Cbz-Glu(OtBu)-OH, Cbz-Phe-OH, Cbz-Asp(OtBu)-OH, Cbz-Gly-OH, Cbz-Asn(Trt)-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Pro-OH, Cbz-Arg(Pbf)-OH·DCHA, Cbz-Pro-OH, and Cbz-D-Phe-OH, and remove the Cbz protecting group. Filter out Pd / C, evaporate the solvent, add 40 mL of ethyl acetate, and use 40 mL of... Wash three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents. Take the upper organic phase solution to obtain a reaction solution containing NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-Tag31.

[0389] (6) Pyrolysis

[0390] Dissolve the NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-Tag31 obtained in step (5) in 25 mL In DCM, TBAF·3H2O (3 equivalents of carrier compound 31) was weighed out and stirred at room temperature for 10 min to completely remove Tag 31. The mixture was washed three times with saturated NaCl solution to remove the solvent and obtain oily NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OH.

[0391] NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OH dissolved in 10-15 times the volume of cutting fluid TFA:DODT:TIS:pure water (V TFA :V DODT :V TIS :V 纯水 = 92.5:2.5:2.5:2.5), and cut at rt~60℃ for 1.5h in a shaker. After cutting, add 10~15 times the volume of settling liquid (V) of cutting fluid. 甲基叔丁基醚 V 正己烷 =1:1) Centrifuge at 3000 r / min in a centrifuge and repeat three times. Each time, discard the liquid and keep the solid at the bottom. Centrifuge for three minutes after each addition of sediment to obtain naked peptide (HD-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH), with a yield of 91% to 95% (based on compound 31) and an HPLC purity of 91% to 94%.

[0392] The mass spectrum of HD-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH is as follows: Figure 8 As shown, HRMS calcd for C 98 H 139 N 24 O 33 [M+H] + : 2180.9965, found 2180.9752

[0393] Example 12:

[0394] Palmitoyl pentapeptide (Pal-Lys-Thr-Thr-Lys-Ser-OH) (Cbz protected) was homogeneously synthesized using carrier compounds 1, 2, 3, 4, 5, and 6 (prepared in Examples 2 and 3).

[0395] The synthesis method in this embodiment is the same as in Example 8. Palmitoyl pentapeptide was synthesized using carrier compound 1, compound 2, compound 3, compound 4, compound 5, and compound 6 (prepared in Example 2 and Example 3, respectively). The total yield and HPLC purity of the final product are shown below:

[0396] Table 1. Palmitoyl pentapeptide (Cbz protected) synthesized homogeneously using different carriers

[0397]

[0398] Example 13:

[0399] Cell adhesion peptides (Fmoc protected) were homogeneously synthesized using carrier compounds 10, 21, 23, 25, 27, and 29 (prepared in Examples 4 and 5).

[0400] The synthesis method in this embodiment is the same as in Example 9, except that the support compound 14 in Example 9 is replaced with support compounds 10, 21, 23, 25, 27, and 29 (prepared in Examples 4 and 5), respectively. The total yield and HPLC purity of the final product are shown below:

[0401] Table 2 Cell adhesion peptides homogeneously synthesized using different carriers (Fmoc protected)

[0402]

[0403] Example 14:

[0404] Palmitoyl hexapeptide (Cbz protected) was homogeneously synthesized using carrier compounds 44, 45, 48, 50, 52, and 53 (Example 7).

[0405] The synthesis method in this embodiment is the same as in Example 10, except that the support compound 43 in Example 10 is replaced with support compounds 44, 45, 48, 50, 52, and 53 (prepared in Example 7), respectively. The total yield and HPLC purity of the final product are shown below:

[0406] Table 3. Palmitoyl hexapeptide (Cbz protected) synthesized homogeneously using different carriers

[0407]

[0408] Example 15:

[0409] Bivalirudin (Cbz protected) was homogeneously synthesized using compounds 5, 26, 42, 47, 50, and 53 as supports.

[0410] The synthesis method in this embodiment is the same as that in Example 11, except that the support compound 31 in Example 11 is replaced with support compound 5 (prepared in Example 3), compound 26 (prepared in Example 5), compound 42 (prepared in Example 7), compound 47 (prepared in Example 7), compound 50 (prepared in Example 7), and compound 53 (prepared in Example 7), respectively. The total yield and HPLC purity of the final product are shown below:

[0411] Table 4. Bivalirudin synthesized homogeneously using different carriers (Cbz protected)

[0412]

[0413] Comparative Example 1:

[0414] Solid-phase synthesis method of bivalirudin: Most existing processes for synthesizing bivalirudin are solid-phase synthesis methods, utilizing CTC resin. Using Fmoc-Leu-CTC resin as a carrier, and the amino groups of amino acids on the resin as reactive sites, the corresponding protected amino acids are coupled one by one using a HOBt / DIC condensation system to obtain a protected peptide resin. Finally, the peptide chain is cleaved from the resin, and the side chain protecting groups of the amino acids are removed.

[0415] The sequence of bivalirudin is shown below:

[0416] HD-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH

[0417] (1) Weigh CTC resin (1g, 1.211mmol / g) and add it to the reactor. Add dichloromethane and allow the resin to swell for 1-2 hours. After swelling, wash with dichloromethane 2-3 times. Based on the measured resin substitution degree and resin weight, weigh Fmoc-Leu-OH (1.28g, 3.633mmol, 3eq) and DIEA (3.633mmol, 3.6eq). Add dichloromethane (40mL) to the reactor and react at 40℃ for 1.5-2 hours. Remove the solvent after the reaction. Prepare a blocking solution (40mL) with a volume ratio of dichloromethane:methanol:DIEA = 17:1:2. Add the blocking solution to the reactor and react at 40℃ for 30 minutes. Repeat this operation twice. After blocking, wash with DMF. After washing, deprotection was performed by adding 20% ​​piperidine (40 mL, dissolved in DMF) to the reactor and reacting at 40°C for 20 min. An indene check was performed, and the reaction was completed. The mixture was then washed 2-3 times with DMF. Next, a coupling reaction was performed with one amino acid, Fmoc-Tyr(tBu)-OH (2 eq), DIC (2.4 eq), and HOBt (2.4 eq). The reaction was carried out at 40°C for 30 min, and an indene check was performed. After the reaction was completed, the mixture was washed with DMF, and deprotection was performed. Repeat the above steps of deprotection and amino acid coupling, sequentially adding Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Pro-OH, Fmoc-Ile-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Phe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gly-OH, Fmoc-Asn(Trt)-OH, and Fmoc-Gly-O H, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Pro-OH, Fmoc-Phe-OH, until HD-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pr o-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-CTC resin synthesis.

[0418] (2) Prepare a TFA / TIS / DODT / H2O (92.5:2.5:2.5:2.5) lysis buffer. Add HD-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pr o-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-CTC to the prepared lysis buffer (lysis buffer volume is 10 mL / g resin). Stir and react at 40℃ for 2 h, then filter. Concentrate the filtrate under reduced pressure until a white flocculent substance appears. Pour the concentrate into cold methyl tert-butyl ether, and a large amount of white precipitate will precipitate. Let stand for 30 min, centrifuge to remove the supernatant. Add cold methyl tert-butyl ether again to wash, centrifuge to remove the supernatant to obtain the filter cake; repeat twice. The filter cake was vacuum dried to obtain bivalirudin, with a yield of 82% and a purity of 79%.

[0419] Comparative Example 2:

[0420] Bivalirudin was synthesized using 2-(trimethylsilyl)ethanol (TMSE) as a support. The structure of the TMSE support is as follows:

[0421] (1) Synthesis of Cbz-Leu-OTMSE

[0422] Z-Leu-OH (0.584 g, 2.2 mmol), DMAP (0.147 g, 0.12 mmol), and EDC·HCl (0.464 g, 2.42 mmol) were weighed and dissolved in 20 mL of ethyl acetate. Then, 2-(trimethylsilyl)ethanol (0.237 g, 2 mmol) was added, and the mixture was reacted at room temperature for 3 h. The mixture was then washed three times with approximately 40 mL of 5% potassium carbonate aqueous solution. The organic phase was evaporated to dryness under reduced pressure and purified by column chromatography. The ratio of ethyl acetate to petroleum ether was 1:8, yielding 0.514 g of colorless oily liquid Z-Leu-OTMSE with a yield of 69.2% and an HPLC purity of 98.4%.

[0423] (2) De-Cbz protection

[0424] The Z-Leu-OTMSE (1.384 mmol, 0.514 g, Mw = 365.545 g / mol) obtained in step (1) was dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1) with 5% Pd / C (the palladium content on carbon is 0.05 equivalent of the carrier TMSE). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, and 40 mL of ethyl acetate was added to obtain a reaction solution containing NH2-Leu-OTMSE (this step does not require washing and can be directly carried out in the next coupling reaction).

[0425] (3) Coupling of Cbz-Tyr(tBu)-OH·DCHA

[0426] Add Cbz-Tyr(tBu)-OH·DCHA (1.2 equivalents of the carrier TMSE), EDC·HCl (1.2 equivalents of the carrier TMSE), and HOBt (1.2 equivalents of the carrier TMSE) to the washing solution containing NH2-Leu-OTMSE obtained in step (2), and maintain the temperature at rt~40℃ for 1 h. After the reaction is complete, wash the reaction solution three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents, and take the upper organic phase solution to obtain the washing solution containing Cbz-Tyr(tBu)-Leu-OTMSE.

[0427] (4) Deprotection

[0428] The washing solution containing Cbz-Tyr(tBu)-Leu-OTMSE obtained in step (3) was mixed with 5% Pd / C (the amount of palladium was 0.05 equivalent of the carrier) and dissolved in 20 mL of ethyl acetate / methanol solvent (volume ratio 1:1). The air in the reaction flask was replaced with hydrogen gas using a water pump (a hydrogen balloon was inserted above the reaction flask). The reaction was stirred for 30 min at rt~40℃ in a hydrogen atmosphere. After the reaction was completed, Pd / C was filtered off, the solvent was evaporated, 40 mL of ethyl acetate was added, and the mixture was washed three times with 40 mL of 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain the washing solution containing NH2-Tyr(tBu)-Leu-OTMSE.

[0429] (5) Following the methods in steps (3) and (4) above, sequentially add amino acids Cbz-Glu(OtBu)-OH, Cbz-Glu(OtBu)-OH, Cbz-Pro-OH, Cbz-Ile-OH·DCHA, Cbz-Glu(OtBu)-OH, Cbz-Glu(OtBu)-OH, Cbz-Phe-OH, Cbz-Asp(OtBu)-OH, Cbz-Gly-OH, Cbz-Asn(Trt)-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Gly-OH, Cbz-Pro-OH, Cbz-Arg(Pbf)-OH·DCHA, Cbz-Pro-OH, and Cbz-D-Phe-OH, and remove the Cbz protecting group. Filter out Pd / C, evaporate the solvent, add 40 mL of ethyl acetate, and use 40 mL of... The solution was washed three times with 5wt% K2CO3 to remove excess amino acids and coupling reagents. The upper organic phase solution was used to obtain a reaction solution containing NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OTMSE.

[0430] (6) Pyrolysis

[0431] The reaction solution containing NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OTMSE obtained in step (5) was dissolved in 25 mL In DCM, TBAF·3H2O (3 equivalents of the carrier TMSE) was weighed out and stirred at room temperature for 10 min to completely remove TMSE. The mixture was washed three times with saturated NaCl solution to remove the solvent and obtain oily NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OH.

[0432] NH2-D-Phe-Pro-Arg(Pbf)-Pro-Gly-Gly-Gly-Gly-Asn(Trt)-Gly-Asp(OtBu)-Phe-Glu(OtBu)-Glu(OtBu)-Ile-Pro-Glu(OtBu)-Glu(OtBu)-Tyr(tBu)-Leu-OH dissolved in 10-15 times the volume of cutting fluid TFA:DODT:TIS:pure water (V TFA :V DODT :V TIS :V 纯水 = 92.5:2.5:2.5:2.5), and cut at rt~60℃ for 1.5h in a shaker. After cutting, add 10~15 times the volume of settling liquid (V) of cutting fluid. 甲基叔丁基醚 V 正己烷 The mixture was centrifuged at 3000 rpm for 1:1 ratio to allow sedimentation, and this process was repeated three times. Each time, the liquid was discarded, and the solid at the bottom was retained. Centrifugation for three minutes was required after each addition of sedimentation solution to obtain naked peptide (HD-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH) with a yield of 59% (based on TMSE) and an HPLC purity of 81%.

[0433] This invention provides a compound containing a 2-phenyl-2-trimethylsilaneethanol structure, its preparation method, and its application. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A compound having the structure of 2-phenyl-2-trimethylsilylethanol, characterized in that, The compound containing a 2-phenyl-2-trimethylsilylethanol structure is shown in the following formula I: wherein, n is an integer selected from 1 to 5; R is independently selected from R1, -OR2or R1 is selected from substituted or unsubstituted C1-C22 alkyl; R2 is selected from substituted or unsubstituted C1-C30 alkyl; R3, R4, R5 are independently selected from substituted or unsubstituted C1-C22 alkyl, or substituted or unsubstituted aromatic group; wherein, the substitution is selected from substitution by C1-C6 alkyl; wherein, the compound containing a 2-phenyl-2-trimethylsilylethanol structure is not a compound in the following group:

2. The compound according to claim 1, wherein, n is an integer selected from 1 to 3; R1 is selected from substituted or unsubstituted C4-C20 alkyl; R2 is selected from substituted or unsubstituted C1-C22 alkyl; R3, R4, R5 are independently selected from substituted or unsubstituted C1-C20 alkyl, or substituted or unsubstituted aromatic group; Preferably, n = 1, 2 or 3; when R is selected from R1, R1 is selected from substituted or unsubstituted C4 alkyl, C8 alkyl, C10 alkyl, C14 alkyl or C20 alkyl; when R is selected from -OR2, R2 is selected from substituted or unsubstituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, C20 alkyl or C22 alkyl; R selection In this case, R3, R4, and R5 are independently selected from substituted or unsubstituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C6 alkyl, C8 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, or C20 alkyl, or substituted or unsubstituted aromatic groups; Further preferably, n = 1, 2 or 3; when n = 1, R is selected from R1, R1 is selected from unsubstituted n-butyl, n-octyl, n-decyl, n-tetradecyl or n-eicosyl; when n = 1, R is selected from -OR2, R2 is selected from unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl or n-docosyl; when n = 2, R is selected from -OR2, R2 is selected from unsubstituted n-butyl, n-octyl or n-dodecyl; when n = 3, R is selected from -OR2, R2 is selected from unsubstituted n-octyl; When n = 1, R is selected R3= R5, R3is selected from methyl, ethyl, propyl, isopropyl, t-butyl or phenyl; R4is selected from methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n- eicosyl or phenyl; when n = 2, R is selected from R3= R5, R3is selected from methyl; R4is selected from methyl; when n = 3, R is selected from R3= R5, R3is selected from methyl; R4is selected from methyl; More preferably, n = 1, 2 or 3; when n = 1, R is selected from R1, R1 is selected from unsubstituted n-butyl, n-octyl, n-octyl, n-decyl, n-tetradecyl or n-eicosyl; when n = 1, R is selected from -OR2, R2 is selected from unsubstituted methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl or n-docosyl; when n = 2, R is selected from -OR2, R2 is selected from unsubstituted n-butyl, two -OR2 groups are ortho substitution and para substitution with respect to the parent nucleus structure respectively; R2 is selected from n-octyl, two -OR2 groups are two meta substitution with respect to the parent nucleus structure respectively; R2 is selected from n-dodecyl, two -OR2 groups are meta substitution and para substitution with respect to the parent nucleus structure respectively; when n = 3, R is selected from -OR2, R2 is selected from unsubstituted n-octyl, the three -OR2 groups are two meta-substituted and one para-substituted, respectively, relative to the parent structure; when n = 1, R is selected from R3= R5, R3is selected from methyl, ethyl, propyl, isopropyl, t-butyl, or phenyl; R4is selected from methyl, ethyl, propyl, isopropyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n- eicosyl, or phenyl; the group is para substituted with respect to the parent structure; when n = 2, R is selected from R3= R5, R3is selected from methyl; R4is selected from methyl; both groups are meta to the parent structure, respectively; R3= R5, R3is selected from methyl; R4is selected from methyl; both groups are meta to the parent structure, respectively; when n = 3, R is selected from R3= R5, R3is selected from methyl; R4is selected from methyl; the three groups are meta to the nucleus structure respectively. two meta and one para to the nucleus structure respectively.

3. The compound of claim 1, wherein the compound containing a 2-phenyl-2-trimethylsilylethanol structure is selected from any one of the following compounds:

4. Process for the preparation of a compound containing the structure of 2-phenyl-2- trimethylsilylethanol according to any one of claims 1 to 3, characterized in that, the halogenated phenyl compound a is subjected to substitution reaction under the action of a lithium reagent, and then subjected to ring-opening reaction with compound b under the action of an additive, to obtain the compound I containing a 2-phenyl-2-trimethylsilylethanol structure; wherein, X is selected from Br or Cl; n is selected from an integer from 1 to 5; R is independently selected from R1, -OR2or R1 is selected from substituted or unsubstituted C1-C22 alkyl; R2 is selected from substituted or unsubstituted C1-C30 alkyl; R3, R4, R5 are independently selected from substituted or unsubstituted C1-C22 alkyl, or substituted or unsubstituted aromatic group; wherein, the substitution is selected from substitution by C1-C6 alkyl; wherein, the compound containing a 2-phenyl-2-trimethylsilylethanol structure is not the following compound:

5. The preparation method according to claim 4, characterized in that, the lithium reagent is n-butyllithium; the additive is cuprous iodide; the molar ratio of the halogenated phenyl compound a, the lithium reagent, compound b, and the additive is 2.0-8.0:2.0-8.0:1.0:1.0-4.0, preferably 3.0-5.0:3.0-5.0:1.0:1.0-3.0, and further preferably 3.5-4.0:3.5-4.0:1.0:2.0; the reaction temperature of the substitution reaction is -40℃ to 12℃; the reaction temperature of the ring-opening reaction is -40℃ to 0℃, and the reaction is carried out under inert gas protection.

6. A protecting reagent for the C-terminus of an amino acid or peptide, characterized in that, the protecting reagent includes the compound containing a 2-phenyl-2-trimethylsilylethanol structure according to any one of claims 1-3.

7. Use of the compound containing a 2-phenyl-2-trimethylsilylethanol structure according to any one of claims 1-3 or the protecting reagent for the C-terminal of the amino acid or peptide according to claim 6 in the synthesis of polypeptides in a homogeneous solvent system.

8. A method of synthesizing a polypeptide, comprising, The compound containing a 2-phenyl-2-trimethylsilylethanol structure according to any one of claims 1-3 is used as a carrier in the homogeneous synthesis of polypeptides; including the following steps: (1) carrier access: the compound containing a 2-phenyl-2-trimethylsilylethanol structure according to any one of claims 1-3 is used as a carrier to connect with N-protected amino acid or N-protected peptide compound through conventional condensation reaction to obtain N-protected amino acid or N-protected peptide compound with 2-phenyl-2-trimethylsilylethanol structure carrier C-terminal protection; (2) N-terminal deprotection: the N-protected amino acid or N-protected peptide compound with 2-phenyl-2-trimethylsilylethanol structure carrier C-terminal protection is mixed with N-terminal protection deprotection reagent and solvent, and N-terminal deprotection is carried out in an organic homogeneous system to obtain a solution of N-deprotected amino acid or N-deprotected peptide compound with 2-phenyl-2-trimethylsilylethanol structure carrier C-terminal protection; (3) peptide chain elongation: adding N-protected amino acid or N-protected peptide compound into the solution of N-deprotected amino acid or N-deprotected peptide compound containing 2-phenyl-2-trimethylsilylethanol structural carrier C-terminal protection, then adding condensation reagent to perform coupling condensation reaction in a homogeneous system, and then performing extraction to remove impurities to obtain a solution of N-protected amino acid or N-protected peptide compound containing 2-phenyl-2-trimethylsilylethanol structural carrier C-terminal protection; (4) repeating step (2) and step (3) to add the next amino acid until the complete peptide chain is obtained; (5) carrier removal and precipitation: after the N-terminal of the complete N-protected amino acid or N-protected peptide compound containing 2-phenyl-2-trimethylsilylethanol structural carrier C-terminal protection is deprotected, removing the C-terminal carrier using a removal reagent, and then adding a precipitation liquid to perform precipitation to obtain the polypeptide.

9. The method of synthesis of claim 8, wherein, In step (5), when the N-terminal of the complete N-protected amino acid or N-protected peptide compound containing 2-phenyl-2-trimethylsilylethanol structural carrier C-terminal protection needs to be amidated, after the N-terminal is deprotected, amidation is performed, and then the C-terminal carrier is removed using a removal reagent after the amidation is completed.

10. The method of synthesis of claim 8, wherein, In step (5), when the complete N-protected amino acid or N-protected peptide compound containing 2-phenyl-2-trimethylsilylethanol structural carrier C-terminal protection contains a side chain protection group, after the C-terminal carrier is removed, a cleavage reaction is performed in a cleavage liquid, and then a precipitation liquid is added to perform precipitation after the cleavage is completed to obtain the polypeptide.

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