A biphenyl bridged cyclic peptide compound and its preparation method and application

Abstract

The present invention discloses a biphenyl bridged cyclic peptide compound and a preparation method and application thereof. Phenylalanine or p-hydroxyphenylalanine, which is easily available, is used as the initial raw material. After methylation, protective groups are installed on the carboxyl group and the amino group to obtain two intermediate compounds. The installed 2-methoxyiminoacyl group (methoxyoxime acyl group) is used to guide the transition metal to activate the carbon-hydrogen bond, and the two intermediates are connected in the form of a carbon-carbon bond. Finally, after hydrogenation reduction, lactamization ring closure is performed to obtain the biphenyl bridged cyclic peptide compound. The present invention utilizes the bidentate ligand guiding function of the 2-methoxyiminoacyl group and the instantaneous guiding function of norbornene (NBE) to guide the transition metal to activate the sp at the meta position of the aromatic ring. 2 The carbon-hydrogen bond is formed, and then an arylation reaction occurs to construct a biphenyl structure. The 2-methoxyiminoacyl group is then hydrogenated to form a dipeptide structure, and finally the biphenyl cyclic peptide is constructed by lactamization. The entire route is simple and efficient, and is expected to be further promoted and applied.

Description

Technical Field

[0001] The invention relates to the technical field of synthesis of pharmaceutical chemistry, and in particular to a class of synthetic biphenyl bridged cyclic peptide compounds and a preparation method thereof and application thereof in antibiotics or antagonists. Background Art

[0002] Biphenyl bridged cyclic peptide compounds are macrocyclic structures formed by biaryl groups connected to multiple amino acids. They have become a hot topic of research in recent years due to their diversity and significant biological activity, and play an important role in medicine. This special structure exists in many drug molecular structures, such as:

[0003] Biphenomycin (antibiotic):

[0004]

[0005] Arylomycin (antibiotic):

[0006]

[0007] RP66453 (neurotensin receptor antagonist):

[0008]

[0009] All of the above-mentioned drug molecular structures have their structures.

[0010] Biphenomycin was originally isolated from the culture medium of Streptomyces and Staphylococcus aureus. It shows strong activity against Gram-positive α-lactam-resistant bacteria, such as Streptococcus aureus or Streptococcus. Arylomycin is a new class of natural products, arylomycins, isolated from Streptomyces. Their antibiotic activity stems from their inhibition of bacterial type I signal peptidase (SPase I), an essential serine protease for processing cell surface binding preproteins. Arylomycin or related derivatives are indicated as a new class of antibiotics. RP66453 and its semisynthetic derivatives specifically bind to neurotensin receptors and are said to be useful for the treatment of psychosis, Alzheimer's disease and Parkinson's disease.

[0011] Biaryl-bridged macrocycles are challenging molecules due to the inherent ring strain associated with double-bridged macrocyclic systems. The two key aspects of the synthesis of this class of compounds are the construction of the biphenyl structure and macrocyclization. After long-term research, the most widely used method for synthesizing their compounds is to combine transition metal catalysis and lactamization to form rings. First, the biaryl coupling intermediate is formed through Suzuki-Miyaura, Stille or Negishi cross-coupling reactions, followed by derivatization and finally assembly into the same ring system through lactamization.

[0012] The literature Org.Lett.7(2005),2981-2984 reported a method for synthesizing Biphenomycin B (see Figure 8 , Route 1). The literature J.Am.Chem.Soc.129(2007),15830–15838 reported a method for synthesizing the core structure of Arylomycin A2 (see Fig. 9 , route 2).

[0013] In the above synthetic routes, the cost of raw materials and reagents used in route one is relatively high; the raw materials used in route two are simple, but the yield effect is not good. At the same time, the common point of the two routes is that both use transition metal catalysis and require pre-activation of functional groups. In addition to producing potential toxic waste, the pre-functionalization required for the coupling reaction catalyzed by this transition metal will also increase costs and reduce the availability of starting reagents. Summary of the invention

[0014] In view of this, the present invention provides a new method for synthesizing biphenyl-bridged cyclic peptide compounds in a simple and efficient manner, using easily available phenylalanine or p-hydroxyphenylalanine / glycine as starting materials to pre-synthesize the desired compounds, and then obtaining the target compounds through hydrogenation reduction and ring-closure reactions.

[0015] An object of the present invention is to solve at least the above problems and / or disadvantages and to provide at least the advantages which will be described hereinafter.

[0016] In order to achieve these purposes and other advantages according to the present invention, a biphenyl bridged cyclic peptide compound is provided, and the structural formula of the biphenyl bridged cyclic peptide compound is the compound shown in Formula I:

[0017]

[0018] in,

[0019] R1 is monosubstituted or disubstituted, and is selected from one of hydroxyl and alkoxy; wherein the monosubstituted is ortho or para; and the alkoxy is one of methoxy, ethoxy and isopropoxy;

[0020] R2 is monosubstituted or disubstituted, and is selected from one of hydroxyl and alkoxy; wherein the monosubstituted is ortho or para; and the alkoxy is one of methoxy, ethoxy and isopropoxy;

[0021] R3 is selected from one of hydrogen and tert-butyloxycarbonyl;

[0022] R4 is selected from one of hydrogen, methyl, isopropyl, phenyl and benzyl;

[0023] R5 is selected from one of hydrogen, tert-butyloxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl;

[0024] R6 is selected from one of methyl, ethyl, isopropyl, tert-butyl, phenyl and benzyl;

[0025] n is 0 or 1.

[0026] Preferably, the structural formula of the biphenyl bridged cyclic peptide compound is:

[0027]

[0028] Where n is 0 or 1;

[0029] The preparation method of the biphenyl bridged cyclic peptide compound is as follows: under the action of a catalyst, compound A and compound B are reacted to obtain a biphenyl bridged cyclic peptide compound (such as Figure 1 shown);

[0030] The structural formula of the compound A is:

[0031]

[0032] The structural formula of the compound B is:

[0033]

[0034] Where n is 0 or 1.

[0035] Preferably, the biphenyl bridged cyclic peptide compound has a structural formula of the compound shown in Formula I-1: Synthesis of Biphenomycin B skeleton:

[0036]

[0037] The preparation method of the compound represented by formula I-1 comprises the following steps (synthetic route is as follows Figure 2 shown):

[0038] Step 1: Compound 1I is subjected to transition metal Pd-catalyzed carbon-hydrogen bond activation methyl etherification to obtain compound 1a;

[0039] The structural formula of the compound II is:

[0040]

[0041] The structural formula of the compound 1a is:

[0042]

[0043] Step 2, compound 1a is successively subjected to acid hydrolysis (removal of 2-methoxyiminoyl (methoxyoxime acyl) to obtain compound 5, the reaction conditions are well known in the art, and this application does not provide specific descriptions), two-step reaction to add protective groups (Boc group and benzyl group are added to the amino and carboxyl groups of compound 5 to obtain compound 6, the reaction conditions are well known in the art, and this application does not provide specific descriptions, and the solvents used in this process are tetrahydrofuran and N,N-dimethylformamide), and aryl iodination to obtain compound 7 (the para-position of the methoxy group of compound 6 undergoes iodination reaction, the reaction conditions are well known in the art, and this application does not provide specific descriptions; the solvent in this process is ethanol);

[0044] The structural formula of the compound 7 is:

[0045]

[0046] Step 3, Compound 1a and Compound 7 are catalyzed by transition metal to obtain Compound 8;

[0047] The structural formula of the compound 8 is:

[0048]

[0049] Step 4: Compound 8 is debenzylated and methoxy oxime is hydrogenated to obtain compound 10;

[0050] The structural formula of the compound 10 is:

[0051]

[0052] Step 5: subjecting the carboxyl group and the amino group in compound 10 to amide condensation to obtain a compound of formula I-1; wherein the compound of formula I-1 has 2-methoxyiminoacyl as the directing group, and the methoxy oxime fragment thereof is hydrogenated to form an S-configuration chiral compound.

[0053] Preferably, the process of step 1 is as follows: dissolving compound 1I in MeOH, then adding Pd(OAc)2, PhI(OAc)2, K2CO3, and nicotinic acid for the first time, stirring and reacting at 35-45°C under inert gas protection for 6-10 hours, then heating to 75-85°C and stirring and reacting for 14-18 hours, cooling the reaction system to room temperature, adding Pd(OAc)2, PhI(OAc)2, and nicotinic acid to the reaction system for the second time, and continuing to react for 18-28 hours under inert gas protection; after the reaction is completed, filtering, concentrating, separating by column chromatography, and rotary evaporating to dryness to obtain compound 1 a; The molar volume ratio of the compound 1I to MeOH is: 0.2-0.6 mmol: 1-5 mL; The molar ratio of the compound 1I to the first added Pd(OAc)2, PhI(OAc)2, K2CO3 and nicotinic acid is: 0.2-0.6: 0.01-0.03: 0.6-1: 0.2-0.6: 0.06-0.1; The molar ratio of the compound 1I to the second added Pd(OAc)2, PhI(OAc)2 and nicotinic acid is: 0.2-0.6: 0.01-0.03: 0.2-0.6: 0.06-0.1;

[0054] The process of step three is: dissolving compound 1a and compound 7 in toluene, adding Pd(OAc)2, NBE, silver pivalate and 3-COOMePy, protecting under inert gas, reacting at 100-120°C for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 8; the molar ratio of compound 1a to compound 7 is 1:1.5-3; the molar volume ratio of compound 1a to toluene is 0.1mmol:0.8-1.2mL; the molar ratio of compound 1a to Pd(OAc)2, NBE, silver pivalate and 3-COOMePy is 0.05-0.15:0.005-0.015:0.0.1-0.3:0.2-0.4:0.01-0.03.

[0055] Preferably, the process of step 4 is: dissolving compound 8 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding 25-35% Pd(OH)2 / C by mass, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 10;

[0056] The process of step five is as follows: pentafluorophenyl diphenyl phosphate and anhydrous DMA are placed in a reactor, protected by inert gas, a mixture of compound 10 is dissolved in anhydrous DMA and then added dropwise to the reaction system; the reaction is performed for 40 to 55 hours; after the reaction is completed, extraction, separation, drying, rotary evaporation, concentration, and column chromatography are performed to obtain compound I-1; the molar volume ratio of pentafluorophenyl diphenyl phosphate and anhydrous DMA is 0.1 to 0.15 mmol: 250 to 350 mL; the molar ratio of compound 10 to pentafluorophenyl diphenyl phosphate is 0.1: 0.12 to 0.15.

[0057] Preferably, the biphenyl bridged cyclic peptide compound has the structural formula of the compound shown in Formula I-2: Synthesis of RP66453 skeleton:

[0058]

[0059] The preparation method of the compound represented by formula I-2 comprises the following steps (such as Figure 3 shown):

[0060] Step A: Compound 13 is used as a substrate, and a protecting group is added through two steps of reaction (Boc group and benzyl group are added to the amino group and carboxyl group of compound 13 respectively to obtain compound 14, and the reaction conditions are well known in the art and are not described in detail in this application), hydroxymethylation (compound 14 is hydroxymethylated to obtain compound 15, and the reaction conditions are well known in the art and are not described in detail in this application), and aryl iodination is performed to obtain compound 16 (the ortho position of the methoxy group of compound 15 undergoes iodination reaction, and the reaction conditions are well known in the art and are not described in detail in this application);

[0061] The structural formula of the compound 13 is:

[0062]

[0063] The structural formula of the compound 16 is:

[0064]

[0065] Step B: Compound 16 and compound 1k are subjected to transition metal Pd-catalyzed carbon-hydrogen bond activated arylation to obtain compound 17;

[0066] The structural formula of the compound 1k is:

[0067]

[0068] The structural formula of the compound 17 is:

[0069]

[0070] Step C: Compound 17 is debenzylated and methoxy oxime is hydrogenated to obtain compound 18;

[0071] The structural formula of the compound 18 is:

[0072]

[0073] Step D: The carboxyl group and aminoamide in compound 18 are condensed to obtain a compound of formula I-2; and the compound of formula I-1 uses 2-methoxyiminoacyl as the directing group, and the methoxy oxime fragment therein is hydrogenated to form an S-configuration chiral compound.

[0074] Preferably, the process of step B is: dissolving compound 1k and compound 16 in toluene, adding PdCl2, NBE, AgOAc and 3-COOMePy, protecting under inert gas, reacting at 100-120°C for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 17; the molar ratio of compound 1k to compound 16 is 1:1.5-3; the molar volume ratio of compound 1k to toluene is 0.4mmol:2-5mL; the molar ratio of compound 1k to PdCl2, NBE, AgOAc and 3-COOMePy is 0.3-0.5:0.06-0.1:0.6-1:1.2-1.8:0.14-0.18;

[0075] The process of step C is as follows: dissolving compound 17 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding Pd(OH)2 / C with a mass fraction of 25-35%, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 18;

[0076] The process of step D is as follows: O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine are dissolved in N-methylpyrrolidone and placed in a reactor, protected by inert gas, a mixture of compound 18 is dissolved in N-methylpyrrolidone and then added dropwise to the reaction system; react for 1 to 3 hours; after the reaction, add water, extract, separate, dry, rotary evaporate to dryness, concentrate, and separate by column chromatography to obtain compound I-2; the molar ratio of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine is 1:1.5-2.5; the molar ratio of compound 18 to O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid is 1.2 to 2:1.

[0077] Preferably, the biphenyl bridged cyclic peptide compound has a structural formula of the compound shown in Formula I-3: Synthesis of ArylomycinA2 Skeleton:

[0078]

[0079] The preparation method of the compound represented by formula I-3 comprises the following steps (such as Figure 4 shown):

[0080] Step a: Compound 20 is used as a substrate, and a protecting group is added (Boc group and benzyl group are added to the amino group and carboxyl group of compound 20, respectively, to obtain compound 21, and the reaction conditions are well known in the art and are not described in detail in this application), hydroxymethylation (compound 21 undergoes hydroxymethylation, and the reaction conditions are well known in the art and are not described in detail in this application), and aryl iodination is performed to obtain compound 23 (the ortho-methoxy position of compound 22 undergoes iodination reaction, and the reaction conditions are well known in the art and are not described in detail in this application);

[0081] The structural formula of the compound 20 is:

[0082]

[0083] The structural formula of the compound 23 is:

[0084]

[0085] Step b: Compound 23 and compound 1k are subjected to transition metal Pd-catalyzed carbon-hydrogen bond activated arylation to obtain compound 24;

[0086] The structural formula of the compound 1k is:

[0087]

[0088] The structural formula of the compound 24 is:

[0089]

[0090] Step c: Compound 24 is debenzylated and methoxy oxime is hydrogenated to obtain compound 25;

[0091] The structural formula of the compound 25 is:

[0092]

[0093] Step d: The carboxyl group and the amino group in compound 25 undergo amide condensation to obtain a compound of formula I-3; and the compound of formula I-1 uses 2-methoxyiminoacyl as the directing group, and the methoxy oxime fragment therein is hydrogenated to form an S-configuration chiral compound.

[0094] Preferably, the process of step b is: dissolving compound 1k and compound 23 in toluene, adding PdCl2, NBE, AgOAc and 3-COOMePy, protecting under inert gas, reacting at 100-120°C for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 24; the molar ratio of compound 1k to compound 23 is 1:1.5-3; the molar volume ratio of compound 1k to toluene is 0.4mmol:2-5mL; the molar ratio of compound 1k to PdCl2, NBE, AgOAc and 3-COOMePy is 0.3-0.5:0.06-0.1:0.6-1:1.2-1.8:0.14-0.18;

[0095] The process of step c is as follows: dissolving compound 24 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding Pd(OH)2 / C with a mass fraction of 25-35%, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 25;

[0096] The process of step d is: dissolving O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine in N-methylpyrrolidone and placing in a reactor, protecting with inert gas, dissolving a mixture of compound 25 in N-methylpyrrolidone and adding dropwise to the reaction system; reacting for 1 to 3 hours; after the reaction, adding water, extracting, separating, drying, rotary evaporation and rotary drying, concentrating, and separating by column chromatography to obtain compound I-2; the molar ratio of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine is 1:1.5-2.5; the molar ratio of compound 25 to O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid is 1.2-2:1.

[0097] The present invention also provides a use of the biphenyl bridged cyclic peptide compound as described above in antibiotics or antagonists.

[0098] The present invention is conceived as follows: using phenylalanine or p-hydroxyphenylalanine / glycine as the initial raw material, after methylation, installing protective groups on the carboxyl group and the amino group to obtain two intermediate compounds. Using the installed 2-methoxyiminoacyl group (methoxyoxime acyl group) to guide the transition metal to activate the carbon-hydrogen bond, the two intermediates are connected in the form of carbon-carbon bonds, and finally hydrogenation reduction is carried out, and finally lactamization ring closure is obtained to obtain the target compound (such as Figure 1 shown).

[0099] The present invention includes at least the following beneficial effects: In the present invention, the most critical factor is the introduction of 2-methoxyiminoacyl (methoxyoxime acyl), which can not only serve as a directing group to guide the transition metal to activate the carbon-hydrogen bond to form a carbon-carbon bond, but also the 2-methoxyiminoacyl (methoxyoxime acyl) does not need to be removed and is easily hydrogenated to form a dipeptide structure, which exists in the drug molecular structure and shows a high atom economy; the process reaction flow is shortened, the route is stable and safe, and the yield of the target product is good.

[0100] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Figure 1 is the chemical reaction formula of the present invention;

[0102] Figure 2 The synthetic route of the compound shown in I-1 of the present invention;

[0103] Figure 3 The synthetic route of the compound shown in I-2 of the present invention;

[0104] Figure 4 The synthetic route of the compound shown in I-3 of the present invention;

[0105] Figure 5 The synthetic route of the compound shown in I-1 described in Example 1 of the present invention;

[0106] Figure 6 The synthetic route of the compound shown in I-2 described in Example 2 of the present invention;

[0107] Figure 7 The synthetic route of the compound shown in I-3 described in Example 3 of the present invention;

[0108] Figure 8 It is the synthetic route of route 1 described in the background technology of the present invention;

[0109] Fig. 9 It is the synthetic route of route 2 described in the background technology of the present invention;

[0110] Fig.10 is the compound 11 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0111] Fig.11 is the compound 11 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0112] Fig.12 is the compound 1a of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0113] Fig.13 is the compound 1a of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0114] Fig.14 is the compound 6 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0115] Fig.15 is the compound 6 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0116] Fig.16 is the compound 7 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0117] Fig.17 is the compound 7 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0118] Fig.18 is the compound 8 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0119] Fig.19 is the compound 8 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0120] Fig. 20 The compound I-1 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0121] Fig.21 The compound I-1 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0122] Fig. 22 is the compound 15 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0123] Fig.23 is the compound 15 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0124] Fig.24 is the compound 16 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0125] Fig.25 is the compound 16 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0126] Fig.26 is the compound 17 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0127] Fig. 27 is the compound 17 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0128] Fig.28 is the compound I-2 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0129] Fig.29 is the compound I-2 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0130] Fig.30 is the compound 1k of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0131] Fig.31 is the compound 1k of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0132] Fig.32 is the compound 21 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0133] Fig.33 is the compound 21 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0134] Fig.34 is the compound 22 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0135] Fig.35 is the compound 22 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0136] Fig.36is the compound 23 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0137] Fig.37 is the compound 23 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0138] Fig.38 is the compound 24 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0139] Fig.39 is the compound 24 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0140] Fig.40 is the compound I-3 of the present invention 1 H NMR spectrum (CDCl3, 400M);

[0141] Fig.41 is the compound I-3 of the present invention 13 C NMR spectrum (CDCl3, 100M);

[0142] Fig.42 A verification reaction formula for constructing a new chiral center for the prochiral induced hydrogenation reaction of the present invention;

[0143] Fig.43 is the compound 3a-HR of the present invention 1 H NMR spectrum (DMSO, 500 M);

[0144] Fig.44 is the compound 3a-HR of the present invention 13 C NMR spectrum (DMSO, 125M);

[0145] Fig.45 is the compound 3a-HR of the present invention 1 H- 1 H COSY spectrum (DMSO, 500 M);

[0146] Fig.46 is the compound 3a-HR of the present invention 1 H- 1 H NOESY spectrum (DMSO, 500 M);

[0147] Fig.47 is the compound 3a-HS of the present invention 1 H NMR spectrum (DMSO, 500 M);

[0148] Fig.48 is the compound 3a-HS of the present invention 13 C NMR spectrum (DMSO, 125M);

[0149] Fig.49 is the compound 3a-HS of the present invention 1 H- 1 H COSY spectrum (DMSO, 500 M);

[0150] Fig.50 is the compound 3a-HS of the present invention 1 H- 1 H NOESY spectrum (DMSO, 500 M);

[0151] Fig.51 The compound 4n-HR of the present invention 1 H NMR spectrum (DMSO, 500 M);

[0152] Fig.52 The compound 4n-HR of the present invention 13 C NMR spectrum (DMSO, 125M);

[0153] Fig.53 The compound 4n-HR of the present invention 1 H- 1 H COSY spectrum (DMSO, 500 M);

[0154] Fig.54 The compound 4n-HR of the present invention 1 H- 1 H NOESY spectrum (DMSO, 500 M);

[0155] Fig.55 The compound 4n-HS of the present invention 1 H NMR spectrum (DMSO, 500 M);

[0156] Fig.56 The compound 4n-HS of the present invention 13 C NMR spectrum (DMSO, 125M);

[0157] Fig.57 The compound 4n-HS of the present invention 1 H- 1 H COSY spectrum (DMSO, 500 M);

[0158] Fig.58 The compound 4n-HS of the present invention 1 H- 1H NOESY spectrum (DMSO, 500 M). DETAILED DESCRIPTION

[0159] The present invention is further described in detail below in conjunction with the accompanying drawings so that those skilled in the art can implement the invention with reference to the description.

[0160] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0161] If the meanings of the terms in the relevant documents cited in the present invention are inconsistent with those in the present invention, the meanings in the present invention shall prevail; if there is no definition in the present invention, they have the meanings generally understood by those skilled in the art. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the commonly known meanings, the meanings expressed in the present invention shall prevail.

[0162] The term "aryl" is used to refer to aromatic carbocyclic groups, including monocyclic or polycyclic aromatic hydrocarbons;

[0163] Dashed and bold lines are used in chemical structures representing one or more stereocenters to indicate the absolute stereochemistry of the stereocenter in the chemical structure;

[0164] In the present invention, the bonds described in the structural diagrams do not represent preferred stereostructures, and chemical structures containing one or more stereocenters include all possible stereoisomer forms and mixtures thereof;

[0165] The term "antibiotic" is used to refer to a class of secondary metabolites produced by microorganisms (including bacteria, fungi, and actinomycetes) or higher animals and plants in the course of their lives that have antipathogenic or other activities and are chemical substances that can interfere with the developmental functions of other living cells.

[0166] The term "antagonist" is used to indicate that binding to a receptor does not cause a biological effect itself, but blocks the effects mediated by the agonist of that receptor.

[0167] The term "treat" is used to include reversing, alleviating or arresting clinical symptoms and related pathological conditions to improve or stabilize the patient's condition.

[0168] The technology of the present invention utilizes the bidentate ligand guiding function of 2-methoxyiminoacyl (methoxyoximeacyl) and the transient guiding function of norbornene to guide the transition metal (Pd) to activate the sp2 carbon-hydrogen bond at the meta position of the aromatic ring, and then an arylation reaction occurs to construct a biphenyl structure. Afterwards, the 2-methoxyiminoacyl (methoxyoximeacyl) is hydrogenated to form a dipeptide structure, and finally the construction of the biphenyl cyclic peptide is completed by lactamization. The entire route is simple and efficient, and is expected to be further promoted and applied.

[0169] Embodiment 1:

[0170] I-1: Synthesis of Bipheomycin B Skeleton:

[0171]

[0172] Synthesis route such as Figure 5 As shown;

[0173] Step 1:

[0174] Compound 11 (128 mg, 0.4 mmol, 1.0 equiv) was dissolved in 3 ml of MeOH and placed in a sealed tube. A rotor was added. Pd(OAc)2 (4.89 mg, 0.02 mmol, 0.05 equiv), PhI(OAc)2 (384 mg, 0.8 mmol, 2.0 equiv), K2CO3 (54.4 mg, 0.4 mmol, 1.0 equiv), and nicotinic acid (9.84 mg, 0.08 mmol, 0.2 equiv) were added. The mixture was protected by argon and stirred. The mixture was reacted in an oil bath at 40 °C for 8 hours. After 8 hours, the temperature was raised to 80 °C for 16 hours. After 16 hours, the reaction system was cooled to room temperature, and Pd(OAc)2 (4.89 mg, 0.02 mmol, 0.05 equiv), PhI(OAc)2 (192 mg, 0.4 mmol, 1.0 equiv), and nicotinic acid (9.84 mg, 0.08 mmol, 0.2 equiv) were added to the reaction system, and argon protection was re-applied to continue the reaction for 24 hours. After the reaction was completed, the reaction system was filtered through diatomaceous earth in a sand core funnel, concentrated, and separated by column chromatography. The eluent was petroleum ether: ethyl acetate = 5:1. Rotary evaporation and drying gave a colorless viscous liquid compound 1a (50%). Rf = 0.48.

[0175] Step 2:

[0176] Compound 1a is a standard reaction substrate in the methodology. Compound 1a (2000 mg, 5.49 mmol, 1.0 equiv) was placed in a round-bottom flask and dissolved in dioxane (10 ml). A rotor was added, and a circulating water condenser was connected. A 6M HCl solution (30 ml) was added, and the reaction system was heated to 100 degrees Celsius in an oil bath for overnight reaction. After the reaction was completed, the crude product Compound 5 was obtained by rotary evaporation and drying.

[0177] Step 3:

[0178] The crude product compound 5 was protected by two steps: the first step was to dissolve compound 5 (969.95 mg, 5.0 mmol, 1.0 equiv) in THF (100 ml) solution and place it in a round-bottom flask, add a rotor, adjust the pH value of the reaction system to 7 with 1M NaOH aqueous solution, then add NaOH (260 mg, 6.5 mmol, 1.3 equiv), slowly add (Boc)2O (1636.88 mg, 7.5 mmol, 1.5 equiv) under ice bath, remove the ice bath after the addition is complete, react at room temperature, and react for 24 hours. The developing solvent is DCM: MeOH = 20:1. After the reaction is completed, add 1M HCl aqueous solution to adjust the pH value of the reaction system to 2-3, extract EA 3 times (50 ml * 3), separate the liquid with a separatory funnel, dry with Na2SO4, and evaporate to dryness. The compound obtained in the previous step was dissolved in DMF (30 ml) and placed in a round-bottom flask. A rotor was added, KHCO3 (1501.65 mg, 15 mmol, 3.0 equiv) was added, and BnBr (1104.81 mg, 6.5 mmol, 1.3 equiv) was gradually added dropwise, and the reaction was allowed to react at room temperature. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 5:1. After the reaction was completed, 300 ml of water was added, and EA was extracted 6 times (30 ml*6), and then the EA organic phase was washed with water 6 times (30 ml*6). The liquid was separated by a separating funnel, dried with Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain the functional group-protected compound 6 (the three-step yield was 40%). Rf = 0.51.

[0179] Step 4:

[0180] Compound 6 (50 mg, 0.13 mmol, 1.0 equiv) was dissolved in ethanol (1 ml) and placed in a round-bottom flask. A rotor was added, and CF3COOAg (34.4 mg, 0.1558 mmol, 1.2 equiv) was added. Stirring was started, and I2 (49.41 mg, 0.1947 mmol, 1.5 equiv) was slowly added. A rubber stopper was inserted and a balloon was connected. The reaction was allowed to react at room temperature for 12 hours. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 6:1. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate was added to quench the excess I2, and DCM was extracted 3 times (10 ml * 3). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 7 (78%). Rf = 0.69.

[0181] Step 5:

[0182] The previously obtained compound 1a (35.04 mg, 0.10 mmol, 1.0 equiv) and the compound 7 (102.6 mg, 0.20 mmol, 2.0 equiv) were placed in a sealed tube, a rotor was added, and the mixture was dissolved with toluene (1 ml). Pd(OAc)2 (2.46 mg, 0.01 mmol, 0.1 equiv), NBE (18.92 mg, 0.20 mmol, 2.0 equiv), silver pivalate (62.7 mg, 0.30 mmol, 3.0 equiv) and 3-COOMePy (2.74 mg, 0.02 mmol, 0.2 equiv) were added, and the mixture was reacted in an oil bath at 110 degrees Celsius for 12 hours under argon protection. After the reaction was completed, the plate was monitored, and the developing solvent was petroleum ether: ethyl acetate = 5:1. Celite was spread in a suction funnel for suction filtration, rotary evaporation and drying, concentration, and column chromatography separation to obtain compound 8 (65%). Rf=0.44.

[0183] Step 6:

[0184] Compound 8 (1000 mg, 1.36 mmol, 1.0 equiv) was dissolved in a solution (30 mL) of MeOH and AcOH in a volume ratio of 1:1 and placed in a hydrogenation reactor. A rotor was added and 30% Pd(OH)2 / C was added. The reaction was carried out at room temperature with a hydrogen pressure of 20 atm for 72 hours. After the reaction was completed, the reaction system was filtered using a sand core funnel covered with diatomaceous earth, and the pH of the reaction system was adjusted to 8 with a saturated Na2CO3 solution. DCM (30 ml * 3) was extracted 3 times, separated by a separatory funnel, dried with Na2SO4, and rotary evaporated to dryness to obtain compound 9 (71%). The developing solvent was petroleum ether: ethyl acetate = 2:1, and then the reaction was carried out twice. Rf = 0.20.

[0185] Step 7:

[0186] Place FDPP (49.96 mg, 0.13 mmol, 1.30 equiv) and anhydrous DMA (300 ml) in a round-bottom flask. Connect an argon balloon to evacuate the air in the flask and add argon. Repeat this evacuation and ventilation process three times. Dissolve the mixture of compound 9 (61.3 mg, 0.10 mmol, 1.0 equiv) in anhydrous DMA (10 ml) in the previous step and add it dropwise to the reaction system with a syringe. The dripping rate is about 1 hour for 1 ml of the mixed solution of compounds 9 and 10. One drop every 30 seconds. React for 48 hours. After the reaction is completed, monitor with a spot plate, and the developing solvent is petroleum ether: ethyl acetate = 2:1. Dissolve DMA in 3000 ml of water, extract EA 3 times (50 ml*3), separate with a separatory funnel, dry with anhydrous sodium sulfate, rotary evaporate to dryness, concentrate, and separate by column chromatography to obtain compound I-1 (42%). Rf = 0.31.

[0187] Embodiment 2:

[0188] I-2: Synthesis of RP66453 skeleton

[0189]

[0190] Synthesis route such as Figure 6 ;

[0191] Step 1:

[0192] Compound 13 was protected by two steps: In the first step, compound 5 (969.95 mg, 5.0 mmol, 1.0 equiv) was dissolved in THF (100 ml) and placed in a round-bottom flask. A rotor was added. The pH value of the reaction system was adjusted to 7 using a 1M NaOH aqueous solution. NaOH (260 mg, 6.5 mmol, 1.3 equiv) was then added. (Boc)2O (1636.88 mg, 7.5 mmol, 1.5 equiv) was gradually added under an ice bath. After the addition was complete, the ice bath was removed and the reaction was carried out at room temperature for 24 hours. The developing solvent was DCM: MeOH = 20:1. After the reaction was completed, an HCl aqueous solution was added to adjust the pH value of the reaction system to 2-3, and EA was extracted 3 times (30 ml*3). The solution was separated by a separatory funnel, dried with Na2SO4, and evaporated to dryness. The compound obtained in the previous step was dissolved in DMF (30 ml) and placed in a round-bottom flask. A rotor was added, KHCO3 (1501.65 mg, 15 mmol, 3.0 equiv) was added, and BnBr (1104.81 mg, 6.5 mmol, 1.3 equiv) was gradually added dropwise. The reaction was allowed to react at room temperature. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 3:1. 300 ml of water was added to dissolve DMF, and EA was extracted 6 times (30 ml*6), and then the EA organic phase was washed with water 6 times (30 ml*6). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 14 (95%) with functional group protection. Rf = 0.35.

[0193] Step 2:

[0194] Compound 14 (149.32 mg, 0.40 mmol, 1.0 equiv) was dissolved in DMF (5 ml) and placed in a round-bottom flask. A rotor was added, K2CO3 (82.93 mg, 0.60 mmol, 1.5 equiv) was added, a rubber stopper was inserted, an argon balloon was connected, and MeI (68.13 mg, 0.48 mmol, 1.2 equiv) was slowly added dropwise using a syringe in a fume hood. The reaction was carried out at room temperature and the plate was monitored until the reaction was complete. The developing solvent was petroleum ether: ethyl acetate = 3:1. After the reaction was completed, 50 ml of water was added to the reaction system, and EA was extracted 3 times (10 ml*3). The EA organic phase was washed with water 3 times (30 ml*3). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 15 (90%). Rf = 0.58.

[0195] Step 3:

[0196] Compound 15 (50 mg, 0.13 mmol, 1.0 equiv) was dissolved in ethanol (1 ml) and placed in a round-bottom flask. A rotor was added, and CF3COOAg (34.4 mg, 0.1558 mmol, 1.2 equiv) was added. Stirring was started, and I2 (49.41 mg, 0.1947 mmol, 1.5 equiv) was slowly added in portions. A rubber stopper was inserted and a balloon was connected on top. The reaction was allowed to react at room temperature for 12 hours. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 3:1. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate was added to quench the excess I2, and DCM was extracted 3 times (10 ml * 3). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 16 (80%). Rf = 0.56.

[0197] Step 4:

[0198] The previously obtained compound 1k (140.16 mg, 0.40 mmol, 1.0 equiv) and the compound 16 (410.4 mg, 0.80 mmol, 2.0 equiv) were placed in a sealed tube, a rotor was added, and the mixture was dissolved with toluene (3 ml). PdCl2 (14.19 mg, 0.08 mmol, 0.2 equiv), NBE (75.68 mg, 0.80 mmol, 2.0 equiv), AgOAc (265.87 mg, 1.60 mmol, 4.0 equiv) and 3-COOMePy (21.94 mg, 0.16 mmol, 0.4 equiv) were added, and the mixture was reacted in an oil bath at 110 degrees Celsius for 12 hours under argon protection. After the reaction was completed, the plate was monitored, and the developing solvent was petroleum ether: ethyl acetate = 3:1. Celite was spread on a suction funnel for suction filtration, rotary evaporation and drying, concentration, and column chromatography separation to obtain compound 17 (45%). R f =0.26.

[0199] Step 5:

[0200] Compound 17 (1000 mg, 1.36 mmol, 1.0 equiv) was dissolved in a solution (30 mL) of MeOH and AcOH in a volume ratio of 1:1 and placed in a hydrogenation reactor. A rotor was added and 30% Pd(OH)2 / C was added. The reaction was carried out at room temperature with a hydrogen pressure of 20 atm for 72 hours. After the reaction was completed, the reaction system was filtered using a sand core funnel covered with diatomaceous earth, and the pH of the reaction system was adjusted to 8 with a saturated Na2CO3 solution. DCM was extracted 3 times (50 ml*3), separated with a separatory funnel, dried with Na2SO4, and rotary evaporated to dryness to obtain compound 18 (76%). The developing solvent was petroleum ether: ethyl acetate = 2:1, and then the reaction was carried out twice. Rf = 0.20.

[0201] Step 6:

[0202] Dissolve TBTU (160.5 mg, 0.5 mmol, 1.5 equiv) and NMM (101.15 mg, 1.0 mmol, 3.0 equiv) in NMP (10 ml) and place in a round-bottom flask. Add a rotor and connect an argon balloon. Dissolve compound 18 (200 mg, 0.333 mmol, 1.0 equiv) in NMP (2 ml) and slowly add it to the reaction system with a syringe at a rate of about 5 ml per hour. After the addition is complete, react at room temperature for 2 hours. Monitor with a spot plate, and the developing solvent is petroleum ether: ethyl acetate = 2:1. After the reaction is complete, slowly add 20 ml of water. Extract with EA 3 times (10 ml*3), separate with a separatory funnel, dry with Na2SO4, rotary evaporate to dryness, concentrate, and separate by column chromatography to obtain compound I-2 (33%). R f =0.40.

[0203] Embodiment 3:

[0204] I-3: Synthesis of Arylomycin A2 Skeleton:

[0205]

[0206] Synthesis route such as Figure 7 As shown;

[0207] Step 1:

[0208] Compound 20 was protected by two steps: In the first step, compound 5 (969.95 mg, 5.0 mmol, 1.0 equiv) was dissolved in THF (100 ml) and placed in a round-bottom flask. A rotor was added. The pH value of the reaction system was adjusted to 7 using a 1M NaOH aqueous solution. NaOH (260 mg, 6.5 mmol, 1.3 equiv) was then added. (Boc)2O (1636.88 mg, 7.5 mmol, 1.5 equiv) was gradually added under an ice bath. After the addition was complete, the ice bath was removed and the reaction was carried out at room temperature for 24 hours. The developing solvent was DCM: MeOH = 20:1. After the reaction was completed, an HCl aqueous solution was added to adjust the pH value of the reaction system to 2-3, and EA was extracted 3 times (30 ml*3). The solution was separated by a separatory funnel, dried with Na2SO4, and evaporated to dryness. The compound obtained in the previous step was dissolved in DMF (30 ml) and placed in a round-bottom flask. A rotor was added, KHCO3 (1501.65 mg, 15 mmol, 3.0 equiv) was added, and BnBr (1104.81 mg, 6.5 mmol, 1.3 equiv) was gradually added dropwise. The reaction was allowed to react at room temperature. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 3:1. After the reaction was completed, 300 ml of water was added to dissolve DMF, and EA was extracted 6 times (30 ml*6), and the EA organic phase was washed with water 6 times (30 ml*6). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain the functional group-protected compound 21 (two-step yield was 93%). Rf = 0.25.

[0209] Step 2:

[0210] Compound 21 (149.32 mg, 0.40 mmol, 1.0 equiv) was dissolved in DMF (5 ml) and placed in a round-bottom flask. A rotor was added, and K2CO3 (82.93 mg, 0.60 mmol, 1.5 equiv) was added. A rubber stopper was inserted, and an argon balloon was connected. MeI (68.13 mg, 0.48 mmol, 1.2 equiv) was slowly added dropwise using a syringe in a fume hood. The reaction was carried out at room temperature and the plate was monitored until the reaction was complete. The developing solvent was petroleum ether: ethyl acetate = 3:1. After the reaction was completed, 50 ml of water was added to the reaction system, and EA was extracted 3 times (10 ml*3), and then the EA organic phase was washed with water 3 times (30 ml*3). The liquid was separated using a separatory funnel, dried with Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 22 (91%). R f =0.40.

[0211] Step 3:

[0212] Compound 22 (50 mg, 0.13 mmol, 1.0 equiv) was dissolved in ethanol (1 ml) and placed in a round-bottom flask. A rotor was added, and CF3COOAg (34.4 mg, 0.1558 mmol, 1.2 equiv) was added. Stirring was started, and I2 (49.41 mg, 0.1947 mmol, 1.5 equiv) was slowly added in portions. A rubber stopper was inserted and an argon balloon was connected. The reaction was allowed to react at room temperature for 12 hours. The reaction was monitored by a spot plate until the reaction was completed. The developing solvent was petroleum ether: ethyl acetate = 5:1. After the reaction was completed, a saturated aqueous solution of sodium thiosulfate was added to quench the excess I2, and DCM was extracted 3 times (10 ml * 3). The liquid was separated by a separatory funnel, dried by Na2SO4, rotary evaporated and dried, concentrated, and separated by column chromatography to obtain compound 23 (78%). Rf = 0.35.

[0213] Step 4:

[0214] The previously obtained compound 1k (140.16 mg, 0.40 mmol, 1.0 equiv) and the compound 23 (410.4 mg, 0.80 mmol, 2.0 equiv) were placed in a sealed tube, a rotor was added, and the mixture was dissolved with toluene (3 ml). PdCl2 (14.19 mg, 0.08 mmol, 0.2 equiv), NBE (75.68 mg, 0.80 mmol, 2.0 equiv), AgOAc (265.87 mg, 1.60 mmol, 4.0 equiv) and 3-COOMePy (21.94 mg, 0.16 mmol, 0.4 equiv) were added, and the mixture was reacted in an oil bath at 110 degrees Celsius for 12 hours under argon protection. After the reaction was completed, the plate was monitored, and the developing solvent was petroleum ether: ethyl acetate = 5:1, and the reaction was repeated twice. Celite was spread on the filtration funnel for filtration, the mixture was evaporated to dryness, concentrated, and separated by column chromatography to obtain compound 24 (40%). Rf = 0.45.

[0215] Step 5:

[0216] Compound 24 (1000 mg, 1.39 mmol, 1.0 equiv) was dissolved in a solution (30 mL) of MeOH and AcOH in a volume ratio of 1:1 and placed in a hydrogenation reactor. A rotor was added and 30% Pd(OH)2 / C was added. The reaction was carried out at room temperature with a hydrogen pressure of 20 atm for 72 hours. After the reaction was completed, the reaction system was filtered using a sand core funnel covered with diatomaceous earth, and the pH of the reaction system was adjusted to 8 with a saturated Na2CO3 solution. DCM was extracted 3 times (30 ml*3), separated with a separatory funnel, dried with Na2SO4, and rotary evaporated to dryness to obtain compound 25 (65%). The developing solvent was petroleum ether: ethyl acetate = 2:1, and then the reaction was carried out twice. Rf = 0.20.

[0217] Step 6:

[0218] Dissolve TBTU (160.5 mg, 0.5 mmol, 1.5 equiv) and NMM (101.15 mg, 1.0 mmol, 3.0 equiv) in NMP (10 ml) and place in a round-bottom flask. Add a rotor and connect an argon balloon. Dissolve compound 25 (200 mg, 0.333 mmol, 1.0 equiv) in NMP (2 ml) and slowly drop it into the reaction system with a syringe at a rate of about 5 ml per hour. After the addition is complete, react at room temperature for 2 hours. Monitor with a spot plate, and the developing solvent is petroleum ether: ethyl acetate = 2:1. After the reaction is complete, slowly add 20 ml of water. Extract with EA 3 times (10 ml*3), separate with a separatory funnel, dry with Na2SO4, rotary evaporate to dryness, concentrate, and separate by column chromatography to obtain compound I-3 (32%). Rf = 0.20.

[0219] Verification of the construction of new chiral centers by prochiral induced hydrogenation reactions (e.g. Fig.42 shown):

[0220] This section aims to explore the selectivity of the chiral center of the newly generated amine after hydrogenation of the methoxy oxime fragment in 2-methoxyiminoacyl. Fig.42 As shown in the figure, two substrates with different aromatic substituents were selected for hydrogenation exploration. Under the action of palladium hydroxide on carbon and hydrogen, an amine of the corresponding structure was obtained. However, the chiral center of the structure was difficult to determine. Therefore, the amine structure and the carboxyl end of the amino acid fragment in the molecule were intramolecularly amided to obtain a six-membered cyclic lactam. Then, through 1H-1HNOESY detection, the following was obtained: Fig.42 The hydrogenation selectivity results are shown; for the 3a system, the dr ratio between S and R is 4:1 (new chiral configuration), while for the 4n system, the dr ratio between S and R is 2:1 (new chiral configuration).

[0221] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes, and they can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to the specific details and the illustrations shown and described herein.

Claims

1. A method for preparing a biphenyl bridged cyclic peptide compound, characterized in that: The structural formula of the biphenyl bridged cyclic peptide compound is: Where n is 0 or 1; The preparation method of the biphenyl bridged cyclic peptide compound comprises: reacting compound A and compound B under the action of a catalyst to obtain the biphenyl bridged cyclic peptide compound; The structural formula of the compound A is: The structural formula of the compound B is: Where n is 0 or 1.

2. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 1, characterized in that: The structural formula of the biphenyl bridged cyclic peptide compound is the compound shown in Formula I-1: The preparation method of the compound represented by formula I-1 comprises the following steps: Step 1: Compound 1I is subjected to transition metal Pd-catalyzed carbon-hydrogen bond activation methyl etherification to obtain compound 1a; The structural formula of the compound II is: The structural formula of the compound 1a is: Step 2: Compound 1a is subjected to acid hydrolysis, two-step reaction to add protective groups, and aryl iodination to obtain compound 7; The structural formula of the compound 7 is: Step 3, Compound 1a and Compound 7 are catalyzed by transition metal to obtain Compound 8; The structural formula of the compound 8 is: Step 4: Compound 8 is debenzylated and methoxy oxime is hydrogenated to obtain compound 10; The structural formula of the compound 10 is: Step 5: subjecting the carboxyl group and the amino group in compound 10 to amide condensation to obtain a compound of formula I-1, wherein the compound of formula I-1 has a 2-methoxyiminoacyl group as a directing group, and the methoxy oxime fragment thereof is hydrogenated to form an S-configuration chiral compound.

3. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 2, characterized in that: The process of step 1 is as follows: dissolving compound 1I in MeOH, then adding Pd(OAc)2, PhI(OAc)2, K2CO3, and nicotinic acid for the first time, stirring and reacting at 35-45° C. for 6-10 hours under the protection of inert gas, then heating to 75-85° C. for 14-18 hours, cooling the reaction system to room temperature, adding Pd(OAc)2, PhI(OAc)2, and nicotinic acid to the reaction system for the second time, and continuing to react for 18-28 hours under the protection of inert gas; after the reaction is completed, filtering, concentrating, separating by column chromatography, and rotary evaporating to dryness to obtain compound 1a; The molar volume ratio of the compound 1I to MeOH is: 0.2-0.6 mmol: 1-5 mL; the molar ratio of the compound 1I to the first added Pd(OAc)2, PhI(OAc)2, K2CO3 and nicotinic acid is: 0.2-0.6: 0.01-0.03: 0.6-1: 0.2-0.6: 0.06-0.1; the molar ratio of the compound 1I to the second added Pd(OAc)2, PhI(OAc)2 and nicotinic acid is: 0.2-0.6: 0.01-0.03: 0.2-0.6: 0.06-0.1; The process of step three is: dissolving compound 1a and compound 7 in toluene, adding Pd(OAc)2, NBE, silver pivalate and 3-COOMePy, protecting under inert gas, reacting at 100-120°C for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 8; the molar ratio of compound 1a to compound 7 is 1:1.5-3; the molar volume ratio of compound 1a to toluene is 0.1mmol:0.8-1.2mL; the molar ratio of compound 1a to Pd(OAc)2, NBE, silver pivalate and 3-COOMePy is 0.05-0.15:0.005-0.015:0.0.1-0.3:0.2-0.4:0.01-0.

03.

4. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 2, characterized in that: The process of step 4 is as follows: dissolving compound 8 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding Pd(OH)2 / C with a mass fraction of 25-35%, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 10; The process of step five is as follows: pentafluorophenyl diphenyl phosphate and anhydrous DMA are placed in a reactor, protected by inert gas, a mixture of compound 10 is dissolved in anhydrous DMA and then added dropwise to the reaction system; the reaction is performed for 40 to 55 hours; after the reaction is completed, extraction, separation, drying, rotary evaporation, concentration, and column chromatography are performed to obtain compound I-1; the molar volume ratio of pentafluorophenyl diphenyl phosphate and anhydrous DMA is 0.1 to 0.15 mmol: 250 to 350 mL; the molar ratio of compound 10 to pentafluorophenyl diphenyl phosphate is 0.1: 0.12 to 0.

15.

5. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 1, characterized in that: The structural formula of the biphenyl bridged cyclic peptide compound is the compound shown in Formula I-2: The preparation method of the compound represented by formula I-2 comprises the following steps: Step A: Compound 13 is used as a substrate, and compound 16 is obtained by sequentially performing two steps of reaction: adding a protective group, hydroxymethylation, and aryl iodination; The structural formula of the compound 13 is: The structural formula of the compound 16 is: Step B: Compound 16 and compound 1k are subjected to transition metal Pd-catalyzed carbon-hydrogen bond activated arylation to obtain compound 17; The structural formula of the compound 1k is: The structural formula of the compound 17 is: Step C: Compound 17 is debenzylated and methoxy oxime is hydrogenated to obtain compound 18; The structural formula of the compound 18 is: Step D: The carboxyl group and aminoamide in compound 18 are condensed to obtain a compound of formula I-2; and the compound of formula I-2 has 2-methoxyiminoacyl as the directing group, and the methoxy oxime fragment therein is hydrogenated to form an S-configuration chiral compound.

6. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 5, characterized in that: The process of step B is as follows: dissolving compound 1k and compound 16 in toluene, adding PdCl2, NBE, AgOAc and 3-COOMePy, protecting under inert gas, reacting at 100-120° C. for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 17; the molar ratio of compound 1k to compound 16 is 1:1.5-3; the molar volume ratio of compound 1k to toluene is 0.4mmol:2-5mL; the molar ratio of compound 1k to PdCl2, NBE, AgOAc and 3-COOMePy is 0.3-0.5:0.06-0.1:0.6-1:1.2-1.8:0.14-0.18; The process of step C is as follows: dissolving compound 17 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding Pd(OH)2 / C with a mass fraction of 25-35%, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 18; The process of step D is as follows: O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine are dissolved in N-methylpyrrolidone and placed in a reactor, protected by inert gas, a mixture of compound 18 is dissolved in N-methylpyrrolidone and then added dropwise to the reaction system; react for 1 to 3 hours; after the reaction, add water, extract, separate, dry, rotary evaporate to dryness, concentrate, and separate by column chromatography to obtain compound I-2; the molar ratio of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine is 1:1.5-2.5; the molar ratio of compound 18 to O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid is 1.2 to 2:

1.

7. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 1, characterized in that: The structural formula of the biphenyl bridged cyclic peptide compound is the compound shown in Formula I-3: The preparation method of the compound represented by formula I-3 comprises the following steps: Step a: Compound 20 is used as a substrate, and compound 23 is obtained by sequentially performing two steps of reaction: adding a protective group, hydroxymethylation, and aryl iodination; The structural formula of the compound 20 is: The structural formula of the compound 23 is: Step b: Compound 23 and compound 1k are subjected to transition metal Pd-catalyzed carbon-hydrogen bond activated arylation to obtain compound 24; The structural formula of the compound 1k is: The structural formula of the compound 24 is: Step c: Compound 24 is debenzylated and methoxy oxime is hydrogenated to obtain compound 25; The structural formula of the compound 25 is: Step d: The carboxyl group and the amino group in compound 25 undergo amide condensation to obtain a compound of formula I-3; and the compound of formula I-3 uses 2-methoxyiminoacyl as the directing group, and the methoxy oxime fragment therein is hydrogenated to form an S-configuration chiral compound.

8. The method for preparing the biphenyl bridged cyclic peptide compound according to claim 7, characterized in that: The process of step b is: dissolving compound 1k and compound 23 in toluene, adding PdCl2, NBE, AgOAc and 3-COOMePy, protecting under inert gas, reacting at 100-120°C for 10-15 hours, filtering after the reaction, rotary evaporation and drying, concentrating, and separating by column chromatography to obtain compound 24; the molar ratio of compound 1k to compound 23 is 1:1.5-3; the molar volume ratio of compound 1k to toluene is 0.4mmol:2-5mL; the molar ratio of compound 1k to PdCl2, NBE, AgOAc and 3-COOMePy is 0.3-0.5:0.06-0.1:0.6-1:1.2-1.8:0.14-0.18; The process of step c is as follows: dissolving compound 24 in a solution of MeOH and AcOH in a volume ratio of 1:1, placing the solution in a hydrogenation reactor, adding Pd(OH)2 / C with a mass fraction of 25-35%, reacting at room temperature, a hydrogen pressure of 20 atm, and reacting for 65-80 hours; after the reaction is completed, filtering, adjusting the pH of the reaction system to 8; extracting, separating, drying, and rotary evaporating to obtain compound 25; The process of step d is: dissolving O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine in N-methylpyrrolidone and placing in a reactor, protecting with inert gas, dissolving a mixture of compound 25 in N-methylpyrrolidone and adding dropwise to the reaction system; reacting for 1 to 3 hours; after the reaction, adding water, extracting, separating, drying, rotary evaporation and rotary drying, concentrating, and separating by column chromatography to obtain compound I-2; the molar ratio of O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid and N-methylmorpholine is 1:1.5-2.5; the molar ratio of compound 25 to O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid is 1.2-2:

1.

9. Use of a biphenyl-bridged cyclic peptide compound prepared by the preparation method according to any one of claims 1 to 8 in the preparation of antibiotics or antagonists.

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