WO2010012222A1 - Peptidyl boric aicd and its ester derivatives, synthesis and use thereof - Google Patents

Abstract

The present invention provides a kind of boric aicd and its ester compounds as follows of formular I, in which R¹ and R² are substituted or unsubstituted C_1-10 alkyl, C_3-6 or heteroalkyl, benzyl, menaphthyl or indylmethyl, the said substituent of R¹ and R² is C_1-4 alkyl, cyano, hydroxyl, sulfhydryl, amino or halogen; Z₁ or Z₂ independently is hydroxyl, C_1-10 alkyl, C_1-10 alkoxy or aryloxy, or B, Z₁ and Z₂ can form a heterocycle including N, S or O; Pg is substituted or unsubstituted bicycle or tricycle acyl including an unsaturated cycle at least, the said substituent is C_1-4 alkyl, C_1-4 alkoxy, halogen or C_1-4 haloalkyl. The present invention also provides the preparation method of such compounds and their anticancer uses.

Description

 Peptide boric acid and ester compound thereof, preparation method and use thereof

Technical field

 The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a novel peptide boric acid and an ester compound thereof and the application thereof in pharmacodynamics. Background technique

 Currently, malignant tumors are still one of the major diseases that threaten people's lives. The American Cancer Society reported in the December 17th, 2007, Global Cancer Facts and Data that in 2007, there were 12 million new cancer patients worldwide, and 7.6 million people died of cancer, equivalent to 20,000 deaths per day. Among them, 6.7 million new cancer patients in developed countries, 4.7 million died of cancer; 5.4 million new cancer patients in developing countries, and 2.9 million died of cancer. In China, according to statistics from the Ministry of Health, the national prevalence of malignant tumors in China has reached 1.15%. According to the current total population of 1.3 billion, the number of newly-increased patients in China is about 1.485 million, and the national prevalence of benign tumors is 0.93%. According to the national total population of 1.3 billion, the number of benign tumor patients in China is about 1.2 million, and the total number of cancer patients is about 2.685 million. From the perspective of tumor mortality, the annual mortality rate of cancer patients in China is about 119.54 deaths per 100,000 people in the country. That is to say, the number of cancer deaths in the country is about 1.54 million per year, and the urban death rate is slightly higher than that in rural areas. mortality rate. Although cancer treatment has made great progress, it has not yet been able to fundamentally treat cancer. Although the anti-cancer drugs currently on the market have certain curative effects, they are mostly cytotoxic drugs with serious side effects. Therefore, how to develop targeted new anticancer drugs from effective tumor targets has become a top priority.

It has been confirmed that the degradation pathway of ubiquitin-proteasome plays a very important role in the regulation of many physiological processes and the development of many important human diseases. For example, if this process excessively degrades the tumor suppressor _P 53 and the cyclin-dependent kinase inhibitor ρ27 ^Ώρ1 , it causes tumorigenesis and leads to uncontrolled proliferation of human cancer cells. At the same time, this process has also played a key role in immune surveillance, muscle atrophy, regulation of metabolic processes, acquisition of long-term memory, and regulation of circadian rhythms. Recently, this process has also been found in neurodegenerative diseases, Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), and Parkinson' disease (PD). Huntington's disease (HD), cortical striatum-Creutzfeld-Jacob disease (CJD), and the onset of diabetes have a large impact.

In this critical pathway, the proteasome plays a very important catalytic role. Proteasome is ATP dependent The protease hydrolysis complex is the main enzyme system for decomposing endogenous proteins in eukaryotic cells and belongs to the family of threonine proteases. The largest proteasome component is the largest and most complex protein ever discovered, accounting for approximately 1-2% of all gene products. The proteasome density gradient centrifugal sedimentation coefficient is 26S, so it is also called 26S proteasome. It consists of catalytic particles (CP) and regulatory particles (RP). The sedimentation coefficient of CP is 20S, so it is also called 20S proteasome, molecular weight 700~750kD, CP consists of multiple catalytic subunits with molecular weight of 20~30kD; RP has triploid ATPase subunit (RP triple ATPase, Rpt) and non-ATPase subunit (RP non- ATPase) , RPn), molecular weight between 30~110kD.

 The 26S proteasome is a cylindrical symmetrical structure with two "caps"-like 19S proteasomes at the ends and two "bucket"-like 20S proteasomes in the middle. Although this proteasome is generally referred to as the 26S proteasome and was originally considered to have a molecular weight of 1000 kD or 1500 kD, more precise measurements in recent years have shown a sedimentation coefficient of 30 s and a molecular weight of 2000 kD. Baumeister et al. used digital mirror analysis coupled with electron microscopy to show that the complexes extracted from amphibians, mammals, higher plants and yeast have a fairly consistent structure.

 X-rays showed that the 20S proteasome of the archaeal heat source T. acidophilur was cylindrical, with a length of 148 people, a maximum diameter of 113 A, and a minimum diameter of 75 A. It consisted of four rings with a total of 28 subunits. According to the (0C1-0C7, β1-β7)^ method, they are stacked in an orderly manner and are expressed as 7 symmetry. The center is the channel that runs through the entire particle. There are three large cavities inside the particle, and the larger cavity in the middle is the place where the protein is hydrolyzed. The entrance to the chamber is located in the center of each ring, which is narrow enough to control the entry of proteins on the one hand and the partially hydrolyzed substrate from the active site on the other hand. In recent years, X-ray confirmed that the 20S proteasome and yeast of mammalian cattle have the same sequence of subunits, and the primary structural characteristics are similar to those of yeast, which is highly conserved. However, the high-grade structure of the 20S proteasome of cattle is different from that of yeast. Among them, subunits such as oc2, β1, β5, β6 and β7 are different. Moreover, in the 20S proteasome of bovine, the β7 subunit has the activity of a terminal nucleophilic hydrolase, and the cleft of this active site is smaller than that of the β1, β2 and β5 subunits.

Small molecule inhibitors generally only act on the catalytic site of the 20S proteasome. The eukaryotic 20S proteasome contains six active sites, three on each beta loop, located on the β1, β2 and β5 subunits, respectively. The 20S proteasome has been found to have three distinct enzymatic activities: 1. chymotrypsin-like (CT-L) activity, hydrolyzing peptide bonds after large hydrophobic amino acid residues, the active site is mainly located on the β5 subunit 2, trypsin-like (TL) activity, hydrolyze peptide bonds after basic amino acid residues, the active site is mainly located in the β2 subunit; 3, polypeptide-glutamyl-peptide hydrolase activity (postglutamyl-hydrolase) , PGPH), hydrolyzes the peptide bond after the acidic amino acid residue, and the active site is mainly located in the βΐ subunit. However, it was later found that the decomposition of aspartic acid residues at this site is faster than glutamic acid, so it is called half. Caspase-like activity. (Caspase is an intracellular lysine-degrading enzyme that acts on the cell's metabolic apoptotic pathway and acts only on aspartate residues). It should be noted that these names only express their similarities with traditional proteolytic enzymes and are not to be construed as the same catalytic or physiological function.

 If the above three activities are inhibited, the proteasome shows two other activities: one is to preferentially hydrolyze the peptide bond activity (BrAAP activity) after the amino acid residue with the branched side chain; the other is small The activity of the peptide bond after hydrolysis of the neutral amino acid residue (SNAAP activity). However, studies using methods such as X-ray diffraction, kinetics, and site-directed mutagenesis have shown that new sites with these two activities do not exist. Moreover, the decomposition of branched chain amino acids (such as leucine, isoleucine and valine) is mainly carried out by a caspase site, and the chymotrypsin-like site is slightly weak. Therefore, the names of the proteasome active sites do not reflect all of their properties.

 Currently reported proteasome inhibitors can be divided into two broad categories: covalent bond inhibitors and non-covalent bond inhibitors. Covalent bond inhibitors include peptide aldehydes, α-ketoamides, peptide boronic acids and esters thereof, peptide vinyl sulfones, natural products TMC-95-AD, β-lactone compounds, epoxy ketone compounds, and the like; Non-covalent bond inhibitors include tea polyphenols and 2-substituted aminobenzyl statines. Among these inhibitors, a dipeptide boronic acid Bortezomib (PS-341) has been marketed. The drug is a new anti-tumor drug developed by Millennium Pharmaceuticals. It was approved by the US FDA on May 13, 2003 under the trade name VelcadeTM (each containing bortezomib sterile powder 3.5mg, only For intravenous injection) is listed in the United States. In April 2004, the drug was approved for listing in the European Union. On September 21, 2005, the drug was first listed in Guangzhou, China by Xi'an Yangsen. In 2005, the drug won the "PrixGalien" award for the Nobel Prize in medicine in France, Belgium and the Netherlands. On July 11, 2007, the drug was approved by the US FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). It is currently the only drug approved by the FDA for the treatment of MCL. The successful launch of this drug has further demonstrated that the proteasome can be used as a new target for the design of anti-tumor drugs.

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 SUMMARY OF THE INVENTION An object of the present invention is to provide a novel boric acid and borate compound having a novel structure and having a function of inhibiting proteasome. As a 20S proteasome inhibitor, they can block tumor cell proliferation and induce tumor cell apoptosis, which can be used for the treatment and prevention of various diseases such as malignant tumors in humans and animals.

 Another object of the present invention is to provide a process for producing the above-described peptide boronic acid and an ester compound thereof.

 Still another object of the present invention is to provide an application of the above-described peptide boronic acid and an ester compound thereof for the preparation of an antitumor drug.

 The object of the present invention can be specifically achieved by the following measures:

a peptide boric acid and an ester compound thereof, the structure of which is as shown in formula I,

Where _:

1^ or independently a substituted or unsubstituted fluorenyl group of 10 to 10, a C3 to 6 cyclodecyl or heterocyclic fluorenyl group, a benzyl group, a naphthylmethyl group or a fluorenylmethyl group, 1 or 1 ₂ is preferred. Each is independently substituted or unsubstituted decyl, benzyl, naphthylmethyl or fluorenylmethyl, most preferably substituted or unsubstituted decyl, benzyl, 1-naphthyl The group, 2-naphthylmethyl or fluorenylmethyl, R _{2 is} most preferably a substituted or unsubstituted fluorenyl or benzyl group of Cl 10 . The substitution or substitution of R ₂ or R _{2 does} not mean narrowly the sulfhydryl group of Cl 10 , but extends to all such groups, ie substituted or unsubstituted C 3 -6 cyclodecyl or hetero a fluorenyl group, a substituted or unsubstituted benzyl group, a substituted or unsubstituted naphthylmethyl group, a substituted or unsubstituted fluorenylmethyl group, etc., wherein the substituent is a fluorenyl group, a cyano group, a hydroxy group of Cl 1-4 A mercapto group, an amino group or a halogen, preferably a fluorenyl group or a halogen of Cl 4 .

¾ or Σ ₂ are each independently hydroxy, Cl~10 the embankment group, Cl~10 the embankment or aryloxy group, or B, ¾, and Σ ₂ - is formed from N, S or a heterocyclic group containing 0 3⁄4 or ∑ ₂ is preferably independently a hydroxyl group, a decyl group of Cl~10, a decyloxy group or an aryloxy group of Cl~10, or B, 3⁄4 and ∑ _{2 together} to form a boric acid-a-decanediol ester. 3⁄4 or Z _{2 is} most preferably independently a hydroxyl group, or B, 3⁄4 and ∑ _{2 together} form a boronic acid-a-decanediol ester.

 Pg is a substituted or unsubstituted bicyclic acyl or tricyclic acyl group containing at least one unsaturated ring, preferably a substituted or unsubstituted tetrahydronaphthoyl group, wherein the substituent is a fluorenyl group of Cl 4 , a decyloxy group of Cl~4, a halogen or a halogenated fluorenyl group of Cl~4. Further, Pg is preferably:

Wherein R ₃ or R 4 are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl.

 The term "mercapto" is used to mean a saturated hydrocarbon group, the fluorenyl group of Cl~10 means a saturated hydrocarbon group having 1 to 10 carbon atoms, and the fluorenyl group of Cl~4 means a saturated hydrocarbon group having 1 to 10 carbon atoms.

The term "cycloalkyl" refers to a non-aromatic carbocyclic group, including a cyclized fluorenyl group. Cyclodecyl groups may include bicyclic or polycyclic systems System. Examples of the cyclodecyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclodecyl group of C3 to 6 means a cyclodecyl group having 1 to 10 carbon atoms.

The term "benzyl" refers to benzyl, and substituted benzyl means that at least one hydrogen atom on the phenyl ring of the benzyl group is substituted by a non-hydrogen moiety, and the substituent of the benzyl group may be halogen, -CN, -OH, - SH, -NH ₂ , a linear or branched fluorenyl group of 1 to 6 carbons, a substituted linear or branched fluorenyl group of 1 to 6 carbons.

 The term "heterocyclic fluorenyl" refers to a non-aromatic heterocarbocyclyl group including a cyclized fluorenyl group in which one or more ring-forming carbon atoms are replaced by a hetero atom such as a 0, N or S atom. The heterocyclic fluorenyl group preferably has 3, 4, 5, 6 or 7 ring-forming atoms.

 "1-naphthylmethyl" means

'2-naphthylmethyl" means

"吲哚methyl" means

"Methoxy group" means an -O-fluorenyl group having a carbon number of usually 1 to 10. Examples of the decyloxy group include methoxyethoxy group, propoxy group (e.g., _n -propoxy group and isopropoxy group), t-butoxy group and the like.

 "Aryl" means an aromatic carbocyclic group including monocyclic or polycyclic aromatic hydrocarbons such as phenyl, naphthyl, anthracenyl, phenanthryl and the like.

The "aryloxy group" means a -0-aryl group, and the concept of the aryl group is as described above, and the most preferable example of the aryloxy group is a phenoxy group.

"Halogen" includes fluorine, chlorine, bromine and iodine.

 The compounds of the present invention can be used to prepare antitumor drugs, and the overall preparation route is as follows:

ΙΠ-6 ΙΠ-7 ΙΠ-8 III

I The definition of each group Pg, Ri, R ₂ , Zi, Z ₂ in the reaction formula is as described above, and the formula (II-1) is reacted with methanol under the action of S0C1 ₂ to obtain the formula (11-2), formula (II). -2) Condensation with Pg under peptide condensing agent to form formula (II-3) or formula (II-2) reacts with Pg of acid chloride to form formula (11-3), formula (II-3) saponification and reacidification (II) On the other hand, (III-6) reacts with the metal reagent R ₂ MgX and is further hydrated at room temperature by ^ _{2 2} catalytic formula (111-7), formula (III-7) and MN (SiMe) ₃ ) ₂ reaction to form formula (111-8), formula (III-8) is deprotected under acidic conditions to form formula (III); and finally (II) and (III) are reduced to formula (1). The group attached to B can also be removed by formula (I) to give a boric acid product.

 The preparation of the compounds of the invention is detailed below:

 Ri

Z ₁ )(Z ₂ )

HCI.NH ₂丫B KZ ) pg- B(

 G- OH +

R ₂ OR;

III I

The definitions of Pg, Ri, R ₂ , Z _l7 Z ₂ are as described above.

 The preparation method of the compound (II) includes the following steps:

1) an amino acid of the formula (II-1) is reacted with methanol under the action of SOCl ₂ to obtain a compound of the formula (II-2);

2) A compound of the formula (II-3) can be produced by the following two routes: a. A compound of the formula (II-2) is condensed with Pg in the presence of a peptide condensing agent to form a formula (II-3). a compound; b, Pg reacts with SOCl _{2 to form} an acid chloride, and then reacts with a compound of the formula (II-2) to form a compound of the formula (II-3).

3) A compound of the formula (II-3) is subjected to saponification under basic conditions to form a sodium salt thereof, and then a compound (11) is produced under acidic conditions.

II- II-2 II-3 where, ? The definitions of _§ and 1^ are as described above.

 The peptide condensing agent commonly used in the above reaction is hydrazine, fluorene-dicyclohexyl-carbodiimide (abbreviated as DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. (abbreviated as EDGHC1), 1-hydroxybenzotriazole (abbreviated as HOBt) or isobutyl chloroformate.

The preparation method of the compound (III) includes the following steps (taking B, 3⁄4 and Z _{2 together} to form boric acid - 0C-nonanediol ester as an example):

1) a-pinene represented by formula (III-1) forms chiral decanediol (III-2) under the action of oxidant 804 ₄ ; 2) The dried CH ₂ C1 ₂ is reacted with n-butyllithium at -110 ° C to form an organometallic intermediate represented by the formula (III-3);

 3) a compound of the formula (III-3) is reacted with a boronic acid ester of the formula (III-4) at -11 CTC to form a homologous boronic acid ester of the formula (III-5);

 4) The compound of the formula (III-5) is transesterified with a chiral decanediol of the formula (III-2) to form a formula

a borate ester as shown in (III-6);

5) a compound of the formula (III-6) is reacted with a metal reagent R ₂ MgX at -78 ° C, and then catalyzed by anhydrous ZnCl ₂ at room temperature to form a compound of the formula (III-7);

6) a compound of the formula (III-7) is reacted with MN(SiMe ₃ ) ₂ to form a bis(trimethylsilyl) protected amino boronate such as the compound of the formula (III-8);

 7) A compound represented by the formula (III-8) is subjected to removal of a protective group bis(trimethylsilyl) under acidic conditions to give an amino group-exposed borate compound represented by the formula (III).

Wherein, R1 is as defined above, R ₅ is a linear, branched or substituted anthracene of 1 to 4 carbon atoms, X represents a halogen such as F, Cl, Br, I, and M represents an alkali metal such as Li, Na, K, etc.

- Ί - Finally, compounds (II) and (III) are reacted in the presence of a certain condensing agent to form (1). The condensing agent used is TBTU (0-benzotriazole-oxime, oxime, Ν', Ν,-tetramethyluronium tetrafluoroborate), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (abbreviated as EDOHCl), 1-hydroxybenzotriazole (abbreviated as HOBt) or isobutyl chloroformate.

 If the compound represented by (I) is a boric acid ester, the ester group can be removed to form boric acid by the following reaction: pg,

 I IV

 There are two methods for removing ester groups: First, under the action of sodium periodate, the diol is broken to form the sodium salt of boric acid, and the pH of the system is adjusted to be acidic to obtain boric acid. Second, the boric acid ester and space Boric acid with a higher steric hindrance (such as isobutylboronic acid, phenylboronic acid) is transesterified to obtain the desired product boric acid, and the product is obtained by some separation means.

 The inventors of the present invention have confirmed by experiments that the compounds of the present invention have good proteasome-inhibiting activity and anti-tumor activity, and all of the compounds exhibit better proteasome inhibitory activity and antitumor activity at a nanomolar level, and have broad Value. At the same time, the preparation method of the compound designed by the invention has high yield and simple process, and is suitable for industrial production. ^

 Part I Synthesis of Compounds The preparation of the compounds of the present invention can be carried out as follows:

1. Preparation of Compound (II)

 II-l II-2 II-3 II

1. Preparation of amino acid methyl ester II-2:

The amino acid II-1 without any protecting group was dissolved in anhydrous methanol, and SOCl ₂ was added dropwise to the reaction system at -5 ° C, and the mixture was slowly warmed to room temperature, and then reacted for 1 hour, and refluxed for 1 hour. The solvent was evaporated, and the obtained solid was recrystallized (methanol / diethyl ether) to give the hydrochloride salt of the amino acid methyl ester (form 11-2). 2. Preparation of amino-protected amino acid methyl ester II-3:

 Method a:

 The amino acid methyl ester oxime-2 prepared in the amino protecting agent Pg and 1 was dissolved in THF, and N-methylmorpholine and a suitable peptide condensation reaction reagent (DCC + HOBt) were added at 0 °C. Slowly warm to room temperature and continue to react for a certain period of time until TLC shows the reaction is complete. The insoluble solid was removed by filtration, the filtrate was evaporated to dryness, and an appropriate amount of ethyl acetate was added to dissolve the obtained viscous liquid, and the organic phase was washed with alkali (5% sodium hydrogencarbonate), pickled (10% citric acid), and alkali-washed ( Wash with 5% sodium bicarbonate) and saturated brine. The desiccant was dried (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated to dryness under reduced pressure to give the crude product of amino-protected amino acid methyl ester. The crude product was used in the next step without saponification.

 Method b:

The amino protecting agent Pg was dissolved in SOC1 ₂ at 0 ° C, and a catalytic amount of dry DMF was added thereto, and the mixture was reacted at room temperature for 20 minutes, and heated to 50 ° C for a certain period of time to evaporate unreacted SOCl ₂ . The acid chloride of the protective agent Pg is obtained. Dissolve in an appropriate amount of dry toluene, dry and set aside.

 The amino acid methyl ester II-2 was dissolved in an organic solvent (toluene), an excess of N-methylmorpholine was added, and a toluene solution of the Pg acid chloride prepared above was added dropwise at 0 °C. The reaction was carried out at 0 ° C for a certain period of time, and then slowly raised to room temperature for a certain period of time until TLC showed completion of the reaction. The solvent was distilled off under reduced pressure, and the obtained solid was dissolved with an organic solvent (ethyl acetate), respectively, and washed with alkali (5% sodium hydrogen carbonate), acid (10% citric acid), and alkali (5% sodium hydrogencarbonate) Wash with saturated saline. The desiccant was dried (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a crude product of amino-protected amino acid methyl ester. The crude product was used directly in the next step of saponification without purification.

3. Preparation of compound II:

 The crude product of the above prepared II-3 was dissolved in an organic solvent (acetone), and an aqueous solution of an inorganic base (2N NaOH) was added at 0 ° C to maintain the pH of the system between 11 and 13, until TLC showed The reaction is complete. The organic solvent was distilled off under reduced pressure, and the aqueous phase was extracted twice with an organic solvent (ethyl acetate), and aqueous aqueous solution (5N HCl) was added dropwise at 0 ° C until the pH of the system was between 1 and 3. The organic layer was extracted with an organic solvent (ethyl acetate) and the organic phase was dried (dry sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give the product II.

2. Preparation of Compound (III)

1. Preparation of compound III-a:

III-3 _ln . ₅ III-6a

R ₂ MgX

III-7a ni-8a ^nl - ^a

•OR ₅

ΙΠ-4: R ₅ 0-

OR ₅

1) Preparation of III-2a: Με ₃ ΝΟ·2Η _{20 is} dissolved in water, and III-la, tert-butanol, a small amount of pyridine and a catalytic amount of osmium tetroxide are added to the reaction system. The mixture was heated to reflux for 24 hours at a certain temperature (10 CTC), and the reaction was completed by TLC. Naturally, it was cooled to room temperature, and an appropriate amount of reducing agent (NaHS0 ₃ ) and solid salt were added. The liquid layer was separated, and the aqueous layer was extracted with an organic solvent (diethyl ether), and the organic phase was combined, and the organic phase was dried (dry sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a viscous liquid. The product III-2a was isolated by column chromatography.

2) Preparation of compound III-3:

 Under -11CTC, slowly add n-butyl lithium solution to the anhydrous dichloromethane and anhydrous tetrahydrofuran system protected by inert gas (such as ?? or 八!" gas), and keep -11CTC after the addition is completed. The reaction was carried out for 1 hour to obtain a solution of the compound III-3, which was used in the next step.

3) Preparation of compound III-5:

Under the reaction system of compound III-3 prepared in 2), the boric acid triester of the formula III-4 was slowly added dropwise at -11 CTC, and the -11 CTC was stirred for 1 hour, and then a mineral acid solution (5N HCl) was added. The reaction was quenched and naturally raised to room temperature. The liquid layer was separated, and the aqueous layer was extracted with an organic solvent (diethyl ether), and the organic phase was dried. The desiccant was filtered off, and the solvent was evaporated to dryness to dryness crystals. The product was used in the next step without purification. 4) Preparation of compound III-6a:

 Compound III-5 was dissolved in an organic solvent (anhydrous diethyl ether or dichloromethane), and the prepared III-2a was added thereto. After stirring at room temperature for 18 hours, TLC showed the reaction was completed. The liquid phase was separated, and the aqueous phase was extracted with an organic solvent (ethyl acetate), and the organic phase was combined, and the organic phase was dried with a drying solvent (aqueous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, the solvent was evaporated to dryness under reduced pressure, and the compound III-6a was obtained by column chromatography.

5) Preparation of format reagent ^3⁄4:

Magnesium chips, an anhydrous organic solvent (anhydrous THF or anhydrous ether) and a small iodine tablet were placed in a strictly dried reaction flask. A mixed solution of a halogenated hydrocarbon R ₂ X and an anhydrous organic solvent (anhydrous THF or anhydrous diethyl ether) was added dropwise to the reaction mixture at room temperature. The reaction system was heated to a slightly boiling state with a water bath. After most of the magnesium reaction was completed, the refluxing system was heated for 30 minutes to completely react the remaining magnesium. The reaction system was slowly cooled and set aside.

6) Preparation of compound III-7a:

Under the protection of an inert gas such as N ₂ or Ar gas, III-6a is dissolved in an anhydrous organic solvent (anhydrous THF or diethyl ether), and the reaction system is cooled to a temperature of 78 °C. A solution of the prepared R ₂ MgX format reagent in an organic solvent (anhydrous THF or diethyl ether) in 5) was slowly added dropwise thereto. After the dropwise addition was completed, the dried ZnCl ₂ powder was added. The reaction system was naturally warmed to room temperature, and stirring was continued for 18 h at room temperature. The solid was removed by filtration, and concentrated to give the compound III-7a.

7) Preparation of compound III-8a:

Dissolve III-7a prepared in 6) with an anhydrous organic solvent (anhydrous THF). The reaction system is protected with an inert gas (such as ^ or 八!" gas) and cooled to a temperature of 78 ° C, then slowly added dropwise MN (SiMe ₃ ) ₂ solution. After the addition is completed, it is naturally raised to room temperature and stirring is continued at room temperature. TLC detection shows that the reaction is completed after 20 h. The solvent is evaporated under reduced pressure to give a viscous liquid, dissolved in n-hexane, filtered to remove insoluble. To obtain a positive ruthenium solution of III-8a.

8) Preparation of compound III-a:

The above prepared hexanyl solution of III-8a is protected with an inert gas such as N ₂ or Ar gas and cooled to a temperature of 78 °C. A solution of an organic solvent (e.g., dioxane, diethyl ether) in which hydrogen chloride gas is dissolved is added to the reaction system, and then naturally raised to room temperature to precipitate a solid. After filtration, the filter cake was washed with an organic solvent (diethyl ether) to give Compound III-a. The product was used in the next step without purification. 2. Preparation of compound III-b:

III-lb III-2b

DR ₅

III-4: R ₅ 〇 - B

OR ₅

1) Preparation of III-2b:

Με ₃ ΝΟ·2Η _{20 is} dissolved in water, and III-lb, tert-butanol, a small amount of pyridine, and a catalytic amount of osmium tetroxide are added to the reaction system. The mixture was heated under reflux at a certain temperature (10 CTC) for 48 hours, and the reaction was completed by TLC. Naturally, it was cooled to room temperature, and an appropriate amount of reducing agent (NaHS0 ₃ ) and solid salt were added. The organic solvent was distilled off under reduced pressure, and the organic solvent (diethyl ether and ethyl acetate) was added to the mixture of the mixture of the liquid and the solid, and the aqueous layer was extracted with an organic solvent (diethyl ether and ethyl acetate). It is dried with a drying agent (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a viscous liquid. The product III-2b was obtained by distillation under reduced pressure at a high vacuum.

2) Preparation of compound III-3:

Under -11CTC, slowly add n-butyl lithium solution to anhydrous dichloromethane and anhydrous tetrahydrofuran system protected by inert gas (such as N ₂ or Ar gas), and keep -11CTC to continue reaction after the addition. hour. A solution of compound III-3 was obtained. Used directly in the next step of the reaction.

3) Preparation of compound III-5: The boronic acid triester of the formula III-4 was slowly added dropwise to the reaction system of the compound III-3 prepared in 2) at -110 ° C, and the -11 CTC was stirred for 1 hour, and then a mineral acid solution (5N) was added. HC1) quenched the reaction and naturally rose to room temperature. The liquid layer was separated, and the aqueous layer was extracted with an organic solvent (diethyl ether), and the organic phase was dried. The desiccant was filtered off, and the solvent was evaporated to dryness to dryness crystals. The product was used in the next step without purification.

4) Preparation of compound III-6b:

 Compound III-5 was dissolved in an organic solvent (anhydrous diethyl ether or dichloromethane), and the prepared III-2b was added. After stirring at room temperature for 24 hours, TLC showed the reaction was completed. The organic solvent is distilled off under reduced pressure, and the organic extractant (ethyl acetate or diethyl ether) is added to the remaining viscous liquid, and the aqueous phase is extracted with an organic solvent (ethyl acetate or diethyl ether), and the organic phase is combined, and the organic phase is dried. The agent was dried (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, the solvent was evaporated to dryness under reduced pressure, and the compound III-6b was obtained by column chromatography.

5) Preparation of format reagent ^3⁄4:

Magnesium chips, an anhydrous organic solvent (anhydrous THF or anhydrous ether) and a small iodine tablet were placed in a strictly dried reaction flask. A mixed solution of a halogenated hydrocarbon R ₂ X and an anhydrous organic solvent (anhydrous THF or anhydrous diethyl ether) was added dropwise to the reaction mixture at room temperature. The reaction system was heated with a water bath. The solution was brought to a slightly boiling state. After most of the magnesium reaction was completed, the system was heated to reflux for 30 minutes to completely react the remaining magnesium. The reaction system was slowly cooled and set aside.

6) Preparation of compound III-7b:

Under the protection of an inert gas such as N ₂ or Ar gas, III-6b is dissolved in an anhydrous organic solvent (anhydrous THF or diethyl ether), and the reaction system is cooled to a temperature of 78 °C. A solution of the organic solvent (anhydrous THF or diethyl ether) of the prepared R ₂ MgX format reagent in 5) was slowly added dropwise thereto. After the dropwise addition was completed, the dried ZnCl ₂ powder was added. The reaction system was naturally warmed to room temperature, and stirring was continued for 24 h at room temperature. The solid was removed by filtration, and concentrated to give the compound III-7b.

7) Preparation of compound III-8b:

Dissolve III-7b prepared in 6) with an anhydrous organic solvent (anhydrous THF). The reaction system is protected with an inert gas (such as ^ or 八!" gas) and cooled to a temperature of 78 ° C, then slowly added dropwise MN (SiMe ₃ ) ₂ solution. After the addition is completed, naturally rise to room temperature and continue stirring at room temperature. TLC detection shows that the reaction is completed after 24 hours. The solvent is distilled off under reduced pressure to obtain a viscous liquid. , insoluble matter was removed by filtration to obtain a petroleum ether solution of III-8b. spare.

8) Preparation of compound III-b:

The petroleum ether solution of the above prepared III-8b is protected with an inert gas such as N ₂ or Ar gas and cooled to a temperature of 78 °C. A solution of an organic solvent (e.g., dioxane, diethyl ether) in which hydrogen chloride gas is dissolved is added to the reaction system, and then naturally raised to room temperature to precipitate a solid. Filtration and washing of the filter cake with dry organic solvent (diethyl ether) afforded compound III-b. The product was used in the next step without purification. 3. Preparation of Compound (I)

 II III b !b

1. Preparation of borate ester (I):

Dissolve II and III in an organic solvent (such as THF, CH ₂ C1 ₂ ), cool to -5 ° C, add N-methylmorpholine and a condensing agent (TBTU or EDGHC1 + HOBt or isobutyl chloroformate), After reacting for 2 hours, the mixture was allowed to react to room temperature for 1 hour. The insoluble solid was removed by filtration, and the solvent was evaporated to dryness. The obtained solid was dissolved in an organic solvent (ethyl acetate), and the organic phase was washed with alkali (5% sodium hydrogen carbonate), acid (0.1N hydrochloric acid), alkali (5% sodium hydrogen carbonate) and saturated brine. The organic phase is dried with a drying agent (anhydrous sodium sulfate and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated under reduced pressure to give a glassy solid compound boronic acid I.

 La IVa

Method a: transesterification

The boronic acid ester I prepared in 1 is dissolved in an organic solvent such as diethyl ether and CH ₂ C _{1 2} , and water and phenylboronic acid are added. After stirring the reaction for 4 hours at room temperature, TLC showed the reaction was completed. The organic phase was extracted 3 times with water, the aqueous phases were combined and evaporated to dryness. The resulting viscous solid was washed with a small amount of diethyl ether to give a solid compound of boronic acid IV.

Method b: Oxidative fracture method

The boric acid ester I prepared in 1 was dissolved in an organic solvent (acetone or methanol), and then an aqueous solution of ammonium acetate and NaI0 _{4 were added} . After stirring at room temperature for 24 hours, TLC showed the reaction was completed. The organic solvent is distilled off under reduced pressure, the aqueous phase is adjusted to pH 3 with a mineral acid (hydrochloric acid), extracted with an organic solvent (ethyl acetate or CH ₂ C1 ₂ ), and the organic phase is combined, and the organic phase is dried with a drying agent (anhydrous sulfuric acid) Sodium and anhydrous magnesium sulfate). The desiccant was filtered off, and the solvent was evaporated to dryness under reduced pressure to give the crude compound boric acid IV. The preparation of the compounds of the invention is described below by the synthesis of specific compounds:

1. Preparation of a compound of formula (II):

RI : a = PhCH ₂ ; b = (CH ₃ ) ₂ CHCH ₂ ; c = l-naCH ₂ ; d = 2-naCH ₂ ; e = (CH ₃ ) ₂ CH; f = 3-IndolC g = CH ₃ CH ₂ (CH ₃ )CH;

Pg: A = l-THna _; B = 2-THna; C = l-naTH. Wherein the 1-na structure is; the 3-Indol structure is

The stereo configuration may be a racemate (m) of G), (r) or both;

Type can be (s), (r) or both races; Ι-naTH knot

 1. Preparation of N-1-S)-1,2,3,4-tetrahydronaphthoyl-L-phenylalanine (3aA)

 (1) Preparation of L-phenylalanine methyl ester hydrochloride (la)

ΝΗ ₂ ■ HCI

Add 25 mL of anhydrous methanol to a 100 mL reaction flask, cool to below -10 °C in an ice salt bath, slowly add SOCl ₂ (7 mL, 96 mmol) with stirring, then react at -10 ° C for 10 min, then add L-Benzene. Alanine ( 1.65 g, lOmmol) was reacted at low temperature for 40 min. The ice salt bath was removed, and the mixture was reacted at room temperature for 48 h, concentrated under reduced pressure, and then 15 mL of methanol was added and then concentrated twice under reduced pressure. Add 50 mL of diethyl ether, place it, precipitate the needle crystals, filter and dry, and recrystallize the crude product with methanol-ethyl ether to obtain white crystal L-phenylalanine methyl ester hydrochloride 2.0 g, yield 95%, [a] _D ²⁵ = +37.2 ° (c = 1, CH ₃ CH ₂ OH), mp _: 155-158 ° C.

The hydrochloride of the other amino acid methyl ester used in the present invention can be produced by the above procedure, the compound lb: synthesized by the method of synthesizing the compound la using L-leucine; and the compound lc: by the method of synthesizing the compound la using ί-( Synthesis of β-1-naphthyl)alanine; Compound Id: synthesized by the method of synthesizing compound la using L-(P-2-naphthyl)alanine; Compound le: L-oxime according to the method of synthesizing compound la Acid synthesis; Compound If: synthesized by the method of synthesizing compound la using L-tryptophan; Compound lg _: synthesized by the method of synthesizing compound la using L-isoleucine. The specific compounds synthesized and their properties are shown in the following table.

(2) Preparation of N-l-S)-1,2,3,4-tetrahydronaphthoyl-L-phenylalanine methyl ester (s-2aA)

Method a: DCC condensation method

Compound la (1.12 g, 5.2 mmol) was dissolved in EtOAc (EtOAc) (EtOAcjjjjjj Add 1-(S)-1,2,3,4-tetrahydronaphthoic acid (0.92 g, 5.2 mmol) to another reaction flask, dissolve in THF 20 mL, cool in ice water, and add dicyclohexyl group at 0 ° C. The carbodiimide (DCC) (1.07 g, 5.2 mmol), HOBt (0.84 g, 6.2 mmol) was reacted at 0 ° C for 40 min, then a solution of the neutralized la in THF which had been prepared and cooled was added. The reaction was detected by TLC. After 4 hours, the reaction was completed. The insoluble material N, Ν'-dicyclohexylurea (DCU) was removed by filtration, and the filtrate was added with ethyl acetate 150 mL, respectively, with 5% NaHC0 ₃ solution (30 mL), 10% citric acid solution. (30mL), washed with 5% NaHC0 ₃ solution (30mL) and saturated aqueous sodium chloride (2X20mL). The ethyl acetate layer was dried over anhydrous Na ₂ S0 _4, filtered, and the solvent was evaporated under reduced pressure to give 1.72 g compound, a white solid product, yield 98%. The product was used in the next step without purification.

Method b: acid chloride method To 0 (1), S0C1 ₂ (3.8 ml, 52 mmol) was added to 1-(S)-1,2,3,4-tetrahydronaphthoic acid (0.92 g, 5.2 mmol), followed by a catalytic amount of dry DMF. . The mixture was slowly warmed to room temperature, reacted for 20 minutes, and further heated to 50 ° C for 1 hour to stop the reaction. Unreacted S0C1 _{2 was} distilled off. 1-(S)-1,2,3,4-tetrahydronaphthoyl chloride was obtained. This was dissolved in 10 ml of dry toluene and was used.

The compound la (1.12 g, 5.2 mmol) was dissolved in 20 mL of THF, and N-methylmorpholine (NMM) (0.7 mL, 6.2 mmol) was added, and the 1-(S) prepared above was added dropwise at 0 °C. a toluene solution of -1,2,3,4-tetrahydronaphthoyl chloride. The reaction was carried out at 0 ° C for 2 hours, and then slowly raised to room temperature for 1 hour, and TLC showed the reaction was completed. The solvent was evaporated under reduced pressure, and the obtained solid was dissolved in 30 ml of ethyl acetate, and washed with 5% sodium hydrogen carbonate (30mL), 10% citric acid (30mL), 5% sodium hydrogencarbonate (30mL) and saturated brine (2 X 20mL). The organic phase was dried over anhydrous Na ₂ SO ₄ . The desiccating agent was filtered off, and the solvent was evaporated to dryness to dryness to give a white solid. The product was used in the next step without saponification.

 In view of the fact that the product obtained by the DCC condensation method has high yield and good color, other amino-protected amino acid methyl esters used in the present invention can be prepared by the DCC condensation method described in the embodiment (2), all methyl esters. None of them were purified and used directly in the next step.

Compound m-2aA _: synthesized by 1-1,2,3,4-tetrahydronaphthoic acid and la according to DCC condensation method; r-2aA _: using 1-(R)-1,2,3,4 by DCC condensation method - tetrahydronaphthoic acid and la synthesis; s-2bA _: by DCC condensation method using 1-(5)-1,2,3,4-tetrahydronaphthoic acid and lb synthesis; s-2dA: using DCC condensation method - (S) -1,2,3,4-tetrahydronaphthoic acid and Id synthesis; m-2dA: synthesized by 1-1,2,3,4-tetrahydronaphthoic acid and Id according to DCC condensation; s- 2eA: synthesized by DCC condensation using 1-(S)-1,2,3,4-tetrahydronaphthoic acid and le; s-2fA _: using 1-(S)-1,2,3 by DCC condensation method 4-tetrahydronaphthoic acid and If synthesis; m-2 _g A: synthesized by DCC condensation using 1-(S)-1,2,3,4-tetrahydronaphthoic acid and lg; s-2aB _: reduced by DCC Legitimate use of 2-(S)-1,2,3,4-tetrahydronaphthoic acid and la synthesis; *-2aC: 1-(S)-5,6,7,8-tetrahydronaphthalene by DCC condensation Formic acid and la synthesis; s-2bC: synthesized by DCC condensation method using 1-«)-5,6,7,8-tetrahydronaphthoic acid and lb; s-2cC: using 1-")-5 by DCC condensation method ,6,7,8-tetrahydronaphthoic acid and lc synthesis; s-2dC _: synthesis by 1-C (S)-5,6,7,8-tetrahydronaphthoic acid and Id according to DCC condensation; s-2eC _: Using 1-(S) -5,6,7 by DCC condensation method, Synthesis of 8-tetrahydronaphthoic acid and le. The specific compounds synthesized and their properties are shown in the following table.

(3) Preparation of N-(5)-1,2,3,4-tetrahydronaphthoyl-L-phenylalanine (s-3aA)

The compound 2aA (1.Og, 2.96 mmol) was dissolved in 10 mL of acetone, and 2N NaOH was slowly added dropwise to a pH of 12 to 13 in an ice water bath, and the reaction was continued in an ice water bath. TLC was detected, and the reaction was completed after 2 hours. Hydrochloric acid was added dropwise to an ice water bath to a pH of 2 to 3, and a large amount of a white solid was obtained. The resulting precipitate was filtered, washed with water and diethyl ether, and dried in vacuo to give white product (yield _: </ RTI></RTI></RTI> . 1H-NMR (DMSO-d ₆ , 300MHz): 51.50~1.57 (1H, m), 1.67-1.86 (3H, m), 2.61~2.69(2H, m), 2.88-3.16(2H, m), 3.67(1H, t, J = 6.9), 4.49~4.57 (1H, m), 7.03-7.10(4H, m), 7.20~7.33(5H, m), 8.31(1H, d, /= 8.2), 12.74(1H, s). MS (ESI): observed: m/z 322.2 [MH]", calcd: 323.3.

Other amino protected amino acids used in the present invention can be prepared by the methods described in Example (3). m-3aA: m-2aA was synthesized by the method of Example (3); r-3aA: r-2aA was synthesized by the method of Example (3); s-3bA: ^2bA was used of Example (3) Method synthesis; s-3cA: 2 2cA was synthesized by the method of Example (3); s-3dA _: 2 2dA was synthesized by the method of Example (3); m-3dA _: m-2dA was used as an example (3) Method synthesis; s-3eA _: 2 2eA is synthesized by the method of the embodiment (3); s-3fA _: ^ 2f A is synthesized by the method of the embodiment (3); *-3gA: 2 2gA is used as an example (3) Method synthesis; *-3aB: Combine 2 2B with the method of Example (3); s-3aC _: Combine 2 2C with the method of Example (3); s-3bC _: Adopt s-2bC Synthesis of the method of Example (3); s-cC: Synthesis of ^2cC by the method of Example (3); *-3dC: Synthesis of 2dC by the method of Example (3); s-3eC _: ^2eC The synthesis was carried out by the method of Example (3).

2. Preparation of the compound of formula (III): Preparation of U compound III-a:

 (1) Preparation of (+)-α-decanediol (Compound III-2a)

Oh,

Ή

 1 a 2a

Me ₃ NO2H ₂ 0 (165.6 g, 1.49 mol) was dissolved in 216 mL of water, and (+) (X-decene lb (191.4 g, 1.4 mol), 1 L of tert-butanol, 108 mL of pyridine and osmium tetroxide were added sequentially with stirring. (lg, 3.9 mmol). Then, nitrogen gas was introduced, and after 10 minutes, it was heated to reflux at 100 ° C. TLC detection showed that the reaction was completed in 72 hours. Naturally cooled to room temperature, and NaHS0 ₃ (20 g, 0.19 mol) was added and stirred for 60 minutes. When the color of the solution was changed to pale yellow, 60 g of NaCl was further added, and the mixture was stirred for additional 10 minutes, and then the organic solvent was evaporated under reduced pressure. The organic solvent was evaporated under reduced pressure, and the obtained red-brown liquid was purified under vacuo to afford white solid (230.1 g, yield: 96.5 %, [ _d ] _D ²⁰ = + 8.3 (c = 6.5, toluene), mp _: 53- 56 ° C. _3⁄4 -NMR (CDC1 ₃ , 500MHz): δθ.94 (3H, s), 1.27(3H, s), 1.31(3H, s), 1.37(1H, d, 7 = 5.4), 1.62- 1.66 (1H, m), 1.91~1.93(1H, m), 2.01(1H, t, 7= 5.8), 2.18~2.21(1H, m), 2.44~2.48(1H, m), 2.81~2.95(2H , m), 3.97~4.00 (2H, q, J = 5.0). ¹³ C-NMR (CDC1 ₃ , 125MHz): δ 24.15, 27.89, 2 8.08, 29.64, 38.18, 39.00, 40.60, 54.10, 69.27, 73.88.

(2) Preparation of lithium dichloromethylene (compound III-3a)

 Anhydrous dichloromethane (4.26 mL, 66 mmol) and 120 mL of anhydrous tetrahydrofuran were added to a 250 mL three-necked flask, nitrogen gas was passed through, and the temperature was lowered to 110 ° C, and then n-butyl lithium n-hexane solution was slowly added dropwise (25.2 mL, 60 mmol), stirring was continued for 1 hour at low temperature. The solution was used directly in the next step.

 (3) Preparation of dimethyl dichloromethylene borate (compound III-4a)

Cl, OCH ₃

 CI OCH3

 Trimethyl borate (7.5 mL, 66 mmol) was added to a solution of the above-prepared compound III-3a at 110 ° C, and stirring was continued for 1 hour, and then 12 mL of 5N HCl solution was added, and the temperature was naturally raised to room temperature. The reaction mixture was transferred to a sep. funnel, and the organic layer was evaporated. The solvent was evaporated to give a white solid, 9.3 g, yield 99.4%. The product was used in the next step without purification.

(4) Preparation of diisopropyl methylene chloride borate (compound III-5a)

 To a solution of the prepared compound III-3a, triisopropyl borate (9.3 mL, 40 mmol) was added at 110 ° C, and stirring was continued for 2 hours, and then 10 mL of 5N HCl solution was added, and the mixture was allowed to warm to room temperature. The reaction mixture was transferred to a sep. funnel, and the organic layer was separated. The solvent was evaporated to give a white solid, 8.73 g, yield >100%. The product was used in the next step without purification.

(5) Preparation of dichloromethylene borate-(+)-α-decanediol ester (Compound III-6a)

Method a: Starting from compound III-4a

Compound II-2a (32.2 g, 0.19 mol) and compound III-4a (51.6 g, 0.33 mol) were added to a 25 mL bottle. Further, it was dissolved by adding 30 mL of THF, and stirred at room temperature. After TLC detection, the reaction was completed after 20 hours. Column chromatography (ethyl acetate: petroleum ether = 1 : 18) gave 49.4 g of a colorless liquid, yield 98.9%. ^-NMR (CDC1 ₃ , 500ΜΗζ) _: δ0.85(3Η, s), 1.21(1Η, d, 7 = 11.2), 1.31(3Η, s), 1.46(3Η, s), 1.93~1.97(2Η, m), 2.13 (1Η, t, 7 = 5.2), 2.27~2.30(1H, m), 2.38~2.39(1H, m), 4.47(2H, dd, 7 = 8.8), 5.40(1H, s;) . ¹³ C-NMR (CDC1 ₃ , 125 MHz): 823.90, 26.19, 26.95, 28.19, 35.00, 38.32, 39.23, 51.17, 79.43, 88.03.

Method b: Starting from compound III-5a

 Compound II-2a (2 g, 0.012 mol) and compound III-5a (6.36 g, 0.03 mmol) were added to a 60 mL bottle. Further, it was dissolved by adding 20 mL of THF, and stirred at room temperature. After TLC detection, the reaction was completed after 48 hours. Column chromatography (ethyl acetate: petroleum ether = 1 : 15) gave a colorless liquid (yield: 2.92 g).

 (6) 2-Methyl-4-chloro-butylboronic acid -(+)-α-decanediol ester (Compound III-7a)

 To a 250 mL three-necked flask, a crushed magnesium strip (1.45 g, 60 mmol), 70 mL of anhydrous tetrahydrofuran was added, and a small amount of iodine was added thereto. 30 ml of a solution of tert-butyl bromide (8.22 g, 60 mmol) in tetrahydrofuran was added dropwise at room temperature. After heating, the mixture was slightly boiled until the magnesium strip was dissolved, and the solution was cooled to a tetrahydrofuran solution of a t-butyl format reagent. Dry and set aside.

Dichloromethylborate -0C-decanediol ester III-6a ( 15.78 g, 60 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. Pass dry nitrogen, and cool to a temperature of 78 ° C, then slowly add the above prepared t-butyl format reagent four After the dropwise addition, the dried ZnCl ₂ powder (4.09 g, 30 mmol was naturally warmed to room temperature, and the mixture was stirred at room temperature. After TLC detection, the reaction was completed after 18 h. The solid was removed by filtration, and concentrated by column chromatography. Acetate acetate: petroleum ether = 1 : 200 ) 15.26 g of colorless liquid, yield SS ^ H-NMR (CDC1 ₃ , 500 MHZ): S 0.85 (-CH ₃ , s, 3H), 0.92 (-CH ₃ , q, J = 6.6, 6H), 1.19(-CH ₂ , d, J = 11.0, 1H), 1.30(-CH ₃ , s, 3H), 1.42(-CH ₃ , s, 3H), 1.60~1.66 (-CH ₂ , m, 1H), 1.78-1.80 (-CH ₂ , m, 1H), 1.88~1.94 (-CH ₂ , -CH, m, 3H), 2.09 (-CH, t, 7 = 5.1, 1H), 2.24~2.26(-CH, m, 1H), 2.34~2.37(-CH ₂ , m, 1H), 3.51~3.55(-CH, m, 1H), 4.35~4.37(-CH, m, 1H ¹³ C-NMR (CDC1 ₃ , 125 MHz): 821.22, 21.27, 22.85, 23.94, 25.58, 25.64, 26.30, 27.02, 28.41, 35.28, 38.25, 39.40, 42.81, 51.26, 78.50, 86.63.

 (7) 5-Chloro-pentylboronic acid -(+)-oc-decanediol ester (Compound III-8a)

 Add 100 g of magnesium strips (0.14 g, 6 mmol), 20 mL of anhydrous ether, and add a small amount of iodine to a 100 mL three-necked flask. Add 10 ml of n-butyl bromide (0.82 g, 6 mmol) in ether at room temperature. After heating, the mixture was slightly boiled until the magnesium strip was dissolved, and it was naturally cooled to obtain a diethyl ether solution of the n-butyl format reagent. Place it in a dry place for later use.

Dichloromethylene borate-OC-decanediol ester III-6a ( 1.58 g, 6 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a diethyl ether solution of the prepared n-butyl format reagent was slowly added dropwise. After the dropwise addition was completed, dried ZnCl ₂ powder (0.41 g, 3 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 18 hours. The solid was removed by filtration, and the residue was purified by chromatography (ethyl acetate: petroleum ether = 1:250) to yield 1.44 g of colorless liquid. ^-NMR (CDC1 ₃ , 500MHz): δ0.85(3Η, s), 0.91(3H, t, J = 7.2), 1.18(1H, dd, J = 11.0), 1.30(3H, s), 1.31~ 1.41(3H, m), 1.42(3H, s), 1.48~1.51(1H, m), 1.82~1.95(4H, m), 2.09(1H, t, J = 5.2), 2.23~2.28(1H, m ), 2.33~2.39(1H, m), 3.44~3.48(1H, m), 4.36 (1H, dd, 7 = 8.8)0 ¹³ C-NMR (CDC1 ₃ , 125MHz): 813.91, 22.19, 23.94, 26.34, 27.02, 28.45, 29.50, 33.91, 35.29, 38.22, 39.41, 51.24, 78.51, 86.65.

 (8) 1-Phenyl-2-chloro-ethylboronic acid -(+)-α-decanediol ester (Compound III-9a)

Add 100 g of magnesium strips (0.12 g, 5 mmol), 20 mL of anhydrous ether to a 100 mL three-neck bottle, then add a small Granular iodine, 10 ml of a solution of benzyl chloride (0.63 g, 5 mmol) in diethyl ether was added dropwise at room temperature. After the completion of the dropwise addition, the mixture was heated to a slight boiling until the magnesium strip was dissolved, and the mixture was cooled to give a solution of the benzyl chloride format reagent. Place it in a dry place for later use.

Dichloromethylene borate-0C-decanediol ester III-6a ( 1.31 g, 5 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a solution of the prepared benzyl chloride format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dried ZnCl ₂ powder (0.41 g, 3 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours. The solid was removed by filtration, and the residue was purified (jjjjjjjjjjj - wake up 1 (CDC1 ₃ , 500ΜΗζ) _: δ0.83(3Η, s), 1.07(1H, d, J = 11.0), 1.28(3H, s), 1.37(3H, s), 1.84~1.90(2H, m), 2.05(1H, t, = 4.8), 2.15~2.17(1H, m), 2.30~2.34(1H, m), 3.08~3.23(2H, m), 3.64(1H, q, J = 8.6) , 4.32 (1H, q, J = 8.8), 7.21~7.30 (5H, m;). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 823.92, 26.18, 26.99, 28.33, 29.68, 35.14, 38.21, 39.34, 40.42, 51.19, 78.54, 86.77, 126.71, 126.76, 128.34, 129.17, 129.23, 138.40.

 (9) 1-p-Tolyl-2-chloro-ethylboronic acid -(+)-oc-decanediol ester (Compound Ill-lOa)

 Add 100 g of magnesium strips (0.48 g, 20 mmol), 30 mL of anhydrous ether, and add a small amount of iodine to a 100 mL three-necked flask. Add 15 ml of p-methylbenzyl chloride (2.81 g, 20 mmol) in diethyl ether at room temperature. After heating, the mixture is slightly boiled until the magnesium strip is dissolved, and the solution of the methylbenzyl chloride format reagent in diethyl ether is naturally cooled. Place it in a dry place for later use.

Dichloromethylene borate-0C-decanediol ester III-6a (4.52 g, 20 mmol) was dissolved in 30 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to 78 ° C, and then a solution of the prepared methylbenzyl chloride format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dried ZnCl ₂ powder (0.55 g, 4 mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours. The solid was removed by filtration, and the residue was purified by chromatography (ethyl acetate: petroleum ether = 1 : 15 ) to yield 5.33 g of colorless liquid, yield, SOJ, H-NMR (CDC1 ₃ , 300 MHz): δ 0.83 (3 Η, s ), 1.09(1H, d, J = 11.1), 1.28(3H, s), 1.38(3H, s), 1.83~1.92(2H, m), 2.06(1H, t, J = 5.0), 2.14~2.21 (1H, m), 2.29~2.37(4H, m), 3.01~3.21(2H, m), 3.58~3.66(1H, m), 4.29-4.36 (1H, m), 7.08-7.16(4H, m; ). ¹³ C-NMR (CDCI3, 75MHz): 821.02, 23.91, 26.10, 26.23, 27.00, 28.33, 35.15, 38.21, 39.35, 40.01, 51.21, 78.52, 86.71, 128.26, 128.96, 129.02, 129.08, 135.30, 136.21.

(10) 1-p-fluorophenyl-2-chloro-ethylboronic acid-(+)-oc-decanediol ester (Compound 111-lla)

 Add 100 g of magnesium strips (0.24 g, 10 mmol), 15 mL of anhydrous ether, and add a small amount of iodine to a 100 mL three-necked flask. Add 10 ml of a solution of p-fluorobenzyl bromide (3.36 g, 10 mmol) in ether at room temperature. After heating, the micro-boiling is completed until the magnesium strip is dissolved, and the solution of the fluorobenzyl bromide format reagent in diethyl ether is naturally cooled. Place it in a dry place for later use.

Dichloromethylene borate-OC-decanediol ester III-6a (2.66 g, 10 mmol) was dissolved in 20 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to a temperature of 78 ° C, and then a solution of the prepared fluorobenzyl bromide format reagent in diethyl ether was slowly added dropwise. After the dropwise addition was completed, dry ZnCl ₂ powder (0.27 g, ₂ mmol) was added. Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 24 hours. The solid was removed by filtration, and the residue was purified (jjjjjlili iH-NMR (CDC1 ₃ , 500MHz): δ0.82(3Η, s), 1.00(1H, dd, J = 11.1), 1.28(3H, s), 1.36(3H, s), 1.83~1.90 (2H, m), 2.06(1H, t, 7 = 5.3), 2.31~2.35(1H, m), 3.04-3.19(2H, m), 3.58~3.63(1H, m), 4.30-4.35 (1H, m), 6.95~6.99(2H, m), 7.22~7.26(2H, m;). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 823.95, 26.16, 26.99, 28.40, 35.19, 39.35, 39.65, 51.23, 71.49, 78.68, 86.92, 115.21, 130.79, 134.22, 162.90.

(11) 2-Methyl-4-amino-butylboronic acid-(+)-oc-decanediol ester hydrochloride (Compound III-12a)

Add LiN(SiMe ₃ ) ₂ (10 mL, 10 mmol) to a 150 mL single-mouth bottle, pass nitrogen, and cool to a temperature of 78 ° C, then slowly add 2-methyl-4-chloro-butylboronic acid with a syringe - 10 mL of a solution of OC-nonanediol ester III-7a ( 2.85 g, 10 mmol) in THF was added, and then the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 20 hours. The solvent was evaporated under reduced pressure, dissolved in 30 mL of hexanes and filtered to remove insolubles. The filtrate was cooled to a temperature of 78 V, and 23 mL of a solution of 1.3 M hydrogen chloride in diethyl ether was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared. The solid was completely precipitated by freezing, and the product was washed with diethyl ether to give a white solid (yield: 2.11 g). -NMR (DMSO-d ₆ , 500MHz) : δ0.82(3Η, s), 0.85~0.88(6Η, m), 1.12~1.16(1Η, m), 1.26(3Η, s), 1.37(3Η, s ), 145~1.55(2Η, m), 1.72~1.78(2Η, m), 1.87~1.89(1Η, m), 2.00(1Η, t, J = 5.4), 2.17~2.20(1H, m), 2.70 ~2.76(1H, m), 4.42~4.45(1H, m), 7.42(3H, t, = 50.7), 7.98 (3H, s,)o ¹³ C-NMR (CDC1 ₃ , 125MHz): 822.07, 22.43, 23.53, 24.41, 25.82, 26.75, 28.07, 34.59, 37.76, 38.33, 38.79, 50.69, 75.49, 77.52, 86.55. MS (ESI): observed: m/z 266.3 [M+H] ⁺ , calcd: 265.2.

 (12) 5-Amino-pentylboronic acid -(+)-oc-decanediol ester hydrochloride (Compound III-13a)

Add LiN(SiMe ₃ ) ₂ (15mL, 15mmol) to a 150mL single-mouth bottle, pass nitrogen gas, and cool to a temperature of 78 °C, then slowly add 5-chloro-pentylboronic acid -0C-蒎垸2 with a syringe. 15 mL of a solution of the alcohol ester III-8a (4.28 g, 15 mmol) in THF was added, and the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 18 hours. The solvent was evaporated under reduced pressure, dissolved in 30 mL of hexanes and filtered to remove insolubles. The filtrate was cooled to a temperature of 78 ° C, and 34.5 mL of a diethyl ether solution of a concentration of 1.3 M hydrogen chloride was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared. Freezing allows the solid to completely precipitate. Filtration and diethyl ether washing afforded 3.86 g of a white solid. -NMR (DMSO-d ₆ , 500MHz): δ0.83(3Η, s), 0.86(3Η, J = 6.6), 1.12~1.16(1Η, m), 1.24~1.32(5Η, m), 1.38(3Η , s), 161~1.63(2Η, m), 1.76 (2Η, d, J = 14.5), 1.88~1.90(1H, m), 2.01(1H, t, J = 5.6), 2.19~2.21(1H, m), 2.32~2.36(1H, m), 2.72~2.74(1H, m), 4.45 (1H, d, J = 8.9), 7.30(3H, t, J = 50.7), 7.90(3H, s;) . ¹³ C-NMR (CDC1 ₃ , 125 MHz): 813.60, 21.79, 23.51, 24.41, 25.87, 26.74, 28.00, 28.85, 34.63, 37.76, 38.79, 50.67, 75.45, 77.53, 86.58. MS (ESI): observed: m/z 266.3 [M+H] ⁺ , calcd: 265.2.

 (13) 1-Phenyl-2-amino-ethylboronic acid -(+)-oc-decanediol ester hydrochloride (Compound III-14a)

LiN(SiMe ₃ ) ₂ (10 mL, 10 mmol) was added to a 100 mL single-mouth bottle, nitrogen gas was passed through, and the temperature was lowered to 78 ° C, and then 1-phenyl-2-chloro-ethylboronic acid was slowly added by a syringe. 10 mL of a solution of 0C-nonanediol ester III-9a ( 3.19 g, 10 mmol) in THF was added, and after the dropwise addition, the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 24 hours. The solvent was evaporated under reduced pressure, dissolved in 30 mL of hexanes and filtered to remove insolubles. The filtrate was cooled to a temperature of 78 V, and 23 mL of a solution of 1.3 M hydrogen chloride in diethyl ether was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared. Freezing allows the solid to completely precipitate. Filtration and diethyl ether washing afforded 2.31 g of a white solid. -NMR (DMSO-d ₆ , 500MHz): δ0.78(3Η, s), 1.06 (1Η, d, J = 10.9), 1.23(3H, s), 1.26(3H, s), 1.62~1.66(2H , m), . ^园晷'^ 丢^目^mmm^ mm η£·ι yat

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2. Preparation of compound III-b:

Preparation of (-)-α-decanediol (Compound III-2b)

Dissolve Me ₃ NO * 2H ₂ 0 ( 11.3 g, 102 mmol) in 16 mL of water, and add (-) (X-pinene lb ( 13.2 g, 96.9 mmol), 74 mL of t-butanol, 7.4 mL of pyridine and Niobium oxide (60 mg, 0.24 mmol). Then nitrogen was passed through, and after 10 minutes, it was heated to reflux. TLC detection, 18 hours reaction was completed. Naturally cooled to room temperature, NaHS0 ₃ (1.2 g, 11.5 mmol) was added and stirred for 10 minutes. When the color of the solution turns yellow, 20 g of NaCl is added. The organic phase is separated, and the aqueous layer is extracted with diethyl ether (3×20 mL). The organic phase is combined and dried over anhydrous sodium sulfate. : petroleum ether = 1 : 30), yielded 15.33 g of white solid, yield 92.9 %, [a] _D ²⁰ = -10.79 ° (c = 5.5, toluene), mp: 52-54 ° C. ^-NMR (CDC1 ₃ , 300MHz): δ0.94(3Η, s), 1.28(3H, s), 1.32(3H, s), 1.37(1H, d), 1.66(1H, m), 1.93(1H, m), 2.01 (1H, t), 2.20(1H, m), 2.33(2H, s), 2.49(1H, m), 4.00(1H, q); ¹³ C-NMR (CDC1 ₃ , 75MHz): δ 24.11, 27.80, 28.00, 29.54, 38.21, 38.99, 40.51, 53.98, 69.26, 73.88; Anal. Calcd. for C ₁₀ H ₁₈ O ₂ : C, 70 .55; H, 10.66. Found: C, 70.55; H, 10.67.

(2) Preparation of lithium dichloromethylene (compound III-3b)

Anhydrous dichloromethane (7.1 mL, llOmmol) and 200 mL of anhydrous tetrahydrofuran were cooled under nitrogen to a temperature of 110 ° C, then a solution of n-butyl lithium in n-hexane (44 mL, llOmmol) was added dropwise. Low temperature after adding Stirring was continued for 1 hour. The solution was used directly in the next step.

(3) Preparation of dimethyl dichloromethylene borate (compound III-4b)

 To a solution of the above-prepared compound III-3b, a solution of the above-prepared compound III-3b was added trimethyl borate (12.5 mL, llOmmol), and the mixture was stirred at low temperature for 1 hour, and then 20 mL of a 5N HCl solution was added, and the mixture was allowed to warm to room temperature. The reaction mixture was transferred to a sep. funnel, and the organic layer was evaporated. The solvent was evaporated to give a white viscous solid, 17.6 g, yield 10.1%. The product was used in the next step without purification.

(4) Preparation of diisopropyl methylene chloride borate (compound III-5b)

 To a solution of the prepared compound III-3b, triisopropyl borate (10.2 mL, 44 mmol) was added at 11 CTC, and stirring was continued for 2 hours, then 15 mL of 5N HCl solution was added, and the mixture was allowed to warm to room temperature. The reaction mixture was transferred to a sep. funnel, and the organic layer was evaporated. The solvent was evaporated to give a white viscous solid, 10.32 g, yield >110.2%. The product was used in the next step without purification.

(5) Preparation of dichloromethylene borate-(-)-α-decanediol ester (Compound III-6b)

Method a: Starting from compound III-4b

Compound II-2b (3.23 g, 0.019 mol) and compound III-4b (5.38 g, 0.035 mol) were added to a 25 mL vial. Further, it was dissolved by adding 10 mL of THF, and stirred at room temperature. After TLC detection, the reaction was completed after 18 hours. Column chromatography (ethyl acetate: petroleum ether = 1 : 20) gave 4.92 g of a colorless liquid. ^-NMR (CDC1 ₃ , 500ΜΗζ) _: δ0.85(3Η, s), 1.22(1Η, d, 7 = 11.2), 1.31(3Η, s), 1.46(3Η, s), 1.94~1.96(2Η, m), 2.13 (1Η, t, 7 = 5.1), 2.27~2.30(1H, m), 2.36~2.41(1H, m), 4.47(2H, dd, 7 = 8.9), 5.40(1H, s;) . ¹³ C-NMR (CDC1 ₃ , 125 MHz): 823.87, 26.15, 26.92, 28.17, 34.97, 38.29, 39.20, 51.14, 79.40, 88.00. .

Method b: Starting from compound III-5b

Compound II-2b (1.70 g, O. Olmol) and compound III-5b (5.30 g, 0.025 mmol) were added to a 50 mL bottle. Further, 15 mL of THF was added to dissolve, and the mixture was stirred at room temperature. After TLC detection, the reaction was completed after 48 hours. Column chromatography (ethyl acetate: petroleum ether = 1 : 15) gave a colorless liquid 2, 38 g, yield 9.8%. (6) 2-Methyl-4-chloro-butylboronic acid-(-)-α-decanediol ester (Compound III-7b)

 Add 100 g of magnesium strips (l.lg, 45.8 mmol), 30 mL of anhydrous ether, and add a small amount of iodine to a lOOmL three-necked flask. Add a solution of tert-butyl bromide in diethyl ether (6.0 mL, 45 mmol) at room temperature. After heating, the mixture was slightly boiled until the magnesium strip was dissolved, and the solution was cooled to a solution of tert-butyl format in diethyl ether. Dry and set aside.

Dichloromethylborate -0C-decanediol ester III-6b ( 1.18 g, 4.49 mmol) was dissolved in 12 mL of diethyl ether and stirred at room temperature. Nitrogen gas was introduced, and the temperature was lowered to 78 ° C. Then, a solution of the prepared tert-butyl format reagent in diethyl ether (6 mL, 4.50 mmol) was slowly added dropwise. After the dropwise addition, dry ZnCl ₂ powder (0.44 g) was added. , 3.25mmol). Raise to room temperature naturally and continue stirring at room temperature. After TLC detection, the reaction was completed after 18 hours. The solid was removed by filtration, and the residue was purified (jjjjjlili

500MHz): δ0.85(3Η, s), 0.90~0.94(6H, m), 1.19(1H, dd, J = 11.0), 1.30(3H, s), 1.42(3H, s), 1.63~1.66( 1H, m), 1.78-1.80(1H, m), 1.88~1.93(3H, m), 2.09(1H, t, 7 = 5.2), 2.24~2.26(1H, m), 2.33~2.38(1H, m ), 3.51~3.55(1H, m), 4.36 (1H, dd, 7 = 8.9). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 821.29, 21.34, 22.88, 23.97, 25.68, 26.36, 27.07, 28.46, 35.34, 38.30, 39.47, 42.90, 51.35, 78.56, 86.66.

 (11) 2-Methyl-4-amino-butylboronic acid -(-)-oc-decanediol ester hydrochloride (Compound III-8b)

LiN(SiMe ₃ ) ₂ (5 mL, 5 mmol) was added to a 100 mL single-mouth bottle, nitrogen gas was passed through, and the temperature was lowered to 78 ° C, and then slowly added with a syringe containing 2-methyl-4-chloro-butylboronic acid - 10 mL of a solution of 0C-nonanediol ester III-7b ( 1.42 g, 5 mmol) in THF was added, and after the dropwise addition, the mixture was allowed to warm to room temperature and then stirred at room temperature. After TLC detection, the reaction was completed after 20 hours. The solvent was distilled off under reduced pressure, dissolved in 20 mL of hexanes and filtered to remove insolubles. The filtrate was cooled to a temperature of 78 ° C, and 12 mL of a solution of 1.3 M hydrogen chloride in diethyl ether was added, and then naturally warmed to room temperature, and a large amount of milky white solid appeared. The solid was completely precipitated by freezing, filtered, and the product was washed with diethyl ether to give 1.12 g of a white solid. -NMR (DMSO-d ₆ , 500MHz) : δ0.82(3Η, s), 0.86~0.89(6Η, m), 1.11~1.16(1Η, m), 1.25(3Η, s), 1.37(3Η, s ), 144~1.55(2Η, m,), 1.71~1.79(2Η, m), 1.86~1.88(1Η, m), 1.99(1Η, t, 7 = 5.3), 2.17~2.20(1Η, m), 2.30~2.34(1Η, m), 2.70~2.75(1Η, m), 4.41~4.44(1Η, m), 7.45(3Η, t, 7 = 50.7), 8.01(3Η, s;). ¹³ C-NMR (CDCI3, 125MHz): 822.04, 22.45, 23.54, 24.42, 25.83, 26.76, 28.06, 34.60, 37.77, 38.33, 38.80, 50.68, 75.48 77.52, 86.55. MS (ESI): observed: m/z 266.3 [M+H] ⁺ , calcd: 265.2. .

3. Preparation of formula (I):

 1. Preparation of borate compound (I):

 Preparation of (1) N-1-S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucineboronic acid-(+)-α-decanediol ester (1-1)

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylalanine (s-3aA) (0.12 g, 0.37 mmol) in Example 1 under nitrogen atmosphere Dissolved in 10 ml of dry THF, the system was cooled to -5 °C, HOBt (0.06 g, 0.44 mmol) was added, and after reacting for 20 minutes, the system was cooled to -15 ° C, and EDC.HCl (0.37 mmol) was added. Finally, 2-methyl-4-amino-butylboronic acid-0C-decanediolate hydrochloride III-12a (O.llg, 0.37 mmol) and NMM (0.041 mL, 0.37 mmol) in Example 2 were added. . The reaction was continued at -15 ° C for 1 hour, and the reaction was allowed to rise to room temperature for 2 hours, and TLC showed the reaction was completed. Insolubles were removed by filtration, the solvent was distilled off under reduced pressure, dissolved with ethyl acetate and 20mL, respectively, with 5% NaHC0 ₃ solution (20mL), 10% citric acid solution (20mL), 5% NaHC0 ₃ solution (20M1), brine Wash with aqueous solution (2 x 20 mL). The ethyl acetate layer was dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated.

500MHz): 80.80~0.86(-CH ₃ , m, 9H), 1.19~1.38(-CH ₃ , -CH ₂ , m, 9H), 1.49-1.70 (-CH ₂ , -CH, m, 5H), 1.78 -1.83 (-CH ₂ , m, 2H), 1.88~1.93(-CH, m, IH), 2.05~2.07(-CH, m, IH), 2.24~2.26(-CH ₂ , m, IH), 2.58 ~2.67(-CH ₂ , m, 2H), 2.80~2.88(-CH, m, IH), 2.96-3.11(-CH ₂ , m, 2H), 3.64(-CH, t, J = 6.5, IH) , 4.15~4.23(-CH, m, IH), 4.65~4.69(-CH, m, IH), 6.98~7.08(-Ph, m, 4H), 7.21~7.30(-Ph, m, 5H), 8.27 (-CONH, dd, J = 8.4, IH), 8.85 (-CONH, d, J = 3.2, 1H) ₀ ¹³ C-NMR (DMSO-d ₆ , 125 MHz): 820.34, 21.93, 23.02, 24.02, 25.43, 26.28, 27.14, 28.04, 28.60, 29.11, 29.67, 35.49, 38.23, 39.64, 40.08, 46.88, 51.50, 53.73, 69.29, 77.90, 85.89, 126.19 126.80, 127.31, 128.56, 128.65, 129.23, 129.31, 129.73, 129.97, 133.13 , 136.56, 137.75, 170.88, 175.09. MS (ESI): observed: m/z 571.4 [M+H] ⁺ , calcd: 570.6.

The method of synthesizing other similar compounds of the present invention can employ the above method. 1-2: preparing m-3aA by reacting with III-12a; 1-3: preparing r-3aA by reacting with III-12a; 1-4: preparing s-3aA by reacting with III-13a; 1-5: Preparing s-3aA by reaction with III-14a; 1-6: preparing s-3aA by reaction with III-15a; 1-7: preparing s-3aA by reacting with III-16a; 1-8: s-3bA and Preparation of III-12a reaction; 1-9: Preparation of s-3cA by reaction with III-12a; 1-10: Preparation of m-3dA by reaction with III-12a; 1-11: Preparation of s-3dA by reaction with III-12a 1-12: s-3eA is reacted with III-12a; 1-13: s-3fA is reacted with III-12a; 1-14: m-3gA is reacted with III-12a; 1-15: s-3aB is prepared by reaction with III-12a; 1-16: s-3aB is reacted with III-14a; 1-17: s-3aB and III-15a are prepared

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-norleucine boronic acid-(+)-α-decanediol ester

^-NMR (CDC1 ₃ , 500MHz): δ0.82~0.90(6Η, m), 1.15~1.33(8H, m), 1.37(3H, s), 1.42-1.59 (2H, m), 1.60-1.77 ( 3H, m), 1.79-1.83 (1H, m), 1.88-1.93 (2H, m), 2.02 (1H, q, 7 = 5.4), 2.16-2.21(2H, m), 2.31~2.35(1H, m ), 2.73~2.79(2H, m), 2.91~3.03(2H, m), 3.59(2H, t, 7 = 5.3),-4 〉 4.28(1H, dd, J = 8.9), 4.65 (1H, q , 7 = 7.6), 5.75 (1H, d, 7 = z 7.8), 6.13 (1H, ά, J = 5.2), 6.76 (1H, ά, J = 7.5),

O 7.01~7.11(4H, m), 7.15~7.27(4H, m;). ¹³ C-NMR (CDC1 ₃ , L- ^z 125 MHz): 813.89, 20.30, 22.54, 23.98, 26.29, 27.07, 27.33

 28.60, 29.17, 30.66, 35.44, 37.30, 38.18, 39.56, 40.56, 46.86, 51.35, 53.77, 59.27, 77.99, 86.04, 126.22, 126.82, 127.37, 128.55, 129.36, 129.80, 130.05, 133.17, 136.60, 137.80, 170.87, 175.10.

 MS (ESI): observed: m/z 569.1 [M-H] -, calcd: 570.6.

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-phenylalanine Boric acid -(+)-α-decanediol ester

 ^-NMR (CDCI3, 500MHz): δ0.82~0.86(3Η, m), 1.18(9H, d, J = 10.6), 1.27~1.39(6H, m), 1.62~1.66(1H, m), 1.75 -2.05 (3H, m), 2.14~2.22(1H, m), 2.32~2.35(1H, m), 2.43~2.47(2H, m), 2.74~2.92(6H, m), 3.02~3.05(2H, m), 3.26~3.34(1H, m), 4.28~4.32(1H, m), 4.59~4.67(1H, m), -5 5.80~5.90(1H, m), 6.08~6.16(1H, m), 7.01~7.06(4H, m),

 7.08-7.12(2H, m), 7.13~7.25(7H, m), 7.28~7.30(1H, m;).

1 ³ C-NMR (CDCI3, 125MHz): 823.99, 26.28, 27.09, 28.54, 29.55, 32.17, 35.40, 36.80, 38.19, 39.59, 40.56, 41.71, 51.47, 53.30, 53.62, 54.08, 69.28, 78.01, 86.00, 125.87 , 126.49, 127.03, 128.53, 128.64, 128.80, 129.01, 129.38, 129.58, 134.99, 135.59, 136.58, 139.17, 171.36, 174.94.

 MS (ESI): observed: m/z 603.0 [M-H]", calcd: 604.6.

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-(4-methyl-phenyl)-alanine boronic acid-(+)·α · decanediol ester

 ^-NMR (CDCI3, 500MHz): δθ.83 (9Η, s), 1.17(1H, ά, J = 10.9), 1.24-1.39 (6H, m), 1.45~1.68(2H, m), 1.80-1.88 (4H, m), 1.99~2.13(4H, m), 2.27~2.35(4H, m), 2.63-2.71 (3H, m,), 2.84~2.98(2H, m), 3.57 (1H, t, 7 = 5.4), 4.23~4.31(1H, m), 4.65(1H, q, 7 = 7.0), 5.68(1H, d, 7 = 8.1), 5.98~6.01(1H,-6 m), 6.70~6.78( 1H, m), 6.86~6.88(2H, m), 7.01~7.09(6H, m),

7.16~7.23(5H, m;). ¹³ C-NMR (CDC1 ₃ , 125MHz): 820.35, 24.03, 26.17, 27.27, 28.04, 29.01, 29.58, 35.42, 37.55, 38.21, 39.61, 46.89, 51.46, 53.44, 69.27, 70.56, 77.89, 85.91, 126.17, 126.87 , 127.30, 128.55, 128.85, 129.09, 129.39, 129.74, 129.98, 133.06, 135.70, 136.10, 136.27, 137.75, 171.25, 174.87.

MS (ESI): observed: m/z 619.3 [M+H] ⁺ , calcd: 618.6.

123.82, 124.15, 125.34, 126.82, 126.17, 126.66, 127.34,

 127.99, 128.72, 129.25, 129.62, 129.87, 133.19, 137.74, 170.89, 175.08.

 MS (ESI): observed: m/z 619.0 [M-H] -, calcd: 620.6.

 N-(ll,2,3,4-tetrahydronaphthalene)formyl-L-(p-2-naphthyl)-propionamide-D-leucine boronic acid-(+)-α-decanediol ester

^-NMR (CDC1 ₃ , 500MHz): δ0.80~0.89(9Η, m), 1.25~1.40(9H, m), 1.60-1.80 (4H, m), 1.87~2.48(6H, m),

, Λ 2.71~2.78(2H, m), 3.07~3.25(3H, m), 3.54~3.56(1H, m),

4.24~4.29(1H, m), 4.71~4.78(1H, m), 5.75-5.86(1H, t, J = 7.9), 6.18~6.31(1H, m), 6.77~6.86(1H, m), 6.94 ~6.96(1H,-10 3⁄4 , m), 7.06-7.10(2H, m), 7.24~7.28(1H, m), 7.42~7.50(3H, m), 7.70~7.79(3H, m;). ¹³ C-NMR (CDC1 ₃ , 125MHz): 820.29, 22.05, 22.94, 24.01, 25.37, 26.27, 27.11, 28.02, 28.53, 29.08, 35.58, 37.47, 38.18, 39.52, 40.57, 46.83, 51.43, 53.79, 69.26, 77.92 , 85.89, 123.98, 125.63, 126.03, 126.96, 127.31, 127.62, 127.90, 128.27, 128.36, 129.26, 129.70, 132.45, 133.09, 133.46, 134.07, 137.66, 171.00, 175.23.

 MS (ESI): observed: m/z 619.0 [M-H] -, calcd: 620.6.

 N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-(p-2-naphthyl)-propionamide-D-leucine boronic acid-(+)-α-蒎Alkylene glycol ester

 ^-NMR (CDCI3, 500MHz): δ0.77~0.83(9Η, m), 1.20~1.40(9H, m), 1.70-1.76 (4H, m), 1.86-1.91 (2H, m), 2.00~2.06 (1H, m), 2.15~2.17(2H, m), 2.26~2.27(1H, m), 2.68~2.80(2H, m), 3.08~3.21(3H, m), 3.54~3.58(1H, m) , 4.23~4.26(1H, m), 4.74~4.79(1H, m), 5.82(1H, t, J = 7.9), 6.17~6.18(1H, m), 6.61(1H, d, J = 7.7), 6.75~6.80(1H, m), -11

7.05-7.11(2H, m), 7.26~7.28(1H, m,), 7.44~7.50(3H, m), 7.73~7.82(3H, m;). ¹³ C-NMR (CDC1 ₃ , 125MHz): 820.30, 21.88, 22.95, 24.02, 25.38, 26.25, 27.25, 27.95, 28.54, 29.09, 35.45, 37.41, 38.20, 39.60, 40.58, 46.84, 51.44, 53.70, 69.26, 77.93 , 85.90, 125.64, 126.04, 126.09, 127.07, 127.20, 127.29, 127.63, 128.15, 128.28, 129.71, 129.85, 132.46, 132.99, 133.49, 134.09, 137.65, 170.90, 175.22.

 MS (ESI): observed: m/z 619.0 [M-H] -, calcd: 620.6.

 N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phthalamide-D-leucine boronic acid -(+)-α-decanediol ester

^-NMR (CDCI3, 500MHz): δ0.81~1.02 (-CH ₃ , m, 15H), 1.24~1.41 (-CH ₃ , -CH ₂ , m, 7H), 1.42~1.65 (-CH ₂ , - CH, m, -12 4H), 1.80~1.93 (-CH ₂ , m, 4H), 1.99-2.01 (-CH ₂ , m, 4H),

2.15-2.23 (-CH ₂ , -CH, m, 3H), 2.30~2.34(-CH, m, 1H), 2.43~2.48(-CH ₂ , m, 1H), 3.20~3.37(-CH, m, 2H), 4.28~4.48(-CH, m, 2H), 6.15~6.23(-CONH, m, 1H), 6.29~6.37(-CONH, m, 1H), 6.77~6.82(-Ph, m, 1H) , 7.10(-Ph, dd, J = 8.4, 2H), 7.49-7.51(-Ph, m, 2H)» ¹³ C-NMR

(CDC1 ₃ , 125MHz): 814.21, 18.47, 19.33, 22.43, 22.92, 23.98, 25.88, 26.37, 27.13, 28.05, 28.57, 29.36, 31.34, 35.73, 37.93, 39.50, 40.59, 51.44, 54.10, 59.09, 69.30, 77.90 , 124.01, 127.83, 129.29, 137.51, 141.44, 171.15.

MS (ESI): observed: m/z 523.3 [M+H] ⁺ , calcd: 522.5.

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-carboxamide-D-leucine boronic acid -(+)-α-decanediol ester

^-NMR (CDCI3, 500MHz): δ0.82~0.85 (-CH ₃ , m, 9H), 1.24~1.38 (-CH ₃ , -CH ₂ , -CH, m, 10H), 1.62-1.68 (-CH , m, 1H), 1.72~1.82(-CH ₂ , m, 4H), 1.87-1.91 (-CH ₂ , m, 1H), 2.16-2.19 (-CH ₂ , m, 1H), 2.30~2.33 (- CH, m, 1H),

H 2.46~2.62(-CH, m, 1H), 2.70~2.76(-CH ₂ , -CH, m, 2H),

3.08-3.21(-CH ₂ , -CH, m, 3H), 3.44-3.57 (-CH, m, 1H), 4.23-4.31 (-CH, m, 1H), 4.73~4.79 (-CH, m, H ),-13 5.90~6.03(-CONH, m, 1H), 6.12~6.27(-CONH, m, 1H),

6.89~6.92(-Ph, m, 2H), 7.06-7.19 (-Ph, m, 5H), 7.31~7.38(-Ph, m, 1H), 7.54~7.64(-Ph, m, 1H), 8.19~ 8.31 (-NH, m, 1H;). ¹³ C-NMR (CDC1 ₃ , 125MHz) : 820.38, 21.01, 21.88, 22.92, 24.05, 25.41, 26.30, 27.15, 28.91, 29.58, 35.61, 38.17, 39.67, 40.57, 51.60, 46.84, 52.93, 60.36, 69.23, 77.69 , 85.67, 111.01, 118.94, 119.75, 122.19, 123.04, 124.02, 126.04, 127.16, 127.83, 129.65, 133.28, 136.20, 137.38, 141.35, 171.56, 175.05.

MS (ESI): observed: m/z 610.0 [M+H] ⁺ , calcd: 609.6.

N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-isoleuxamide-D-leucine boronic acid -(+)-α-decanediol ester

 ^-NMR (CDCI3, 500MHz): δ0.81~0.98(15Η, m), 1.26~1.40(11Η, m), 1.55-1.65 (2Η, m), 1.76-1.92 (4H, m), 1.99~2.02 (2H, m), 2.12~2.25(2H, m), 2.28~2.33(1H, m), 2.74~2.87(3H, m), 3.19~3.27(1H, m), 3.66~3.72(1H, m) , -14 4.24~4.34(1H, m), 5.78~6.32(2H, m), 6.61(1H, d, J = 7.7),

7.05~7.21(4H, m;). ¹³ C-NMR (CDC1 ₃ , 125 MHz): δ ΐ θ.90, 15.35, 20.37, 21.99, 23.00, 24.03, 24.73, 26.35, 27.57, 28.58, 29.15, 35.62, 36.18, 37.73, 38.50, 39.64, 40.58, 47.07, 51.51 , 57.84, 69.28, 77.78, 85.84, 124.00, 126.03, 127.44, 129.86, 133.41, 137.87, 171.40, 175.23.

MS (ESI): observed: m/z 537.4 [M+H] ⁺ , calcd: 536.5.

N-2-(S)-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid -(+)-α-decanediol ester

-15 (χΛ. ^-NMR (CDCI3, 500MHz): δ0.83~0.88(9Η, m),

1.25~1.40(10Η, m), 1.75-1.84 (2Η, m), 1.89-1.91 (1H, m), ), 1.95-2.05 (2H, m), 2.15~2.22(1H, m), 2.28~2.35 (1H, m), 2.45~2.51(1H, m), 2.78~3.21(7H, m), 4.27~4.31(1H, m),

4.65~4.68(1H, m), 5.62~5.93(1H, m), 6.28~6.31(1H, m), 7.05-7.10(4H, m), 7.22~7.29(5H, m;). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 822.00, 22.95, 24.00, 25.44, 26.31, 27.09, 28.54, 32.12 35.47, 38.61, 39.56, 41.75, 51.39, 53.76, 77.98, 85.87, 125.82, 126.88, 128.76, 129.35, 134.90, 136.76, z. 171.02, 175.01.

MS (ESI): observed: m/z 571.3 [M+H] ⁺ , calcd: 570.6.

N-2-(S)-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-phenylalanine boronic acid -(+)-α-decanediol ester

^-NMR (CDC1 ₃ , 500MHz): δ0.83(3Η, s), 1.16(9H, d, J = 10.5), 1.28(3H, s), 1.36(3H, s), 1.51-1.66 (4H, m), 1.80-2.35 (5H, m), 2.66~2.75(3H, m), 2.89~2.99(3H, m), 3.26~3.35(1H, m), 3.55~3.58(1H, m), 4.23~ 4.36(1H, m), 4.68(1H, q, 7 = 7.7), 5.62~5.67(1H, m), 6.01~6.12(1H, m),-16 6.71~6.78(1H, m), 6.94~7.01 (2H, m), 7.04-7.10(4H, m),

7.14~7.25(7H, m;). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 823.98, 26.13, 27.29, 28.59, 28.99, 29.54, 35.38, 37.25, 38.19, 39.58, 40.56, 46.86, 51.44, 53.43, 69.28, 77.78, 77.94, 85.96, 126.23, 126.36 , 126.94, 127.38, 128.43, 128.62, 128.99, 129.06, 129.26, 129.43, 129.83, 130.05, 133.11, 136.32, 137.82, 139.35, 171.39, 175.01.

 MS (ESI): observed: m/z 603.0 [M-H]", calcd: 604.6.

N-2-(S)-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-(4-methyl-phenyl)-alanine boronic acid-(+)·α · decanediol ester

 ^-NMR (CDCI3, 500MHz): δθ.85 (9Η, s), 1.95~1.41(1H, m), 1.50~1.56(2H, m), 1.81-1.93 (3H, m), 1.99~2.06(1H , m), 2.10~2.19(1H, m), 2.28~2.33(4H, m), 2.40~2.46(1H, m),-17

 2.61~2.66(1H, m), 2.80~3.08(4H, m), 3.28~3.55(3H, m), 4.29~4.32(1H, m), 4.5~4.62(1H, m), 5.66~5.69(1H , m), 6.11~6.14(1H, m), 6.86~6.91(1H, m), 7.03~7.09(4H, m), 7.11~7.28(8H, m).

 MS (ESI): observed: m/z 617.3 [M-H]", calcd: 618.6.

N-l-(S)-5,6,7,8-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid -(+)-α-decanediol ester

 ^-NMR (CDCI3, 500MHz): δ0.82~0.90(9Η, m), 1.23~1.44(10Η, m), 1.68-1.75 (4Η, m), 1.81-1.84 (1H, m), 1.89-1.91 (1H, m), 2.00~2.05(1H, m), 2.17~2.21(1H, m), -18 2.26~2.34(1H, m), 2.64~2.76(4H, m), 3.11~3.25(3H, m),

 4.28~4.31(1H, m), 4.82~4.84(,1H m), 5.79~6.15(1H, m), 6.28~6.35(1H, m), 6.96~7.09(3H, m), 7.24~7.30(5H , m;).

1 ³ C-NMR (CDCI3, 125 MHz): 822.00, 22.63, 22.95, 24.04, 25.35, 26.34, 26.63, 27.13, 28.58, 29.82, 32.12 35.56, 38.32, 39.60, 40.00, 40.61, 51.43, 54.08, 69.30, 77.93, 85.91, 123.99, 125.18, 126.94, 128.66, 129.34, 131.05, 134.99,

 135.99, 136.78, 138.19, 170.14, 170.91.

MS (ESI): observed: m/z 571.3 [M+H] ⁺ , calcd: 570.6.

 Nl-(S)-5,6,7,8-tetrahydronaphthoyl-L-(pl-naphthyl)-propionamide-D-leucineboronic acid-(+)-α-decanediol ester

^-NMR (CDC1 ₃ , 500MHz): δ0.72~0.84(9Η, m), 1.17~1.39(10H, m), 1.70-1.79 (5H, m), 1.87-1.91 (1H, m), ), 198~2.03(1H, m), 2.16~2.18(1H, m), 2.25~2.33(1H, m), 2.68~2.78(4H, m), 3.05~3.13(1H, m), 3.43~3.50(1H , m), 3.72~3.77(1H, m), 4.24~4.28(1H, m), 4.93~4.99(1H, m), 5.43~5.77(1H, m), 6.52~6.60(1H, m), 6.95 ~7.11(3H, m), -19 7.36~7.43(2H, m), 7.48~7.52(1H, m), 7.58~7.62(1H, m),

7.74~7.78(1H, m), 7.85(1H, t, = 7.1), 8.38(1H, d, J = 8.5). 1 ³ C-NMR (CDCI3, 125 MHz): 822.00, 22.58, 22.89, 23.98, 25.34, 26.23, 26.60, 27.08, 28.55, 29.77, 35.39, 38.14, 39.57, 51.39, 53.85, 66.64, 77.93, 85.90, 123.96, 124.11 , 125.18, 125.41, 125.86, 126.69, 127.84, 128.16, 128.77, 131.05, 132.06, 132.83, 133.93, 134.94, 136.04, 138.17, 170.29, 170.90.

 MS (ESI): observed: m/z 619.3 [M-H]", calcd: 620.6.

 Nl-(S)-5,6,7,8-tetrahydronaphthoyl-L-(p-2-naphthyl)-propionamide-D-leucineboronic acid-(+)-α-decane Alcohol ester

^-NMR (CDCI3, 500MHz): 80.77~0.83(-CH ₃ , m, 9H), 1.12~1.24(-CH ₂ , -CH, m, 2H), 1.27~1.28(-CH ₃ , m, 3H) , 1.33~1.45(-CH ₃ , -CH ₂ , -CH, m, 6H), 1.70~1.73(-CH ₂ , m, 2H), 1.76~1.80(-CH, m, 1H), 1.86-1.88 ( -CH ₂ , -CH, m, 2H), 1.99~2.05(-CH ₂ , -CH, m, 2H), 2.15~2.17(-CH ₂ , m, 2H), 2.28~2.30(-CH, m, 1H), 2.70~2.76(-CH ₂ , m, 2H), 3.05-3.19(-CH ₂ , m, 2H), 3.54~3.57(-CH, m, 1H), 4.23~4.26(-CH, m, 1H), 4.74~4.79(-CH, m, 1H), 5.78-5.85(-CONH, m, 1H), 6.18(-CONH, s, 1H), -20 3⁄4χ 6.75~6.79 (-Ph, m, 1H), 7.07~7.09 (-Ph, m, 2H),

7.26~7.28(-Ph, m, 1H), 7.44~7.50(-Ph, m, 3H), 7.58~7.62(-Ph, m, 1H), 7.74~7.78(-Ph, m, 1H), 7.73~ 7.76(-Ph, m, 2H), 7.79~7.82(-Ph, m, 1H) ₀ ¹³ C-NMR (CDCI3, 125MHz): 820.31, 21.90, 22.98, 24.04, 25.55, 26.37, 27.14, 27.33, 28.56, 28.78, 29.11, 35.48, 37.60, 38.22, 39.85, 46.75, 51.42, 53.77, 65.84, 77.94, 85.93, 125.71, 126.07, 127.08, 127.22, 127.34, 127.41, 127.65, 128.09, 128.37, 129.73, 129.88, 132.49, 133.05, 133.52, 134.11, 137.64, 170.93, 175.24.

MS (ESI): observed: m/z 619.3 [MH]", calcd: 620.6. Nl-(S)-5,6,7,8-tetrahydronaphthoyl-L-leucamide-D-leucine boronic acid

 -(+)-α-decanediol ester

^-NMR (CDC1 ₃ , 500MHz): S0.84 (-CH ₃ , s, 3H), 0.89 to 0.92 (-CH ₃ , m, 6H), 0.96 to 0.98 (-CH ₃ , m, 6H), 1.25 ~1.28(-CH ₃ , -CH ₂ , m, 4H), 1.37~1.39(-CH ₃ , m, 3H), o 1.44~1.50(-CH ₂ , m, 2H), 1.59-1.68 (-CH ₂ , m, 2H), z 1.73-1.78 (-CH ₂ , -CH, m, 6H), 1.83-1.84 (-CH, m, 1H),

1.86~1.89(-CH ₂ , m, 1H), 1.99~2.05(-CH, m, 1H),

/worker z

-21 2.17~2.19(-CH ₂ , m, 1H), 2.30~2.35(-CH ₂ , m, 1H),

〉,■· β 2.78(-CH ₂ , s, 2H), 2.83(-CH ₂ , s, 2H), 3.08~3.31(-CH, m,

1H), 4.28-4.31(-CH, m, 1H), 4.62~4.67(-CH, m, 1H), 6.17(-CONH, dd, 7 = 8.5, 13.9, 1H), 6.43~6.60(-CONH, m, 1H), 7.06-7.12 (-Ph, m, 3H). ¹³ C-NMR (CDC1 ₃ , 125 MHz): 822.14, 22.37, 22.50, 22.67, 22.85, 23.00, 24.07, 24.88, 25.68, 26.35, 26.74, 27.17, 28.65, 29.88, 35.61, 38.27, 39.67, 40.05, 41.21, 50.94 , 51.53, 78.02, 85.90, 124.08, 125.33, 131.18, 135.05, 136.24, 138.37, 170.41, 172.12.

 MS (ESI): observed: m/z 535.3 [M-H]", calcd: 536.5.

 N-l-(S)-5,6,7,8-tetrahydronaphthoyl-L-phthalamide-D-leucine boronic acid -(+)-α-decanediol ester

^-NMR (CDCI3, 500MHz): S0.84 (-CH ₃ , s, 3H), 0.87~0.92 (-CH ₃ , m, 6H), 0.99~1.04 (-CH ₃ , m, 6H), 1.20 ( -CH ₂ , t, 7 = 7.0, 1H), 1.24~1.30 (-CH ₃ , -CH, m, 4H), 1.36~1.38 (-CH ₃ , m, 3H), 1.43-1.51 (-CH ₂ , m, 2H), 1.64~1.66(-CH, m, 1H), 1.77-1.85 (-CH ₂ , -CH, m, 5H), 1.89(-CH ₂ , s, 1H), 2.01~2.04(-CH , m, 1H), 2.15~2.18(-CH ₂ , -CH, m, 2H), 2.30~2.33(-CH ₂ , m, 1H), 2.78~2.89(-CH ₂ , m,-22 β 4H) , 3.16~3.28(-CH, m, 1H), 4.28~4.30(-CH, m, 1H),

4.42~4.47(-CH, m, 1H), 6.29(-CONH, s, 0.5H), 6.36(-CONH, q, J = 9.3, 1H), 6.46(-CONH, s, 0.5H), 7.06- 7.12(-Ph, m, 2H), 7.06~7.12(-Ph, d, J = 7.0, 1H) ₀ 1 ³ C-NMR (CDCI3, 125MHz): δ 18.42, 19.11, 22.01, 22.59, 22.93, 23.98, 25.58, 26.24, 26.71, 27.07, 28.57, 29.80, 31.38, 35.53, 38.18, 39.56, 39.86, 51.41, 58.09, 60.33, 65.80, 77.93, 85.82, 124.06, 125.24, 131.00, 134.86, 136.46, 138.22, 170.35, 171.20.

 MS (ESI): observed: m/z 521.4 [M-H]", calcd: 522.5.

 N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid -(-)-α-decanediol ester

-23 ^-NMR (DMSO-d ₆ , 500MHz): S0.82~0.88 (-CH ₃ , m, 9H),

1.19~1.28(-CH ₃ , -CH ₂ , m, 4H), 1.31-1.48 (-CH ₃ , -CH ₂ , -CH, m, 6H), 1.71-1.83 (-CH ₂ , m, 3H), 1.87~1.92(-CH ₂ , m, 2H), 2.00~2.05(-CH, m, 1H), 2.16~2.19(-CH ₂ , -CH, m, 2H), 2.28~2.33(-CH ₂ , m, IH), 2.72~2.80(-CH ₂ , m, 2H), 2.91-3.02

(-CH ₂ , m, 2H), 3.07-3.11(-CH, m, IH), 3.59(-CH, q, 7 = 5.3, IH), 4.25~4.29(-CH, m, IH), 4.63~ 4.69(-CH, m, IH), 5.80(-CONH, dd, J = 7.7, 22.8, IH), 5.96-6.19(-CONH, m, IH), 6.77(-Ph, dd, J = 7.6, 12.4 , IH), 7.03-7.10(-Ph, m, 4H), 7.17 (-Ph, t, J = 7.4, IH), 7.20-7.27 (-Ph, m, 3H)» ¹³ C-NMR (DMSO-d ₆ , 125MHz): 820.34, 21.82, 23.12, 24.06, 25.32, 26.37, 27.17, 28.59, 29.12, 35.62, 37.38, 38.22, 39.66, 40.04, 46.90, 51.52, 53.64, 77.85, 85.79, 126.32, 126.93, 127.46, 128.67 , 129.41, 129.87, 130.13, 133.18, 136.58, 137.86, 171.25, 175.23 o

MS (ESI): observed: m/z 593.3 [M+Na] ⁺ , calcd: 570.6.

Preparation of N-1-(S)-1,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid (IV)

Method a: Transesterification

Nl-(-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid-O- decyl glycol ester (0.5 g, 0.876 mmol) with 6 mL of methanol Dissolved, 2-methylpropylboronic acid (0.27 g, 2.63 mmol) and 6 mL of hexanes were added, and finally HCl solution (2N, 1.5 mL) was added, and the reaction was stirred at room temperature. After 4 hours, TLC showed the reaction was completed. 10 mL of hexane was washed once, and evaporated to dryness. The column was washed with ethyl acetate, and then washed with methanol to give a colorless solid, 0.33 g, yield: 87.3%. iH-NMR (CDC1 ₃ , 500 MHz): 80.81~ 0.88(-CH ₃ , m, 6H), 1.30~1.66(-CH ₂ , m, 6H), 1.76~1.78(-CH, m, IH), 2.63~2.65(-CH ₂ , m, 2H), 2.77 ~2.80(-CH, m, IH), 2.98~3.05(-CH ₂ , m, 2H), 3.63~3.65(-CH, m, IH), 4.52~4.61(-CH, m, IH), 5.98- 6.14(-CONH, m, IH), 6.73~6.80(-CONH, m, IH), 7.04~7.25(-Ph, m, 7H), 7.35~7.42(-Ph, m, IH), 7.52~7.73( -Ph, m, IH). ¹³ C-NMR (CDC1 ₃ , 125MHz): 820.47, 20.52, 24.00, 26.87, 28.69, 29.53, 37.42, 38.13, 45.24, 53.65, 55.78, 71.1, 125.28, 125.96, 126.13, 127.88 , 128.08, 128.78, 129.19, 135.07, 136.86, 137.91, 170.62, 173.6 4. MS (ESI): observed: m/z 437.1 [M+H]+, calcd: 436.4.

Method b: Oxidative fracture method

Nl-(-l,2,3,4-tetrahydronaphthoyl-L-phenylpropanamide-D-leucine boronic acid-oc-decanediol ester (0.1 g, 0.175 mmol) with 5 mL of acetone Dissolve, add NH ₄ OAC solution (0.1 N, 4 mL), and finally add NaIO ₄ (0.11 g, 0.525 mmol), and stir the reaction at room temperature. TLC detection showed that the reaction was complete after 10 h. Add NaOH to the reaction solution. Solution _{(2N, 3mL), CH 2} C1 2 extraction. The pH of the solution was adjusted to about 3 with concentrated hydrochloric acid. The combined organic phases were dried and extracted CH ₂ C1 ₂ (3 X 15mL) dried over anhydrous Na ₂ S0 _4, filtered and evaporated to dryness to give 62.1 mg of colorless solid, yield 81.3%. The second part inhibits the determination of proteasome activity

Proteasome inhibitory activity

The method utilizes the fluorescent substrate polypeptide Suc-Leu-Leu-Val-Tyr-AMC (abbreviated as Suc-LLVY-AMC, Sue represents succinyl group, AMC represents 7-amide-4-methylcoumarin) under the action of proteasome Hydrolysis will occur, releasing the principle of fluorescent AMC (Ex: 380nm, Em: 460nm). By changing the concentration of the test compound, the fluorescence value of the product obtained by the proteasome-catalyzed substrate after different concentrations of the drug is determined. The degree of inhibition of the enzyme, thereby calculating the IC _5Q value of the drug against proteasome inhibition.

The proteasome used in this experiment was the human erythrocyte 20S proteasome, and the enzyme, fluorescent substrate and test buffer were purchased from Biomol. The experimental system is 100 ul, which contains the proteasome 90 μl (0.2 g), the substrate 10 μl, the final concentration is 50 μΜ, the drug (inhibitor) 0.1 μ1, and the final concentration is 10-? ^!~^ ¹¹ ^! , The actual configuration concentration is 10 - ⁴ Μ ~ 10 - ⁸ Μ. The specific experimental process is as follows:

 1, drug configuration:

The drug was accurately weighed and dissolved in DMSO to 10 - ² Torr. Pipette 90 lDMSO ΙΟμΙ was added to give 10- ³ M, and then added 90 lDMSO suction ΙΟμΙ 10- ⁴ M obtained from 10- ³ M concentration of the drug in the same manner to obtain ^{10- 5 M, 10- 6 M,} 10 - ⁷ M, 10- ⁸ M concentration of the drug.

 2. Substrate preparation:

 Dissolve 5 mg of substrate Suc-LLVY-AMC (mw: 763.9) powder in 654 l DMSO to obtain a 10 mM stock solution, store at -20 ° C, dilute 20 times with buffer, and add 10 μl to each sample to make the reaction The substrate concentration in the system was 50 μΜ.

 3. Preparation of reaction system:

The 20S proteasome (1μ _§ /μ1) was diluted to a concentration of 0.0022μ _§ /μ1 in a buffer solution, 90μ1 was added to each well of a 96-well fluorescent plate, and then Ο.ΐμΐ sample was added to each well. The listed drug Wanxi was used as a positive control drug, and 0.1 l DMSO was added to the blank control group and the background control group, and the reaction was carried out at 37 ° C for 20 min. After completion of the reaction, a ΙΟμΙ fluorescent substrate was added to each well, and the reaction was carried out at 37 ° C for 1 hour in the dark, and the fluorescence value was measured by a 380 nm / 460 nm fluorescent microplate reader (Tecan, Infinite M200).

 4, data processing

Calculate the fluorescence value of the product obtained by different concentrations of the drug after deducting the background, and calculate the drug using SPSS software. IC _5Q concentration for proteasome inhibition.

The results of some of the compounds are as follows:

Among them, Velcade-diol (diol base)

Chemical structure of Veilcade

The therapeutic dose of the compound of the present invention may vary depending, for example, on the particular use of the treatment, the mode of administration of the compound, the health of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition will vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the invention may be provided for parenteral administration in an aqueous physiological buffer containing from about 0.1 to about 10% w/v of the compound. Some typical dosage ranges range from about 1 μg/kg to about lg/kg body weight per day. In some embodiments, the dosage ranges from about 0.01 mg/kg body weight to about 100 mg/kg body weight per day. The dose is highly likely to depend on such variables as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and the route of administration. Effective doses can be derived from dose response curves from in vitro or animal model test systems.

Claims

Claim

1. A peptide boric acid and an ester compound thereof, the structure of which is as shown in Formula I,

 among them:

1^ or 1 ₂ are each independently a substituted or unsubstituted fluorenyl group of 10 to 10, a cycloalkyl or a heterocyclic fluorenyl group of C3 to 6, a benzyl group, a naphthylmethyl group or a D-indenylmethyl group, wherein The substituent is a fluorenyl group, a cyano group, a hydroxyl group, a decyl group, an amino group or a halogen of Cl~4;

¾ or Σ ₂ are each independently hydroxy, Cl~10 the embankment group, Cl~10 the embankment or aryloxy group, or B, ¾, and Σ ₂ - is formed from N, S or a heterocyclic group containing 0 ;

 Pg is a substituted or unsubstituted bicyclic acyl group or a tricyclic acyl group containing at least one unsaturated ring, wherein the substituent is a fluorenyl group of Cl 4 , a decyloxy group of Cl 4 , a halogen or a Cl~ 4 halogenated fluorenyl groups.

2. The peptide boronic acid and ester compound thereof according to claim 1, wherein

! And R ₂ are each independently a substituted or unsubstituted fluorenyl group, a benzyl group, a naphthylmethyl group or a fluorenylmethyl group of Cl 10 , wherein the substituent is a fluorenyl group or a halogen of Cl 4 .

3. The peptide boronic acid and ester compound thereof according to claim 2, wherein

 It is a substituted or unsubstituted fluorenyl group, a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group or a fluorenylmethyl group of Cl~10, wherein the substituent is a fluorenyl group or a halogen of Cl~4.

4. The peptide boronic acid and ester compound thereof according to claim 2, wherein

R ₂ is a substituted or unsubstituted fluorenyl or benzyl group of Cl 10 , wherein the substituent is a fluorenyl group or a halogen of Cl 4 .

The peptide boronic acid and ester compound thereof according to claim 1, wherein

3⁄4 or ∑ ₂ are independently a hydroxyl group, a decyl group of Cl 10 , a decyloxy group or an aryloxy group of Cl 10 , or B, 3⁄4 and Z _{2 together} form a boric acid -0C-decanediol ester.

6. The peptide boronic acid and ester compound thereof according to claim 5, wherein

3⁄4 or Z ₂ are each independently a hydroxyl group, or B, 3⁄4 and Z _{2 together} form a boric acid -0C-decanediol ester.

7. The peptide boronic acid and ester compound thereof according to claim 1, wherein

 Pg is a substituted or unsubstituted tetrahydronaphthoyl group, wherein the substituent is a fluorenyl group of Cl~4, a decyloxy group of Cl~4, a halogen or a halogenated fluorenyl group of Cl~4.

8. The peptide boronic acid and ester compound thereof according to claim 7, wherein

 Pg is:

R ₃ or R 4 are each independently hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo or trifluoromethyl _t

A method for producing a peptide acid or an ester compound according to claim 1, wherein the reaction route is:

Wherein R ₂ , ΊΛ, Z ₂ and Pg are as defined in claim 1

The use of the peptide boronic acid and the ester compound thereof according to any one of claims 1 to 8 for the preparation of an antitumor drug.