Synthesis method of polycyclic compound and intermediate

Abstract

The invention relates to a synthesis method of a polycyclic compound and an intermediate, a long chain is synthesized firstly, then two-step ring closing is performed to form a key intermediate, and simple derivation is performed on the basis of the key intermediate to obtain a PCSK9 antagonist compound. According to the invention, a ring closing route and an intermediate are optimized, and the ring closing yield is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a synthetic method of polycyclic compounds, more particularly to a synthetic method of MK-0616 compound. BACKGROUND

[0002] MK-0616 is a PCSK9 antagonist compound developed by Merck & Co. for treating cardiovascular diseases and conditions associated with PCSK9 activity, such as atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular and cardiovascular metabolic conditions. The compound is first recorded in WO2019246349A1 and its Chinese counterpart CN112313243A, and has entered clinical phase III. It is a drug with great market potential.

[0003] The molecular formula of MK-0616 is as follows, which is referred to as compound 1-1 in the present application.

[0004]

[0005] There are few records of the synthesis method of such compounds in the prior art. The synthesis route recorded in patent CN112313243A (priority date June 21, 2018) of Merck & Co. is as follows. The ring closure sequence of this route is "right-middle-left". The yield is not recorded in the literature, and the inventors found that the ring closure of compounds 89 to 90 was difficult and the yield was very low when repeating the experiment.

[0006]

[0007] Another synthesis route also comes from Merck & Co., see J. Am. Chem. Soc. 2025, 147, 11036-11048. According to the common sense in the field, this route is an improvement made by Merck & Co. after the compound entered the clinical stage in order to mass production, and its technical effect should be superior to that of the compound patent. As shown below, the ring closure sequence can be described as "left-middle-right". The yield of this method is 70% when the intermediate ring is closed, i.e. compound 63 is prepared to compound 64, and the yield is only 40% when the right ring is closed, i.e. compound 64 is prepared to compound 65. The overall yield of ring closure is 28%.

[0008]

[0009] These molecules possess multiple macrocycles and multiple chiral centers, making their synthesis relatively difficult. During the synthesis process, after the formation of the polycyclic structure, derivatization and modification of functional groups can be carried out according to the methods described in CN112313243A or other common knowledge in the field. The main technical challenge lies in how to form the polycyclic structure in high yield and at low cost, i.e., to prepare the intermediate compound II-e. Summary of the Invention

[0010] Therefore, the technical problem to be solved by the present invention is to overcome the deficiency of low yield of cyclization reaction in the prior art, thereby providing a method for synthesizing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure:

[0011]

[0012] in:

[0013] R 1 Selected from:

[0014] (a)-H; or

[0015] (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for:

[0016] (i)-H;

[0017] (ii)–NH2;

[0018] (iii)-N + H3;

[0019] (iv)-N + (CH3)3;

[0020] (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3;

[0021] (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3;

[0022] (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and

[0023] (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for:

[0024] (ai)–O-(CH2)2-N + (CH3)3;

[0025] (aii)-N + (CH3)3;

[0026] (aiii) The following part:

[0027]

[0028] R 2 Selected from:

[0029] (a)-H; and

[0030] (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from:

[0031] (i)-H;

[0032] (ii)–NH2;

[0033] (iii)-N + H3;

[0034] (iv)-N + (CH3)3;

[0035] (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3;

[0036] (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3;

[0037] (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C -O-(CH2)3-4-N + (CH3)3; and

[0038] (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for:

[0039] (ai)–O-(CH2)2-N + (CH3)3;

[0040] (aii)-N + (CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3;

[0041] (aiii) The following part:

[0042]

[0043] (aiv) The following part:

[0044]

[0045] Where R 14Cb and R 14Cc The range is 1 to 4;

[0046] A is selected from: -CH2CH2- or -CH=CH-;

[0047] R 8 Selected from: C1-6 alkyl groups, wherein the C1-6 alkyl group can be -OR 8a Instead, the R 8a Selected from H and straight-chain, branched, or cyclic alkyl groups with no more than 6 carbon atoms;

[0048] X is selected from H, F, Cl, or Br;

[0049] The method includes the following steps:

[0050] (1) Use compound III-1 to synthesize compound III-2;

[0051]

[0052] Where R 1a Selected from:

[0053] (a)-H; or

[0054] (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for:

[0055] (i)-H;

[0056] (ii)–NH-amino protecting group;

[0057] (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B It is a -NH-amino protecting group;

[0058] (iv)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B It is a -NH-amino protecting group;

[0059] (v)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for:

[0060] (ai) The following part:

[0061]

[0062] (2) Use compound III-2 to synthesize compound III-3;

[0063]

[0064] (3) Use compound III-3 to synthesize compound III-4;

[0065]

[0066] (4) Use compound III-4 to synthesize compound I or a pharmaceutically acceptable salt thereof;

[0067]

[0068] The term "salt" as used herein, and its use in the phrase "pharmaceutically acceptable salt," includes any of the following: acid salts formed with inorganic and / or organic acids, base salts formed with inorganic and / or organic bases, zwitterions, and quaternary ammonium complexes. Salts of the compounds of the present invention can be formed by methods known to those skilled in the art, for example by reacting the compounds of the present invention with a certain amount (e.g., a certain equivalent) of an acid or base in a medium such as salt precipitation or an aqueous medium, followed by lyophilization.

[0069] Examples of pharmaceutically acceptable acid salts include, but are not limited to, acetates (including trifluoroacetate), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, diglucuronates, dodecyl sulfates, ethanesulfonates, fumarates, glucohepate, glycerophosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, dihydroxynaphthalate, pectates, persulfates, 3-phenylpropionate, phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates (also known as tosylates, undecanoates, etc.).

[0070] Examples of pharmaceutically acceptable alkali salts include, but are not limited to, ammonium salts, alkali metal salts (such as sodium, lithium, and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts, aluminum salts, and zinc salts), salts containing organic bases (e.g., organic amines) (such as benzathines, diethylamine, dicyclohexylamine, hydrabamines (formed from N,N-bis(dehydrorosinyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, piperazine, phenylcyclohexylamine, choline, and tromethamine), and salts containing amino acids (such as arginine and lysine). Basic nitrogen-containing groups can be converted into ammonium ions or quaternized with agents such as: lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and other agents.

[0071] The term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts.

[0072] As a preferred option, R1 Selected from:

[0073] (a)-H; or

[0074] (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for:

[0075] (i)-H;

[0076] (ii)-N + (H3C)3;

[0077] (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B -N + (CH3)3;

[0078] As a preferred option, R 2 Selected from:

[0079] (a)-H; and

[0080] (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from:

[0081] (i)-H;

[0082] (ii)–NH2;

[0083] (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: or -N + (CH3)3;

[0084] (iv)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and

[0085] (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for:

[0086] (ai)–O-(CH2)2-N + (CH3)3;

[0087] (aii)-N+(CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3;

[0088] (aiii) The following part:

[0089]

[0090] As a preferred option, R 8 For -CH3 or the following part:

[0091]

[0092] Where R 8a It is -H, or a straight-chain, branched, or cyclic alkyl group with up to four carbon atoms.

[0093] Preferably, the compound of formula I is compound 1-1.

[0094]

[0095] G - This represents a pharmaceutically acceptable anion.

[0096] Preferably, Zhan(1B) catalyst is used in step (3) and the reaction is carried out at 40-50°C.

[0097] This invention also provides intermediate compounds III-2 and III-3, which have the following structures:

[0098]

[0099] The substituents have the same definition as above, and are preferably compounds 7-2 and 7-3, respectively.

[0100]

[0101] The present invention also provides the use of the above-mentioned intermediate compounds III-2, III-3 and preferred compounds 7-2 and 7-3 in the preparation of compounds of formula I.

[0102] The present invention also provides a method for synthesizing compound III-4, comprising the following steps:

[0103] (1) Use compound III-2 to synthesize compound III-3;

[0104]

[0105] (2) Use compound III-3 to synthesize compound III-4;

[0106]

[0107] Its substituents and reaction conditions have the same definitions as above.

[0108] In this invention, "formula* compound" and "compound*" have the same meaning. For example, "compound 1-1" can also be written as "formula 1-1" compound.

[0109] The technical solution of this invention has the following advantages:

[0110] The new synthesis method provided by this invention uses a new cyclic closure sequence, which significantly improves the yield.

[0111] In the cyclization reaction of compound 7-2 to compound 7-3, the yield was 58.9%, and in the cyclization reaction of compound 7-3 to compound 7-4, the yield was 81.3%, with an overall two-step cyclization yield of 47.9%. This is a significant improvement over existing technologies. Attached Figure Description

[0112] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0113] Figure 1 This is the H NMR spectrum of compound 1-1 of the present invention;

[0114] Figure 2 This is the C10 NMR spectrum of compound 1-1 of the present invention. Detailed Implementation

[0115] Unless otherwise specified, all chemicals used in this application were purchased directly from reagent companies. Reactions without specific instructions were conducted under argon protection. Purification reagents and solvents were performed according to the Purification of Laboratory Chemicals. Reaction progress was monitored by TLC using HSGF 254 silica gel plates (0.2 mm). The silica gel plates were observed under UV light, and color development was performed in phosphomolybdic acid ethanol solution or ninhydrin solution. The silica gel used for column chromatography was Qingdao Marine Silica Gel 60 (300-400 mesh). The eluent used for column chromatography separation was generally a petroleum ether / ethyl acetate or dichloromethane / methanol system, prepared by volume ratio. 1 H NMR and 13C10 NMR was performed using a Bruker Avance 400MHz and Bruker Avance 600MHz NMR spectrometer, with deuterated chloroform, deuterated methanol, and deuterated DMSO as solvents. High-resolution mass spectrometry (HMS) was performed using a QExactive Focus (Thermo) instrument under ESI conditions. Peptide LCMS analysis was performed using an API 4000 Thermo Fisher Scientific LC-MS system with a Thermo C18 column (0.3 x 100 mm, 3 μm particle size) and a mobile phase flow rate of 0.3 mL / min. Peptide analysis was performed using an Agilent 1260 Infinity HPLC system with a Daisogel-C18 column (10 x 250 mm, 5 μm particle size) and a mobile phase flow rate of 1.5 mL / min. The instrument used for peptide preparation and purification was an innovative Tongheng LC3050N high-performance liquid chromatograph. The chromatographic column used was a Daisogel-C18 (20×250mm, 10μm particle size), and the mobile phase flow rate was 5mL / min. All detector wavelengths were set to 215nm. Mobile phase A pump contained acetonitrile (first-grade chromatographic grade) with 0.1% TFA, and mobile phase B pump contained water with 0.1% TFA. The resin, HATU, Fmoc-amino acid, and Boc-amino acid used for solid-phase peptide synthesis in this experiment were all purchased from Jier Biochemical (Shanghai) Co., Ltd.

[0116] Example 1

[0117] Synthesis of key intermediate compounds 1-2.

[0118] The reaction equation is shown below.

[0119]

[0120] The specific reactions are as follows:

[0121] Synthesis of compound 2-2:

[0122]

[0123] Commercially available compound 2-1 (2.00 g, 8.65 mmol, 1.0 eq.) was dissolved in MeOH (30 mL, 0.29 M). The reaction flask was cooled to 0 °C in an ice bath. TMS-diozamethane (21.60 mL, 43.24 mmol, 5.0 eq.) was added, and the ice bath was removed. The mixture was then allowed to rise naturally to room temperature and stirred for 20 minutes. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product. Column chromatography was then used to separate the crude product into a colorless oily compound 2-2 (2.01 g, 95% yield). TLC: R f=0.2 (silica gel, ethyl acetate / petroleum ether = 1:4).

[0124] Synthesis of compounds 2-3:

[0125]

[0126] Compound 2-2 (2.50 g, 10.22 mmol, 1.0 eq.) was dissolved in dry dichloromethane (40 mL, 0.25 M). [Rh(OAc)2]2 (450 mg, 1.02 mmol, 0.1 eq.) and tert-butyl diazonyl acetate were added to the reaction solution at 0 °C. The reaction was maintained at 0 °C with stirring for 4 hours. The mixture was then quenched with water (20 mL) at 0 °C, extracted with dichloromethane (2 × 100 mL), washed with saturated brine (100 mL), and dried over anhydrous Na2SO4. The crude product was obtained by filtration and concentration under reduced pressure. After column chromatography, the purified yellow oil product 2-3 (1.49 g, yield 40.7%, 1.32 g recovered feed) was finally obtained. TLC: R f =0.3 (silica gel, ethyl acetate / petroleum ether = 1:4).

[0127] Synthesis of compounds 2-6:

[0128]

[0129] Compounds 2-3 (1.32 g, 3.67 mmol, 1.0 eq.) were dissolved in a mixed solvent of TFA (5 mL) / DCM (25 mL) at room temperature and stirred overnight. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0130] Compounds 2-4 obtained in the previous step were dissolved in a mixed solvent of 1,4-dioxane (18 mL) / H₂O (12 mL). The reaction flask was cooled to 0°C in an ice bath. Na₂CO₃ (941 mg, 8.88 mmol, 2.4 eq.) and Boc₂O (1.21 mL, 5.18 mmol, 1.4 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 4 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump, then diluted with water (15 mL), and the pH was adjusted to 3-4 with 1 M HCl aqueous solution in an ice bath. The mixture was extracted with ethyl acetate (2 × 100 mL), washed with saturated brine (50 mL), and dried over anhydrous Na₂SO₄. After filtration, the crude product was concentrated under reduced pressure and used directly in the next step.

[0131] Compound 2-5 obtained in the previous step was dissolved in DMF (20 mL). The reaction flask was cooled to 0 °C in an ice bath. K₂CO₃ (613 mg, 4.44 mmol, 1.2 eq.) and AllylBr (0.48 mL, 5.55 mmol, 1.5 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL), and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography separation, the purified yellow oil product 2-6 (890 mg, total yield of three steps 70.1%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:4).

[0132] Synthesis of compound 3-3:

[0133]

[0134] The commercially available compound 3-1 (1.00 g, 2.25 mmol, 1.0 eq.) was dissolved in MeCN (20 mL, 0.11 M). The reaction flask was cooled to 0 °C in an ice bath, and Et₂NH (21.60 mL, 43.24 mmol, 5.0 eq.) was added. After removing the ice bath, the mixture was allowed to rise to room temperature and stirred overnight. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was directly used in the next step.

[0135] The compound obtained in the previous step was dissolved in MeOH (30 mL). The reaction flask was cooled to 0 °C in an ice bath. Et3N (0.94 mL, 6.75 mmol, 3.0 eq.) and Boc2O (0.62 mL, 2.70 mmol, 1.2 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 4 hours. The experiment was monitored using TLC (thin-layer chromatography). When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump, diluted with water (15 mL), and the pH was adjusted to 3-4 with 1 M HCl aqueous solution in an ice bath. The mixture was extracted with ethyl acetate (2 × 100 mL), washed with saturated brine (50 mL), and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white solid product 3-3 (652 mg, 90% overall yield of the two steps) was finally obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol / formic acid = 20:1:0.01).

[0136] Synthesis of compounds 3-4:

[0137]

[0138] Compound 3-3 (814 mg, 2.53 mmol, 1.0 eq.) was dissolved in DMF (30 mL, 0.08 M). The reaction flask was cooled to 0 °C in an ice bath. NaH (222 mg, 5.6 mmol, 2.2 eq.) was added, and the reaction was maintained at 0 °C with stirring for 1 hour. Then, AllylBr (0.24 mL, 2.78 mmol, 1.1 eq.) was slowly added dropwise, and the reaction was maintained at 0 °C with stirring for 1.5 hours. The experiment was monitored by TLC column chromatography. When the starting material disappeared, the reaction was quenched with 1 M HCl aqueous solution in an ice bath. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white solid product 3-4 (714 mg, yield 78.8%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether / formic acid = 1:1:0.01).

[0139] Synthesis of compounds 2-7:

[0140]

[0141] Compound 2-13 (677 mg, 1.97 mmol, 1.0 eq.) was dissolved in a mixed solvent of TFA (5 mL) / DCM (25 mL) in an ice bath, and the reaction was stirred at 0 °C for 1.5 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0142] Synthesis of compounds 3-5:

[0143]

[0144] Compound 2-7 (1.97 mmol, 1.0 eq.) obtained in the previous step was dissolved in DMF (20 mL, 0.10 M). The reaction flask was cooled to 0 °C in an ice bath. Compound 3-4 (714 mg, 1.97 mmol, 1.0 eq.), DIPEA (0.83 mL, 4.73 mmol, 2.4 eq.), and HATU (899 mg, 2.36 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction was quenched by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 3-5 (1.12 g, yield 96.4%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:2).

[0145] Synthesis of compounds 3-8:

[0146]

[0147] Compounds 3-5 (1.12 g, 1.91 mmol, 1.0 eq.) were dissolved in a mixed solvent of TFA (5 mL) / DCM (25 mL) in an ice bath, and the reaction was stirred at 0 °C for 1.5 h. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0148] Compound 3-6 obtained in the previous step was dissolved in DMF (20 mL, 0.10 M). The reaction flask was cooled to 0°C in an ice bath. Compound 3-7 (1.18 g, 2.28 mmol, 1.2 eq.), DIPEA (1.7 mL, 9.54 mmol, 5.0 eq.), and HATU (867 mg, 2.28 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction was quenched by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 3-8 (1.79 g, overall yield of 95.3%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:2).

[0149] Synthesis of compounds 3-9:

[0150]

[0151] Compound 3-8 (1.78 g, 1.82 mmol, 1.0 eq.) was dissolved in anhydrous DCM (20 mL, 0.09 M). The reaction flask was cooled to 0 °C in an ice bath. PhSiH3 (1.12 mL, 9.10 mmol, 5.0 eq.) and Pd(PPh3)4 (210 mg, 0.18 mmol, 0.1 eq.) were added. The reaction was maintained at 0 °C and stirred for 40 minutes. The experiment was monitored by TLC thin-layer column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure to obtain the crude product. After column chromatography separation, the purified and deprotected product was obtained.

[0152] The deprotected product from the previous step was dissolved in a mixed solvent of TFA (5 mL) / DCM (25 mL) in an ice bath, and the reaction was stirred at 0 °C for 1.5 hours. The experiment was monitored by TLC thin-layer column chromatography. When the starting material spot disappeared, the reaction solution was concentrated using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0153] The deprotected product from the previous step was dissolved in a mixed solvent of DCM (200 mL) / DMF (10 mL). The reaction flask was cooled to 0 °C in an ice bath, and DIPEA (1.16 mL, 9.00 mmol, 5.0 eq.) and HATU (821 mg, 2.16 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 2 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 3-9 (1.26 g, total yield of three steps 86.7%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:1).

[0154] Synthesis of compounds 1-2:

[0155]

[0156] Compound 3-9 (1.26 g, 1.52 mmol, 1.0 eq.) was dissolved in a mixed solvent of THF (15 mL) / MeOH (10 mL) / H₂O (5 mL). The reaction flask was cooled to 0 °C in an ice bath, and LiOH (110 mg, 4.57 mmol, 3.0 eq.) was added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 6 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the pH was adjusted to 7 with 1 M HCl aqueous solution in an ice bath, and the crude product was concentrated under reduced pressure for direct use in the next step.

[0157] The product obtained in the previous step was dissolved in a mixed solvent of 1,4-dioxane (15 mL) / H2O (15 mL). The reaction flask was cooled to 0 °C in an ice bath. Na2CO3 (477 mg, 4.57 mmol, 3.0 eq.) and FmocOSu (557 mg, 1.65 mmol, 1.1 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 6 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump, then diluted with water (15 mL), and the pH was adjusted to 3-4 with 1 M HCl aqueous solution in an ice bath. The mixture was extracted with 30% IPA / DCM (3 × 50 mL), washed with saturated brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the crude product was concentrated under reduced pressure. After column chromatography, the purified white solid product 1-2 (1.00 g, total yield of two steps 80.9%) was finally obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol / formic acid = 10:1:0.01). 11H NMR (400 MHz, Chloroform-d) δ 9.68 (s, 2H), 7.91 (d, J = 18.0 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.29 (q, J = 8.7, 7.9 Hz, 3H), 7.17 (d, J = 7.5 Hz, 1H), 7.08 (dd, J = 19.8, 7.0 Hz, 2H), 6.99 (s, 1H), 6.84 (s, 2H), 6.78 (s, 2H), 5.99 (d, J = 8.0 Hz, 1H), 5.78 (ddt, J = 16.8, 11.6, 5.7 Hz, 1H), 5.01 (dd, J = 16.0, 8.5 Hz, 2H), 4.89 (d, J = 17.1 Hz, 1H), 4.75 (d, J = 14.7 Hz, 2H), 4.63 (d, J = 7.2 Hz, 1H), 4.49 (d, J = 6.6 Hz, 3H), 4.35 (t, J = 8.9 Hz, 1H), 4.20 (s, 3H), 4.06 (d, J = 15.6 Hz, 1H), 3.89 (dd, J = 41.6, 10.5 Hz, 1H), 3.69–3.64 (m, 1H), 3.10 (d, J = 37.3 Hz, 6H), 2.10–1.80 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 171.80, 170.11, 163.65, 159.03, 156.01, 143.71, 141.40, 141.37, 137.28, 136.25, 133.36, 132.78, 129.40, 129.17, 128.40, 128.31, 128.18, 127.87, 127.36, 127.17, 127.15, 125.26, 120.11, 117.21, 80.40, 67.66, 67.39, 64.02, 55.15, 53.55, 51.06, 50.49, 48.98, 48.03, 47.14, 44.93, 42.90, 38.93, 30.59, 29.07, 23.52. HRMS: (ESI, m / z); calculated for C 46 H 44 FN5O8Na + [M + Na] + ​​​​​​​

[0160] The commercially available compound 3-10 (400 mg, 1.01 mmol, 1.0 eq.) was dissolved in DMF (10 mL, 0.1 M). The reaction flask was cooled to 0 °C in an ice bath. DIPEA (0.35 mL, 2.02 mmol, 2.0 eq.) and AllylBr (0.13 mL, 1.52 mmol, 1.5 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 3 hours. The experiment was monitored by TLC column chromatography. When the starting material disappeared, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL), and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified colorless oily product (410 mg, yield 93.8%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:10).

[0161] The product obtained in the previous step (410 mg, 0.94 mmol, 1.0 eq.) was dissolved in MeCN (10 mL, 0.09 M), and Et₂NH (0.19 mL, 1.86 mmol, 2.0 eq.) was added. The mixture was stirred overnight at room temperature. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0162] The product obtained in the previous step was dissolved in DMF (10 mL, 0.09 M). The reaction flask was cooled to 0 °C in an ice bath. Compounds 1-2 (611 mg, 0.75 mmol, 0.8 eq.), DIPEA (0.39 mL, 2.26 mmol, 2.4 eq.), and HATU (429 mg, 1.13 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified yellow amorphous product (830 mg) was obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol = 50:1).

[0163] The compound obtained in the previous step (830 g, 0.82 mmol, 1.0 eq.) was dissolved in anhydrous DCM (10 mL, 0.08 M). The reaction flask was cooled to 0 °C in an ice bath. PhSiH3 (0.50 mL, 4.10 mmol, 5.0 eq.) and Pd(PPh3)4 (95 mg, 0.08 mmol, 0.1 eq.) were added. The reaction was maintained at 0 °C and stirred for 40 minutes. The experiment was monitored by TLC thin-layer column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure to obtain the crude product. After column chromatography separation, the purified yellow amorphous compound 1-6 (758 mg, total yield of three steps 83.4%) was obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol / formic acid = 10:1:0.01). 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=22.7Hz,2H),7.77(d,J=7.6Hz,2H),7.64(d,J=5.4Hz,2H),7.39(t,J=7.6Hz,2H),7.36–7.20(m,3H),7.08(dt ,J=23.4,11.6Hz,4H),6.97–6.82(m,2H),6.82–6.68(m,2H),5.84(ddt,J=1 6.8,11.0,5.4Hz,1H),5.62(d,J=8.2Hz,1H),5.28(d,J=2.2Hz,1H),5.08(t ,J=9.0Hz,3H),4.87(t,J=20.3Hz,3H),4.62–4.50(m,4H),4.36(s,2H),4.2 6(q,J=7.4,6.8Hz,3H),4.15(d,J=14.8Hz,1H),3.96(d,J=15.2Hz,1H),3.7 9(d,J=9.5Hz,1H),3.63(d,J=2.2Hz,1H),3.21–3.09(m,2H),3.01(t,J=6.9 Hz,2H),2.89(d,J=13.3Hz,1H),2.12–2.07(m,2H),1.13(d,J=6.3Hz,14H). 13C NMR (101MHz, CDCl3) δ172.90,172.01,170.04,168.66,163.41,159.05,156.72,155.90,144.06,143.88,141.46,137.20,135.99, 134.87,133.45,132.90,130.78,129.21,128.91,128.73,128.35,128.26,128.12,127.86,127.19,126.70,125.35,125.24,120.1 3,120.09,117.11,110.70,110.40,108.66,103.66,103.43,79.62,77.48,77.16,76.84,75.38,67.47,67.23,64.53,57.79,54.55 ,53.56,50.97,50.63,49.01,47.29,45.42,42.39,38.91,30.84,29.69,28.33,23.62,19.80,11.50.HRMS: (ESI, m / z); calculated for C 54 H 59 FN6O 10 Na + [M+Na] + :993.4169,found:993.4163.

[0164] Example 2

[0165] Synthesis of intermediate compounds 1-3

[0166]

[0167] The specific synthesis method is as follows:

[0168] Synthesis of compound 4-2:

[0169]

[0170] n-BuLi (5.87 mL, 14.67 mmol, 2.2 eq.) was dissolved in anhydrous THF (10 mL) and added to the reaction flask, which was then cooled to -78 °C. Commercially available compound 4-1 (2.00 g, 6.67 mmol, 1.0 eq.) was dissolved in anhydrous THF (50 mL) and slowly added dropwise to the reaction flask, maintaining the reaction temperature at -78 °C with stirring for 1 hour. Anhydrous DMF (1.29 mL, 16.68 mmol, 2.5 eq.) was added to the reaction flask, and the reaction temperature was maintained at -78 °C with stirring for another 1 hour. The experiment was monitored using TLC column chromatography. When the starting material disappeared, water was added to quench the reaction. The reaction solution was concentrated under reduced pressure using a vacuum water pump, and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was obtained. Following column chromatography, the purified white solid product 4-2 (1.26 g, yield 75.8%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:5).

[0171] Synthesis of compound 4-4:

[0172]

[0173] Hydroxylamine hydrochloride (335 mg, 4.82 mmol, 2.0 eq.) was dissolved in EtOH (20 mL), added to a reaction flask, and then Et3N (1.00 mL, 7.23 mmol, 3.0 eq.) was added. The mixture was stirred at room temperature for 30 minutes. Then, compound 4-2 (600 mg, 2.41 mmol, 1.0 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump, dissolved in water, and the aqueous phase was extracted with ethyl acetate (2 × 100 mL). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white solid product (570 mg) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:4).

[0174] The product obtained in the previous step was dissolved in a mixed solvent of AcOH (15 mL) / EtOH (15 mL), and Pd / C (50 mg) was added. The mixture was then aerated three times using a vacuum water pump to remove all O2 from the reaction system. The mixture was stirred under H2 conditions for 6 hours. The experiment was monitored using TLC thin-layer column chromatography until the starting material was completely eliminated. The mixture was then filtered with diatomaceous earth, and the filtrate was concentrated to obtain the crude product, which was directly used in the next step.

[0175] Compound 4-3 obtained in the previous step was dissolved in ACN (30 mL), and propylene bromide (0.30 mL, 2.50 mmol, 1.2 eq.) was added. The mixture was then refluxed at 80 °C for 48 hours. The experiment was monitored by TLC thin-layer column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product. After column chromatography separation, the purified colorless oily product 4-4 (310 mg, total yield of three steps 40.4%) was finally obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol = 20:1).

[0176] Synthesis of compounds 4-6:

[0177]

[0178] Compound 4-4 (250 mg, 0.79 mmol, 1.0 eq.) was dissolved in DMF (10 mL, 0.08 M). The reaction flask was cooled to 0 °C in an ice bath. Compound 4-5 (125 mg, 0.94 mmol, 1.2 eq.), DIPEA (0.33 mL, 1.88 mmol, 2.4 eq.), and HATU (358 mg, 0.94 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The solution was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 4-6 (281 mg, yield 82.4%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:4).

[0179] Synthesis of compounds 4-8:

[0180]

[0181] Compounds 4-6 (116 mg, 0.27 mmol, 1.0 eq.) were dissolved in a mixed solvent of TFA (2 mL) / DCM (5 mL) in an ice bath, and the reaction was stirred at 0 °C for 1.5 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0182] The product obtained in the previous step was dissolved in DMF (10 mL, 0.03 M). The reaction flask was cooled to 0°C in an ice bath, and 4-7 (114 mg, 0.32 mmol, 1.2 eq.), DIPEA (0.12 mL, 0.65 mmol, 2.4 eq.), and HATU (124 mg, 0.32 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction was quenched by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (3 × 20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 4-8 (170 mg, overall yield of two steps 94.7%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:1).

[0183] Synthesis of compound 4-11:

[0184]

[0185] Compound 4-8 (182 mg, 0.27 mmol, 1.0 eq.) was dissolved in MeCN (10 mL, 0.03 M), and Et₂NH (0.06 mL, 0.54 mmol, 2.0 eq.) was added. The mixture was stirred at room temperature for 2 hours. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was then used directly in the next step.

[0186] The product obtained in the previous step was dissolved in DMF (10 mL, 0.03 M). The reaction flask was cooled to 0°C in an ice bath, and 4-10 (137 mg, 0.33 mmol, 1.2 eq.), DIPEA (0.12 mL, 0.66 mmol, 2.4 eq.), and HATU (125 mg, 0.33 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (3 × 20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the crude product was concentrated under reduced pressure. After column chromatography, the purified white amorphous product 4-11 (220 mg, overall yield of 95.3% for both steps) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:1). 11H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.1 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.28–7.22 (m, 1H), 7.16 (dd, J = 14.2, 6.2 Hz, 3H), 7.03 (d, J = 8.0 Hz, 2H), 6.92–6.63 (m, 3H), 5.75 (ddq, J = 17.5, 12.8, 6.7 Hz, 1H), 5.56 (dd, J = 21.2, 8.6 Hz, 1H), 5.05–4.89 (m, 2H), 4.65 (q, J = 7.9 Hz, 1H), 4.52 (d, J = 22.1 Hz, 2H), 4.35 (dt, J = 34.2, 9.9 Hz, 2H), 4.20 (d, J = 7.5 Hz, 1H), 3.73 (s, 3H), 3.72–3.66 (m, 3H), 3.66–3.08 (m, 6H), 3.03–2.55 (m, 9H), 2.53–2.38 (m, 1H), 2.01 (t, J = 7.6 Hz, 2H), 1.83–1.54 (m, 9H). 13 13C NMR (101 MHz, CDCl3) δ 173.80, 173.37, 171.55, 171.29, 158.79, 155.82, 143.91, 141.42, 138.00, 137.26, 135.94, 130.55, 129.55, 129.18, 128.25, 127.86, 127.18, 126.65, 125.24, 120.12, 115.86, 115.06, 114.06, 77.48, 77.16, 76.84, 68.95, 67.13, 55.36, 54.35, 51.91, 50.81, 48.31, 47.24, 46.47, 46.11, 41.24, 38.54, 38.09, 35.42, 31.22, 30.92, 29.40, 29.26, 28.27, 28.03, 27.45, 26.75, 23.41, 22.56. HRMS: (ESI, m / z); calculated for C 50 H 58 N4O8Na + [M+Na] + : 865.4147, found: 865.4132.

[0187] Synthesis of Compounds 1 - 3:

[0188]

[0189] Compound 4-11 (220 mg, 0.27 mmol, 1.0 eq.) was dissolved in MeCN (10 mL, 0.03 M), and Et₂NH (0.06 mL, 0.54 mmol, 2.0 eq.) was added. The mixture was stirred at room temperature for 2 hours. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was then used directly in the next step.

[0190] Example 3

[0191] Synthesis of intermediate compounds 1-4.

[0192]

[0193] The commercially available compound 5-1 (500 mg, 1.17 mmol, 1.0 eq.) was dissolved in DMF (10 mL, 0.12 M). The reaction flask was cooled to 0 °C in an ice bath. NaHCO3 (118 mg, 1.40 mmol, 1.2 eq.) and AllylBr (0.15 mL, 1.76 mmol, 1.5 eq.) were added. After removing the ice bath, the mixture was allowed to warm to room temperature and stirred overnight. The experiment was monitored by TLC column chromatography. When the starting material disappeared, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL), and dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified yellow oily product (538 mg, yield 98.3%) was finally obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:2).

[0194] The product obtained in the previous step (538 mg, 1.15 mmol, 1.0 eq.) was dissolved in MeCN (10 mL, 0.03 M), and Et₂NH (0.24 mL, 2.30 mmol, 2.0 eq.) was added. The mixture was stirred at room temperature for 3 hours. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was used directly in the next step.

[0195] The product obtained in the previous step was dissolved in DMF (10 mL, 0.12 M). The reaction flask was cooled to 0°C in an ice bath, and Fmoc-Ala-OH (430 mg, 1.38 mmol, 1.2 eq.), DIPEA (0.48 mL, 2.76 mmol, 2.4 eq.), and HATU (524 mg, 1.38 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified yellow amorphous product 5-2 (600 mg, total yield of two steps 97.4%) was obtained. TLC: R f =0.2 (silica gel, ethyl acetate / petroleum ether = 1:1). 1 H NMR(400MHz,Chloroform-d)δ7.74(d,J=7.6Hz,2H),7.59(d,J=7.5Hz,2H),7.44(d,J=7.2 Hz,1H),7.38(t,J=7.7Hz,2H),7.29(dt,J=9.0,4.5Hz,2H),5.91–5.82(m,1H),5.73(d,J= 7.1Hz,1H),5.30(d,J=17.1Hz,1H),5.22(d,J=10.7Hz,1H),4.61(t,J=6.7Hz,3H),4.38(p ,J=8.1,6.7Hz,2H),4.21(d,J=7.4Hz,1H),3.56(d,J=6.4Hz,2H),1.40(d,J=23.1Hz,12H). 13 C NMR (101MHz, CDCl3) δ172.7,169.9,156.7,143.8,141.3,131.5,127.8,127.1,125.2,120.0 ,119.0,80.0,66.4,60.5,53.9,50.7,47.1,41.9,28.3,18.9.HRMS:(ESI,m / z);calculated for C 29 H 35 N3O7Na + [M+Na] + :560.2367,found:560.2358.

[0196] Compound 5-2 (600 mg, 1.12 mmol, 1.0 eq.) was dissolved in anhydrous DCM (30 mL, 0.04 M). The reaction flask was cooled to 0 °C in an ice bath. PhSiH3 (0.69 mL, 5.60 mmol, 5.0 eq.) and Pd(PPh3)4 (129 mg, 0.11 mmol, 0.1 eq.) were added. The reaction was maintained at 0 °C and stirred for 1 hour. The experiment was monitored by TLC thin-layer column chromatography. When the starting material spot disappeared, the reaction solution was concentrated under reduced pressure to obtain the crude product. After column chromatography separation, the purified product 1-4 (505 mg, yield 90.4%) was finally obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol / formic acid = 20:1:0.01).

[0197] Example 4

[0198] Synthetic routes of intermediate compounds 1-5

[0199]

[0200] The commercially available compound 6-1 (200 mg, 1.46 mmol, 1.0 eq.) was dissolved in a mixed solvent of H2O (5 mL) / IPAc (5 mL). The reaction flask was placed in an ice bath and cooled to 0 °C. NaH2PO4·2H2O (571 mg, 3.66 mmol, 2.5 eq.), TEMPO (11 mg, 0.07 mmol, 0.05 eq.), NaClO (108 mg, 1.46 mmol, 1.0 eq.), and NaClO2 (264 mg, 2.92 mmol, 2.0 eq.) were added. After removing the ice bath, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The experiment was monitored using TLC (thin-layer chromatography). When the starting material spot disappeared, 10 mL of Na₂S₂O₃ aqueous solution was added to quench the reaction. After separating the organic phase, the aqueous phase was adjusted to pH 3-4 with 1 M HCl solution, extracted with IPAc (2 × 50 mL), and the organic phase was washed with saturated brine (50 mL). The mixture was then dried over anhydrous Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was obtained and used directly in the next step.

[0201] The compound obtained in the previous step was dissolved in H2O (5 mL), and Me3N dissolved in ethanol (4.97 mL, 16.64 mmol, 11.4 eq.) was added. The reaction temperature was raised to 80 °C and stirred overnight. The experiment was monitored by TLC column chromatography. When the starting material disappeared, the temperature was lowered to room temperature, IPAc was added, and the mixture was stirred for 6 hours. The reaction solution was filtered, and the filter cake was washed with IPAc. The filter cake was purified by slurrying with methanol and acetonitrile to obtain a white solid compound 1-5 (191 mg, overall yield of 75.2%). 1H NMR (400MHz, DMSO-d6) δ12.18(s,1H),3.31(t,J=8.7Hz,2H),3.07(s,9H),2.25( t,J=7.4Hz,2H),1.68(d,J=9.2Hz,2H),1.54(t,J=7.8Hz,2H),1.31–1.22(m,2H). 13 CNMR(101MHz,DMSO)δ174.25,64.96,52.04,33.42,25.25,23.98,21.81.

[0202] Example 5

[0203] Synthesis route for intermediate fragment docking

[0204]

[0205] The specific reaction route is as follows.

[0206] Synthesis of compound 7-1 (first, right-side cyclization):

[0207]

[0208] Compounds 1-6 (230 mg, 0.24 mmol, 1.0 eq.) and 1-3 (149 mg, 0.24 mmol, 1.0 eq.) were dissolved in DMF (10 mL, 0.02 M). The reaction flask was cooled to 0 °C in an ice bath, and DIPEA (0.22 mL, 1.20 mmol, 5.0 eq.) and HATU (110 mg, 0.29 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction was quenched by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with water (3 × 50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 7-1 (344 mg, yield 91.3%) was finally obtained. TLC:R f =0.2 (silica gel, dichloromethane / methanol = 40:1). 1H NMR(400MHz,Chloroform-d)δ7.78(d,J=7.5Hz,2H),7.62(d,J=8.1Hz,3H),7.41(t,J=7.6Hz,2H),7.33(dd,J=8.0,4.2Hz,3H),7.21(d,J=7.8Hz,1H),7.13(d,J=9.2Hz,3H),7.04(d,J=8.0Hz,3H),6.89(t,J=9.2Hz,1H),6.77(d,J=7.8Hz,3H),6.50(s,1H),5.80(dddt,J=49.5,17.0,11.5,5.5Hz,2H),5.53(d,J=11.0Hz,1H),5.29(d,J=3.0Hz,2H),5.10(d,J=10.6Hz,1H),4.99(q,J=9.3,7.6Hz,1H),4.97–4.86(m,4H),4.87–4.66(m,1H),4.61–4.55(m,2H),4.53(s,2H),4.48(s,1H),4.30(d,J=10.2Hz,3H),4.24(d,J=5.5Hz,1H),4.19–4.07(m,3H),3.96(dd,J=27.4,11.1Hz,1H),3.74(s,4H),3.68(d,J=8.9Hz,3H),3.58–3.43(m,1H),3.35(dt,J=26.0,7.1Hz,3H),3.24–3.14(m,1H),3.08(dd,J=14.5,5.4Hz,1H),2.96(s,1H),2.86(d,J=5.2Hz,1H),2.71(dq,J=14.2,6.4,5.4Hz,3H),2.61(dd,J=13.8,5.0Hz,2H),2.31(d,J=8.2Hz,1H),2.10–1.97(m,4H),1.61(dd,J=17.7,9.0Hz,2H),1.49(d,J=3.1Hz,3H),1.43(d,J=23.3Hz,4H),1.24(s,9H),0.97(d,J=6.2Hz,3H). 13CNMR(101MHz, CDCl3)δ173.73,173.65,173.36,173.32,172.43,171.52,171.24,170.57,169.57,168.6 2,168.05,159.05,158.75,156.72,155.73,143.95,143.88,141.41,138.65,138.24,137.95,137.55,1 37.22,136.11,135.83,134.90,133.45,132.88,130.33,129.46,129.19,129.07,128.51,128.42,128.19,127.86,127.18,126.52,125.33,125.19,120.11,120.08,117.15,115.81,115.01,114.44,114.09, 110.80,110.71,110.49,110.23,103.75,80.19,77.48,77.16,76.84,75.50,68.92,67.88,67.18,66.06,65.19,57.76,55.36,53.55,52.94,51.86,51.82,50.76,50.55,49.09,48.99,48.23,47.28,46.38,4 6.06,45.29,42.60,41.18,39.91,38.91,38.51,37.84,35.44,31.17,30.87,30.66,29.59,29.38,29.2 3,28.25,28.21,27.99,27.39,26.70,23.68,23.13,22.31,17.29,11.53.HRMS: (ESI, m / z); calculated for C 89 H 105 FN 10 O 15 Na + [M+Na] + :1595.7637,found:1595.7621.

[0209] Synthesis of compound 7-2:

[0210]

[0211] Compound 7-1 (190 mg, 0.12 mmol, 1.0 eq.) was dissolved in MeCN (5 mL, 0.06 M), and Et₂NH (0.03 mL, 0.24 mmol, 2.0 eq.) was added. The mixture was stirred at room temperature for 3 hours. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product, which was then used directly in the next step.

[0212] The product obtained in the previous step was dissolved in DMF (10 mL, 0.01 M). The reaction flask was cooled to 0°C in an ice bath, and 1-4 (65 mg, 0.13 mmol, 1.1 eq.), DIPEA (0.10 mL, 0.60 mmol, 5.0 eq.), and HATU (55 mg, 0.14 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the reaction was quenched by adding saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (3 × 20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4. After filtration, the crude product was concentrated under reduced pressure. After column chromatography, the purified white amorphous product 7-2 (210 mg, overall yield of two steps 95.1%) was obtained. TLC: R f =0.2 (silicagel, dichloromethane / methanol = 20:1). 1H NMR(400MHz,Chloroform-d)δ7.72(d,J=7.6Hz,2H),7.55(t,J=7.8Hz,3H),7.36(t,J=7.6Hz,2H),7.29–7.19(m,4H),7.14(d,J=8.2Hz,5H),7.08–7.00(m,3H),6.89(q,J=9.6Hz,1H),6.77(d,J=8.1Hz,3H),6.58(s,2H),5.90(dtt,J=16.1,9.8,5.0Hz,1H),5.74(dd,J=11.6,5.6Hz,1H),5.29(s,1H),5.18–4.98(m,5H),4.94(s,1H),4.83(q,J=7.8Hz,2H),4.65(d,J=20.5Hz,3H),4.51(d,J=17.1Hz,3H),4.35(t,J=14.1Hz,3H),4.20(d,J=5.7Hz,2H),4.09(d,J=13.7Hz,2H),3.93(d,J=12.9Hz,1H),3.73(s,4H),3.69(d,J=8.3Hz,5H),3.55(s,1H),3.36(dt,J=12.9,6.6Hz,4H),3.19(d,J=8.0Hz,2H),3.08–2.76(m,4H),2.71(dq,J=14.3,6.5,5.7Hz,4H),2.60(dd,J=12.1,5.0Hz,2H),2.32(s,1H),2.00(h,J=7.5Hz,5H),1.69–1.54(m,5H),1.50(s,5H),1.40(s,8H),1.21(s,10H),0.96(d,J=6.2Hz,3H). 13CNMR (101MHz, CDCl3) δ173.76,173.70,173.39,173.36,171.54,171.26,168. 69,168.27,158.78,156.69,141.34,138.69,138.27,137.97,137.52,137.24, 135.85, 134.94, 133.59, 132.84, 130.52, 130.41, 129.49, 129.10, 128.22, 128.16, 127.83, 127.21, 127.15, 126.54, 125.20, 120.08, 117.14, 115.83, 115.0 3,114.06,80.16,77.48,77.16,76.84,75.41,68.95,67.27,57.88,55.36,53.56,52.98,51.88,51.86,50.78,49.17,49.01,48.25,47.17,46.40,46.10,45 .22,41.24,38.54,37.78,35.46,31.19,30.89,29.40,29.25,28.44,28.27,2 8.02,27.42,26.73,23.20,22.34,17.46,11.58.HRMS:(ESI,m / z);calculated for C 100 H 124 FN 13 O 19 Na + [M+Na] + :1852.9013,found:1852.8973.

[0213] Synthesis of compound 7-3 (left-side cyclization):

[0214]

[0215] Compound 7-2 (50 mg, 0.027 mmol) was dissolved in MeCN (5 mL), and Et₂NH (0.05 mL) was added. The mixture was stirred at room temperature for 3 hours. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product. After column chromatography, the purified white amorphous product was obtained. TLC: R f =0.2 (silicagel, dichloromethane / methanol = 10:1).

[0216] The product obtained in the previous step was dissolved in a mixed solvent of THF (2 mL) / MeOH (2 mL) / H₂O (2 mL). The reaction flask was cooled to 0°C in an ice bath, and LiOH (2 mg, 0.049 mmol, 3.0 eq.) was added. The reaction temperature was maintained at 0°C and stirred overnight. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, the organic phase was concentrated under reduced pressure and evaporated to dryness. The pH was adjusted to 5-6 with 1M HCl aqueous solution in an ice bath. The aqueous phase was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous Na₂SO₄. The crude product was obtained by concentration under reduced pressure and used directly in the next step.

[0217] The product obtained in the previous step was dissolved in a mixed solvent DMF (2 mL) / DCM (100 mL). The reaction flask was cooled to 0 °C in an ice bath, and DIPEA (0.02 mL, 0.08 mmol, 5.0 eq.) and HATU (8 mg, 0.02 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The experiment was monitored by TLC column chromatography. When the starting material spot disappeared, a saturated NaHCO3 aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (3 × 20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous Na2SO4. After filtration and concentration under reduced pressure, the crude product was obtained. After column chromatography, the purified white amorphous product 7-3 (25 mg, total yield of three steps 58.9%) was obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol = 20:1). 1H NMR(400MHz,Chloroform-d)δ7.84–7.26(m,4H),7.18(s,2H),7.10(s,3H),6.98(d,J=52.1Hz,5H),6.84–6.74(m,2H),5.92(t,J=13.3Hz,1H),5.72(tq,J=16.2,7.3Hz,1H),5.12(t,J=9.3Hz,1H),4.98(d,J=15.5Hz,3H),4.77(s,1H),4.66(s,2H),4.61–4.39(m,1H),4.26(dd,J=16.5,7.6Hz,4H),4.18–3.93(m,3H),3.77(s,4H),3.74–3.40(m,3H),3.29–2.82(m,5H),2.77(s,3H),2.51(d,J=113.0Hz,2H),2.06(s,3H),2.02–1.73(m,4H),1.72–1.51(m,3H),1.42(d,J=10.5Hz,13H),1.27(s,3H),1.21(s,3H),1.16(s,9H). 13 C NMR(101MHz,CDCl3)δ173.40,172.89,172.29,172.10,171.27,169.96,168.60,159.01,158.74,158.69,156.67,137.67,137.01,135.45,133.70,132.91,130.45,130.37,129.62,129.34,129.16,128.25,126.93,117.03,116.90,115.92,115.24,114.09,114.01,110.92,80.01,77.48,77.16,76.84,74.94,74.58,66.23,60.49,55.41,55.36,53.54,53.07,52.90,50.66,49.08,48.18,45.43,42.11,38.04,31.49,31.04,30.81,28.48,28.42,28.36,28.13,27.28,26.44,23.03,22.30,21.14,17.39,14.28,11.57.HRMS:(ESI,m / z);calculated for C 84 H 110 FN 13 O 16 Na + [M+Na]+ :1598.8070,found:1598.8056.

[0218] Synthesis of compound 7-4 (intermediate docking cyclization):

[0219]

[0220] Compound 7-3 (25 mg, 0.016 mmol) was dissolved in DCM (5 mL). Zhan (1 B) (1 mg) was added at room temperature, and the reaction temperature was raised to 45 °C and stirred overnight. The experiment was monitored using TLC (thin-layer chromatography). When the starting material disappeared, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain the crude product. After column chromatography separation, the purified yellow solid product 7-4 (20 mg, yield 81.3%) was obtained. TLC: R f =0.2 (silica gel, dichloromethane / methanol = 20:1). 1H NMR(400MHz,DMSO-d6)δ8.14(t,J=10.0Hz,2H),8.01(d,J=8.6Hz,1H),7.91–7.81(m,1H),7.68(s,1H),7.56(d,J=6.3Hz,1H),7.41(d,J=9.4Hz,1H),7.22(dd,J=25.9,9.2Hz,6H),7.03(td,J=14.7,13.1,7.9Hz,7H),6.89(td,J=10.8,9.2,5.5Hz,6H),6.63(d,J=6.1Hz,1H),5.90(s,1H),5.52(d,J=15.3Hz,1H),5.27(dt,J=15.6,7.0Hz,1H),4.85–4.74(m,1H),4.73–4.56(m,2H),4.44(d,J=7.4Hz,3H),4.31–4.25(m,2H),4.21(s,1H),4.10–3.93(m,3H),3.83(d,J=15.9Hz,2H),3.71(d,J=2.3Hz,3H),3.68–3.46(m,3H),3.30–3.14(m,2H),2.91(dt,J=20.2,10.2Hz,3H),2.76(dt,J=17.3,12.9Hz,2H),2.62(d,J=12.2Hz,1H),2.40(d,J=49.1Hz,5H),2.07(t,J=17.9Hz,2H),1.86(dt,J=21.7,9.0Hz,1H),1.77–1.58(m,3H),1.57–1.42(m,1H),1.33(d,J=8.4Hz,9H),1.29–1.21(m,4H),1.08(d,J=9.8Hz,9H),0.91(d,J=7.6Hz,6H). 13C NMR (101MHz, DMSO) δ172.3,172.2,171.4,171.1,170.5,168.9,168.7,168.6,168.0,158.0,155.6,155.3,13 8.7,138.1,138.0,135.6,132.4,130.1,129.6,129.0,128.6,128.4,128.2,128.1,127.9,127.8,127.0,113 .9,79.3,77.8,74.0,66.6,64.6,55.0,54.3,52.3,51.4,48.0,47.7,41.9,40.1,39.9,39.7,39.5,39.3,39. 1,38.9,35.8,33.9,31.7,28.9,28.2,28.0,27.9,25.9,22.1,20.6,18.4,18.0.HRMS: (ESI, m / z); calculated for C 82 H 106 FN 13 O 16 Na + [M+Na] + :1570.7757,found:1570.7764.

[0221] Following the synthesis of intermediate 7-4, the remaining synthesis involves reactions already disclosed in the prior art, such as the reduction of the C=C double bond (which may or may not be reduced), and the derivation of R1 and R2 groups. The synthesis method of compound 1-1 is exemplarily provided in this embodiment.

[0222] Synthesis of compound 1-1:

[0223]

[0224] Compound 7-4 was dissolved in MeOH (5 mL), and ethyl acetate solution of hydrochloric acid (1 mL) and Pd / C (5 mg) were added. After mixing and stirring for 30 minutes, the mixture was ventilated three times using a vacuum water pump to remove all O2 from the reaction system. The mixture was then stirred overnight under H2 conditions. The experiment was monitored using TLC thin-layer column chromatography until the starting material was completely eliminated. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product, which was used directly in the next step.

[0225] The product obtained in the previous step was dissolved in a mixed solvent of TFA (2 mL) / DCM (5 mL) and stirred at room temperature for 6 hours. The reaction was monitored by LCMS until the starting material was completely eliminated. Then, the reaction solution was concentrated under reduced pressure using a vacuum water pump to obtain a crude product, which was used directly in the next step.

[0226] The product obtained in the previous step was dissolved in ACN (5 mL), and the reaction flask was cooled to 0 °C in an ice bath. Compounds 1-5 (5 mg, 0.02 mmol, 1.2 eq.), DIPEA (0.02 mL, 0.11 mmol, 5.0 eq.), and HATU (9 mg, 0.02 mmol, 1.2 eq.) were added. The ice bath was removed, and the mixture was heated to room temperature and stirred for 1 hour. The reaction was monitored by LCMS until the starting material was completely eliminated. After adding IPAc (20 mL), a white solid precipitated. The precipitate was filtered, washed with IPAc, and collected. The precipitate was then purified by HPLC to obtain the purified trifluoroacetate white solid product. This was then converted to the final hydrochloride product 1-1 (15 mg, overall yield of four steps 41.5%) using a hydrochloric acid-methanol solution. 1 H NMR(400MHz, Methanol-d4)δ7.48–7.37(m,1H),7.33(s,1H),7.21(d,J=26.1Hz,4H) ,7.12(d,J=18.3Hz,2H),7.05–6.97(m,4H),6.90(d,J=7.8Hz,4H),5.35(d,J=5.2Hz ,1H),4.71(s,2H),4.69–4.31(m,2H),4.28(s,2H),4.26–4.20(m,5H),4.15(t,J=15 .0Hz,1H),4.09–3.97(m,1H),3.86–3.81(m,1H),3.80(s,5H),3.72(s,1H),3.69–3. 42(m,2H),3.12(s,16H),3.10(s,8H),3.07–2.98(m,1H),2.98–2.75(m,3H),2.70(s ,1H),2.58(d,J=19.5Hz,1H),2.23(dd,J=23.0,7.4Hz,5H),2.04(t,J=6.3Hz,3H),1 .94(s,1H),1.83–1.75(m,7H),1.68(q,J=7.3Hz,4H),1.48(s,3H),1.39(d,J=9.0Hz ,2H),1.29(s,6H),1.17(d,J=5.0Hz,4H),1.10–0.97(m,2H),0.91(d,J=5.4Hz,3H). 13C NMR(201MHz,MeOD)δ176.2,175.7,175.4,174.4,173.8,173.4,171.5,171.1, 170.8,170.5,170.0,169.8,159.9,158.1,139.6,139.2,137.5,136.7,133.2 ,132.1,131.4,130.8,130.6,130.3,130.1,129.8,129.6,128.8,128.3,114.8,112.5,111.8,110.2,104.9,81.8,68.8,68.7,67.4,64.1,57.2,55.5,54.6 ,53.3,51.8,51.4,49.2,49.0,48.9,48.8,48.7,48.6,48.5,47.2,46.7,45.5,43.6,40.6,38.4,36.8,36.5,36.2,36.0,35.2,34.6,32.8,30.6,30.5,30.5 ,30.4,30.4,30.2,30.1,28.8,28.5,27.9,26.7,26.5,26.4,25.9,25.8,23.5 ,23.4,23.4,21.7,21.4,20.4,19.7,17.6,17.0.HRMS:(ESI,m / z);calculated for C 82 H 110 FN 14 O 15 + [M] + :1549.8254,found:1549.8256.

[0227] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for synthesizing a compound of formula I or a pharmaceutically acceptable salt thereof, said compound of formula I having the following structure: in: R 1 Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)3; (aiii) The following part: R 2 Selected from: (a)-H; and (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C -O-(CH2)3-4-N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3; (aiii) The following part: (aiv) The following part: Where R 14Cb and R 14Cc The range is 1 to 4; A is selected from: -CH2CH2- or -CH=CH-; R 8 Selected from: C1-6 alkyl groups, wherein the C1-6 alkyl group can be -OR 8a Instead, the R 8a Selected from H and straight-chain, branched, or cyclic alkyl groups with no more than 6 carbon atoms; X is selected from H, F, Cl, or Br; The method includes the following steps: (1) Use compound III-1 to synthesize compound III-2; Where R 1a Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)–NH-amino protecting group; (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B It is a -NH-amino protecting group; (iv)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B It is a -NH-amino protecting group; (v)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai) The following part: (2) Use compound III-2 to synthesize compound III-3; (3) Use compound III-3 to synthesize compound III-4; (4) Use compound III-4 to synthesize compound I or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, characterized in that: R 1 Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)-N + (H3C)3; (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B -N + (CH3)3; R 2 Selected from: (a)-H; and (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from: (i)-H; (ii)–NH2; (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: or -N + (CH3)3; (iv)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N+(CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3; (aiii) The following part: R 8 For -CH3 or the following part: Where R 8a It is -H, or a straight-chain, branched, or cyclic alkyl group with up to four carbon atoms.

3. The method according to claim 1, characterized in that, The compound of formula I is compound 1-1. G - This represents a pharmaceutically acceptable anion.

4. The method according to claim 1, characterized in that, In step (3), the Zhan (1B) catalyst was used and the reaction was carried out at 40-50°C.

5. Compound III-2 or compound III-3, having the following structure: Where R 1a Selected from: (a)-H; or (b)-(CH2)zR 14A ,in: z is 1-6, and R 14A for: (i)-H; (ii)–NH-amino protecting group; (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B It is a -NH-amino protecting group; (iv)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B It is a -NH-amino protecting group; (v)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai) The following part: R 8 Selected from: C1-6 alkyl groups, wherein the C1-6 alkyl group can be -OR 8a Instead, the R 8a Selected from H and straight-chain, branched, or cyclic alkyl groups with no more than 6 carbon atoms; X is selected from H, F, Cl, or Br.

6. The compound according to claim 5, having the following structure:

7. Use of the compound according to any one of claims 5 or 6 in the preparation of compound of formula I, in: R 1 Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)3; (aiii) The following part: R 2 Selected from: (a)-H; and (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C -O-(CH2)3-4-N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3; (aiii) The following part: (aiv) The following part: Where R 14Cb and R 14Cc The range is 1 to 4; A is selected from: -CH2CH2- or -CH=CH-; R 8 Selected from: C1-6 alkyl groups, wherein the C1-6 alkyl group can be -OR 8a Instead, the R 8a Selected from H and straight-chain, branched, or cyclic alkyl groups with no more than 6 carbon atoms; X is selected from H, F, Cl, or Br.

8. A method for synthesizing compound III-4, comprising the following steps: (a) Using compound III-2, compound III-3 was synthesized; (b) Using compound III-3, compound III-4 was synthesized; in R 1 Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C For -O-(CH2) 3-4 -N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)3; (aiii) The following part: R 2 Selected from: (a)-H; and (b)-(CH2)zR 14A Where: z is 1-6, and R 14A Selected from: (i)-H; (ii)–NH2; (iii)-N + H3; (iv)-N + (CH3)3; (v)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vi)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B For: -NH2; -N + H3; -N(CH3)2; or -N + (CH3)3; (vii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C -O-(CH2)3-4-N + (CH3)3; and (viii)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai)–O-(CH2)2-N + (CH3)3; (aii)-N + (CH3)2R 14ca , where R 14ca For –CH3 or –(CH2) 1-4 -OCH3; (aiii) The following part: (aiv) The following part: Where R 14Cb and R 14Cc The range is 1 to 4; R 1a Selected from: (a)-H; or (b)-(CH2)zR 14A Where: z is 1-6, and R 14A for: (i)-H; (ii)–NH-amino protecting group; (iii)-NH-C(O)-[(CH2)2-O-]2-(CH2)2R 14B , where R 14B It is a -NH-amino protecting group; (iv)-NH-C(O)-[(CH2) y12 -O-]2-(CH2) y13 R 14B Where: y12 and y13 are not both 2 and are independently 2 to 4; and R 14B It is a -NH-amino protecting group; (v)-NH-C(O)-(CH2) y R 14C Where y = 1 to 6 and R 14C for: (ai) The following part: A is selected from: -CH2CH2- or -CH=CH-; R 8 Selected from: C1-6 alkyl groups, wherein the C1-6 alkyl group can be -OR 8a Instead, the R 8a Selected from H and straight-chain, branched, or cyclic alkyl groups with no more than 6 carbon atoms; X is selected from H, F, Cl, or Br.

9. The method according to claim 8, characterized in that, In step (b), a Zhan (1B) catalyst is used, and the reaction is carried out at 40-50°C.

10. The method according to claim 8, characterized in that, The compound III-2 is compound 7-2, and the compound III-3 is compound 7-3;

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