Key intermediate for synthesizing PM060184 compounds, synthesis method of key intermediate and method for synthesizing PM060184 compounds

Abstract

The invention discloses a key intermediate for synthesizing a PM060184 compound, a synthesis method of the key intermediate and a method for synthesizing the PM060184 compound, and belongs to the field of pharmaceutical chemistry synthesizing.The method comprises the steps that a compound shown in the formula (I) and a compound shown in the formula (II) are subjected to a coupling reaction to obtain a compound shown in the formula (III); then, constructing a C1-C5 ring system of PM060184 through alkali-driven domino cyclization reaction of the compound as shown in the formula (IV), and obtaining the compound as shown in the formula (XI) through two times of wittig reaction and one time of reduction reaction by taking commercially available (R)-3-((tert-butyldiphenylsilyl) oxy)-5-oxo ethyl valerate as a raw material; the longest linear steps of the whole synthetic route for synthesizing PM060184 are 12 steps, the total steps are 24 steps, the total yield is 22%, and the total yield exceeds the reported longest linear steps of 17 steps, the reported longest linear steps of 33 steps and the reported total yield of 14%; in addition, 1.2 g-level scale preparation of PM060184 can be realized by the route, and a firm foundation is laid for subsequent industrial synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a key intermediate for synthesizing PM060184 compounds, a synthesis method thereof, and a method for synthesizing PM060184 compounds. Background Art

[0002] In 2007, PharmaMar first disclosed the marine natural product PM060184 (plocabulin) and its C24 chloro analog PM050489 with strong anti-tumor activity in its patent WO 2007 / 144423. The structures are shown below:

[0003] .

[0004] The above two polyketides derived from the Madagascar sponge Lithoplocamia lithistoides have unique structural characteristics: they contain α,β-unsaturated-δ-lactone, conjugated triene system, L-tert-leucine module, diene structure and carbamate group.

[0005] PM060184 and PM050489 have been shown to have strong anticancer activity in preclinical studies, especially in epithelial ovarian cancer (EOC), gastrointestinal stromal tumor (GIST), colorectal cancer and soft tissue sarcoma models. The existing research systematically elucidated the mechanism of action of PM050489 and PM060184 in inhibiting tubulin, and confirmed that the binding site of PM060184 with tubulin is the region where asparagine 100 (Asn100) is located in tumor cell β-tubulin. At the same time, they also evaluated the antiproliferative activity of PM050489, PM060184, vinblastine and paclitaxel in 23 human tumor cell lines, confirming that the in vitro activity of PM060184 and PM050489 is generally superior to paclitaxel and vinblastine, which are currently the first-line clinical drugs. Currently, PM060184 is undergoing a Phase II clinical trial for the treatment of advanced colorectal cancer (CRC).

[0006] However, the isolation efficiency of this natural product was extremely low: only 2.6 mg PM060184 (yield 0.00003%) was obtained from 7.66 kg frozen sponge sample, which highlights the limitations of natural extraction and also restricts further clinical and preclinical studies.

[0007] Due to the scarcity of resources, scientists have been exploring methods for the chemical synthesis of PM060184 in order to produce the drug on a large scale. For example, WO 2007 / 144423 discloses a total synthesis route:

[0008] ;

[0009] The total number of steps (TS) of this route is 33, and the longest linear step (LLS) is 17. However, since the yields of some steps are not provided in the original text, the total yield is roughly judged to be 14% based on the cited literature. This method is also the only synthesis method of PM060184 at present. However, the method reported in this patent application has at least the following disadvantages: (1) The overall modularity is low and the convergence is insufficient. In particular, the synthesis of the key intermediate compound C of PM060184 involves a total of 16 transformations, and the longest linear step reaches 14 steps. The cumbersome steps for the synthesis of compound C seriously limit the overall steps and total yield of the final product PM060184. In addition, the introduction of the chiral center of compound C requires the use of chiral auxiliary groups. The early introduction and later removal of the auxiliary groups greatly reduce the atomic economy of the route, which also causes the cumbersome steps to some extent; (2) The introduction of the chiral center of the key intermediate compound F requires the use of hydrolysis kinetic resolution with a maximum yield of only 50%. In addition, the synthesis of compound F requires 8 steps, which is cumbersome and complex, and is not easy to prepare in large quantities and at low cost. Summary of the invention

[0010] One of the purposes of the present invention is to provide a key intermediate for synthesizing PM060184 compounds. In order to achieve the above purpose, the technical solution adopted by the present invention is as follows: the key intermediate has the structure shown in the following formula (III), formula (V) and formula (VII):

[0011] ,

[0012] Among them, R 4 , R 5 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms; 6 , R 7 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; 9 is selected from H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; R 10 , R 11 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; 12 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms; R 14 , R 15are selected from the same or different H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms.

[0013] The second object of the present invention is to provide a method for synthesizing the above key intermediate to solve the above problems.

[0014] The method for synthesizing the compound of formula (III) is as follows: the compound of formula (I) and the compound of formula (II) are dissolved in a solvent, and then Lewis acid is added to carry out Sakurai reaction to obtain the compound of formula (III), and the reaction formula is shown below:

[0015] ;

[0016] In the above formula, R 1 , R 2 , R 3 is selected from alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, R 1 , R 2 , R 3 Same or different. 4 , R 5 , R 6 , R 7 As described in one of the aforementioned invention objectives.

[0017] As a preferred technical solution, the Lewis acid is selected from one of trimethylsilyl trifluoromethanesulfonate, 4-methylbenzenesulfonate pyridinium, magnesium bromide ethyl ether, boron trifluoride ethyl ether, titanium tetrachloride, tin tetrachloride, zinc dichloride, aluminum trichloride, and bis(perfluorophenyl)(3,4,5-trifluoro-2-methylphenyl)borane. Titanium tetrachloride is further preferred, and the reaction yield and diastereoselectivity of the Lewis acid are better.

[0018] As a preferred technical solution, the reaction solvent is selected from one or a mixture of diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran, and toluene. Dichloromethane is further preferred, as the reaction solvent has better reaction yield and diastereoselectivity.

[0019] As a preferred technical solution, the molar ratio of the compound of formula (I) to the Lewis acid is 1:1 to 1:2, and more preferably 1:1.1, which has better reaction yield and diastereoselectivity.

[0020] As a preferred technical solution, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:1 to 1:6, and more preferably 1:2, which has better reaction yield and diastereoselectivity.

[0021] As a preferred technical solution, the concentration of the reaction system is 0.05 mol / L to 0.5 mol / L, and more preferably 0.1 mol / L, which has better reaction yield and diastereoselectivity.

[0022] As a preferred technical solution, the reaction temperature is -45°C to -90°C, and more preferably -78°C. The reaction system concentration has better reaction yield and diastereoselectivity.

[0023] The above-mentioned synthesis method of the present invention achieves a yield of up to 60%, a diastereoselectivity of dr≥20:1 and excellent enantioselectivity, and at the same time achieves an efficiency of introducing two chiral centers that is much higher than that previously reported, so the atom economy of the above-mentioned synthesis method is much higher than that previously reported.

[0024] The method for synthesizing the compound of formula (V) is as follows: the compound of formula (IV) is dissolved in a solvent, a base is added, and a domino cyclization reaction is performed to obtain a compound of formula (V), and the reaction formula is shown below:

[0025] ;

[0026] In the above formula, R 9 , R 10 , R 11 , R 12 As described in one of the aforementioned invention objects, R 8 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms; R 13 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, aromatic or aromatic substituted by various heteroatoms.

[0027] As a preferred technical solution, the base is selected from one of bis(trimethylsilyl)lithium amide, bis(trimethylsilyl)sodium amide, bis(trimethylsilyl)potassium amide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide. Potassium tert-butoxide is further preferred, as the reaction yield of the base is better.

[0028] As a preferred technical solution, the solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran. Tetrahydrofuran is more preferred because the reaction yield of the solvent is better.

[0029] As a preferred technical solution, the molar ratio of the compound of formula (IV) to the base is 1:1 to 1:2, and more preferably 1:1.5, as the reaction yield of this molar ratio is better.

[0030] As a preferred technical solution, the concentration of the reaction system is 0.05 mol / L to 0.5 mol / L, and more preferably 0.1 mol / L, which has a better reaction yield.

[0031] As a preferred technical solution, the reaction temperature is -20°C to 50°C, and more preferably 25°C, as the reaction system concentration has a better reaction yield.

[0032] The above-mentioned synthesis method of the present invention achieves a yield of up to 60%, and the efficiency of ring closure is much higher than that previously reported, so the atom economy is much higher than that previously reported.

[0033] The method for synthesizing the key intermediate of formula (XI) comprises the following steps:

[0034] (1) Under the protection of inert gas, (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester is reacted by Wittig reaction to obtain a compound of formula (VIII);

[0035] ;

[0036] (2) Under the protection of inert gas, the compound of formula (VIII) is subjected to reduction reaction to obtain the aldehyde compound of formula (IX):

[0037] ;

[0038] (3) Under the protection of inert gas, the compound of formula (IX) and the compound of formula (X) are reacted by Wittig reaction to obtain the compound of formula (XI):

[0039] ;

[0040] In the above formula, R 16 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, aromatic or aromatic substituted by various heteroatoms;

[0041] As a preferred technical solution, during the reaction of step (1) and step (3), the base used is one of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, and n-butyl lithium.

[0042] For step (1), sodium bis(trimethylsilyl)amide is further preferred, as the reaction yield and Z / E ratio of this base are better.

[0043] For step (3), n-butyl lithium is further preferred because the reaction yield and Z / E ratio of this base are better.

[0044] As a preferred technical solution, during the reaction of steps (1) and (3), the solvent used is at least one of acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, ether, n-hexane, methyl tert-butyl ether, toluene, and isopropanol, and the water content of the solvent is preferably less than 10 ppm. Tetrahydrofuran is more preferred, as the reaction yield and Z / E ratio of this solvent are better.

[0045] As a preferred technical solution, the reaction temperature of steps (1) and (3) is -90°C to -45°C, and more preferably -78°C, which has better reaction yield and Z / E ratio.

[0046] As a preferred technical solution, the concentration of the reaction system in steps (1) and (3) is 0.05 mol / L to 0.5 mol / L.

[0047] For step (1), 0.1 mol / L is further preferred, as this reaction concentration has better reaction yield and Z / E ratio.

[0048] For step (3), 0.08 mol / L is further preferred, as this reaction concentration has better reaction yield and Z / E ratio.

[0049] As a preferred technical solution, the reaction equivalents of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester, iodomethyl-triphenylphosphine iodide, and base in step (1) can also be changed accordingly. However, in order to ensure the yield and Z / E ratio, the optimal equivalents are 1.0 molar equivalent of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester, 1.4 molar equivalent of iodomethyl-triphenylphosphine iodide, and 1.4 molar equivalent of base.

[0050] As a preferred technical solution, during the reaction in step (2), the solvent used is at least one of acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, ether, n-hexane, methyl tert-butyl ether, toluene, and isopropanol, and the water content of the solvent is preferably less than 10 ppm. Dichloromethane is more preferred, as the reaction yield of this solvent is better.

[0051] As a preferred technical solution, during the reaction of step (2), the reducing agent used is one of lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium triacetoxyborohydride, lithium tri-tert-butoxyaluminum hydride, and palladium carbon hydrogen.

[0052] Diisobutylaluminum hydride is more preferred because the reaction yield of this reducing agent is better.

[0053] As a preferred technical solution, the reaction temperature of step (2) is -90°C to -45°C, and more preferably -78°C, as the reaction yield is better at this temperature.

[0054] As a preferred technical solution, the concentration of the reaction system in step (2) is 0.1 mol / L to 0.5 mol / L, and more preferably 0.3 mol / L, as the reaction yield at this temperature is better.

[0055] As a preferred technical solution, the reaction equivalents of the compound of formula (VIII) and the reducing agent in the reaction of step (2) can also be changed accordingly, but in order to ensure the yield, the optimal equivalents are 1.0 molar equivalent of the compound of formula (VIII) and 1.3 molar equivalent of the reducing agent.

[0056] As a preferred technical solution, the reaction equivalents of the compound of formula (IX), the compound of formula (X), and the base in step (3) can also be changed accordingly. However, in order to ensure the yield and Z / E ratio, the optimal equivalents are 1.0 molar equivalent of the compound of formula (IX), 2.6 molar equivalents of the compound of formula (X), and 2.2 molar equivalents of the base.

[0057] The chemical starting reagent used in the method for synthesizing the key intermediate of formula (XI) of the present invention is commercially available (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester; the total number of steps for finally synthesizing the key intermediate of formula (XI) from this reagent is 3 steps, the total yield is as high as 39%, and the Z:E of the two-step Wittig reaction is ≥ 10:1, and its synthesis efficiency and the efficiency of introducing the chiral center are much higher than those previously reported.

[0058] The synthesis method of the compound of formula (VII) is as follows: under the protection of inert gas, the compound of formula (VI) is used as a raw material, and a tin hydrogenation reduction reaction catalyzed by a catalyst is performed to obtain an alkenyl metal compound of formula (VII):

[0059] ;

[0060] R 9 , R 10 , R 11 , R 14 , R 15 As described in one of the aforementioned invention objectives.

[0061] As a preferred technical solution, the catalyst used is one of tetrakistriphenylphosphine palladium, ditriphenylphosphine palladium dichloride, palladium acetate, dibenzylideneacetone palladium, diphenylphosphinothiocene palladium dichloride, and allyl palladium chloride dimer, or there is no transition metal reagent.

[0062] More preferably, palladium acetate is used, as the reaction yield of this transition metal reagent is better.

[0063] As a preferred technical solution, the solvent A used is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, and the water content of the solvent is preferably less than 10 ppm. More preferably, n-hexane is used, and the reaction yield of the solvent A is better.

[0064] As a preferred technical solution, the solvent B is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, and the water content of the solvent is preferably less than 10 ppm. Tetrahydrofuran is further preferred, and the reaction yield of the solvent B is better.

[0065] As a preferred technical solution, the volume ratio of solvent A to solvent B is 5:1 to 1:1. More preferably, it is 2.3:1, and the reaction yield of this molar ratio is better.

[0066] As a preferred technical solution, the concentration of the reaction system is 0.1 mol / L to 0.5 mol / L.

[0067] A more preferred concentration is 0.13 mol / L, as the reaction yield is better at this temperature.

[0068] The third object of the present invention is to provide a method for synthesizing PM060184, the technical scheme adopted is, comprising the following steps:

[0069] (1) synthesizing the compound of formula (III) by the above-mentioned synthesis method;

[0070] (2) synthesizing the compound of formula (V) by the above-mentioned synthesis method;

[0071] (3) synthesizing the compound of formula (VII) by the above-mentioned synthesis method;

[0072] (4) synthesizing the compound of formula (XI) by the above-mentioned synthesis method;

[0073] (5) reacting a compound of formula (XII) with a compound of formula (XIII) to obtain a compound of formula (XIV):

[0074] ;

[0075] Among them, R 17 is selected from acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, alkyloxycarbonyl, benzyloxycarbonyl, tetrahydropyranyl, methoxymethyl, p-methoxybenzyl, benzyl, allyl, methylthiomethyl, alkynyl, halogen, amino, aromatic group or aromatic group substituted by heteroatom.

[0076] Preferably, the base used is one of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, pyridine, tetramethylguanidine, imidazole, and diisopropylamine, and diisopropylethylamine is more preferred.

[0077] Preferably, the condensing agent used is N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, benzotriazole-1-tris(trimethylamino)-hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O -benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate, N-hydroxy-7-azabenzotriazole, preferably N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate and N-hydroxy-7-azabenzotriazole.

[0078] Preferably, the solvent used is one or more of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, and N,N-dimethylformamide and dichloromethane are further preferred; the water content of the solvent is preferably less than 10 ppm.

[0079] (5) reacting a compound of formula (VII) with a compound of formula (XIV) to obtain a compound of formula (XV):

[0080] ;

[0081] Among them, R 17 is selected from acetyl, benzoyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, alkyloxycarbonyl, benzyloxycarbonyl, tetrahydropyranyl, methoxymethyl, p-methoxybenzyl, benzyl, allyl, methylthiomethyl, alkynyl, halogen, amino, aromatic group or aromatic group substituted by heteroatom.

[0082] Preferably, the catalyst used is one of cuprous iodide, cuprous bromide, cuprous chloride, cupric oxide, cuprous cyanide, copper thiophene-2-carboxylate, copper acetate, and copper trifluoromethanesulfonate, and copper thiophene-2-carboxylate is more preferred.

[0083] Preferably, the solvent used is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, and N-methylpyrrolidone is more preferred; the water content of the solvent is preferably less than 10 ppm.

[0084] The present invention achieves a total of 24 steps, and the longest linear step reaches 12 steps, which are much shorter than those previously reported; the present invention achieves a total yield of 22%, which is much higher than those previously reported. And it can achieve the 1.23 gram scale preparation of PM060184, laying the foundation for the subsequent industrial synthesis.

[0085] Compared with the prior art, the advantages of the present invention are: the present invention quickly and efficiently introduces the two chiral centers of C5 and C6 of PM060184 with good yield and extremely high diastereoselectivity through the coupling reaction of the compound of formula (I) and the compound of formula (II), and its efficiency is much higher than that of the existing reports, and its atom economy is much better than that of the existing reports; then, the present invention efficiently completes the construction of the C1-C5 ring system of PM060184 with good yield through the base-driven domino cyclization reaction of the compound of formula (IV), and its efficiency is much higher than that of the existing reports; thirdly, the present invention uses commercially available (R)-3-((tert-butyldi)- Using ethyl 5-oxopentanoate (phenylsilyl)oxy) as the raw material, the compound of formula (XI) is obtained with good yield and Z / E selectivity through three steps of two wittig reactions and one reduction reaction. The efficiency of introducing the C21 chiral center of PM060184 is much higher than that reported previously. The steps for synthesizing the compound of formula (XI) are extremely short and the efficiency is extremely high, which is much better than that reported previously. The longest linear step of the entire synthetic route for synthesizing PM060184 is 12 steps, the total steps are 24 steps, and the total yield is 22%, which exceeds the longest linear step of 17 steps, the total steps are 33 steps, and the total yield is 14% reported previously. In addition, this route can achieve the 1.2 gram scale preparation of PM060184, laying a solid foundation for the subsequent industrial synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 and Figure 2 They are respectively the hydrogen spectrum and carbon spectrum of compound 8 in Example 1 of the present invention;

[0087] Figure 3 and Figure 4 They are respectively the hydrogen spectrum and carbon spectrum of compound 14 of Example 1 of the present invention;

[0088] Figure 5 and Figure 6 They are respectively the hydrogen spectrum and carbon spectrum of compound 15 of Example 1 of the present invention;

[0089] Figure 7and Figure 8 They are respectively the hydrogen spectrum and carbon spectrum of PM060184 in Example 3 of the present invention. DETAILED DESCRIPTION

[0090] The present invention will be further described below in conjunction with the accompanying drawings.

[0091] Embodiment 1:

[0092] The method for synthesizing the C1-C8 fragment of PM060184 is as follows:

[0093] The specific synthesis steps are:

[0094] 1) To a solution of lithium chloride (36.3 g, 855.9 mmol) and (R)-3-butyn-2-ol 1 (20.0 g, 285.3 mmol) in tetrahydrofuran (1000 mL) was added dropwise at -78°C with n-butyllithium (238 ml, 2.4 M / L n-hexane solution, 570.6 mmol); after stirring at -78°C for 1 h, trimethylsilyl chloride (37.8 mL, 299.6 mmol) was added dropwise; after stirring at room temperature for 12 h (monitored by thin layer chromatography), the reaction mixture was quenched with hydrochloric acid (1 M / L, 428 ml, 427.9 mmol) at 0°C and stirred at room temperature for 1 h; after the reaction was completed, the mixture was extracted with ether (3 × 200 mL), the organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a pale yellow liquid crude product 2 (39.0 g, 274.1 mmol); the crude product can be used directly in the next step without purification, or can be purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1→25:1) to obtain the pure product of compound 2;

[0095] Structural identification of compound 2: 1 H NMR (400 MHz, CDCl 3 ) δ 4.53-4.47 (m, 1H), 2.22(d, J = 5.2 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H), 0.15 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 107.9, 88.4, 58.8, 24.3, 0; IR (neat) cm -13444, 1276, 1261, 749, 765; HRMS (MALDI, m / z) calcd for C 7 H 14 OSiNa (M+Na) + 165.0706, found 165.0702; [α] D 25 = + 24.6 o (c = 0.69 in CHCl 3 ).

[0096] 2) To a solution of compound 2 (39.0 g, 274.1 mmol) in dichloromethane (1000 mL) was added triethylamine (57.2 mL, 411.1 mmol) and methanesulfonyl chloride (27.6 mL, 356.3 mmol) dropwise at -78°C; the reaction mixture was stirred at -78°C for 2 h, then quenched with saturated aqueous sodium bicarbonate solution (500 mL), and extracted with ethyl acetate (3 × 300 mL); the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1→30:1) to obtain compound 3 (56.6 g, total yield of two steps was 90%);

[0097] Structural identification of compound 3: 1 H NMR (400 MHz, CDCl 3 ) δ 5.25 (q, J = 6.8 Hz, 1H), 3.11 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 0.18 (s, 9H); 13 C NMR (101 MHz, CDCl 3 )δ 101.4, 93.8, 68.7, 39.2, 22.6, 0.3; IR (neat) cm -1 2952, 1362, 1252, 1178,921, 845; HRMS (MALDI, m / z) calcd for C 8 H 16 O 3 SSiNa (M+Na) + 243.0481, found243.0476;[α] D 25 = +199.2 o(c = 2.2 in CHCl 3 ).

[0098] 3) Methylmagnesium chloride (3.0 M in tetrahydrofuran, 177.2 mL, 531.7 mmol) was added dropwise to a solution of copper bromide (76.3 g, 531.7 mmol) and lithium bromide (46.2 g, 531.7 mmol) in tetrahydrofuran (700 mL) at 0°C; the reaction solution was stirred at 0°C for 30 min, and then a solution of compound 3 (65.1 g, 295.4 mmol) in tetrahydrofuran (300 mL) was added at -78°C; the reaction solution was stirred at -78°C for 40 min, and then stirred at room temperature for 2 h; then, the reaction solution was slowly poured into a solution containing pentane (1868 mL), water (934 mL) and saturated aqueous ammonium chloride (1868 mL). After stirring at room temperature for 30 min, the organic phase was washed twice with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and carefully concentrated in vacuo (note: the water bath temperature was below 20°C). The concentrate was purified by atmospheric distillation (to remove residual tetrahydrofuran) and reduced pressure distillation (boiling point: 0.1 atm at 43°C) to obtain chiral silylene (R)-4 (28.7 g, 69% yield);

[0099] Structural identification of compound (R)-4: 1 H NMR (400 MHz, CDCl 3 ) δ 4.73-4.66 (m, 1H), 1.66 (d, J = 2.8 Hz, 3H), 1.60 (d, J = 6.8 Hz, 3H), 0.07 (s, 9H); 13 C NMR (101MHz, CDCl 3 ) δ 206.8, 90.6, 78.6, 15.7, 14.0, 1.7; IR (neat) cm -1 2956, 2922,2899, 2861, 1938, 1447, 1363, 1249, 877, 835; HRMS (MALDI, m / z) calcd forC 7 H 16 SiNa (M+Na) + 151.0913, found 151.0910; [α] D 25 = -59.4 o (c = 3.8 in CHCl 3 ).

[0100] 4) To a solution of 1, 3-dithiane 5 (40.0 g, 332.8 mmol) in tetrahydrofuran (680 mL) was added n-butyl lithium (139.2 ml, 2.4 M / L n-hexane solution, 332.8 mmol) dropwise at -78°C; after the addition was completed, the mixture was stirred at room temperature for 1 h, and then 2-bromo-1,1-dimethoxyethane 6 (35.0 mL, 302.5 mmol) was added dropwise at -78°C; after the addition was completed, the mixture was stirred at room temperature for 3 h, and then an aqueous hydrochloric acid solution (6 M / L, 176 mL) was slowly added dropwise; then, the reaction solution was stirred at room temperature for 16 h; after the reaction was completed, it was extracted with ethyl acetate (3 × 300 mL), the organic layers were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 30:1 → 10:1) to obtain fatty aldehyde compound 7 (34.6 g, 47% yield);

[0101] Structural identification of compound 7: 1 H NMR (400 MHz, CDCl 3 ) δ 9.69 (t, J = 1.6 Hz, 1H), 4.47 (t, J = 6.8 Hz, 1H), 2.94-2.87 (m, 2H), 2.85-2.79 (m, 2H), 2.77 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 2H), 2.12-2.05 (m, 1H), 1.89-1.78 (m, 1H); 13 C NMR (101MHz, CDCl 3 ) δ 198.1, 48.3, 40.2, 30.1, 25.0; IR (neat) cm -1 2934, 2903, 2827,2728, 1724, 1420, 1277, 1120, 1033, 1004; HRMS (MALDI, m / z) calcd forC 6 H 10 OS 2 Na (M+Na) + 185.0065, found 185.0064.

[0102] 5) Titanium tetrachloride (12.3 mL, 112.4 mmol) was added dropwise to a solution of chiral silylene (R)-4 (14.3 g, 102.1 mmol) and fatty aldehyde 7 (33.2 g, 204.2 mmol) in dichloromethane (1021 mL) at -78°C. After the addition, the mixture was stirred at -78°C for 3 h, quenched with saturated aqueous ammonium chloride solution (400 mL), and extracted with dichloromethane (3× 300 mL); the organic layers were combined, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Then, sodium borohydride (5.8 g, 112.4 mmol) was added in batches to a solution of the concentrate in methanol (340 mL) at 0°C. After the addition was completed, the mixture was stirred at 0°C for 3 h, and the reaction was quenched with water (200 mL), and extracted with ethyl acetate (3 × 200 mL); the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo; the concentrate was purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1 →30:1) to obtain compound 8 (14.2 g, 60% yield, dr > 20:1);

[0103] Structural identification of compound 8: 1 H NMR (400 MHz, CDCl 3 ) δ 4.29 (dd, J 1 = 6.8 Hz, J 2 = 3.2 Hz, 1H), 3.83-3.79 (m, 1H), 2.95-2.89 (m, 1H), 2.87-2.82 (m, 3H), 2.60-2.54 (m, 1H), 2.15-2.10 (m, 1H), 2.06 (d, J = 4.4 Hz, 1H), 2.03 (ddd, J 1 =10.0 Hz, J 2 = 6.8 Hz, J 3 = 1.6 Hz, 1H), 1.94-1.86 (m, 2H), 1.79 (d, J = 1.6Hz, 3H), 1.14 (d, J = 4.8 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 79.9, 78.8, 71.4,44.4, 39.2, 33.2, 30.6, 30.1, 26.1, 16.7, 3.7; IR (neat) cm-1 3421, 2933, 2900,1423, 1242, 1092, 1008, 910, 870; HRMS (MALDI, m / z) calcd for C 11 H 18 OS 2 Na (M+Na) + 253.0691, found 253.0686; [α] D 25 = -45.7 o (c = 6.9 in CHCl 3 ); see Figure 1 and Figure 2 .

[0104] 6) Add 4-dimethylaminopyridine (970 mg, 7.9 mmol) and acetic anhydride (18.8 mL, 198.5 mmol) to a solution of compound 8 (18.3 g, 79.4 mmol) in pyridine (749 mL) at room temperature. Then, stir at room temperature for 2 h. After the reaction, quench the reaction with water (2000 mL), extract with ethyl acetate (4 × 500 mL), combine the organic phases, wash with aqueous hydrochloric acid solution (0.2 M / L, note: until the aqueous phase is acidic), then wash twice with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. The concentrate was purified by rapid silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1 → 20:1) to obtain compound 9 (21.2 g, 98% yield);

[0105] Structural identification of compound 9: 1 H NMR (400 MHz, CDCl 3 ) δ 4.96-4.92 (m, 1H), 4.01(dd, J 1 = 8.8 Hz, J 2 = 5.6 Hz, 1H), 2.89-2.77 (m, 4H), 2.70-2.62 (m, 1H), 2.13-2.08 (m, 2H), 2.06-2.02 (m, 1H), 2.04 (s, 3H), 1.88-1.79 (m, 1H), 1.74 (d, J = 2.4 Hz, 3H), 1.07 (d, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCl 3) δ170.6, 79.0, 78.4, 73.6, 43.8, 37.0, 30.7, 30.3, 30.0, 25.8, 21.3, 17.6, 3.6; IR (neat) cm -1 2936, 2901, 1737, 1424, 1372, 1232, 1024; HRMS (MALDI, m / z)calcd for C 13 H 20 O 2 S 2 Na (M+Na) + 295.0797, found 295.0792; [α] D 25 = -35.3 o (c = 4.3in CHCl 3 ).

[0106] 7) At room temperature, iodomethane (8.1 mL, 127 mmol), water (33 mL) and calcium carbonate (13.0 g, 127 mmol) were added to a solution of compound 9 (3.5 g, 12.7 mmol) in acetonitrile (130 mL) in sequence; after stirring at room temperature for 36 h, the reaction solution was concentrated, water (220 mL) was added, and extracted with methyl tert-butyl ether (7 × 30 mL); the organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of compound 10 (2.3 g, 97% yield), which was used directly in the next step without purification; it was also obtained by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 25:1 → 10:1) to obtain pure compound 10, which was fully characterized, and the results are as follows:

[0107] Structural identification of compound 10: 1 H NMR (400 MHz, CDCl 3 ) δ 9.72 (dd, J 1 = 2.8 Hz, J 2 = 1.6 Hz, 1H), 5.12 (ddd, J 1 = J 2 = 7.2 Hz, J 3= 4.0 Hz, 1H), 2.85-2.78 (m,1H), 2.76-2.68 (m, 2H), 2.02 (s, 3H), 1.75 (d, J = 2.4 Hz, 3H), 1.11 (d, J =7.2 Hz); 13 C NMR (101 MHz, CDCl 3 ) δ 199.5, 170.4, 79.3, 78.8, 71.8, 46.1, 30.7,21.0, 17.8, 3.5; IR (neat) cm -1 2983, 2922, 2736, 1725, 1371, 1227, 1052, 1018,957; HRMS (MALDI, m / z) calcd for C 10 H 15 O 3 (M+H) + 183.1016, found 183.1019; [α] D 25 = -24.7 o (c = 1.8 in CHCl 3 ).

[0108] 8) To a solution of lithium bistrimethylsilylamide (230 mL, 230 mmol, 1 M / L in THF) in tetrahydrofuran (150 mL) was added dropwise a solution of methyl methoxyacetate 11 (20 g, 192 mmol) in tetrahydrofuran (50 mL) at -78 °C (the addition time was greater than 30 min); after the addition was completed, after stirring at -78 °C for 30 min, trimethylsilyl chloride (36.5 mL, 288 mmol) was added dropwise; after the addition was completed, after stirring at room temperature for 30 min, petroleum ether (150 mL) was added for dilution; after filtering, vacuum concentrating, sufficient petroleum ether was added for dilution, filtering again, and vacuum concentrating to obtain a mixture of compound 12 and bistrimethylsilylamine (43.9 g, mass fraction of 77%, 99% yield); the mixture was directly carried out to the next step without purification;

[0109] At -78°C, boron trifluoride ether complex (4.2 mL, 34.4 mmol) was added dropwise to a solution of fatty aldehyde 10 (5.7 g, 31.1 mmol) and enol silyl ether 12 (8.3 g, 46.9 mmol) in dichloromethane (390 mL) at -78°C; after the addition, the mixture was stirred at -78°C for 3 h, quenched with saturated aqueous sodium bicarbonate solution (300 mL), and extracted with dichloromethane (3 × 100 mL). The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by rapid silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 5:1 → 3:1) to obtain compound 13 (8.7 g, yield 97%);

[0110] Structural identification of compound 13: 1 H NMR (400 MHz, CDCl 3 ) δ 4.91-4.72 (m, 1H), 4.00-3.64 (m, 5H), 3.40-3.36 (m, 3H), 3.05-2.51 (m, 2H), 2.05-1.97 (m, 4H), 1.76-1.64 (m, 4H), 1.07-1.04 (m, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.7, 171.2,171.2, 171.2, 171.0, 170.9, 170.8, 84.2, 83.6, 83.6, 82.4, 79.3, 79.3, 79.3,78.2, 78.1, 78.1, 78.1, 74.6, 74.2, 73.5, 73.4, 70.3, 70.2, 68.6, 68.3, 59.0,58.9, 58.7, 52.0, 52.0, 51.9, 35.3, 34.6, 34.6, 34.5, 30.9, 30.8, 30.7, 21.2,21.1, 21.1, 21.0, 17.5, 17.5, 17.4, 3.5, 3.4; IR (neat) cm -1 3496, 2987, 2926,2839, 1736, 1436, 1371, 1238, 1204, 1116, 1024; HRMS (MALDI, m / z) calcd forC 14 H 22 O 6 Na (M+Na) + 309.1309, found 309.1303;[α] D 25 = -27.5 o (c = 7.5 in CHCl 3 ).

[0111] 9) At -78°C, add a solution of potassium tert-butoxide in tetrahydrofuran (49.1 mL, 49.1 mmol, 1M / L in THF) dropwise to a solution of compound 13 (9.35 g, 32.7 mmol) in tetrahydrofuran (163 mL); after the addition, stir at -78°C for 30 min and then place the reaction solution at 25°C for 16 h; after the reaction, quench the reaction with saturated sodium bicarbonate aqueous solution (200 mL) and extract with ethyl acetate (3 × 100 mL); combine the organic phases, wash three times with water, wash once with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. The concentrate is purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 5:1 → 3:1) or recrystallization to obtain compound 14 (3.8 g, 60% yield);

[0112] Structural identification of compound 14: 1 H NMR (400 MHz, CDCl 3 ) δ 5.63 (dd, J 1 = 6.4 Hz, J 2 = 2.8 Hz, 1H), 4.13 (ddd, J 1 = 11.6 Hz, J 2 = 8.0 Hz, J 3 = 4.0 Hz, 1H), 3.61(s, 3H), 2.78-2.67 (m, 1H), 2.63 (ddd, J 1 = 17.6 Hz, J 2 = 6.4 Hz, J 3 = 4.0Hz), 2.52 (ddd, J 1 = 17.6 Hz, J 2 = 11.6 Hz, J 3 = 3.2 Hz, 1H), 1.74 (d, J = 2.4Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, CDCl 3) δ 161.3, 145.0,108.4, 81.0, 79.2, 78.6, 55.5, 31.0, 26.2, 17.6, 3.5; IR (neat) cm -1 2976,2919, 2845, 1736, 1646, 1454, 1380, 1207, 1167, 1109, 1028; HRMS (MALDI, m / z)calcd for C 11 H 14 O 3 Na (M+Na) + 217.0835, found 217.0830;[α] D 25 = -112.4 o (c = 2.2in CHCl 3 ); see Figure 3 and Figure 4 .

[0113] 10) Palladium acetate (57.8 mg, 0.26 mmol) and tricyclohexylphosphine (144.5 mg, 0.52 mmol) were added to the reaction tube, and n-hexane (30 mL) was added after evacuating argon three times, and stirred at room temperature for 10 min; then, a mixture of compound 14 (1.0 g, 5.2 mmol), n-hexane (6 mL) and tetrahydrofuran (16 mL) was added to the reaction solution. Subsequently, tributyltin hydride (4.9 mL, 18.0 mmol, dropwise addition time: 2 h) was added dropwise at room temperature; after the dropwise addition, the mixture was stirred at room temperature for 1 h (TLC monitoring); after the reaction, the mixture was directly concentrated in vacuo and purified by silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 100:0 → 30:1) to obtain compound 15 (2.32 g, 93% yield);

[0114] Structural identification of compound 15: 1 H NMR (400 MHz, CDCl 3 ) δ 5.60 (dd, J 1 = 5.6 Hz, J 2 = 3.6 Hz, 1H), 5.35-5.15 (m, 1H), 4.10 (ddd, J 1 = 10.0 Hz, J 2= 8.4 Hz, J3 =5.6 Hz, 1H), 3.64 (s, 3H), 3.01-2.91 (m, 1H), 2.44-2.32 (m, 2H), 1.92-1.80(m, 3H), 1.57-1.39 (m, 6H), 1.34-1.25 (m, 6H), 1.10 (d, J = 6.8 Hz, 3H), 0.95-0.79 (m, 15H); 13 C NMR (101 MHz, CDCl 3 ) δ 161.9, 145.4, 140.7, 140.7,108.4, 82.4, 55.5, 36.7, 29.3, 27.4, 26.7, 19.8, 17.1, 13.8, 9.3; IR (neat)cm -1 2956, 2926, 2872, 1742, 1647, 1461, 1377, 1202, 1171, 1031, 967; HRMS(MALDI, m / z) calcd for C 23 H 43 O 3 Sn (M+H) + 487.2229, found 487.2228;[α] D 25 = -46.1 o (c = 1.9 in CHCl 3 ). See Figure 5 and Figure 6 .

[0115] The comprehensive yield of all the above steps in Example 1 is 17%.

[0116] Embodiment 2:

[0117] The method for synthesizing the C9-C25 fragment of PM060184 is as follows:

[0118] 1) Sodium iodide (22.5 g, 150.0 mmol), glacial acetic acid (67 mL) and ethyl propiolate 16 (10.1 mL, 100.0 mmol) were added to a 250 mL round-bottom flask in sequence; the mixture was stirred at 70 °C for 12 h and then cooled to room temperature; the reaction was quenched with water (100 mL) and diethyl ether (100 mL), extracted with diethyl ether (3 × 100 mL), the organic phases were combined, washed with potassium hydroxide aqueous solution (3 M / L) until the aqueous phase became alkaline, then washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product 17 (21.6 g, 95% yield, Z:E > 20:1), which was used directly in the next step without purification.

[0119] 2) Diisobutylaluminum hydride (58.0 mL, 1M / L in hexane, 57.5 mmol) was added dropwise to a solution of crude compound 17 (10.0 g, 44.3 mmol) in dichloromethane (147 mL) at -78 °C, ensuring that the internal temperature of the reaction solution was below -60 °C during the addition. After the addition was completed, the reaction was stirred at -78 °C for 20 min, and then quenched with methanol (9 mL) and saturated sodium potassium tartrate aqueous solution (238 mL). The reaction mixture was warmed to room temperature and diluted with ether (70 mL) and water (200 mL); then, it was extracted with ether (3 × 50 mL), the organic phases were combined, washed twice with saturated sodium chloride aqueous solution, dried over anhydrous potassium carbonate, filtered, and carefully concentrated in vacuo (water bath temperature below 20 °C) to obtain the crude aldehyde, which was immediately subjected to the next step without purification.

[0120] 3) To a solution of 18-crown-6 (46.8 g, 177.0 mmol) and Still-Gennari phosphonate (12.6 mL, 53.1 mmol) in tetrahydrofuran (200 mL) was added KHMDS (49.0 mL, 1M / L in THF, 48.7 mmol) dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 30 min, and then a solution of the crude aldehyde obtained in the previous step in tetrahydrofuran (20 mL) was added dropwise. After the addition was completed, the mixture was stirred at -78°C for 60 min, and then quenched with saturated aqueous ammonium chloride solution (200 mL); then, the mixture was extracted with diethyl ether (3 × 100 mL), the organic phases were combined, washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo; the concentrate was purified by rapid silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 200:1 →100:1) to obtain compound 18 (7.8 g, 70% yield, Z:E > 15:1);

[0121] Structural identification of compound 18: 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (ddd, J 1 = 10.4 Hz,J 2 = 7.6 Hz, J 3 = 1.2 Hz, 1H), 6.84 (dt, J 1 = 7.6 Hz, J 2 = 1.2 Hz, 1H), 6.72(ddd, J 1 = 11.6 Hz, J 2 = 10.4 Hz, J 3 = 1.2Hz, 1H), 5.89 (dt, J 1 = 11.6 Hz, J 2 =1.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13 C NMR (101MHz, CDCl 3 ) δ 166.0, 142.9, 134.8, 121.9, 93.8, 60.6, 14.4; IR (neat) cm -1 2983, 2937, 1713, 1622, 1409, 1287, 1204, 1162, 1029, 831; HRMS (MALDI, m / z)calcd for C 7 H 9 IO 2 Na (M+Na) + 274.9539, found 274.9535.

[0122] 4) At room temperature, lithium hydroxide (2.38 mg, 99.0 mmol) was added to a solution of compound 18 (5.0 g, 19.8 mmol) in methanol (165 mL) and water (33 mL); the mixture was stirred at 40°C for 1 h and then concentrated in vacuo; water (300 mL) was added to the residue, and the pH value of the reaction solution was adjusted to 1 with aqueous hydrochloric acid solution (1 M / L). The mixture was extracted with ethyl acetate (5 × 80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product 19 (4.04 g, 91% yield), which was used directly in the next step without purification;

[0123] Structural identification of compound 19:1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (ddd, J 1 = 10.8 Hz,J 2 = 8.0 Hz, J 3 = 1.2 Hz, 1H), 6.94 (dt, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H), 6.85(ddd, J 1 = 11.6 Hz, J 2 = 10.8 Hz, J 3 = 1.2 Hz, 1H), 5.93 (dt, J 1 = 11.6 Hz, J 2 = 1.2 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) δ 171.2, 145.2, 134.7, 120.8, 95.5;IR(neat) cm -1 3048, 2949, 1688, 113, 1435, 1281, 1240, 1174, 896, 833;HRMS(MALDI, m / z) calcd for C 5 H 6 IO 2 (M+H) + 224.9407, found 224.9405。

[0124] 5) To a solution of iodomethyl-triphenylphosphine iodide (8.78 g, 16.56 mmol) in tetrahydrofuran (65 mL) was slowly added NaHMDS (16.6 mL, 1.0 M / L in THF, 16.56 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 min, and then a solution of (R)-ethyl 3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoate 20 (4.72 g, 11.83 mmol) in tetrahydrofuran (49 mL) was added dropwise at -78 °C. The reaction mixture was then stirred at -78 °C for 2 h, stirred at room temperature for 10 min, diluted with ethyl acetate, filtered through celite, rinsed with ethyl acetate, and the filtrates were combined and concentrated under reduced pressure. The concentrate was purified by flash silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 200:1 → 100:1) to obtain compound 21 (3.53 g, 57% yield, Z:E = 10:1);

[0125] Structural identification of compound 21: 1 H NMR (400 MHz, CDCl 3 ) δ 7.76-7.70 (m, 4H), 7.48-7.38 (m, 6H), 6.29 (dt, J 1 = 7.2 Hz, J 2 = 1.2 Hz, 1H), 6.20 (q, J = 6.8 Hz, 1H), 4.44-4.38 (m, 1H), 4.10-4.01 (m, 2H), 2.57 (dd, J 1 = 15.2 Hz, J 2 = 6.8Hz, 1H), 2.48 (dd, J 1 = 15.2 Hz, J 2 = 6.0 Hz, 1H), 2.40 (ddd, J 1 = 6.8 Hz, J 2 = 5.6 Hz, J 3 = 1.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.09 (s, 9H); 13 C NMR (101 MHz, CDCl 3) δ 171.1, 136.9, 136.0, 135.9, 133.7, 133.7, 129.9, 129.8,127.7, 127.7, 85.1, 68.9, 60.5, 42.2, 41.8, 27.0, 19.3, 14.2; IR (neat) cm -1 2932, 2858, 1735, 1428, 1375, 1311, 1189, 1108, 1081, 822, 703; HRMS (MALDI,m / z) calcd for C 24 H 31 IO 3 SiNa (M+Na) + 545.0979, found 545.0974;[α] D 25 = -43.1 o (c = 1.6 in CHCl 3 ).

[0126] 6) Diisobutylaluminum hydride (10.6 mL, 1.0 M / L in hexane, 10.6 mmol) was added dropwise to a solution of compound 21 (4.27 g, 8.16 mmol) in dichloromethane (27 mL) at -78°C. After the addition was completed, the mixture was stirred at -78°C for 1 h, and then the reaction was quenched with methanol (2 mL) and saturated sodium potassium tartrate aqueous solution (50 mL). The reaction solution was warmed to room temperature, diluted with ether (20 mL) and water (20 mL), and extracted with ether (3 × 20 mL). The organic phases were combined, washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by rapid silica gel column chromatography (gradient eluent: petroleum ether / ethyl acetate = 200:1 → 100:1) to obtain compound 22 (3.54 g, 91% yield).

[0127] Structural identification of compound 22: 1 H NMR (400 MHz, CDCl 3 ) δ 9.67 (dd, J 1 = J 2 = 2.0Hz, 1H), 7.69-7.65 (m, 4H), 7.47-7.37 (m, 6H), 6.31 (dt, J 1 = 7.6 Hz, J 2=1.6Hz, 1H), 6.14 (q, J = 6.8 Hz, 1H), 4.42-4.36 (m, 1H), 2.57-2.46 (m, 2H),2.40 (ddd, J 1 = 7.2 Hz, J 2 = 6.0 Hz, J 3 = 1.2 Hz, 2H), 1.05 (s, 9H); 13 C NMR(101 MHz, CDCl 3 ) δ 201.3, 136.7, 136.0, 133.5, 133.4, 130.1, 130.1, 128.0,127.9, 127.9, 85.7, 67.7, 50.2, 42.5, 27.1, 19.4, 1.2;IR (neat) cm -1 2930,2857, 1725, 1472, 1428, 1363, 1261, 1108, 1081, 1007, 822, 743, 702;HRMS(MALDI, m / z) calcd for C 22 H 28 IO 2 Si (M+H) + 479.0898, found 479.0901;[α] D 25 = -41.7 o (c = 0.8 in CHCl 3 )。

[0128] 7) At -78°C, n-butyl lithium (5.6 mL, 2.4 M / L in hexane, 13.5 mmol) was added dropwise to a solution of ethyl triphenylphosphonium iodide (6.68 g, 16.0 mmol) in tetrahydrofuran (60 mL). After stirring at -78°C for 1 h, a solution of compound 22 (2.94 g, 6.13 mmol) in tetrahydrofuran (17 mL) was added dropwise, stirred at -78°C for 2 h, and then stirred at 0°C for 30 min, and then quenched with saturated aqueous ammonium chloride solution (200 mL). Then, the reaction mixture was warmed to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The concentrate was purified by flash silica gel column chromatography (eluent: petroleum ether) to obtain compound 23 (2.24 g, 75% yield, Z:E>20:1);

[0129] Structural identification of compound 23: 1 H NMR (400 MHz, CDCl 3 ) δ 7.75-7.71 (m, 4H), 7.48-7.38 (m, 6H), 6.34-6.25 (m, 2H), 5.55-5.46 (m, 1H), 5.40-5.32 (m, 1H), 3.98-3.92 (m, 1H), 2.36-2.33 (m, 2H), 2.26-2.18 (m, 2H), 1.48 (dt, J 1 = 6.8 Hz, J 2 = 1.2 Hz, 3H), 1.11 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 138.1, 136.1, 136.1,134.3, 134.2, 129.8, 129.7, 127.7, 127.7, 126.3, 125.9, 84.1, 71.8, 41.5,34.4, 27.2, 19.5, 13.1; IR (neat) cm -1 2959, 2931, 2857, 1472, 1427, 1108,1064, 822, 739, 701, 612; HRMS (MALDI, m / z) calcd for C 24 H 31 IOSiNa (M+Na) +513.1081, found 513.1085;[α] D 25 = -14.9 o (c = 4.1 in CHCl 3 ).

[0130] 8) At room temperature, di-tert-butyl dicarbonate (29.8 mL, 129.8 mmol) and pyridine (12.8 mL, 155.7 mmol) were added to a solution of N-Boc-L-tert-leucine 24 (20.0 g, 86.5 mmol) in 1, 4-dioxane (132 mL); after stirring at room temperature for 30 min, ammonium bicarbonate (19.2 g, 243.1 mmol) was added, and then stirring was continued at room temperature for 24 h; after the reaction was completed, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed twice with aqueous hydrochloric acid solution (0.1 M / L) and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product 25 (18.2 g, 92% yield), which was directly used in the next step without purification;

[0131] Structural identification of compound 25: 1 H NMR (400 MHz, CDCl 3 ) δ 6.68 (s, 1H), 6.12 (s,1H), 5.41 (d, J = 9.6 Hz, 1H), 4.00 (d, J = 9.6 Hz, 1H), 1.39 (s, 9H), 0.98(s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.9, 156.1, 79.8, 61.7, 34.2, 28.4, 26.6; IR (neat) cm -1 3322, 3210, 2974, 2874, 1671, 1509, 1393, 1364, 1248, 1165,1062, 1008, 738; HRMS (MALDI, m / z) calcd for C 11 H 23 N 2 O 3 (M+H) + 231.1703, found231.17031;[α] D 25 = +12.4o (c = 1.4 in CHCl 3 ).

[0132] 9) At room temperature, cuprous iodide (261 mg, 1.4 mmol), cesium carbonate (3.0 g, 9.2 mmol) and N, N'-dimethylethylenediamine (0.3 mL, 2.8 mmol) were added to a solution of compound 25 (2.1 g, 9.2 mmol) and compound 23 (2.24 g, 4.6 mmol) in ethylene glycol dimethyl ether (35 mL); stirred at 55 °C in the dark for 24 h and then cooled to room temperature; after the reaction, filtered through celite and rinsed with ethyl acetate. After vacuum concentration of the filtrate, the residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1 → 30:1) to obtain compound 26 (2.4 g, 89% yield);

[0133] Structural identification of compound 26: 1 H NMR (400 MHz, CDCl 3 ) δ 7.71-7.68 (m, 4H), 7.46-7.36 (m, 6H), 7.14 (d, J = 10.4 Hz, 1H), 6.68 (t, J = 10.0 Hz, 1H), 5.55-5.47(m, 1H), 5.37-5.30 (m, 2H), 4.85-4.79 (m, 1H), 3.89-3.78 (m, 2H), 2.28-2.04(m, 4H), 1.46-1.44(m, 12H), 1.07 (s, 9H), 0.98 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 168.4, 155.8, 136.0, 134.2, 134.2, 129.8, 129.8, 129.7, 127.7,127.7, 127.6, 126.5, 126.0, 121.7, 108.5, 79.8, 72.5, 34.8, 33.9, 32.5, 28.4,27.1, 26.6, 19.4, 13.0; IR (neat) cm -1 3326, 2961, 2932, 2860, 1660, 1500,1366, 1172, 1109, 1064; HRMS (MALDI, m / z) calcd for C 35 H53 N 2 O 4 Si (M+H) + 593.3769, found 593.3771;[α] D 25 = -5.8 o (c = 2.0 in CHCl 3 ).

[0134] 10) Compound 26 (2.48 g, 4.2 mmol) and ethylene glycol (140 mL) were added to a 500 mL round-bottom flask in sequence; after stirring at 200 °C for 30 min, the mixture was cooled to room temperature; the reaction mixture was diluted with dichloromethane (50 mL), the reaction was quenched with saturated aqueous sodium chloride solution (50 mL), the reaction solution was poured into water, and the pH was adjusted to 14 with aqueous sodium hydroxide solution (3M / L); the mixture was extracted with dichloromethane (3 × 100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was purified by rapid silica gel column chromatography (gradient eluent: dichloromethane / methanol = 50:1 → 30:1) to obtain compound 27 (1.9 g, 91% yield);

[0135] Structural identification of compound 27: 1 H NMR (400 MHz, CDCl 3 ) δ 8.51 (d, J = 11.2 Hz,1H), 7.71-7.68 (m, 4H), 7.45-7.34 (m, 6H), 6.72 (dd, J 1 = 11.2 Hz, J 2 = 9.2Hz, 1H), 5.50-5.42 (m, 1H), 5.37-5.30 (m, 1H), 4.83-4.77 (m, 1H), 3.90-3.84(m, 1H), 3.09 (s, 1H), 2.23-2.14 (m, 4H), 1.44 (dd,J 1 = 6.8 Hz, J 2 = 1.6 Hz, 3H), 1.07 (s, 9H), 0.98 (s, 9H); 13 C NMR (101 MHz, CDCl 3) δ 170.9, 136.0,134.4, 134.3, 129.7, 129.7, 127.6, 127.6, 126.2, 126.0, 122.0, 107.5, 72.5,64.3, 34.3, 33.9, 32.7, 27.1, 26.8, 19.5, 13.0; IR (neat) cm -1 3330, 2958,2932, 2858, 1660, 1482, 1428, 1108, 1062, 702; HRMS (MALDI, m / z) calcd forC 30 H 45 N 2 O 2 Si (M+H) + 493.3245, found 493.3243; [α] D 25 = -16.3 o (c = 3.5 in CHCl 3 ).

[0136] 11) To a solution of compound 27 (1.0 g, 2.03 mmol) and compound 19 (545 mg, 2.44 mmol) in dichloromethane (17.6 mL) and DMF (4.4 mL) were added N, N-diisopropylethylamine (0.53 mL, 3.05 mmol), N-hydroxy-7-azabenzotriazole (276 mg, 2.03 mmol) and N, N, N′, N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (926 mg, 2.44 mmol) at 0°C; the mixture was stirred at 0°C in the dark for 30 min and at room temperature for 2 h. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, washed three times with water, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo; the residue was purified by triethylamine-neutralized silica gel (soaked overnight with petroleum ether / triethylamine = 50:1) and flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 50:1 → 20:1) to obtain compound 28 (1.13 g, 80% yield);

[0137] Structural identification of compound 28: 1 H NMR (400 MHz, CD 3 OD) δ 8.04 (ddd, J 1 = 10.4 Hz,J 2= 7.6 Hz, J3 = 1.2 Hz, 1H), 7.68-7.65 (m, 4H), 7.41-7.32 (m, 6H), 6.72(dt, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H), 6.60-6.52 (m, 2H), 6.15 (dt, J 1 = 11.6 Hz,J 2 = 1.2 Hz, 1H), 5.44-5.36 (m, 1H), 5.32-5.26 (m, 1H), 4.83-4.76 (m, 1H), 4.51 (s, 1H), 3.85-3.77 (m, 1H), 2.36-2.08 (m, 4H), 1.38 (dd,J 1 = 6.4 Hz, J 2 = 1.6 Hz, 3H), 1.03 (s, 9H), 1.00 (s, 9H); 13 C NMR (101 MHz, CD 3 OD) δ 170.4,167.6, 140.6, 137.0, 137.0, 136.1, 135.3, 135.2, 130.8, 128.6, 128.6, 127.1,126.8, 125.3, 122.7, 111.0, 92.3, 73.9, 61.5, 35.5, 35.0, 33.6, 27.6, 27.2,20.2, 13.2;IR (neat) cm -1 3311, 2967, 2856, 1639, 1513, 1370, 1229, 1172,1107, 1057;HRMS (MALDI, m / z) calcd for C 35 H 48 IN 2 O 3 Si (M+H) + 699.2474, found699.2478; [α] D 25 = +40.1 o (c = 3.5 in MeOH).

[0138] The comprehensive yield of all the above steps in Example 2 is 46%.

[0139] Embodiment 3:

[0140] The method for synthesizing PM060184 has the following reaction formula:

[0141]

[0142] 1) To a solution of compound 15 (660 mg, 1.36 mmol) and compound 28 (1.05 g, 1.50 mmol) in N-methylpyrrolidone (14 mL) at 0°C, copper thiophene-2-carboxylate (389 mg, 2.04 mmol) was added; the mixture was stirred at 0°C in the dark for 45 min and then stirred at room temperature for 8 h (TLC monitoring); after the reaction, the mixture was filtered through neutral alumina and rinsed with a mixture of ethyl acetate: methyl tert-butyl ether = 1:1. The filtrate was washed twice with aqueous hydrochloric acid (0.5 M / L), dried over anhydrous sodium sulfate, and concentrated in vacuo; the residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 10:1→3:1) to obtain compound 29 (911.6 mg, 87% yield).

[0143] 1 H NMR (400 MHz, CDCl 3 ) δ 7.68-7.66 (m, 4H), 7.44-7.35 (m, 6H), 7.30(d, J = 10.8 Hz, 1H), 7.24 (td, J 1 = 11.6 Hz, J 2 = 1.2 Hz, 1H), 6.87 (td , J 1 = 11.6 Hz, J 2 = 1.2 Hz, 1H), 6.63 (dd, J 1 = 10.8 Hz, J 2 = 8.8 Hz, 1H), 6.35(d, J = 9.2 Hz, 1H), 6.14 (d, J = 11.6 Hz, 1H), 5.66 (d, J = 11.6 Hz, 1H), 5.61 (dd, J 1 = 6,0 Hz, J 2 = 3.2 Hz, 1H), 5.52-5.44 (m, 1H), 5.34-5.29 (m, 1H), 5.26 (d, J = 9.6 Hz, 1H), 4.89-4.74 (m, 1H), 4.30 (d, J = 9.2 Hz, 1H), 4.19(ddd,J 1= 7.6 Hz, J 2 = 10.4 Hz, J 3 = 5.2 Hz, 1H), 3.86-3.08 (m, 1H), 3.64 (s,3H), 2.88-2.79 (m, 1H), 2.45-2.32 (m, 2H), 2.25-2.07 (m, 4H), 1.83 (s, 3H),1.42 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.04 (s,9H), 0.98 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) δ 168.2, 166.2, 161.7, 145.3,140.2, 137.2, 136.0, 134.2, 134.2, 134.2, 129.8, 129.8, 127.7, 127.7, 126.5,126.0, 124.2, 121.6, 121.0, 109.0, 108.2, 81.9, 72.5, 60.4, 55.5, 37.4, 35.1,33.9, 32.6, 27.1, 26.7, 26.4, 19.4, 17.3, 16.8, 13.0;IR (neat) cm -1 3318,2960, 2932, 2860, 1734, 1648, 1514, 1370, 1206, 1172, 1108, 822;HRMS (MALDI,m / z) calcd for C 46 H 63 N 2 O 6 Si (M+H) + 767.4450, found 767.4447;[α] D 25 = -6.6 o (c =2.4 in CHCl 3 )。

[0144] 2) Tetrabutylammonium fluoride (1.94 mL, 1.94 mmol, 1 M / L in THF) was slowly added dropwise to a solution of compound 29 (742.7 mg, 0.97 mmol) in tetrahydrofuran (11.5 mL) at 0°C; after the addition, the mixture was stirred at room temperature for 2 h; after the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo; the residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 5:1→2:1) to obtain compound 30 (420.5 mg, 82% yield);

[0145] 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (d, J = 10.4 Hz, 1H), 7.25 (t, J = 11.6Hz, 1H), 6.85 (td, J 1 = 11.6 Hz, J 2 = 1.2 Hz, 1H), 6.73 (t, J = 9.6 Hz, 1H), 6.58 (d, J = 9.2 Hz, 1H), 6.13 (d, J = 11.6 Hz, 1H), 5.67 (d, J = 11.2 Hz, 1H), 5.65-5.57 (m, 2H), 5.43-5.36 (m, 1H), 5.26 (d, J = 9.6 Hz, 1H), 4.90-4.81 (m, 1H), 4.38 (d, J = 9.6 Hz, 1H), 4.20 (ddd, J 1 = 7.6 Hz, J 2 = 10.4 Hz,J 3 = 5.2 Hz, 1H), 3.75-3.69 (m, 1H), 3.63 (s, 3H), 2.99 (br, 1H), 2.89-2.78(m, 1H), 2.46-2.33 (m, 2H), 2.31-2.11 (m, 4H), 1.82 (s, 3H), 1.61 (dd, J 1 =6.8 Hz, J 2 = 2.0 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.02 (s, 9H); 13 C NMR (101MHz, CDCl 3) δ 168.6, 166.5, 161.7, 145.3, 140.2, 137.4, 134.3, 134.2, 127.6,125.9, 124.3, 123.6, 120.9, 108.9, 108.3, 81.9, 72.0, 60.8, 55.6, 37.4, 34.9,34.7, 33.2, 26.8, 26.4, 17.3, 16.8, 13.2; IR (neat) cm -1 3306, 2964, 2935,2917, 1730, 1647, 1517, 1372, 1206, 1171, 1032; HRMS (MALDI, m / z) calcd forC 30 H 45 N 2 O 6 (M+H) + 529.3272, found 529.3276;[α] D 25 = +40.0 o (c = 2.5 in CHCl 3 ).

[0146] 3) At 0°C, trichloroacetyl isocyanate (0.31 mL, 2.6 mmol) was added to a solution of compound 30 (1.16 g, 2.2 mmol) in dichloromethane (22 mL); then, the mixture was stirred at 0°C for 30 min (TLC monitoring). After the reaction, neutral alumina (6.6 g) was added and stirred at room temperature until the new spots disappeared on TLC (generally 12 h); after the reaction, the mixture was directly filtered, rinsed with a mixture of dichloromethane: methanol = 50:1, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether / ethyl acetate = 1:1 → 1:2) to obtain compound PM060184 (1.23 g, 98% yield); its structural identification data:

[0147] 1 H NMR (400 MHz, CDCl 3 ) δ 8.94 (d, J = 10.4 Hz, 1H), 7.28 (dd, J 1 = J 2 = 11.6 Hz, 1H), 6.87 (dd, J 1 = J 2= 11.6 Hz, 1H), 6.79 (dd, J 1 = 10.4 Hz, J 2 =8.8 Hz, 1H), 6.61 (d, J = 9.6 Hz, 1H), 6.12 (d, J = 11.6 Hz, 1H), 5.97 (br,2H), 5.69 (d, J = 11.6 Hz, 1H), 5.61 (dd, J 1 = 6.4 Hz, J 2 = 3.2 Hz, 1H), 5.58-5.52 (m, 1H), 5.41-5.34 (m, 1H), 5.26 (d, J = 10.0 Hz, 1H), 4.84-4.76 (m,1H), 4.41-4.34 (m, 1H), 4.38 (d, J = 9.6 Hz, 1H), 4.20 (ddd, J 1 = 11.6 Hz, J 2 = 7.6 Hz, J 3 = 4.8 Hz, 1H), 3.63 (s, 3H), 2.82 (ddq, J 1 = 10.0 Hz, J 2 = 7.2Hz, J 3 = 6.8 Hz, 1H), 2.45 (m, 1H), 2.42 (m, 1H), 2.35 (m, 1H), 2.32 (m, 2H),2.14-2.06 (m, 1H), 1.80 (s, 3H), 1.60 (dd, J 1 = 6.8 Hz, J 2 = 2.0 Hz, 3H), 1.13(d, J = 6.4 Hz, 3H), 1.00 (s, 9H); 13 C NMR (101 MHz, CDCl 3) δ 168.3, 166.3,161.7, 158.7, 145.2, 140.1, 137.4, 134.1, 134.0, 127.0, 125.1, 124.4, 124.1,120.9, 108.4, 106.2, 81.9, 75.8, 60.5, 55.5, 37.3, 35.2, 31.4, 31.2, 26.7,26.3, 17.2, 16.6, 13.1; IR (neat) cm -1 3301, 2969, 2936, 2874, 1709, 1646,1518, 1381, 1327, 1203, 1165, 1049, 1028, 825, 780, 734, 701; HRMS (MALDI, m / z) calcd for C 31 H 46 N 3 O 7 (M+H) + 572.3331, found 572.3336;[α] D 25 = -38.2 o (c = 3.2in CHCl 3 ); see Figure 7 and Figure 8 .

[0148] The comprehensive yield of all the above steps in Example 3 is 70%.

[0149] Embodiment 4-8:

[0150] Compared with Example 1, the Lewis acid titanium tetrachloride in step (5) was adjusted to trimethylsilyl trifluoromethanesulfonate, 4-methylbenzenesulfonate pyridinium, magnesium bromide ethyl ether, boron trifluoride ethyl ether, and tin tetrachloride, respectively. The rest was the same as step (5) of Example 1. The yields of the corresponding compound 8 were 55%, 45%, 45%, 50%, and 30%, respectively, and the corresponding diastereoselectivities were dr=10:1, dr=5:1, dr=3:1, dr=7:1, and dr=14:1, respectively.

[0151] Embodiment 9-13:

[0152] Compared with Example 1, the reaction solvent dichloromethane in step (5) was adjusted to diethyl ether, methyl tert-butyl ether, isopropyl ether, methanol, and tetrahydrofuran, respectively. The rest was the same as step (5) of Example 1. The corresponding yields were 15%, 19%, 33%, 56%, and 20%, respectively. The corresponding diastereoselectivities were dr=1:1, dr=5:1, dr=14:1, dr=17:1, and dr=15:1, respectively.

[0153] Embodiment 14-18:

[0154] Compared with Example 1, the molar ratio of compound (R)-4 to Lewis acid in step (5) was adjusted from 1:1.1 to 1:1, 1:1.3, 1:1.7, 1:1.9, and 1:2, respectively. The rest was the same as step (5) of Example 1. The corresponding yields were 55%, 56%, 54%, 51%, and 50%, respectively. The corresponding diastereoselectivities were dr=15:1, dr=17:1, dr=18:1, dr=15:1, and dr=14:1, respectively.

[0155] Embodiment 19-23:

[0156] Compared with Example 1, the molar ratio of compound (R)-4 to compound 7 in step (5) was adjusted from 1:2 to 1:1, 1:3, 1:4, 1:5, and 1:6, respectively. The rest was the same as step (5) of Example 1. The corresponding yields were 51%, 49%, 48%, 42%, and 55%, respectively. The corresponding diastereoselectivities were dr=12:1, dr=10:1, dr=5:1, dr=4:1, and dr=15:1, respectively.

[0157] Embodiment 24-28:

[0158] Compared with Example 1, the reaction concentration of 0.1 mol / L in step (5) was adjusted to 0.05 mol / L, 0.08 mol / L, 0.2 mol / L, 0.4 mol / L, and 0.5 mol / L, respectively. The rest was the same as step (5) of Example 1. The corresponding yields were 55%, 53%, 40%, 42%, and 57%, respectively. The corresponding diastereoselectivities were dr=16:1, dr=18:1, dr=14:1, dr=10:1, and dr=18:1, respectively.

[0159] Examples 29-33:

[0160] Compared with Example 1, the reaction temperature of -78°C in step (5) was adjusted to -45°C, -50°C, -60°C, -70°C, and -90°C, respectively. The rest was the same as step (5) of Example 1. The corresponding yields were 56%, 53%, 41%, 44%, and 52%, respectively. The corresponding diastereoselectivities were dr=1:1, dr=2:1, dr=8:1, dr=10:1, and dr=18:1, respectively.

[0161] Embodiment 34-38:

[0162] Compared with Example 1, the base potassium tert-butoxide in step (9) was adjusted to lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium methoxide, and sodium methoxide, respectively. The rest was the same as step (9) of Example 1. The corresponding yields were 55%, 53%, 52%, 12%, and 0%, respectively.

[0163] Examples 39-43:

[0164] Compared with Example 1, the solvent tetrahydrofuran in step (9) was adjusted to N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, and ethyl acetate, respectively. The rest was the same as step (9) of Example 1. The corresponding yields were 51%, 41%, 42%, 30%, and 10%, respectively.

[0165] Embodiment 44-48:

[0166] Compared with Example 1, the molar ratio of compound 13 to base in step (9) was adjusted from 1:1.5 to 1:1, 1:1.2, 1:1.1.3, 1:1.7, and 1:2. The rest was the same as step (9) of Example 1. The corresponding yields were 44%, 51%, 58%, 55%, and 43%, respectively.

[0167] Examples 49-53:

[0168] Compared with Example 1, the concentration of the reaction system in step (9) was adjusted from 0.1 mol / L to 0.05 mol / L, 0.08 mol / L, 0.2 mol / L, 0.3 mol / L, and 0.5 mol / L. The rest was the same as step (9) of Example 1. The corresponding yields were 55%, 57%, 52%, 51%, and 45%, respectively.

[0169] Examples 54-58:

[0170] Compared with Example 1, the reaction temperature of 25°C in step (9) was adjusted to -25°C, -10°C, 30°C, 40°C, and 50°C. The rest was the same as step (9) of Example 1. The corresponding yields were 40%, 41%, 55%, 45%, and 42%, respectively.

[0171] Examples 59-63:

[0172] Compared with Example 1, the catalyst palladium acetate in step (10) is adjusted to tetrakistriphenylphosphine palladium, ditriphenylphosphine palladium dichloride, dibenzylideneacetone palladium, diphenylphosphinocene palladium dichloride, and allylpalladium chloride dimer. The rest is the same as step (10) of Example 1, and the corresponding yields are 20%, 10%, 56%, 9% and 25%, respectively.

[0173] Examples 64-68:

[0174] Compared with Example 1, the solvent A in step (10) was adjusted from n-hexane to N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, and acetone. The rest was the same as step (10) in Example 1. The corresponding yields were 12%, 5%, 51%, 3%, and 50%, respectively.

[0175] Examples 69-73:

[0176] Compared with Example 1, the solvent B tetrahydrofuran in step (10) was adjusted to N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, and acetone. The rest was the same as step (10) of Example 1. The corresponding yields were 5%, 11%, 3%, 0%, and 6%, respectively.

[0177] Embodiment 74-78:

[0178] Compared with Example 1, the ratio of solvent A to solvent B in step (10) was adjusted from 2.3:1 to 5:1, 4:1, 3:1, 2:1, and 1:1, and the rest was the same as step (10) of Example 1. The corresponding yields were 72%, 83%, 82%, 85%, and 80%, respectively.

[0179] Examples 79-83:

[0180] Compared with Example 1, the concentration of the reaction system in step (10) was adjusted from 0.13 mol / L to 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, 0.4 mol / L, and 0.5 mol / L. The rest was the same as step (10) of Example 1. The corresponding yields were 90%, 87%, 85%, 80%, and 78%, respectively.

[0181] Embodiment 84-88:

[0182] Compared with Example 2, the base sodium bis(trimethylsilyl)amide in step (5) was adjusted to lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and the rest was the same as step (5) of Example 2. The corresponding yields were 52%, 55%, 50%, 51%, and 54%, respectively, and the corresponding Z:E ratios were 5:1, 8:1, 4.2:1, 5.3:1, and 6:1, respectively.

[0183] Embodiment 89-93:

[0184] Compared with Example 2, the reaction solvent tetrahydrofuran in step (5) was adjusted to dichloromethane, n-hexane, ether, ethyl acetate, toluene, and the rest was the same as step (5) of Example 2. The corresponding yields were 10%, 12%, 51%, 40%, and 30%, respectively, and the corresponding Z:E ratios were 1:1, 2:1, 8:1, 3:1, and 2:1, respectively.

[0185] Embodiment 94-98:

[0186] Compared with Example 2, the reaction temperature of -78°C in step (5) was adjusted to -90°C, -70°C, -60°C, -50°C, and -45°C. The rest was the same as step (5) of Example 2. The corresponding yields were 51%, 55%, 53%, 41%, and 30%, respectively, and the corresponding Z:E ratios were 8:1, 9:1, 7:1, 6:1, and 5:1, respectively.

[0187] Examples 99-103:

[0188] Compared with Example 2, the reaction temperature and reaction system concentration of 0.1 mol / L in step (5) were adjusted to 0.05 mol / L, 0.15 mol / L, 0.2 mol / L, 0.4 mol / L, and 0.5 mol / L, and the rest was the same as step (5) of Example 2. The corresponding yields were 52%, 55%, 51%, 45%, and 47%, respectively, and the corresponding Z:E ratios were 7:1, 8:1, 9:1, 6:1, and 4:1, respectively.

[0189] Examples 104-108:

[0190] Compared with Example 2, the molar equivalent ratio of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester, iodomethyl-triphenylphosphine iodide and base in step (5) was adjusted from 1:1.4:1.4 to 1:1:1, 1:1.2:1.2, 1:1.5:1.5, 1:1.7:1.7 and 1:2:2, and the rest was the same as step (5) of Example 2. The corresponding yields were 52%, 53%, 54%, 50% and 45%, respectively, and the corresponding Z:E ratios were 9:1, 8:1, 8:1, 7:1 and 9:1, respectively.

[0191] Examples 109-113:

[0192] Compared with Example 2, the solvent dichloromethane in step (6) was adjusted to tetrahydrofuran, ether, 2-methyltetrahydrofuran, toluene, and methyl tert-butyl ether. The rest was the same as step (6) of Example 2. The corresponding yields were 75%, 70%, 68%, 85%, and 72%, respectively.

[0193] Embodiments 114-118:

[0194] Compared with Example 2, the reducing agent diisobutylaluminum hydride in step (6) is adjusted to lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, lithium tri-tert-butoxyaluminum hydride, and palladium carbon hydrogen. The rest is the same as step (6) of Example 2. The corresponding yields are 40%, 32%, 70%, 85%, and 80%, respectively.

[0195] Examples 119-123:

[0196] Compared with Example 2, the reaction temperature of -78°C in step (6) was adjusted to -90°C, -70°C, -60°C, -50°C, and -45°C. The rest was the same as step (6) of Example 2. The corresponding yields were 85%, 80%, 75%, 65%, and 62%, respectively.

[0197] Embodiment 124-128:

[0198] Compared with Example 2, the reaction temperature and reaction system concentration of 0.3 mol / L in step (6) were adjusted to 0.1 mol / L, 0.2 mol / L, 0.25 mol / L, 0.4 mol / L, and 0.5 mol / L, and the rest was the same as step (6) of Example 2. The corresponding yields were 81%, 83%, 88%, 84%, and 85%, respectively.

[0199] Examples 129-133:

[0200] Compared with Example 2, the reaction temperature and reaction system concentration of 0.3 mol / L in step (6) were adjusted to 0.1 mol / L, 0.2 mol / L, 0.25 mol / L, 0.4 mol / L, and 0.5 mol / L, and the rest was the same as step (6) of Example 2. The corresponding yields were 81%, 83%, 88%, 84%, and 85%, respectively.

[0201] Examples 134-138:

[0202] Compared with Example 2, the molar ratio of compound 21 to the base in step (6) was adjusted from 1:1.3 to 1:1, 1:1.2, 1:1.4, 1:1.5, and 1:2, and the rest was the same as step (6) of Example 2. The corresponding yields were 85%, 88%, 87%, 86%, and 80%, respectively.

[0203] Examples 139-143:

[0204] Compared with Example 2, the base n-butyl lithium in step (7) was adjusted to lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide. The rest was the same as step (7) of Example 2. The corresponding yields were 70%, 71%, 72%, 65%, and 72%, respectively, and the corresponding Z:E ratios were 10:1, 8:1, 5:1, 3:1, and 7:1, respectively.

[0205] Examples 144-148:

[0206] Compared with Example 2, the reaction solvent tetrahydrofuran in step (7) was adjusted to dichloromethane, n-hexane, ether, ethyl acetate, and toluene. The rest was the same as step (7) of Example 2. The corresponding yields were 20%, 12%, 65%, 40%, and 30%, respectively, and the corresponding Z:E ratios were 3:1, 5:1, 10:1, 7:1, and 4:1, respectively.

[0207] Examples 149-153:

[0208] Compared with Example 2, the reaction temperature of -78°C in step (7) was adjusted to -90°C, -70°C, -60°C, -50°C, and -45°C. The rest was the same as step (7) of Example 2. The corresponding yields were 72%, 73%, 68%, 65%, and 61%, respectively, and the corresponding Z:E ratios were 19:1, 19:1, 18:1, 15:1, and 12:1, respectively.

[0209] Embodiment 154-158:

[0210] Compared with Example 2, the reaction temperature and reaction system concentration of 0.08 mol / L in step (7) were adjusted to 0.05 mol / L, 0.1 mol / L, 0.2 mol / L, 0.3 mol / L, and 0.5 mol / L, and the rest was the same as step (7) of Example 2. The corresponding yields were 73%, 72%, 70%, 68%, and 67%, respectively, and the corresponding Z:E ratios were 19:1, 15:1, 14:1, 13:1, and 11:1, respectively.

[0211] Examples 159-163:

[0212] Compared with Example 2, the molar equivalent ratio of compound 22, Wittig reagent and base in step (7) was adjusted from 1:2.6:2.2 to 1:1:1, 1:2:1, 1:3:2, 1:4:3 and 1:5:4, and the rest was the same as step (7) of Example 2. The corresponding yields were 60%, 62%, 70%, 71% and 65%, respectively, and the corresponding Z:E ratios were 15:1, 16:1, 18:1, 17:1 and 19:1, respectively.

[0213] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A key intermediate for synthesizing PM060184 compounds, characterized in that: The key intermediate has the structure shown in the following formula (III), formula (V) and formula (VII): ， Among them, R 4 , R 5 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms; 6 , R 7 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; 9 is selected from H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; R 10 , R 11 R is selected from the group consisting of the same or different H, alkyl, substituted alkyl, alkenyl, alkynyl, halogen, amino, phenyl, substituted phenyl; 12 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms; R 14 , R 15 are selected from the same or different H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, aromatic or aromatic substituted by heteroatoms.

2. The method for synthesizing the key intermediate according to claim 1, characterized in that: in: (1) The synthesis method of the compound represented by formula (III) is as follows: the compound represented by formula (I) and the compound represented by formula (II) are dissolved in a solvent, and then Lewis acid is added to carry out Sakurai reaction to obtain the compound represented by formula (III). The reaction formula is as follows: ； In the above formula, R 1 , R 2 , R 3 are independently selected from alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, R 1 , R 2 , R 3 Same or different; (2) The synthesis method of the compound represented by formula (V) is as follows: the compound represented by formula (IV) is dissolved in a solvent, and then a base is added to carry out a domino cyclization reaction to obtain a compound represented by formula (V). The reaction formula is as follows: ； (3) The synthesis method of the compound represented by formula (VII) is as follows: under the protection of inert gas, the compound represented by formula (VI) is used as a raw material, and a tin hydrogenation reduction reaction catalyzed by a catalyst is performed to obtain an alkenyl metal compound represented by formula (VII); 。 3. The method according to claim 2, characterized in that In reaction (1), The Lewis acid is selected from one of trimethylsilyl trifluoromethanesulfonate, 4-methylbenzenesulfonate pyridinium, magnesium bromide ethyl etherate, boron trifluoride ethyl etherate, titanium tetrachloride, tin tetrachloride, zinc dichloride, aluminum trichloride, and bis(perfluorophenyl)(3,4,5-trifluoro-2-methylphenyl)borane; The reaction solvent is selected from one or a mixture of two of diethyl ether, methyl tert-butyl ether, isopropyl ether, dichloromethane, methanol, tetrahydrofuran and toluene; The molar ratio of the compound of formula (I) to the Lewis acid is 1:1 to 1:2; The molar ratio of the compound of formula (I) to the compound of formula (II) is 1:1 to 1:6; The concentration of the reaction system is 0.05mol / L~0.5mol / L; The reaction temperature is -45°C to -90°C.

4. The method according to claim 3, characterized in that In reaction (1), The Lewis acid is titanium tetrachloride; the reaction solvent is dichloromethane; the molar ratio of the compound of formula (I) to the Lewis acid is 1:1.1; the molar ratio of the compound of formula (I) to the compound of formula (II) is 1:2; the concentration of the reaction system is 0.1 mol / L; and the reaction temperature is -78°C.

5. The method according to claim 2, characterized in that: In reaction (2), The base is selected from the group consisting of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and lithium diisopropylamide; The solvent is selected from one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably tetrahydrofuran; The molar ratio of the compound of formula (IV) to the base is 1:1 to 1:2; The concentration of the reaction system is 0.05mol / L~0.5mol / L; The reaction temperature is -25°C to 50°C.

6. The method according to claim 5, characterized in that In reaction (2), The base is potassium tert-butoxide; the solvent is tetrahydrofuran; the molar ratio of the compound of formula (IV) to the base is 1:1.5; the concentration of the reaction system is 0.1 mol / L; and the reaction temperature is 25°C.

7. The method according to claim 2, characterized in that In reaction (3), The catalyst used is one of tetrakistriphenylphosphine palladium, ditriphenylphosphine palladium dichloride, palladium acetate, dibenzylideneacetone palladium, diphenylphosphinodichloropalladium, and allylpalladium chloride dimer; The solvent A used is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone; The solvent B used is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone; The volume ratio of solvent A to solvent B used is 5:1 to 1:1; The concentration of the reaction system is 0.1 mol / L to 0.5 mol / L.

8. The method according to claim 7, characterized in that In reaction (3), The catalyst used is palladium acetate; the solvent A used is n-hexane, and the water content of solvent A is less than 10 ppm; the solvent B used is tetrahydrofuran, and the water content of solvent B is less than 10 ppm; the volume ratio of solvent A to solvent B used is 2.3:1; and the concentration of the reaction system is 0.13 mol / L.

9. A method for synthesizing a key intermediate of formula (XI), characterized in that: The steps include: (1) Under the protection of inert gas, using (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester as a raw material, a compound of formula (VIII) is obtained by Wittig reaction; ； (2) Under the protection of inert gas, the compound of formula (VIII) is subjected to reduction reaction to obtain the aldehyde compound of formula (IX): ； (3) Under the protection of inert gas, the compound of formula (IX) and the compound of formula (X) are reacted by Wittig reaction to obtain the compound of formula (XI): ； In the above formula, R 16 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, aromatic or aromatic substituted by various heteroatoms; Wherein, in step (1) and step (3), the base used is one of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, and n-butyl lithium; in step (1), sodium bis(trimethylsilyl)amide is preferred; in step (3), n-butyl lithium is preferred; In steps (1) and (3), the solvent used is at least one of acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, n-hexane, methyl tert-butyl ether, toluene, and isopropanol, and the water content of the solvent is preferably less than 10 ppm; preferably tetrahydrofuran; The reaction temperature of steps (1) and (3) is -90°C to -45°C, preferably -78°C; The concentration of the reaction system in steps (1) and (3) is 0.05 mol / L to 0.5 mol / L; step (1) is preferably 0.1 mol / L; step (3) is preferably 0.08 mol / L; 1.0 molar equivalent of (R)-3-((tert-butyldiphenylsilyl)oxy)-5-oxopentanoic acid ethyl ester of step (1), 1.4 molar equivalent of iodomethyl-triphenylphosphine iodide, and 1.4 molar equivalent of a base; In step (2), the solvent used is at least one of acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, n-hexane, methyl tert-butyl ether, toluene, and isopropanol, and the water content of the solvent is preferably less than 10 ppm; dichloromethane is preferred; In step (2), the reducing agent used is one of lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium triacetoxyborohydride, lithium tri-tert-butoxyaluminum hydride, and palladium-carbon hydrogen, preferably diisobutylaluminum hydride; The reaction temperature of step (2) is -90°C to -45°C, preferably -78°C; The concentration of the reaction system in step (2) is 0.1 mol / L to 0.5 mol / L, preferably 0.3 mol / L; In the reaction of step (2), 1.0 molar equivalent of the compound of formula (VIII) and 1.3 molar equivalent of the reducing agent; 1.0 molar equivalent of the compound of formula (IX) in step (3), 2.6 molar equivalent of the compound of formula (X), and 2.2 molar equivalent of the base.

10. A key synthesis step for synthesizing PM060184, characterized in that: The steps include: (1) Under the protection of inert gas, a compound of formula (I) and a compound of formula (II) are used as raw materials to obtain a compound of formula (III) through coupling reaction: ； (2) Under the protection of inert gas, the compound of formula (IV) is used as a raw material, and a domino cyclization reaction promoted by a base is performed to obtain a compound of formula (V): ； (3) Under the protection of an inert gas, the compound of formula (VI) is used as a raw material, and a tin hydrogenation reduction reaction catalyzed by a catalyst is performed to obtain an alkenyl metal compound of formula (VII): 。 11. A method for synthesizing PM060184 and its analogs, characterized in that: The method is: (1) synthesizing the compound of formula (VII) by the synthesis method described in claim 10; (2) reacting a compound of formula (XII) with a compound of formula (XIII) to obtain a compound of formula (XIV): ； Among them, R 17 is selected from H, alkyl, substituted alkyl, cyclic alkyl, alkenyl, alkynyl, halogen, amino, silicon, aromatic or aromatic substituted by heteroatom; The base used is one of triethylamine, diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene, pyridine, tetramethylguanidine, imidazole, and diisopropylamine, preferably diisopropylethylamine; The condensing agent used is one or more of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, benzotriazole-1-tris(trimethylamino)-hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate, and N-hydroxy-7-azabenzotriazole, preferably N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate and N-hydroxy-7-azabenzotriazole; The solvent used is one or more of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, preferably N,N-dimethylformamide and dichloromethane; the water content of the solvent is preferably less than 10 ppm; (3) reacting a compound of formula (VII) with a compound of formula (XIV) to obtain a compound of formula (XV): ； The catalyst used is one of cuprous iodide, cuprous bromide, cuprous chloride, cupric oxide, cuprous cyanide, thiophene-2-carboxylate copper, cupric acetate, and copper trifluoromethanesulfonate, preferably thiophene-2-carboxylate copper; The solvent used is at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, water, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, and N-methylpyrrolidone, preferably N-methylpyrrolidone; the water content of the solvent is preferably less than 10 ppm.

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