Tetracyclic peptide intermediate compound as well as preparation method and application thereof

Abstract

The invention discloses a tetracyclic peptide intermediate compound as well as a preparation method and application thereof. The tetracyclic peptide intermediate compound has a structural formula as shown in formula I: # imgabs0 # R is selected from hydroxyl; or R and the connected carbon form a carbonyl group. The tetracyclic peptide intermediate compound provided by the invention can be used for synthesizing a natural cyclic peptide compound. The tetracyclic peptide intermediate compound for synthesizing the natural cyclic peptide compound also has the advantage of high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a tetracyclic peptide intermediate compound and a preparation method and application thereof. Background Art

[0002] Malaria is a serious infectious disease caused by Plasmodium, and millions of people still die from malaria every year. It is one of the deadliest parasitic infectious diseases in the world. Malaria not only causes symptoms such as fever, chills, and nausea, but may also cause serious complications such as cerebral malaria and renal failure, which endanger the patient's life. Due to the long-term use of the same class of drugs, Plasmodium continues to develop drug resistance, making the original malaria treatment drugs gradually lose their effectiveness. Some conventional antimalarial drugs such as chloroquine, quinine, and artemisinin are already facing serious drug resistance challenges. Therefore, the continuous development of new, efficient, and safe antimalarial drugs has extremely important clinical value and medical significance. Many natural products have accumulated activity against specific biological targets during evolution, providing important lead compounds for the development of antimalarial drugs.

[0003] Koshidacin B is an antimalarial peptide compound isolated by Masato Iwatsuki from the culture medium of the Okinawa fungus Pochonia boninensis FKR-0564. Its structure and absolute configuration were determined by spectral analysis and chemical derivatization. Studies have shown that Koshidacin B exhibits strong inhibitory activity against the malarial parasite Plasmodium falciparum, with an IC 50 The value is 0.83μM. In addition, it can inhibit 41% of Plasmodium in mice by intraperitoneal administration (30mg / kg / day, administration for 4 days), indicating that Koshidacin B also shows good antimalarial activity in vivo. In summary, the results of in vitro and in vivo tests of the natural peptide compound Koshidacin B show that it has certain antimalarial activity and has the potential to be a lead compound for antimalarial drugs. Since the natural sources of Koshidacin B are limited, it is urgent to carry out a total synthesis study of Koshidacin B to obtain sufficient materials. So far, no synthetic research on Koshidacin B has been reported.

[0004] Therefore, it is necessary to develop an intermediate compound for the synthesis of Koshidacin B. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides a tetracyclic peptide intermediate compound, which can synthesize a natural cyclic peptide compound.

[0006] A second aspect of the present invention provides an intermediate compound.

[0007] The third aspect of the present invention provides a method for preparing a tetracyclic peptide intermediate compound.

[0008] The fourth aspect of the present invention provides an application of a tetracyclic peptide intermediate compound.

[0009] The fifth aspect of the present invention provides a method for preparing Koshidacin B.

[0010] According to a first aspect of the present invention, a tetracyclic peptide intermediate compound is provided, having a structural formula shown in Formula I:

[0011]

[0012] R is selected from hydroxyl; or R and the carbon to which it is attached form a carbonyl.

[0013] The tetracyclic peptide intermediate compound according to the present invention has at least the following beneficial effects:

[0014] The tetracyclic peptide intermediate compound provided by the present invention can be used to synthesize natural cyclic peptide compounds. The synthesis of natural cyclic peptide compounds through the tetracyclic peptide intermediate compound also has the advantage of high yield.

[0015] According to the second aspect of the present invention, there is provided an intermediate compound for preparing the tetracyclic peptide intermediate compound described in the first aspect of the present invention, having a structure shown in Formula II:

[0016]

[0017] According to a third aspect of the present invention, there is provided a method for preparing a tetracyclic peptide intermediate compound, comprising the following steps:

[0018] The intermediate compound II and compound 10 are subjected to olefin metathesis reaction under the catalysis of a Grubbs catalyst and a cuprous catalyst to obtain a tetracyclic peptide intermediate compound;

[0019] The structural formula of the compound 10 is as follows:

[0020]

[0021] R is selected from hydroxyl; or R and the carbon to which it is attached form a carbonyl.

[0022] The method for preparing the tetracyclic peptide intermediate compound according to the present invention has at least the following beneficial effects:

[0023] The preparation method has simple reaction conditions and steps, and the yield of the prepared product is high, and is expected to be used in industrial production.

[0024] According to some preferred embodiments of the present invention, the reaction temperature of the olefin metathesis reaction does not exceed 50°C.

[0025] According to some preferred embodiments of the present invention, the reaction temperature of the olefin metathesis reaction is 30-50° C. A lower reaction temperature will result in a slow reaction, and a too high reaction temperature will easily affect the yield of the product. Therefore, a temperature within the range of the present invention has a better yield.

[0026] According to some preferred embodiments of the present invention, the reaction time of the olefin metathesis reaction is 6 to 14 hours. Therefore, if the reaction time is too short, the reaction is incomplete, and if the reaction time is too long, the yield increase is not obvious, which is not economical.

[0027] According to some preferred embodiments of the present invention, the solvent used in the olefin metathesis reaction is selected from at least one of diethyl ether, dichloromethane or dichloroethane.

[0028] According to some preferred embodiments of the present invention, the molar ratio of the intermediate compound II, compound 10, Grubbs catalyst and cuprous catalyst is 1:(3-8):(0.2-1):(0.01-0.5). Thus, within the above molar ratio range, the reaction rate and yield can be increased.

[0029] According to some preferred embodiments of the present invention, the Grubbs-type catalyst includes at least one of a first-generation Grubbs catalyst (CAS: 172222-30-9), a second-generation Grubbs catalyst (CAS: 246047-72-3), a third-generation Grubbs catalyst (CAS: 900169-53-1) or a Hoveyda-Grubbs catalyst (CAS: 301224-40-8).

[0030] According to some preferred embodiments of the present invention, the cuprous catalyst is selected from at least one of cuprous iodide, cuprous chloride and cuprous bromide.

[0031] According to some preferred embodiments of the present invention, the intermediate compound II is prepared by the following method:

[0032] Compound 8 is mixed with a basic substance to remove the Fmoc protecting group and the Fm protecting group to obtain an intermediate I; the intermediate I, HOAt, DIPEA, HATU and a solvent are mixed to react;

[0033] The structural formula of the compound 8 is as follows:

[0034]

[0035] According to some preferred embodiments of the present invention, the molar ratio of compound 8, HOAt, DIPEA and HATU is 1:(1-2):(8-12):(1-2).

[0036] According to some preferred embodiments of the present invention, the alkaline substance is selected from at least one of diethylamine (DEA), 1,8-diazabicycloundec-7-ene (DBU), piperidine or tetrabutylammonium fluoride (TBAF).

[0037] According to some preferred embodiments of the present invention, the compound 8 is prepared by the following method:

[0038] Compound 6 is mixed with an acidic substance for acid hydrolysis to obtain intermediate II, the intermediate II is mixed with dry tetrahydrofuran (THF), DIPEA, DEPBT and compound 7 are added, and the mixture is stirred at room temperature to obtain;

[0039] The structural formulas of the compounds 6 and 7 are as follows:

[0040]

[0041] According to some preferred embodiments of the present invention, the molar ratio of compound 6, DIPEA, DEPBT and compound 7 is 1:(8-12):(1-2):(1-2).

[0042] According to some preferred embodiments of the present invention, the acidic substance is selected from at least one of trifluoroacetic acid (TFA), formic acid, HCl or HBr.

[0043] According to some preferred embodiments of the present invention, the compound 6 is prepared by the following method:

[0044] Compound 4 is mixed with an alkaline substance to remove the Fmoc protecting group to obtain intermediate III; intermediate III is mixed with dichloromethane (DCM), and HOAt, DIPEA, compound 5 and HATU are added at 0°C to 5°C; the reaction is stirred at room temperature to obtain;

[0045] The structural formulas of the compounds 4 and 5 are as follows:

[0046]

[0047] According to some preferred embodiments of the present invention, the alkaline substance is selected from at least one of diethylamine, 1,8-diazabicycloundec-7-ene, piperidine or tetrabutylammonium fluoride.

[0048] According to some preferred embodiments of the present invention, the molar ratio of compound 4, HOAt, DIPEA, compound 5 and HATU is 1:(1-2):(8-12):(1-2):(1-2).

[0049] According to some preferred embodiments of the present invention, the compound 4 is prepared by the following method:

[0050] At 0-5°C, compound 3, DCM, HOAt, DIPEA, compound 2 and HATU were mixed and stirred at room temperature to react to obtain;

[0051] The structural formulas of the compounds 2 and 3 are as follows:

[0052]

[0053] According to some preferred embodiments of the present invention, the molar ratio of compound 3, HOAt, DIPEA, compound 2 and HATU is 1:(1-2):(8-12):(1-2):(1-2).

[0054] According to the fourth aspect of the present invention, there is provided the use of the tetracyclic peptide intermediate compound in the preparation of a natural cyclic peptide compound; the natural cyclic peptide compound includes Koshidacin B (CAS No.: 2925302-01-6), KoshidacinA (CAS No.: 2925301-98-8) or chlamydocin (CAS No.: 53342-16-8).

[0055] A fifth aspect of the present invention provides a method for preparing Koshidacin B, comprising the following steps:

[0056] Under a hydrogen atmosphere, the above tetracyclic peptide intermediate compound, palladium-carbon catalyst and hydrochloric acid methanol solution are mixed and reacted to obtain Koshidacin B.

[0057] A method for preparing Koshidacin B provided by the present invention has at least the following beneficial effects:

[0058] The invention uses a tetracyclic peptide intermediate compound I as a raw material and synthesizes Koshidacin B in one step under the action of a palladium-carbon catalyst. The preparation method has high yield, simple operation steps and is easy for industrial production.

[0059] Furthermore, the R group of compound 10 is changed into the corresponding side chain fragment structure in Koshidacin A and chlamydocin, and then it is subjected to olefin metathesis reaction, deprotection and other operations with the intermediate compound II to prepare Koshidacin A, chlamydocin and other compounds.

[0060] According to some preferred embodiments of the present invention, the palladium-carbon catalyst is selected from at least one of Pd / C, Pd(OH)2 / C or PdCl2 / C.

[0061] According to some preferred embodiments of the present invention, based on the mass of the tetracyclic peptide intermediate compound I, the mass of the palladium-carbon catalyst is 10% to 100% of the tetracyclic peptide intermediate compound I.

[0062] According to some preferred embodiments of the present invention, the reaction temperature is 20-35°C.

[0063] According to some preferred embodiments of the present invention, the product obtained after the reaction in the present invention further comprises a purification step, which comprises washing, extraction, drying, concentration and column chromatography.

[0064] The "room temperature" mentioned in the present invention refers to 20°C to 30°C.

[0065] The structural formulas of "Fm" and "Fmoc" mentioned in the chemical structural formula of the present invention are as follows:

[0066]

[0067] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0068] The following are specific embodiments of the present invention, and the technical solutions of the present invention are further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0069] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0070] The English abbreviations mentioned in the embodiments of the present invention are as follows:

[0071] DEPBT: 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4-one;

[0072] HOAt: N-hydroxy-7-azabenzotriazole;

[0073] DIPEA: N,N-diisopropylethylamine;

[0074] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0075] Compound 2 and Compound 3 in the examples of the present invention are commercially available.

[0076] Some of the raw materials used in the embodiments of the present invention are synthesized as follows:

[0077] Synthesis of compound 4

[0078] Compound 3 (423.0 mg, 1.3 mmol) was dissolved in DCM (20.0 mL) solvent, and HOAt (353.9 mg, 2.6 mmol), DIPEA (2.4 mL, 13.7 mmol), compound 2 (500.0 mg, 2.0 mmol) and HATU (988.6 mg, 2.0 mmol) were added in sequence under ice bath conditions, and then the reaction system was stirred overnight at room temperature. After quenching with saturated ammonium chloride solution, it was extracted with DCM, washed with saturated brine, dried with anhydrous Na2SO4, filtered and concentrated in vacuo, and then the mixture was purified by flash column chromatography (PE:EA = 1:2) to obtain 638.4 mg of compound 4 as a white foamy solid with a yield of 93%.

[0079] The NMR data of compound 4 are as follows:

[0080] 1 H NMR (400MHz, CDCl3) δ7.83–7.75(m,2H),7.65–7.58(m,2H),7.46–7.39(m ,2H),7.38–7.32(m,2H),7.29–7.20(m,3H),7.20–7.14(m,2H),6.63(d,J =7.5Hz,1H),5.48(s,1H),4.74(d,J=6.8Hz,1H),4.51–4.33(m,2H),4.22 (t,J=6.9Hz,1H),3.13(d,J=6.0Hz,2H),1.59–1.46(m,6H),1.43(s,9H).

[0081] 13C NMR (101MHz, CDCl3) δ173.7,170.5,154.9,143.9,141.3,136.2,129.6,128.3,127.7 ,127.1,127.0,125.1,125.1,120.0,82.4,66.7,56.8,53.7,47.2,37.9,28.0,25.5.

[0082] Synthesis of compound 6

[0083] Compound 4 (300.0 mg, 0.6 mmol) was dissolved in MeCN (5.0 mL) solvent, and then DEA (1.0 mL) was added at room temperature. The system was stirred at room temperature for 1.0 h. After TLC detection, the reaction was concentrated in vacuo and directly used in the next step after evacuation. The above evacuated mixed system was dissolved in DCM (10.0 mL), and HOAt (163.3 mg, 1.2 mmol), DIPEA (1.1 mL, 6.3 mmol), compound 5 (303.6 mg, 0.9 mmol) and HATU (456.3 mg, 1.2 mmol) were added in sequence under ice bath conditions, and then the reaction system was stirred overnight at room temperature. After quenching with saturated ammonium chloride solution, it was extracted with DCM, washed with saturated brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was then subjected to rapid column chromatography (PE:EA=1:2) to obtain 310.0 mg of compound 6 as a yellow foamy solid with a yield of 83%.

[0084] The NMR data of compound 6 are as follows:

[0085] 1H NMR (500MHz, CDCl3) δ7.84–7.74(m,2H),7.60(dd,J=7.5,4.4Hz,2H),7.42(t,J=7.5Hz,2H),7.35–7.30(m,2H),7. 30–7.24(m,2H),7.24–7.19(m,1H),7.19–7.14(m,2H),6.76(s,1H),6.69(d,J=7.4Hz,1H),5.87–5.64(m,1H),5.4 3(d,J=7.6Hz,1H),5.16(d,J=11.3Hz,2H),4.72(q,J=6.1Hz,1H),4.53–4.41(m,1H),4.41–4.31(m,1H),4.24(t,J =7.0Hz,1H),4.21–4.11(m,1H),3.11(d,J=6.2Hz,2H),2.62–2.42(m,2H),1.55(s,3H),1.51(s,3H),1.42(s,9H).

[0086] 13 C NMR (126MHz, CDCl3) δ173.5,170.5,170.3,156.1,143.8,143.7,141.3,136.2,132.8,129.6,128.3,127 .8,127.1,127.0,125.1,120.0,119.3,82.4,67.2,57.3,54.5,53.8,47.1,38.6,37.9,28.0,25.2,24.7.

[0087] Synthesis of compound 8

[0088] Compound 6 (500.0 mg, 0.8 mmol) was dissolved in DCM (10.0 mL) solvent, and then TFA (2.0 mL) was added at room temperature. The system was stirred at room temperature for 1.5 h. After TLC detection, the reaction was concentrated in vacuo and directly used in the next step after evacuation. The above-mentioned mixed system after evacuation was dissolved in dry THF (10.0 mL), and DIPEA (1.5 mL, 8.4 mmol), DEPBT (478.6 mg, 1.6 mmol) and compound 7 (360.4 mg, 1.2 mmol) were added in sequence at room temperature, and then the reaction system was stirred overnight at room temperature. After quenching with saturated ammonium chloride solution, EA was used for extraction, washed with saturated brine, dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was then purified by flash column chromatography (PE: EA = 1: 1) to obtain 552.0 mg of compound 8 as a yellow foamy solid with a yield of 82%.

[0089] The NMR data of compound 8 are as follows:

[0090] 1 H NMR(500MHz,Chloroform-d)δ7.85–7.72(m,4H),7.67–7.51(m,4H),7.47–7.36(m,4H),7.36–7.18(m,8H),7.16–7.03(m,1H),7.02–6. 91(m,1H),6.80(s,1H),5.85–5.67(m,1H),5.60–5.50(m,1H),5.23–5.10(m,3H),4.97–4.86(m,1H),4.58–4.49(m,1H),4.49–4.42(m,1 H),4.42–4.38(m,1H),4.38–4.30(m,1H),4.21(dd,J=9.6,6.4Hz,3H),3.56–3.42(m,1H),3.10–3.01(m,1H),3.01–2.92(m,1H),2.74– 2.64(m,1H),2.62–2.53(m,1H),2.53–2.41(m,1H),1.85–1.79(m,1H),1.62–1.56(m,1H),1.54–1.45(m,2H),1.53(s,3H),1.48(s,3H).

[0091] 13 C NMR (126MHz, CDCl3)173.5,171.5,170.3,169.8,143.9,143.3,141.4,14 1.3,136.3,133.0,129.6,129.2,128.4,128.3,127.8,127.8,127.7,127 .2,127.2,127.1,127.0,125.1,125.0,125.0,120.0,120.0,119.3,67.1 ,66.4,58.9,57.2,52.6,47.1,47.0,46.8,28.8,27.0,25.4,24.5,24.3.

[0092] Among them, the structural formulas of compounds 2 to 8 are as follows:

[0093]

[0094] Example 1

[0095] This example provides an intermediate compound II, whose structural formula and preparation method are as follows:

[0096]

[0097] The compound 8 (50.0 mg, 0.06 mmol) prepared above was dissolved in acetonitrile (5.0 mL) solvent, and then DEA (1.0 mL) was added at room temperature. The system was stirred at room temperature for 1.0 h. After TLC detection, the reaction was completed, vacuum concentrated, and directly used in the next step after vacuuming. The mixed system after vacuuming was taken, dissolved in DCM (10.00 mL), and then slowly injected with an injector under ice bath conditions for 6 h and added to another round-bottom flask pre-filled with HOAt (16.33 mg, 0.12 mmol), DIPEA (112.35 μL, 0.63 mmol) and HATU (45.63 mg, 0.12 mmol) dissolved in DCM (15.00 mL), and then the reaction system was stirred at room temperature for 48 h. After quenching with saturated ammonium chloride solution, it was extracted with DCM, washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and the mixture was purified by flash column chromatography (PE:EA=1:1) to obtain 98.1 mg of the cyclized product compound as a white foamy solid with a yield of 32%.

[0098] The NMR data of intermediate compound II are as follows:

[0099] 1 H NMR(500MHz, CDCl3) δ7.51(d,J=10.2Hz,1H),7.34–7.20(m,5H),7.18(d,J=10.4Hz,1H),6.05(s,1H),5.75(ddt,J= 17.1,10.2,6.8Hz,1H),5.23–5.15(m,2H),5.12(dt,J=10.3,1.4Hz,1H),4.71–4.66(m,1H),4.31(dt,J=10.3,7.6Hz ,1H),3.88(ddd,J=10.1,8.4,4.5Hz,1H),3.33–3.25(m,1H),3.25–3.21(m,1H),2.98(dd,J=13.5,5.7Hz,1H),2.64– 2.56(m,1H),2.45–2.37(m,1H),2.37–2.30(m,1H),2.25–2.14(m,1H),1.83–1.75(m,2H),1.79(s,3H),1.36(s,3H).

[0100] 13C NMR (126MHz, CDCl3) δ175.6,173.9,172.9,171.8,137.0,132.8,129.1,128.6, 126.7,118.4,58.8,57.8,53.9,53.5,47.0,35.8,33.3,26.5,25.0,24.8,23.5.

[0101] Example 2

[0102] This example provides a tetracyclic peptide intermediate compound I-1, and its synthesis route and preparation method are as follows:

[0103]

[0104] The intermediate compound II (8.0 mg, 0.019 mmol) was dissolved in Et2O (5.0 mL) in a pressure tube, followed by the addition of compound 10-1 (17.48 mg, 0.095 mmol), second-generation Grubbs catalyst (CAS: 246047-72-3; 8.1 mg, 0.0095 mmol), and CuI (0.36 mg, 0.0019 mmol), and then the system was subjected to nitrogen bubbling for 30 min, and then the reaction system was placed at 40°C and stirred overnight. After vacuum concentration, the mixture was purified by flash column chromatography (PE:EA=1:1) to obtain 6.1 mg of the product tetracyclic peptide intermediate compound I-1, with a yield of 55%.

[0105] The NMR data of the tetracyclic peptide intermediate compound I-1 are as follows:

[0106] 1H NMR (500MHz, CDCl3) δ7.52(d,J=10.1Hz,1H),7.33–7.20(m,5H),7.15(d,J=10.3Hz,1H),6.10(s,1H),5.56(dt,J=14.1,6 .7Hz,1H),5.42–5.30(m,1H),5.18(td,J=10.1,5.7Hz,1H),4.72–4.66(m,1H),4.43(dd,J=7.8,5.5Hz,1H),4.28–4.17(m ,2H),4.05–3.91(m,1H),3.92–3.81(m,1H),3.31–3.20(m,2H),2.97(dd,J=13.5,5.7Hz,1H),2.74–2.61(m,2H),2.54–2. 48(m,1H),2.44–2.23(m,5H),2.22–2.14(m,1H),1.84–1.70(m,1H),1.79(s,3H),1.50(s,3H),1.41(s,3H),1.36(s,3H).

[0107] 13 C NMR (151MHz, CDCl3) δ210.1,175.6,173.9,172.8,171.8,137.0,132.6,129.1,128.6,126.7,125.3,111 .0,80.2,66.5,58.8,57.8,54.3,53.5,47.0,38.2,35.8,32.1,26.4,26.1,25.9,25.0,25.0,24.7,23.6.

[0108] Example 3

[0109] This example provides a method for preparing the natural cyclic peptide compound Koshidacin B, and its synthesis route and synthesis steps are as follows:

[0110]

[0111] The tetracyclic peptide intermediate compound I-1 (4.0 mg, 6.9 μmol) prepared in Example 2 of the present invention was dissolved in 0.5 mL of hydrochloric acid methanol solution (preparation of hydrochloric acid methanol solution: 7.2 μL of dichlorothionyl was added to 2.0 mL of MeOH), and then a Pd / C catalyst (the content of palladium in the whole catalyst was 5 wt.%; 3 mg) was added. After the reaction system was replaced with hydrogen, it was stirred at room temperature overnight under a hydrogen atmosphere. After filtration with diatomaceous earth, it was concentrated in vacuo, and then the mixture was purified by rapid column chromatography (PE:EA=1:1) to obtain 2.7 mg of the final product Koshidacin B, with a yield of 72%.

[0112] The NMR data of Koshidacin B are as follows:

[0113] 1 H NMR (600MHz, CDCl3) δ7.48(d,J=10.3Hz,1H),7.33–7.19(m,5H),7.15(d,J=10.0Hz,1H),6.10(s,1H),5.16(ddd,J= 10.1,5.7Hz,1H),4.72–4.61(m,1H),4.21(t,J=3.2Hz,1H),4.20–4.14(m,1H),4.00–3.90(m,2H),3.89–3.82(m,1H ),3.29–3.24(m,1H),3.24–3.18(m,1H),2.95(dd,J=13.5,5.7Hz,1H),2.67–2.57(m,1H),2.57–2.48(m,1H),2.38– 2.26(m,1H),2.20–2.11(m,1H),1.86–1.68(m,3H),1.77(s,3H),1.65–1.49(m,3H),1.34(s,3H),1.38–1.24(m,4H).

[0114] 13 C NMR (151MHz, CDCl3) δ209.8,175.6,174.3,172.9,171.9,137.0,129.0,128.6,126.8,77.5,63 .7,58.8,57.8,54.2,53.4,47.0,37.5,35.8,29.7,28.6,26.4,25.0,24.9,24.8,23.6,22.70.

[0115] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge scope of ordinary technicians in the relevant technical field without departing from the purpose of the present invention.

Claims

1. A tetracyclic peptide intermediate compound, characterized in that: It has the structural formula shown in Formula I: R is selected from hydroxyl; or R and the carbon to which it is attached form a carbonyl.

2. An intermediate compound for preparing the tetracyclic peptide intermediate compound according to claim 1, characterized in that: It has the structure shown in formula II:

3. The method for preparing a tetracyclic peptide intermediate compound according to claim 1, characterized in that: The steps include: The intermediate compound II described in claim 2 and the compound 10 are subjected to an olefin metathesis reaction under the catalysis of a Grubbs catalyst and a cuprous catalyst to obtain a tetracyclic peptide intermediate compound; The structural formula of the compound 10 is as follows: R is selected from hydroxyl; or R and the carbon to which it is attached form a carbonyl.

4. The method for preparing a tetracyclic peptide intermediate compound according to claim 3, characterized in that: The reaction temperature of the olefin metathesis reaction does not exceed 50°C; preferably, the reaction temperature of the olefin metathesis reaction is 30-50°C.

5. The method for preparing a tetracyclic peptide intermediate compound according to claim 3, characterized in that: The olefin metathesis reaction is carried out in a solution state, and the solvent used in the solution state is selected from at least one of ether, dichloromethane or dichloroethane.

6. The method for preparing a tetracyclic peptide intermediate compound according to claim 3, characterized in that: The molar ratio of the intermediate compound II, compound 10, Grubbs catalyst and cuprous catalyst is 1:(3-8):(0.2-1):(0.01-0.5).

7. The method for preparing a tetracyclic peptide intermediate compound according to claim 3, characterized in that: The intermediate compound II is prepared by the following method: Compound 8 is mixed with a basic substance to remove the Fmoc protecting group and the Fm protecting group to obtain an intermediate I; the intermediate I, HOAt, DIPEA, HATU and a solvent are mixed to react; The structural formula of the compound 8 is as follows:

8. Use of the tetracyclic peptide intermediate compound according to claim 1 in the preparation of a natural cyclic peptide compound; the natural cyclic peptide compound comprises Koshidacin B, Koshidacin A or chlamydocin.

9. A method for preparing Koshidacin B, characterized in that: The steps include: Under a hydrogen atmosphere, the tetracyclic peptide intermediate compound according to claim 1, a palladium-carbon catalyst and a methanol solution of hydrochloric acid are mixed and reacted to obtain Koshidacin B.

10. The preparation method according to claim 9, characterized in that: The palladium-carbon catalyst is selected from at least one of Pd / C, Pd(OH)2 / C or PdCl2 / C.

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