CN111333634A

CN111333634A - Preparation method and application of natural product Streptochlorin and derivatives thereof

Info

Publication number: CN111333634A
Application number: CN201910154085.1A
Authority: CN
Inventors: 张明智; 施展; 刘畅; 章维华
Original assignee: Nanjing Agricultural University
Current assignee: Nanjing Agricultural University
Priority date: 2019-02-28
Filing date: 2019-02-28
Publication date: 2020-06-26

Abstract

The invention discloses a preparation method of a natural product Streptochlorin derivative. The invention also discloses application of the natural product Streptochlorin and derivatives thereof in killing pathogenic bacteria of crops. The natural product Streptochlorin and the derivatives thereof have good bactericidal activity, can be applied to crop diseases caused by fungi, bacteria and viruses, and show high-efficiency and/or broad-spectrum bactericidal activity.

Description

Preparation method and application of natural product Streptochlorin and derivatives thereof

Technical Field

The invention relates to an agricultural bactericide, in particular to a preparation method of a natural product Streptochlorin and derivatives thereof and application of the natural product Streptochlorin and derivatives thereof in sterilization.

Background

A natural product of Streptochlorin is a micromolecular indole alkaloid separated from marine Streptomyces sp by Japanese scientist H.Watanabe et al in 1988, and the structure of the micromolecular indole alkaloid is identified as 4-chloro-5- (3' -indolyl) -oxazole by an X-ray single crystal diffraction method.

The patent reports about the Streptochlorin and the derivatives thereof are few after the relevant data are reviewed, the research on the inhibition effect on cancer cells is mainly focused, and the relevant reports about the Streptochlorin as an agricultural bactericide are rarely seen. The Streptochlorin and derivatives thereof shown in the invention are not disclosed, and according to the research on bactericidal activity, a series of novel Streptochlorin derivatives are designed and synthesized.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide a derivative of a natural product streptochlorerin.

The invention also aims to solve the technical problem of providing a preparation method of a natural product Streptochlorin derivative.

The invention finally aims to solve the technical problem of providing the application of the natural product Streptochlorin.

The invention achieves the aims of improving the physicochemical property of the streptochlorein derivatives, improving the bactericidal activity and expanding the bactericidal spectrum by modifying and transforming the structure of the streptochlorein. The invention also relates to methods of using these compounds and compositions thereof for sterilization.

The technical scheme is as follows: in order to solve the technical problems, the invention provides a derivative of a natural product Streptochlorin, which has a structural formula shown in a formula (I):

the formula (I) is shown in the specification, wherein X is one of F, Cl or Br; r is respectively selected from H, C₁-C₂Alkyl of (C)₂-C₃Substituted or unsubstituted alkylene of (A), C₂-C₃Substituted or unsubstituted acyl group、C₂-C₄And one of an ester group, an alkylene oxide group, a cycloalkyl group and a substituted phenyl group.

Wherein, the X is F, Cl or Br; r is CH₃、CH₃CH₂、CH₂＝CHCH₂、CCl₂＝CHCH₂、CH₃CO、CH₃CH₂CO、CH₃CH₂SO₂、ClCH₂CO、Cl₂CHCO、CCl₃CO、CH₃CHClCO、CH₃OCO、CH₃OCH₂CO、CH₃CH₂OCOCH₂、CH₃CH₂OCOCO、2，4-di-F-C₆H₃CH₂、

One kind of (1).

According to a preferred embodiment of the invention, X is Cl or Br; r is ClCH₂CO、Cl₂CHCO、CCl₃CO、CH₃OCH₂CO or CH₃CH₂One of OCOCOCO.

According to a particular embodiment, X is Cl; r is ClCH₂CO; alternatively, the first and second electrodes may be,

x is F, R is Cl₂CHCO; alternatively, the first and second electrodes may be,

x is F; r is CCl₃CO; alternatively, the first and second electrodes may be,

x is F; r is CH₃OCH₂CO; alternatively, the first and second electrodes may be,

x is F; r is CH₃CH₂OCOCO; alternatively, the first and second electrodes may be,

x is Cl; r is Cl₂CHCO; alternatively, the first and second electrodes may be,

x is Cl; r is CCl₃CO; alternatively, the first and second electrodes may be,

x is Cl; r is CH₃OCH₂CO; alternatively, the first and second electrodes may be,

x is Cl; r is CH₃CH₂OCOCO; alternatively, the first and second electrodes may be,

x is Br; r is ClCH₂CO; alternatively, the first and second electrodes may be,

x is Br; r is Cl₂CHCO; alternatively, the first and second electrodes may be,

x is Br; r is CH₃OCH₂CO。

The invention also provides a preparation method of the natural product Streptochlorin derivative, which comprises the following steps:

1) indole and phosphorus oxychloride are subjected to Vilsmeier-Haack reaction under an alkaline condition to obtain a compound 2 shown as a formula (II);

formula (II);

2) performing benzenesulfonyl protection on the compound 2 obtained in the step 1) to obtain a compound 3 shown as a formula (III):

formula (III);

3) and (3) carrying out Van Leusen oxazole synthesis reaction on the compound 3 obtained in the step (2) and p-methyl benzenesulfonyl methyl isonitrile, and obtaining a compound 4 shown in a formula (IV) under the action of resin:

formula (IV);

4) carrying out nucleophilic substitution reaction on the compound 4 obtained in the step 3 and N-chlorosuccinimide or N-bromosuccinimide to obtain a compound 5 shown in a formula (V):

formula (V)

Wherein X is Cl or Br;

5) and (2) carrying out a substitution reaction on the compound 5 obtained in the step (4) and a nucleophilic reagent with the general formula of RZ in the presence of a base and a solvent, wherein Z is Cl, Br or F, so as to obtain a compound 6 shown in the formula (I):

formula (I)

Wherein X is Cl or Br; r is respectively selected from H, C₁-C₂Alkyl of (C)₂-C₃Substituted or unsubstituted alkylene of (A), C₂-C₃Substituted or unsubstituted acyl, C₂-C₄And one of an ester group, an alkylene oxide group, a cycloalkyl group and a substituted phenyl group.

The synthetic route of the preparation method of the natural product Streptochlorin derivative is as follows:

the solvent used in the present invention may be tetrahydrofuran or ethylene glycol dimethyl ether. The specific species may be selected according to the selection principles in the art and are well known to those skilled in the art.

It will be understood by those skilled in the art that the method of the present invention may further include a step of purifying the obtained product, and there is no particular requirement for the purification method, and various purification methods conventionally used by those skilled in the art may be employed, for example, extraction with an extractant, drying with a drying agent, and removal of impurities by column chromatography or the like may be employed.

Wherein, the alkali used in the alkaline condition in the step 1) is sodium hydroxide, and the solvent is N, N-dimethylformamide.

The alkali used in the alkaline condition in the step 2) is sodium hydride, the solvent is tetrahydrofuran, the reagent used for benzene sulfonyl protection is benzene sulfonyl chloride, strong alkali is needed to pull hydrogen due to weak acidity of indole NH, so that substituent introduction is facilitated in the next step, and if other alkali is selected, such as NaOH, KOH and the like, the effect of substituent introduction is influenced, so that the reaction time is long and the reaction yield is low.

Wherein, the solvent in the step 3) is tetrahydrofuran and methanol which are 1: 1, and the use of the mixed solvent is beneficial to improving the reaction efficiency; the resin is Ambersep 900 OH-resin, which can provide alkaline condition while catalyzing cyclization reaction of oxazole, so that the removal of the protecting group benzenesulfonyl is facilitated, and the change of two structural sites can be completed by one-step reaction.

Wherein, the solvent in the step 4) is tetrahydrofuran and carbon tetrachloride which are 1: 1, carbon tetrachloride is usually selected as the solvent for the halogenation reaction, the tetrahydrofuran has good solubility to the substrate, and the use of the mixed solvent is favorable for improving the reaction efficiency while ensuring the reaction. The halogenating reagent is N-bromosuccinimide and N-chlorosuccinimide, the molar ratio of the compound with the structure shown in the formula (V) to the halogenating reagent is 1: 1-1.5, preferably 1: 1.1, the halogenating reagent is added in batches for improving the halogenating selectivity because the oxazole ring has more halogenating sites, 0.6 equivalent is firstly added, the reaction progress is monitored by TLC, and the rest 0.5 equivalent is added after a large amount of product points are formed, so that the complete reaction of reactants can be ensured, and the yield is improved.

Wherein, the alkali used in the alkaline condition in the step 5) is sodium hydride, the solvent is tetrahydrofuran, the temperature is 20-50 ℃, preferably 40-45 ℃, the reaction time is long due to low temperature, and the product is deteriorated due to high temperature; the mol ratio of the compound with the structure shown as the formula (V) to the compound with the general formula of RZ and the alkali is 1: 1-2, preferably 1: 2, the complete reaction of reactants can be ensured, and the yield is improved; the reaction time is 5-10 hours, preferably 8 hours, and generally, the TLC monitors the reaction progress, the reaction is incomplete due to short time, and side reactions occur due to long time, so that the yield is influenced. After the heating condition is further optimized, a microwave-assisted heating method is adopted, and after the conditions such as reaction time, temperature, solvent and the like are optimized, the reaction can be completed only by microwave reaction for 15 minutes, so that the yield is improved.

The invention also comprises the application of the natural product Streptochlorin and the derivatives thereof in killing pathogenic bacteria of crops.

Wherein the crop pathogenic bacteria are one or more of potato late blight bacteria, wheat leaf blight bacteria, broad bean single cell rust bacteria, pythium, tomato early blight bacteria, botrytis cinerea and wheat scab bacteria.

Wherein the concentration of the natural product Streptochlorin and its derivatives is 2ppm to 200 ppm.

Has the advantages that: compared with the prior art, the invention has the following advantages:

1. according to the preparation method of the derivative, cheap and easily-obtained indole is used as an initial raw material, and the active natural product Streptochlorin and the derivative thereof can be obtained through four simple reactions of acylation, protection, cyclization and halogenation, wherein the total yield of the Streptochlorin can reach 45% through condition optimization.

2. The natural product Streptochlorin and the derivatives thereof have good bactericidal activity, can be applied to crop diseases caused by fungi, bacteria and viruses, and show high-efficiency and/or broad-spectrum bactericidal activity.

Detailed Description

The present invention will be described in detail below by way of examples. In the following examples, the various starting materials used in the examples are commercially available and all purity grades are analytical, unless otherwise specified. The room temperature was 25 ℃. The reaction time was 12 hours overnight.

The target compound obtained is shown in table a:

TABLE A

The specific synthetic procedures for the above compounds are described in the following specific examples.

Example 1

Synthesis of compound 5(X ═ Cl, Streptochlorin)

1. Synthesis of indole-3-carbaldehyde

Indole (compound 1) is used as a raw material to synthesize indole-3-formaldehyde (compound 2), and the synthetic route is as follows:

taking a 100mL round-bottom flask, adding N, N-dimethylformyl14.0mL of amine, and cooling to 0-5 ℃ in ice water bath; adding POCl by syringe₃2.0mL, stirring in ice-water bath for 30 min; dissolving 2.34g (20.0mmoL) indole in 5mL of N, N-dimethylformamide, adding, and reacting at 35 deg.C for 1 h; cooling, and sequentially adding H₂Heating and refluxing O12.0mL and 26mL of 30% NaOH aqueous solution for 30 min; cooling, and naturally precipitating a large amount of light yellow crystals; performing suction filtration, washing the solid for multiple times by using clear water, and removing alkali and N, N-dimethylformamide in the system; after drying, weighing. The calculated yield was 97%. And Mp: 195.8-198.7 ℃.¹H NMR(400MHz，DMSO)δ12.14(s，1H)，9.94(s，1H)，8.29(s，1H)，8.10(d，J＝7.2Hz，1H)，7.52(d，J＝7.6Hz，1H)，7.24(dtd，J＝17.7，7.2，1.2Hz，2H).¹³C NMR(101MHz，DMSO)δ185.42(s)，138.97(s)，137.58(s)，124.62(s)，123.92(s)，122.59(s)，121.30(s)，118.64(s)，112.92(s).IR v/cm^-1：3164.97(NH)，3098.68(Pyrrolyl-CH)，3040.96(Ar-CH)，1627.17(C＝O)，1240.92(C-N)。

2. Synthesis of benzenesulfonyl protected indole-3-carbaldehyde

Indole-3-formaldehyde (compound 2) and benzenesulfonyl chloride are used as raw materials to synthesize the benzenesulfonyl protected indole-3-formaldehyde (compound 3), and the synthetic route is as follows:

adding 3.0g (20.7mmoL) of indole-3-formaldehyde and 60mL of anhydrous tetrahydrofuran into a 100mL round-bottom flask, and stirring to dissolve; adding sodium hydride (60%, 41.4mmoL) in ice-water bath, and reacting for 0.5h at room temperature; 15mL of anhydrous tetrahydrofuran containing 6.6g of benzenesulfonyl chloride was added to the syringe, the reaction was carried out at room temperature, and after 2 hours, the progress of the reaction was monitored by TLC. After the reaction is finished, evaporating the solvent to dryness under reduced pressure, washing with water, extracting with dichloromethane, and washing with saturated sodium bicarbonate water solution, saturated salt solution and clear water in sequence; adding anhydrous sodium sulfate, drying, and standing. After drying for 2h, filtration and recrystallization gave a large number of pink crystals, which were weighed after drying. The calculated yield was 81%. And Mp: 155.8 to 158.1 ℃.¹H NMR(400MHz，DMSO)δ10.10(s，1H)，8.94(s，1H)，8.14(t，J＝6.9Hz，3H)，8.00(d，J＝8.2Hz，1H)，7.78(t，J＝7.5Hz，1H)，7.67(t，J＝7.8Hz，2H)，7.45(ddd，J＝25.2，11.6，4.3Hz，2H).¹³C NMR(101MHz，DMSO)δ187.27(s)，139.03(s)，136.74(s)，135.91(s)，134.85(s)，130.68(s)，127.69(s)，126.81(s)，126.20(s)，125.66(s)，122.36(s)，122.13(s)，113.68(s).IR v/cm^-1：3129.67(C＝C-H)，1676.20(C＝O)，1374.83(-SO₂-)，1174.24(C-N)。

3. Synthesis of indole-3-oxazoles

The synthetic route of the indole-3-oxazole is as follows:

a200 mL round-bottom flask was taken, and 33.0g (0.6mmoL) of the compound, 60.0mL of self-made anhydrous methanol, 60.0mL of anhydrous tetrahydrofuran, 2.28g of p-toluenesulfonylmethylisocyanamide (TosMIC) and 21g of Ambersep p 900 OH-resin were sequentially added thereto, and the mixture was heated under reflux to react for 2 hours. TLC monitored the progress of the reaction. After the reaction is finished, filtering, evaporating the solvent to dryness under reduced pressure, washing with water, extracting with dichloromethane, and washing with saturated salt solution and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 12-17% acetone/petroleum ether eluent. Pale yellow crystals were obtained, dried and weighed. The calculated yield was 66%. And Mp: 145.0-154.3 ℃.¹H NMR(400MHz，DMSO)δ11.59(s，1H)，8.34(s，1H)，7.83(dd，J＝21.8，5.2Hz，2H)，7.55-7.41(m，2H)，7.18(dt，J＝24.1，7.4Hz，2H).¹³C NMR(101MHz，DMSO)δ150.07(s)，148.13(s)，136.85(s)，124.60(s)，121.31(s)，120.62(s)，119.86(s)，119.17(s)，112.89(s)，104.07(s).IR v/cm^-1：3143.51(NH)，3041.46(C＝C-H)，1629.52(C＝N)1242.21(C-N)，1123.79(C-O-C)。

4. Synthesis of compound 5(X ═ Cl, Streptochlorin)

Synthetic route for compound 5(X ═ Cl, Streptochlorin):

taking a 50mL eggplant-shaped bottle, sequentially adding 0.5g (2.7mmoL) of indole-3-oxazole, 10mL of tetrahydrofuran treated by a molecular sieve, 10mL of carbon tetrachloride and 0.24g (1.8mmoL) of N-chlorosuccinimide, reacting at 50 ℃ for 1h, monitoring the reaction progress by TLC, and adding 0.16g (1.2mmoL) of N-chlorosuccinimide after a large amount of products are generated, and reacting for 0.5 h. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed and extracted by dichloromethane, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 17% acetone/petroleum ether eluent. White crystals were obtained, dried and weighed. The calculated yield was 66%. And Mp: 152.9-155.6 ℃.¹H NMR(400MHz，DMSO)δ11.80(s，1H)，8.50(s，1H)，8.03-7.87(m，2H)，7.51(d，J＝8.0Hz，1H)，7.20(dt，J＝26.2，7.4Hz，2H).¹³C NMR(101MHz，DMSO)δ149.91(s)，143.18(s)，136.38(s)，125.15(s)，124.48(s)，122.93(s)，120.94(s)，120.24(s)，112.71(s)，112.03(s)，101.83(s).IR v/cm^-1：3182.05(NH)，3131.17(Pyrrolyl-CH)，3045.38(Ar-CH)，1627.88(C＝N)，1244.64(C-N)，1125.14(C-O-C)，747.79(C-Cl).

Example 2

After the construction of the strepochlorin skeleton is completed according to the synthetic route of example 1, the structure of the strepochlorin skeleton is modified, the modified site is concentrated at the position of indole ring free NH, and the modified site and different halogenated groups RX react for 0.25-3 hours in the temperature range from room temperature to 100 ℃ under the alkaline condition of sodium hydride. The obtained compounds are all subjected to¹H NMR，¹³Confirmation of C NMR, IR and HRMS.

1. Synthesis of Compound I-3

Compound 5(X ═ Cl) (0.20mmoL) was obtained by the synthetic route described in example 1, and 3mL of anhydrous tetrahydrofuran was taken and dissolved with stirring; adding sodium hydride (60%, 0.30mmoL) under the condition of ice-water bath, and reacting for 30min at room temperature; 2mL of anhydrous tetrahydrofuran containing allyl bromide (0.24mmoL) was added and the reaction was carried out at room temperature for 2 hours, and the progress of the reaction was monitored by TLC. To be treatedAfter the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed by water and extracted by dichloromethane, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 6% acetone/petroleum ether eluent. The yield of the target product compound I-3 is 66%. mp, 42-44 ℃ IR (KBr) cm^-1：642(C-Cl)，1108(C-O-C)，1626(C＝N)，3129(Ar-CH)，3446(Pyrrolyl-CH).¹H NMR(600MHz，CDCl₃)：δ1.51(t，J＝7.2Hz，3H)，4.22(q，J＝7.2Hz，2H)，7.24(dd，J＝9.6，5.4Hz，1H)，7.29-7.32(t，J＝7.2Hz，1H)，7.31-7.32(m，J＝8.4Hz，1H)，7.71(s，1H)，7.83(s，1H)，8.06(d，J＝8.4Hz，1H).¹³C NMR(100MHz，CDCl₃)：δ15.3，41.5，103.4，109.7，119.9，120.8，121.0，121.3，122.7，125.0，125.9，139.0，147.3.HRMS(MALDI)：m/z 247.0686.Calcd.for C₁₃H₁₁ClN₂O：247.0638[M+H]⁺.

2. Synthesis of Compound II-6

Compound 5(X ═ Cl) (0.20mmoL) was obtained by the synthetic route described in example 1, and 2mL of anhydrous N, N-dimethylformamide and 3mL of anhydrous tetrahydrofuran were taken and dissolved with stirring; adding sodium hydride (60%, 0.30mmoL) under the condition of ice-water bath, and reacting for 30min at room temperature; 5mL of anhydrous N, N-dimethylformamide containing propionyl bromide (0.24mmoL) was added, and the reaction was carried out at 40 ℃ for 3 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed and extracted by dichloromethane, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 5-7% acetone/petroleum ether eluent. The target product is obtained, dried and weighed. Obtaining the target product compound II-6, calculating the yield of 84%. mp, 135 ℃. IR (KBr) cm^-1：538(C-Br)，1114(C-O-C)，1573(C＝N)，1709(C＝O)，3124(Ar-CH)，3445(Pyrrolyl-CH).¹H NMR(600MHz，CDCl₃)：δ1.38-1.41(t，J＝7.2Hz，3H)，3.02-3.06(q，J＝7.2Hz，2H)，7.38-7.40(t，J＝7.8Hz，1H)，7.96(s，1H)，8.04-8.05(d，J＝7.8Hz，1H)，8.17(s，2H)，8.53-8.54(d，J＝8.4Hz，1H).¹³CNMR(100MHz，DMSO-d6)：δ8.3，28.4，107.4，110.6，116.1，120.5，124.2，125.8，126.3，128.5，134.8，142.6，151.8，172.6.HRMS(MALDI)：m/z 319.0063.Calcd.C₁₄H₁₁BrN₂O₂：319.0082[M+H]⁺.

3. Synthesis of Compound I-12

Compound 5(X ═ Cl) (0.20mmoL) was obtained by the synthetic route described in example 1, and 2mL of anhydrous N, N-dimethylformamide and 3mL of anhydrous tetrahydrofuran were taken and dissolved with stirring; adding sodium hydride (60%, 0.30mmoL) under the condition of ice-water bath, and reacting for 30min at room temperature; 5mL of anhydrous N, N-dimethylformamide containing methyl bromoformate (0.24mmoL) was added thereto, and the reaction was carried out at 60 ℃ for 3 hours, and the progress of the reaction was monitored by TLC. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed and extracted by dichloromethane, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 5-7% acetone/petroleum ether eluent. The target product is obtained, dried and weighed. Obtaining the target product compound I-12, calculating the yield of 65%. mp, 114 ℃. IR (KBr) cm^-1：614(C-Cl)，1119(C-O-C)，1571(C＝N)，1744(-CO₂-)，3126(Ar-CH)，3447(Pyrrolyl-CH).¹H NMR(600MHz，CDCl₃)：δ4.14(s，3H)，7.33(t，J＝7.2Hz，1H)，7.37-7.44(t，J＝7.2Hz，1H)，7.52(d，J＝7.8Hz，1H)，8.01(s，1H)，8.03(s，1H)，8.13(d，J＝9.0Hz，1H).¹³C NMR(100MHz，DMSO-d6)：δ54.8，106.4，115.5，119.2，124.2，124.4，125.6，125.7，127.7，134.4，137.1，150.0，153.3.HRMS(MALDI)：m/z314.9988.Calcd.C₁₃H₉ClN₂O₃：314.9939[M+K]⁺.

4. Synthesis of Compound II-14:

compound 5(X ═ Cl) (0.20mmoL) was obtained by the synthetic route described in example 1, and 5mL of anhydrous tetrahydrofuran was taken and dissolved with stirring; adding sodium hydride (60%, 0.30mmoL) under the condition of ice-water bath, and reacting for 30min at room temperature; anhydrous tetrahydro-ethylene containing 2-bromomethyloxirane (0.24mmoL) was addedFuran 5mL, reaction at 50 ℃ for 2.5h, TLC monitoring progress of reaction. After the reaction is finished, the solvent is evaporated to dryness under reduced pressure, washed and extracted by dichloromethane, and then washed by saturated salt water and clear water; adding anhydrous sodium sulfate, drying, and standing. Drying for 2 hr, filtering, adding certain amount of silica gel, stirring, and purifying with 5-7% acetone/petroleum ether eluent. The target product is obtained, dried and weighed. Obtaining the target product compound II-14, calculating the yield of 97%. mp, 101 ℃. IR (KBr) cm^-1：539(C-Br)，1119(C-O-C)，1572(C＝N)，3129(Ar-CH)，3442(Pyrrolyl-CH).1H NMR(600MHz，CDCl3)：δ2.51(s，1H)，2.85(s，1H)，3.34(s，1H)，4.19-4.22(dd，J＝15.0，3.6Hz，1H)，4.54(d，J＝15.0Hz，1H)，7.26(t，J＝7.8Hz，1H)，7.33(t，J＝7.2Hz，1H)，7.45(d，J＝7.8Hz，1H)，7.85(s，1H)，7.88(s，1H)，8.08(d，J＝7.8Hz，1H).¹³C NMR(100MHz，DMSO-d6)：δ45.1，48.0，50.6，103.1，107.9，109.8，121.0，121.2，123.1，125.2，127.3，128.5，136.2，148.5.HRMS(MALDI)：m/z 319.0320.Calcd.for C₁₄H₁₁BrN₂O₂：319.0289[M+H]⁺.

The target compound spectra and data obtained using the method of example 2 are as follows:

I-1：

4-chloro-5-(1-methyl-1H-indol-3-yl)oxazole:Reagent,CH₃I.Yield,96％.mp,117-119℃.IR(KBr)cm^-1:642(C-Cl),1111(C-O-C),1623(C＝N),3124(Ar-CH),3443(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ3.88(s,3H),7.25(d,J＝7.8Hz,1H),7.33(t,J＝7.8Hz,1H),7.39(d,J＝8.4Hz,1H),7.67(s,1H),7.86(s,1H),8.08(d,J＝7.8Hz,1H).¹³CNMR(100MHz,CDCl₃):δ33.3,102.1,109.7,120.8,120.9,121.1,122.8,125.0,127.6,128.5,136.6,147.3.HRMS(MALDI):m/z233.0522.Calcd.for C₁₂H₉ClN₂O:233.0482[M+H]⁺.

I-2：

4-chloro-5-(1-ethyl-1H-indol-3-yl)oxazole:Reagent,CH₃CH₂Br.Yield,66％.mp,42-44℃.IR(KBr)cm^-1:642(C-Cl),1108(C-O-C),1626(C＝N),3129(Ar-CH),3446(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.51(t,J＝7.2Hz,3H),4.22(q,J＝7.2Hz,2H),7.24(dd,J＝9.6,5.4Hz,1H),7.29–7.32(t,J＝7.2Hz,1H),7.31–7.32(m,J＝8.4Hz,1H),7.71(s,1H),7.83(s,1H),8.06(d,J＝8.4Hz,1H).¹³C NMR(100MHz,CDCl3):δ15.3,41.5,103.4,109.7,119.9,120.8,121.0,121.3,122.7,125.0,125.9,139.0,147.3.HRMS(MALDI):m/z 247.0686.Calcd.for C₁₃H₁₁ClN₂O:247.0638[M+H]⁺.

I-4:

4-chloro-5-(1-(3,3-dichloroallyl)-1H-indol-3-yl)oxazole:Reagent,1,1,3-trichloroprop-1-ene.Yield,39％.mp,83-85℃.IR(KBr)cm^-1:642(C-Cl),1110(C-O-C),1620(C＝N),3117(Ar-CH),3446(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ4.93–4.92(d,J＝6.6Hz,1H),6.09–6.07(t,J＝6.6Hz,1H),7.38–7.26(t,J＝7.8Hz,1H),7.38–7.34(m,2H),7.69(s,1H),7.87(s,1H),8.09(d,J＝7.8Hz,2H).¹³C NMR(150MHz,CDCl₃):δ45.3,103.2,109.6,121.2,121.3,121.6,123.3,124.4,124.5,125.2,126.0,135.6,142.7,147.5.HRMS(MALDI):m/z 326.9835.Calcd.forC₁₄H₉Cl₃N₂O:326.9859[M+H]⁺.

I-5:

1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)ethanone:Reagent,CH₃COCl.Yield,76％.mp,158-160℃.IR(KBr)cm^-1:642(C-Cl),1113(C-O-C),1620(C＝N),1720(C＝O),3111(Ar-CH),3444(Pyrrolyl-CH).1H NMR(600MHz,CDCl₃):δ2.73(s,3H),7.40(t,J＝7.8Hz,1H),7.46(d,J＝8.4Hz,1H),7.96(s,1H),8.01(s,1H),8.07(d,J＝7.2Hz,1H),8.52(d,J＝8.4Hz,1H).¹³CNMR(100MHz,CDCl₃):δ24.0,109.1,116.7,120.9,123.0,124.4,126.3,126.8,135.4,140.8,141.2,148.6,168.5.HRMS(MALDI):m/z261.0390.Calcd.for C₁₃H₉ClN₂O₂:261.0431[M+H]⁺.

I-6:

1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)propan-1-one:Reagent,CH₃CH₂COCl.Yield,65％.mp,120-122℃.IR(KBr)cm^-1:619(C-Cl),1118(C-O-C),1615(C＝N),1695(C＝O),3127(Ar-CH),3443(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.39(t,J＝7.2Hz,3H),3.05(q,J＝7.2Hz,2H),7.39(t,J＝7.2Hz,1H),7.46(t,J＝8.4Hz,1H),7.95(s,1H),8.06(m,2H),8.54(d,J＝9.0Hz,1H).¹³C NMR(150MHz,CDCl₃):δ8.5,29.2,108.8,116.6,120.8,122.2,124.3,124.4,126.1,126.6,135.4,141.3,148.5,172.0.HRMS(ESI):m/z 275.0599.Calcd.for C₁₄H₁₁ClN₂O₂:275.0587[M+H]⁺.

I-7:

4-chloro-5-(1-(ethylsulfonyl)-1H-indol-3-yl)oxazole:Reagent,CH₃CH₂SO₂Cl.Yield,63％.mp,113-115℃.IR(KBr)cm^-1:614(C-Cl),1136(C-O-C),1364(-SO₂-),1570(C＝N),3141(Ar-CH),3443(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.28(t,J＝7.2Hz,3H),3.40(q,J＝7.2Hz,2H),7.42(t,J＝7.2Hz,1H),7.46(t,J＝7.8Hz,1H),7.92–8.00(m,2H),8.03(s,1H),8.11(d,J＝7.8Hz,1H).¹³C NMR(150MHz,DMSO-d6):δ7.8,48.5,107.0,113.3,119.8,121.2,124.1,124.7,125.8,126.2,134.4,139.8,151.1.HRMS(MALDI):m/z 311.0238.Calcd.C₁₃H₁₁ClN₂O₃S:311.0257[M+H]⁺.

I-8:

2-chloro-1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)ethanone:Reagent,ClCH₂COCl.Yield,62％.mp,157-159℃.IR(KBr)cm^-1:614(C-Cl),1121(C-O-C),1570(C＝N),1713(C＝O),3130(Ar-CH),3444(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ4.66(s,2H),7.44(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),7.97(s,1H),8.03(s,1H),8.08(d,J＝8.4Hz,1H),8.51(d,J＝8.4Hz,1H).¹³C NMR(150MHz,CDCl₃):δ42.3,102.1,111.0,119.6,120.5,121.3,121.9,124.1,125.3,126.8,127.6,135.5,164.1.HRMS(MALDI):m/z295.0115.Calcd.C₁₃H₈Cl₂N₂O₂:295.0041[M+H]⁺.

I-9:

2,2-dichloro-1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)ethanone:Reagent,Cl₂CHCOCl.Yield,59％.mp,129-131℃.IR(KBr)cm^-1:621(C-Cl),1126(C-O-C),1571(C＝N),1726(C＝O),3139(Ar-CH),3456(Pyrrolyl-CH).¹H NMR(600MHz,DMSO-d6):δ7.50(t,J＝7.2Hz,1H),7.56(t,J＝7.2Hz,1H),8.02(t,J＝4.2Hz,2H),8.43–8.45(m,2H),8.71(s,1H).¹³C NMR(100MHz,CDCl₃):δ65.6,102.1,110.9,117.1,121.3,122.0,125.7,126.7,127.1,135.9,140.6,149.0,160.7.HRMS(MALDI):m/z328.9620.Calcd.C₁₃H₇Cl₃N₂O₂:328.9651[M+H]⁺.

I-10:

2,2,2-trichloro-1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)ethanone:Reagent,Cl₃CCOCl.Yield,54％.mp,155-157℃.IR(KBr)cm^-1:623(C-Cl),1120(C-O-C),1570(C＝N),1719(C＝O),3135(Ar-CH),3446(Pyrrolyl-CH).¹H NMR(600MHz,DMSO-d6):δ7.57(t,J＝7.2Hz,1H),7.63(t,J＝7.2Hz,1H),8.08(d,J＝8.4Hz,1H),8.43(d,J＝8.4Hz,1H),8.58(s,1H),8.75(s,1H).¹³CNMR(150MHz,DMSO-d6):δ79.7,101.8,112.7,120.2,120.4,120.9,122.9,124.4,125.1,127.2,136.3,143.2,149.9.HRMS(ESI):m/z362.9283.Calcd.C₁₃H₆Cl₄N₂O₂:362.9262[M+H]⁺.

I-11:

2-chloro-1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)propan-1-one:Reagent,CH₃CHClCOCl.Yield,60％.mp,137-139℃.IR(KBr)cm^-1:617(C-Cl),1125(C-O-C),1571(C＝N),1705(C＝O),3127(Ar-CH),3446(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.91(d,J＝6.6Hz,3H),5.11(q,J＝6.6Hz,1H),7.43(t,J＝8.4Hz,1H),7.49(t,J＝7.2Hz,1H),7.97(s,1H),8.06(d,J＝8.4Hz,1H),8.16(s,1H),8.55(d,J＝9.0Hz,1H).¹³C NMR(100MHz,DMSO-d6):δ20.1,51.8,108.2,116.4,120.8,124.4,124.9,126.4,126.6,127.6,135.1,139.9,151.4,168.0.HRMS(MALDI):m/z309.0170.Calcd.C₁₄H₁₀Cl₂N₂O₂:309.0198[M+H]⁺.

I-13:

1-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)-2-methoxyethanone:Reagent,CH₃OCH₂COCl.Yield,50％.mp,103-105℃.IR(KBr)cm^-1:642(C-Cl),1127(C-O-C),1571(C＝N),1719(C＝O),3108(Ar-CH),3443(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ3.58(s,3H),4.65(s,2H),7.40–7.42(t,J＝7.8Hz,1H),7.46–7.48(t,J＝7.8Hz,1H),7.95(s,1H),8.05(d,J＝8.4Hz,1H),8.11(s,1H),8.52(d,J＝8.4Hz,1H).¹³C NMR(150MHz,DMSO-d6):δ59.7,72.4,109.7,116.5,116.7,121.1,121.6,124.7,126.3,135.4,141.0,147.5,148.8,167.7.HRMS(MALDI):m/z 291.0515.Calcd.C₁₄H₁₁ClN₂O₃:291.0536[M+H]⁺.

I-14:

ethyl 2-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)acetate:Reagent,CH₃CH₂OCOCH₂Br.Yield,40％.mp,60-62℃.IR(KBr)cm^-1:617(C-Cl),1121(C-O-C),1571(C＝N),1747(C＝O),3134(Ar-CH),3446(Pyrrolyl-CH).1H NMR(600MHz,CDCl₃):δ1.27(t,J＝7.2Hz,3H),4.23(q,J＝7.2Hz,2H),4.89(s,2H),7.25(dd,J＝13.2,5.4Hz,2H),7.30–7.37(m,1H),7.71(s,1H),7.85(s,1H),8.08(d,J＝7.8Hz,1H).¹³C NMR(100MHz,CDCl₃):δ14.1,48.0,62.0,103.5,109.4,121.2,121.3,123.4,125.0,127.2,127.6,136.3,142.9,127.6,167.8.HRMS:m/z 305.0678.Calcd.forC₁₅H₁₃ClN₂O₃:305.0693[M+H]⁺.

Streptochlorin:

ethyl 2-(3-(4-chlorooxazol-5-yl)-1H-indol-1-yl)acetate:Reagent,CH₃CH₂OCOCOCl.Yield,56％.mp,111-113℃.IR(KBr)cm^-1:616(C-Cl),1122(C-O-C),1570(C＝N),1746(COCO),3125(Ar-CH),3445(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.50–1.53(t,J＝7.2Hz,3H),4.54–4.58(q,J＝7.2Hz,2H),7.44–7.47(t,J＝7.8Hz,1H),7.48–7.51(t,J＝7.8Hz,1H),7.96(d,J＝7.8Hz,1H),8.08(d,J＝7.8Hz,1H),8.31(s,1H),8.50(s,1H).¹³C NMR(100MHz,DMSO-d6):δ14.0,63.7,111.1,116.9,121.3,123.3,125.5,126.7,127.2,128.5,135.4,140.7,148.9,157.0,159.6.HRMS(MALDI):m/z319.0634.Calcd.C₁₅H₁₁ClN₂O₄:319.0486[M+H]⁺.

I-16:

4-chloro-5-(1-(2,4-difluorobenzyl)-1H-indol-3-yl)oxazole:Reagent,1-(bromomethyl)-2,4-difluorobenzene.Yield,92％.mp,102-104℃.IR(KBr)cm^-1:642(C-Cl),1113(C-O-C),1140(C-F),1604(C＝N),3128(Ar-CH),3444(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ5.40(s,2H),6.78(t,J＝7.8Hz,1H),6.88(t,J＝9.0Hz,1H),6.90–6.98(m,1H),7.27(t,J＝7.8Hz,2H),7.30(t,J＝7.8Hz,1H),7.36(d,J＝8.4Hz,1H),7.77(s,1H),7.88(s,1H),8.10(d,J＝7.8Hz,1H).¹³C NMR(100MHz,CDCl₃):δ43.8,102.8,104.0–104.5(t,JC-F＝247Hz,1C),109.9,111.7–111.9(d,JC-F＝213Hz,1C),118.8,121.1,121.2,123.3,125.2,124.1,126.8,129.8,131.3,135.9,147.5,160.8,164.5.HRMS(MALDI):m/z 345.0569.Calcd.for C₁₈H₁₁ClF₂N₂O:345.0606[M+H]⁺.

I-17:

4-chloro-5-(1-(oxiran-2-ylmethyl)-1H-indol-3-yl)oxazole:Reagent,2-(bromomethyl)oxirane.Yield,61％.mp,85-87℃.IR(KBr)cm^-1:616(C-Cl),1122(C-O-C),1570(C＝N),3131(Ar-CH),3452(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ2.52(t,J＝4.2Hz,1H),2.86(t,J＝4.2Hz,1H),3.34(m,1H),4.55–4.23(dd,J＝15.0,5.4Hz,2H),7.27(t,J＝9.0Hz,1H),7.34(t,J＝7.2Hz,1H),7.45(d,J＝8.4Hz,1H),7.75(s,1H),7.87(s,1H),8.09(d,J＝8.4Hz,1H).¹³C NMR(100MHz,CDCl₃):δ45.2,48.2,50.6,109.8,121.1,121.2,121.7,123.2,124.1,127.0,127.6,128.3,135.5,147.5.HRMS(MALDI):m/z275.0603.Calcd.for C₁₄H₁₁ClN₂O₂:275.0587[M+H]⁺.

II-1:

4-bromo-5-(1-methyl-1H-indol-3-yl)oxazole:Reagent,CH₃I.Yield,99％.mp,131-133℃.IR(KBr)cm^-1:540(C-Br),1110(C-O-C),1571(C＝N),3122(Ar-CH),3454(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ3.88(s,3H),7.24(t,J＝7.8Hz,1H),7.33(t,J＝7.8Hz,1H),7.38(d,J＝8.4Hz,1H),7.78(s,1H),7.89(s,1H),8.08(d,J＝8.4Hz,1H).¹³CNMR(100MHz,CDCl₃):δ33.2,102.2,107.4,109.6,120.8,120.9,122.8,125.1,127.8,136.5,147.3,148.3.HRMS(MALDI):m/z276.9927.Calcd.for C₁₂H₉BrN₂O:276.9976[M+H]⁺.

II-2:

4-bromo-5-(1-ethyl-1H-indol-3-yl)oxazole(II-33b):Reagent,CH₃CH₂Br.Yield,99％.mp,68-70℃.IR(KBr)cm-1:539(C-Br),1122(C-O-C),1572(C＝N),3135(Ar-CH),3450(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.54(t,J＝7.2Hz,3H),4.25(q,J＝7.2Hz,2H),7.24(t,J＝7.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.41(d,J＝7.8Hz,1H),7.84(s,1H),7.89(s,1H),8.08(d,J＝7.8Hz,1H).¹³C NMR(100MHz,CDCl₃):δ15.3,41.5,102.5,106.8,109.7,120.8,121.1,122.7,126.2,127.5,136.7,147.6,148.3.HRMS(MALDI):m/z 291.0088.Calcd.forC₁₃H₁₁BrN₂O:291.0133[M+H]⁺.

II-3:

5-(1-allyl-1H-indol-3-yl)-4-bromooxazole:Reagent,3-bromoprop-1-ene.Yield,47％.mp,65-67℃.IR(KBr)cm^-1:538(C-Br),993(C＝C),1101(C-O-C),1573(C＝N),3130(Ar-CH),3444(Pyrrolyl-CH).1H NMR(600MHz,CDCl₃):δ4.81(d,J＝4.2Hz,2H),5.16(d,J＝16.2Hz,1H),5.28(d,J＝9.6Hz,1H),6.17–5.90(m,1H),7.24(t,J＝7.8Hz,1H),7.32(t,J＝7.2Hz,1H),7.38(d,J＝7.8Hz,1H),7.90(s,1H),7.83(s,1H),8.09(d,J＝7.8Hz,1H).¹³C NMR(100MHz,CDCl₃):δ49.1,102.5,107.6,110.0,117.9,120.9,121.0,122.8,125.2,126.8,132.4,135.9,145.5,148.3.HRMS(ESI):m/z 303.0149.Calcd.forC₁₄H₁₂BrN₂O:303.0133[M+H]⁺.

II-4:

4-bromo-5-(1-(3,3-dichloroallyl)-1H-indol-3-yl)oxazole:Reagent,1,1,3-trichloroprop-1-ene.Yield,43％.mp,95-97℃.IR(KBr)cm^-1:539(C-Br),1123(C-O-C),1571(C＝N),3110(Ar-CH),3441(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ4.94–4.93(d,J＝6.0Hz,1H),6.11–6.08(t,J＝6.6Hz,1H),7.28–7.30(t,J＝6.6Hz,1H),7.35–7.39(m,2H),7.81(s,1H),7.90(s,1H),8.08–8.10(d,J＝8.4Hz,2H).¹³C NMR(100MHz,CDCl₃):δ45.4,103.4,108.1,109.7,121.2,121.3,123.4,124.5,125.4,126.4,132.4,135.7,145.2,148.5.HRMS(MALDI):m/z 370.9328.Calcd.forC₁₄H₉BrCl₂N₂O:370.9354[M+H]⁺.

II-5:

1-(3-(4-bromooxazol-5-yl)-1H-indol-1-yl)ethanone:Reagent,CH3COCl.Yield,99％.mp,150-152℃.IR(KBr)cm^-1:540(C-Br),1109(C-O-C),1570(C＝N),1719(C＝O),3105(Ar-CH),3445(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ2.73(s,3H),7.40(t,J＝7.8Hz,1H),7.46(t,J＝7.8Hz,1H),7.97(s,1H),8.06(d,J＝7.8Hz,1H),8.14(s,1H),8.51(d,J＝8.4Hz,1H).¹³CNMR(100MHz,DMSO-d6):δ23.9,107.4,110.9,116.2,120.6,124.2,125.2,125.8,126.5,134.7,142.6,152.0,169.6.HRMS(MALDI):m/z304.9926.Calcd.C₁₃H₉BrN₂O₂:304.9926[M+H]⁺.

II-7:

4-bromo-5-(1-(ethylsulfonyl)-1H-indol-3-yl)oxazole:Reagent,CH₃CH₂SO₂Cl.Yield,54％.mp,132-135℃.IR(KBr)cm^-1:545(C-Br),1118(C-O-C),1363(-SO₂-),1572(C＝N),3140(Ar-CH),3446(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.28(t,J＝7.2Hz,3H),3.40(q,J＝7.2Hz,2H),7.40–7.43(t,J＝7.2Hz,1H),7.45–7.47(t,J＝7.2Hz,1H),7.97–7.98(m,2H),8.11(d,J＝7.8Hz,1H),8.14(s,1H).¹³C NMR(100MHz,DMSO-d6):δ7.8,48.5,107.3,111.1,113.3,121.3,124.1,124.9,125.8,126.4,134.3,142.2,152.0.HRMS(MALDI):m/z 354.9735.Calcd.C₁₃H₁₁BrN₂O₃S:354.9752[M+H]⁺.

II-8:

1-(3-(4-bromooxazol-5-yl)-1H-indol-1-yl)-2-chloroethanone:Reagent,ClCH₂COCl.Yield,62％.mp,98-100℃.IR(KBr)cm^-1:539(C-Br),1125(C-O-C),1571(C＝N),1731(C＝O),3138(Ar-CH),3444(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ4.66(s,2H),7.44(t,J＝7.2Hz,1H),7.50(t,J＝7.2Hz,1H),8.00(s,1H),8.07(d,J＝7.8Hz,1H),8.18(s,1H),8.51(d,J＝8.4Hz,1H).¹³CNMR(100MHz,DMSO-d6):δ42.3,107.5,110.6,111.9,116.8,121.2,122.2,125.2,126.8,128.5,135.5,149.8,164.1.HRMS(ESI):m/z338.9558.Calcd.C₁₃H₈BrClN₂O₂:338.9536[M+H]⁺.

II-9:

1-(3-(4-bromooxazol-5-yl)-1H-indol-1-yl)-2,2-dichloroethanone:Reagent,Cl₂CHCOCl.Yield,41％.mp,114-116℃.IR(KBr)cm^-1:540(C-Br),1147(C-O-C),1571(C＝N),1724(C＝O),3141(Ar-CH),3442(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ6.61(s,1H),7.46–7.47(t,J＝7.8Hz,1H),7.50–7.51(t,J＝7.8Hz,1H),7.91–7.92(d,J＝7.8Hz,1H),8.01(s,1H),8.07–8.08(d,J＝7.8Hz,1H),8.49(s,1H).¹³C NMR(100MHz,DMSO-d6):δ65.7,111.1,112.3,117.0,121.3,122.4,125.7,126.9,127.1,128.6,135.8,149.9,160.7.HRMS(MALDI):m/z 372.9133.Calcd.forC₁₃H₇BrCl₂N₂O₂:372.9146[M+H]⁺.

II-10:

1-(3-(4-bromooxazol-5-yl)-1H-indol-1-yl)-2-chloropropan-1-one:Reagent,CH₃CHClCOCl.Yield,55％.mp,143-145℃.IR(KBr)cm^-1:554(C-Br),1123(C-O-C),1572(C＝N),1704(C＝O),3124(Ar-CH),3444(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ1.91(d,J＝6.6Hz,3H),5.10(q,J＝6.6Hz,1H),7.43(t,J＝7.2Hz,1H),7.48–7.52(t,J＝7.2Hz,1H),7.99(s,1H),8.06(d,J＝8.4Hz,1H),8.30(s,1H),8.54(d,J＝8.4Hz,1H).¹³C NMR(100MHz,DMSO-d6):δ20.1,51.8,108.5,111.5,120.8,121.1,124.9,126.4,126.7,128.4,135.1,142.2,152.3,167.9.HRMS(MALDI):m/z 352.9699.Calcd.for C₁₄H₁₀BrClN₂O₂:352.9692[M+H]⁺.

II-11:

methyl 3-(4-bromooxazol-5-yl)-1H-indole-1-carboxylate:Reagent,CH₃OCOCl.Yield,72％.mp,149-151℃.IR(KBr)cm^-1:539(C-Br),1113(C-O-C),1571(C＝N),1740(-CO₂-),3127(Ar-CH),3445(Pyrrolyl-CH).¹H NMR(600MHz,CDCl₃):δ4.11(s,3H),7.37(t,J＝7.8Hz,1H),7.44(t,J＝7.8Hz,1H),7.95(s,1H),8.05(d,J＝7.2Hz,1H),8.26(d,J＝8.4Hz,1H),8.29(s,1H).¹³CNMR(100MHz,DMSO-d6):δ54.6,107.4,110.7,114.9,120.8,123.2,123.8,125.6,126.2,134.3,142.5,151.7,161.1.HRMS(MALDI):m/z320.9850.Calcd.for C₁₃H₉BrN₂O₃:320.9875[M+H]⁺.

II-12:

1-(3-(4-bromooxazol-5-yl)-1H-indol-1-yl)-2-methoxyethanone:Reagent,CH₃OCH₂COCl.Yield,63％.mp,101-103℃.IR(KBr)cm^-1:540(C-Br),1126(C-O-C),1572(C＝N),1717(C＝O),3128(Ar-CH)，3443(Pyrrolyl-CH).¹H NMR(600MHz，CDCl₃)：δ3.58(s，3H)，4.66(s，2H)，7.44(t，J＝7.2Hz，1H)，7.47(t，J＝7.2，1H)，7.98(s，1H)，8.05-8.06(d，J＝7.8Hz，1H)，8.27(s，1H)，8.54(d，J＝8.4Hz，1H).¹³C NMR(100MHz，DMSO-d6)：δ58.8，71.1，112.2，116.1，119.9，120.5，120.7，122.5，123.7，124.5，124.8，126.1，150.4，169.0.HRMS(MALDI)：m/z 335.0038.Calcd.C₁₄H₁₁BrN₂O₃：335.0031[M+H]⁺.

II-13：

ethyl 2-(3-(4-bromooxazol-5-yl)-1H-indol-l-yl)-2-oxoacetate：Reagent，CH₃CH₂OCOCOCl.Yield，74％.mp，116-118℃.IR(KBr)cm^-1：541(C-Br)，1115(C-O-C)，1572(C＝N)，1703(COCO)，3127(Ar-CH)，3444(Pyrrolyl-CH).¹H NMR(600MHz，DMSO-d6)：δ1.37-1.40(t，J＝7.2Hz，3H)，4.44-4.47(q，J＝7.2Hz，2H)，7.51-7.55(m，2H)，8.04-8.05(s，1H)，8.40(s，1H)，8.53(s，1H)，8.69-8.70(d，J＝7.8Hz，，1H).¹³C NMR(100MHz，DMSO-d6)：δ13.8，63.4，109.3，111.4，116.2，121.0，125.5，126.4，126.6，128.5，134.9，142.0，152.0，156.5，158.7.HRMS(MALDI)：m/z 362.9973.Calcd.for C₁₅H₁₁BrN₂O₄：362.9980[M+H]⁺.

example 3

The heating conditions in the reaction conditions are further optimized, part of compounds are heated by microwave assistance, and the target compounds can be obtained by microwave reaction for only 15 minutes by screening the conditions of reaction temperature, solvent, radiation intensity and the like. The obtained compounds are all subjected to¹H NMR，¹³Confirmation of C NMR, IR and HRMS.

1. Synthesis of Compound I-18:

after compound 5(X ═ Cl) was obtained by the synthetic route of example 1, microwave-assisted organic synthesis was carried out by sequentially adding microwave magnetons, compound 4(X ═ Cl) (0.20mmol) and anhydrous tetrahydrofuran (5 mL) (dry weight distillation) into a microwave reaction tube, stirring and dissolving, then adding sodium hydride (60%, 0.40mmol), adding a drying tube and reacting for 20min, then adding bromomethylcyclopropane (0.24mmol), closing the system and placing in a microwave reactor for reacting for 15min, wherein the reaction conditions were as follows: the temperature is 90 ℃, and the microwave radiation intensity is Normal. After the reaction is finished, pouring the reaction system into water, neutralizing the reaction system to be neutral by using dilute hydrochloric acid, extracting the reaction system for three times by using dichloromethane, washing an organic phase by using water and saturated saline solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain the product with the yield of 87%. mp, 91-93 ℃ and IR (KBr) cm-1: 634(C-Cl), 1117(C-O-C), 1571(C ═ N), 3138(Ar-CH), 3444(Pyrrolyl-CH).¹H NMR(600MHz，CDCl3)：δ0.43(d，J＝4.8Hz，2H)，0.69(d，J＝7.8Hz，2H)，1.34(m，1H)，4.05(d，J＝6.6Hz，2H)，7.24(m，1H)，7.31(t，J＝7.8Hz，1H)，7.42(d，J＝8.4Hz，1H)，7.88(s，1H)，7.94(s，1H)，8.08(d，J＝7.8Hz，1H).¹³C NMR(100MHz，CDCl₃)：δ4.2，11.1，51.0，102.2，107.5，109.9，120.8，121.0，122.7，125.2，126.6，137.6，136.0，148.3.HRMS(MALDI)：m/z 273.0819.Calcd.for C₁₅H₁₃ClN₂O：273.0795[M+H]⁺.

2. Synthesis of Compound II-15:

after compound 5(X ═ Br) was obtained by the synthetic route of example 1, microwave-assisted organic synthesis was performed by using a microwave reaction tube, and then microwave magnetons, compound 5(X ═ Br) (0.20mmol) and anhydrous tetrahydrofuran (4 mL) (dry weight distillation) were sequentially added, and after stirring and dissolution, sodium hydride (60%, 0.40mmol) was added, and after 30min of reaction in a drying tube, bromomethylcyclopropane (0.24mmol) was added, and after the system was sealed, the reaction was carried out in a microwave reactor for 15min under the following conditions: the temperature is 90 ℃, and the microwave radiation intensity is Normal. After the reaction is finished, pouring the reaction system into water, neutralizing the reaction system to be neutral by using dilute hydrochloric acid, extracting the reaction system for three times by using dichloromethane, washing an organic phase by using water and saturated saline solution in sequence, drying the organic phase by using anhydrous sodium sulfate, and carrying out silica gel column chromatography to obtain a product II-15, wherein the yield is 87% mp, and the yield is 78-80 ℃ IR (KBr) cm^-1：539(C-Br)，1109(C-O-C)，1572(C＝N)，3111(Ar-CH)，3454(Pyrrolyl-CH).¹H NMR(600MHz，CDCl₃)：δ 0.43(d，J＝7.2Hz，2H)，0.69(d，J＝7.2Hz，2H)，1.34(m，1H)，4.05(d，J＝6.6Hz，2H)，7.24(t，J＝6.6Hz，1H)，7.31(t，J＝7.2Hz，1H)，7.43(d，J＝7.2Hz，1H)，7.89(s，1H)，7.95(s，1H)，8.08(d，J＝7.2Hz，1H).¹³CNMR(100MHz，CDCl₃)：δ 4.0，4.1，11.0，51.0，102.5，107.8，109.8，120.8，121.0，122.7，125.7，126.6，136.2，148.3，150.4.HRMS(MALDI)：m/z 317.0249.Calcd.C₁₅H₁₃BrN₂O：317.0289[M+H]⁺.

Experimental example 4

Target Compound fungicidal Activity test

1. Method for testing bactericidal activity

A screening method for the bactericidal activity of the Pimpinine derivatives is established by adopting a 96-hole plate, and a leaf disc method is respectively selected to test potato late blight bacteria (Phytophthora infestans), wheat leaf blight bacteria (Septoria tritici) and broad bean single cell rust bacteria (Uromyces viciae-fabae); the activity of pythium (pythium distemile), tomato early blight (Alternaria solani), Botryostatin (Fuskeliana) and Gibberella tritici (Gibberella zeae) was tested by using a culture medium method. The inhibition rate of hypha growth and the inhibition rate of diseases after 4-14 days of drug administration were visually observed, the details of the activity are shown in Table B, and the inhibition activity was scored on three scales, 99 in the table means an inhibition rate of more than 80%, 55 in the table means an inhibition rate of 50-80%, 27 in the table means an inhibition rate of less than 50%, and 0 in the table means no inhibition effect. The inhibition rate is calculated by measuring the average value for three times or two times. The concentration of the test compound was 2ppm to 200 ppm.

2. Target Compound fungicidal Activity test results

(iii) Streptochlorin derivatives bactericidal Activity data

PHY, potato late blight (Phytophthora infestans); SEP, wheat leaf blight (septoriatiti); URO, broad bean rust disease (Uromyces viciae-fabae); PYT, pythium (pythium dissimile); LT, early blight of tomato (Alternaria solani); BOT, Botryotina viticola (Botryotina fuckeliana); GIB, Gibberella zeae (Gibberella zeae).

As shown in Table B, the next stage of bactericidal activity testing was performed for the primary medium method bactericidal test results with less activity. Although it is difficult to directly derive the apparent regularity from these activity data, we can draw some conclusions from it:

1. among all the compounds, in addition to the natural product streptochlorerin, the compounds I-8, I-9, I-10, I-13, streptochlorerin, II-8, II-9, II-12 and the like show high-efficiency and/or broad-spectrum bactericidal activity.

2. When the concentration is reduced to a low concentration, part of the compounds still show certain bactericidal activity, and the compounds have good application potential as new skeleton bactericidal active compounds.

3. All active compounds have different degrees of sensitivity to the activity of several strains to be tested, and generally have better activity to Pythium dispirile, Alternaria solani and botrytis cinerea.

4. From the activity contrast between the compound II-26 and the oxazole 4-chloro derivative II-30 and bromo derivative II-31, we can conclude that the introduction of halogen at the oxazole 4 position is beneficial to the improvement of bactericidal activity, and in general, the bromo derivative has slightly better bactericidal activity than the chloro derivative, and the activity relationship is: br is not less than Cl > H.

5. The substituents on the indole N atom differ greatly in their activity. The bactericidal activity is best when the antibacterial agent is replaced by naked NH or acyl such as chloracetyl, dichloroacetyl, methoxyacetyl, oxalyl monoethyl ester and the like; however, when the substituent is acetyl or propionyl, the bactericidal activity decreases; when an alkyl group (such as methyl, ethyl), cycloalkane (cyclopropane, propylene oxide), ethanesulfonyl, allyl, dichloropropenyl and substituted aryl are introduced on indole N, the activity decreases to different extents; when carbamate fragments with a wide range of biological activities were introduced, the activity also decreased to varying degrees. Namely, the activity relationship is as follows: h, ClCH₂CO，Cl₂CHCO，CH₃OCH₂CO，CH₃CH₂OCOCO＞CH₃，CH₃CH₂Cyclopropane, propylene oxide, allyl, dichloroallyl, CH₃CH₂SO₂，SO₂Ph＞CH₃CO，CH₃CH₂CO，CH₃OCO。

6. In the Streptochlorin derivatives, when halogen is substituted by Cl or Br, the bactericidal activity is highest; when the indole NH has no substituent or the substituent is chloroacetyl or oxalyl monoethyl ester, the bactericidal activity is highest.

Claims

1. The structural formula of the derivative of natural product Streptochlorin is shown as the formula (I):

the formula (I) is shown in the specification, wherein X is one of F, Cl or Br; r is respectively selected from H, C₁-C₂Alkyl of (C)₂-C₃Substituted or unsubstituted alkylene of (A), C₂-C₃Substituted or unsubstituted acyl, C₂-C₄And one of an ester group, an alkylene oxide group, a cycloalkyl group and a substituted phenyl group.

2. The derivative of the natural product Streptochlorin according to claim 1, wherein X is one of F, Cl or Br; r is CH₃、CH₃CH₂、CH₂＝CHCH₂、CCl2＝CHCH₂、CH₃CO、CH₃CH₂CO、CH₃CH₂SO₂、ClCH₂CO、Cl₂CHCO、CCl₃CO、CH₃CHClCO、CH₃OCO、CH₃OCH₂CO、CH₃CH₂OCOCH₂、CH₃CH₂OCOCO、2，4-di-F-C₆H₃CH₂、

One kind of (1).

3. The method for producing a natural product streptochlorerin derivative according to any one of claims 1-2, characterized by comprising the steps of:

wherein X is Cl or Br;

wherein X is Cl or Br; r is selected from H, C₁-C₂Alkyl of (C)₂-C₃Substituted or unsubstituted alkylene of (A), C₂-C₃Substituted or unsubstituted acyl, C₂-C₄And one of an ester group, an alkylene oxide group, a cycloalkyl group and a substituted phenyl group.

4. The method for preparing a derivative of natural product Streptochlorin according to claim 3, wherein the alkaline condition in step 1 is sodium hydroxide and the solvent is N, N-dimethylformamide.

5. The method for preparing a derivative of natural product Streptochlorin according to claim 3, wherein the alkaline condition in step 2) is sodium hydride, the solvent is tetrahydrofuran, and the reagent for benzene sulfonyl protection is benzene sulfonyl chloride.

6. The method for preparing a derivative of a natural product Streptochlorin according to claim 3, wherein the solvent in step 3) is tetrahydrofuran methanol 1: 1, and the resin is Ambersep p 900OH^-And (3) resin.

7. The method for preparing a derivative of a natural product Streptochlorin according to claim 3, wherein the solvent in the step 4) is tetrahydrofuran to carbon tetrachloride (1: 1).

8. The method for preparing a derivative of natural product Streptochlorin according to claim 3, wherein the base used in the alkaline condition in step 5) is sodium hydride, the solvent is tetrahydrofuran, and the temperature is 20-50 ℃; the mol ratio of the compound with the structure shown as the formula (V) to the compound with the general formula of RZ and the alkali is 1: 1-2.

9. Use of the natural product Streptochlorin and its derivatives according to any one of claims 1-2 for killing pathogenic bacteria of crops.

10. The use of claim 9, wherein the crop pathogenic bacteria are one or more of late blight of potato, leaf blight of wheat, rust of pseudomonas fabae, pythium, early blight of tomato, botrytis cinerea and gibberella zeae.