CN110627705B - N-benzyl indole thiosemicarbazone derivative, preparation and application - Google Patents
N-benzyl indole thiosemicarbazone derivative, preparation and application Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract
The invention discloses an N-benzyl indole thiosemicarbazone derivative, which has a general formula shown as the following formula:
wherein: n is 0 or 1; r1Is H, 5-CN, 6-CH3Or 7-CH3；R2Is H, benzyl chloride, 4-fluorobenzyl bromide, 4-chlorobenzyl chloride, 4-bromobenzyl bromide, 4-methylbenzyl chloride or 2-chlorobenzyl chloride. The inventionThe prepared N-benzyl indole thiosemicarbazone derivative has high activity in inhibiting plant pathogenic fungi, and has high-efficiency and low-toxicity bacteriostatic activity.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an N-benzyl indole thiosemicarbazone derivative, and preparation and application thereof.
Background
Indole is a benzopyrrole compound, and indole and its derivatives were first obtained by reducing isatin in 1866 by Adolf Von Baeyer. It is of great interest because of its biological activity and pharmacological properties in the fields of medicine and pesticides.
Indole and its derivatives have wide biological activities in anti-tumor, anti-HIV, anti-bacterial and anti-fungal fields in the existing literature, such as: the literature [ Huong T T, Van C L, Huong P T, Thao T P, Huong L, Dung P T, Nam N.2017. expansion of sodium indel-based hydroxamic acids as histone deacetylases inhibitors and inhibitors. chemical Papers,71(9):1-11 ] reports the antitumor activity of indole derivatives; the literature [ Wang Y, Huang N, Yu X, Yang L, Zhi X, Zheng Y, Xu H.2012.anti HIV-1agents 6.Synthesis and anti-HIV-1activity of indole glyoxamides. medicinal Chemistry,8(5): 831-; the literature [ Elsayed M T, Suzen S, Altanlar N, Ohlsen K, Hilgethon A, 2016.Discovery of biochemical-understated cyclic-alkylated antibodies as novel class of classes of antibacterial agents S.aureus and MRSA. biological & Medicinal Chemistry Letters,26(1): 218-.
However, the activity research of the N-benzyl indole thiosemicarbazone derivatives in the aspect of inhibiting plant pathogenic fungi is rarely reported, so that the synthesis of the N-benzyl indole thiosemicarbazone derivatives and the research of the N-benzyl indole thiosemicarbazone derivatives in the aspect of inhibiting the plant pathogenic fungi are valuable.
Disclosure of Invention
In view of the above deficiencies and drawbacks of the prior art, the present invention provides an N-benzyl indole thiosemicarbazone derivative, and a preparation method and an application thereof, which solve the technical problem that the prior art lacks a thiosemicarbazone derivative with antibacterial activity.
In order to achieve the purpose, the technical scheme is as follows: the general formula of the N-benzyl indole thiosemicarbazone derivative is shown as the following formula:
wherein: n is 0 or 1;
R1is H, 5-CN, 6-CH3Or 7-CH3；
R2Is H, benzyl chloride, 4-fluorobenzyl bromide, 4-chlorobenzyl chloride, 4-bromobenzyl bromide, 4-methylbenzyl chloride or 2-chlorobenzyl chloride.
The N-benzyl indole thiosemicarbazone derivative has one of the following structures:
(1)n＝0，R1＝H，R2＝H；
(2)n＝0，R1＝5-CN，R2＝H；
(3)n＝0，R1＝6-CH3，R2＝H；
(4)n＝0，R1＝7-CH3，R2＝H；
(5)n＝0，R1＝H，R2＝CH2-Bn；
(6)n＝0，R1＝H，R2＝CH2-(4-CH3)Bn；
(7)n＝0，R1＝H，R2＝CH2-(2-Cl)Bn；
(8)n＝0，R1＝H，R2＝CH2-(4-Cl)Bn；
(9)n＝0，R1＝H，R2＝CH2-(4-Br)Bn；
(10)n＝0，R1＝H，R2＝CH2-(4-F)Bn；
(11)n＝0，R1＝5-CN，R2＝CH2-Bn；
(12)n＝0，R1＝5-CN，R2＝CH2-(4-CH3)Bn；
(13)n＝0，R1＝5-CN，R2＝CH2-(2-Cl)Bn；
(14)n＝0，R1＝5-CN，R2＝CH2-(4-Cl)Bn；
(15)n＝0，R1＝5-CN，R2＝CH2-(4-Br)Bn；
(16)n＝0，R1＝5-CN，R2＝CH2-(4-F)Bn；
(17)n＝0，R1＝6-CH3，R2＝CH2-Bn；
(18)n＝0，R1＝6-CH3，R2＝CH2-(4-CH3)Bn；
(19)n＝0，R1＝6-CH3，R2＝CH2-(2-Cl)Bn；
(20)n＝0，R1＝6-CH3，R2＝CH2-(4-Cl)Bn；
(21)n＝0，R1＝6-CH3，R2＝CH2-(4-Br)Bn；
(22)n＝0，R1＝6-CH3，R2＝CH2-(4-F)Bn；
(23)n＝0，R1＝7-CH3，R2＝CH2-Bn；
(24)n＝0，R1＝7-CH3，R2＝CH2-(4-CH3)Bn；
(25)n＝0，R1＝7-CH3，R2＝CH2-(2-Cl)Bn；
(26)n＝0，R1＝7-CH3，R2＝CH2-(4-Cl)Bn；
(27)n＝0，R1＝7-CH3，R2＝CH2-(4-Br)Bn；
(28)n＝0，R1＝7-CH3，R2＝CH2-(4-F)Bn；
(29)n＝1，R1＝H，R2＝CH2-Bn；
(30)n＝1，R1＝H，R2＝CH2-(4-CH3)Bn；
(31)n＝1，R1＝H，R2＝CH2-(4-Cl)Bn；
(32)n＝1，R1＝H，R2＝CH2-(4-Br)Bn；
a preparation method of N-benzyl indole thiosemicarbazone derivatives comprises the following steps:
the method comprises the following steps: preparing 3-formyl substituted indole derivatives;
dissolving phosphorus oxychloride in a DMF solution, stirring and cooling the solution to about 0 ℃ in an ice bath, dissolving substituted indole in the DMF solution, adding the solution into the solution, naturally returning the solution to room temperature for reaction, and tracking and detecting by TLC; after the reaction is finished, adding ice water under the cooling of the ice water, adjusting the pH value to be 8-9 by using a 30% NaOH aqueous solution, carrying out reflux reaction, pouring the reaction solution into water, stirring until the reaction solution is solidified, and recrystallizing a filter cake by using methanol to obtain the 3-formyl substituted indole derivative;
step two: preparing N-benzyl-3-formyl indole derivatives;
dissolving 3-formyl substituted indole in redistilled dichloromethane, adding anhydrous potassium carbonate and a small amount of benzyltriethylammonium chloride, stirring at room temperature for 5-10min, adding substituted benzyl chloride or substituted benzyl bromide into the solution, stirring at room temperature for reaction, performing TLC tracking detection, filtering potassium carbonate after the reaction is finished, performing reduced pressure concentration on the filtrate, and performing column chromatography separation to obtain an N-benzyl-3-formyl indole derivative;
step three: preparing N-benzyl-3-acryloyl indole derivatives;
dissolving NaH in redistilled tetrahydrofuran solution, sequentially adding trimethylphosphonoacetic acid ester and N-benzyl-3-formylindole compounds, continuously stirring for reaction, tracking and detecting by TLC, quenching reaction after the reaction is finished, performing column chromatography separation to obtain an intermediate 1, and taking AlCl3Dissolving in redistilled tetrahydrofuran solution, sequentially adding LiAlH4Reacting with the intermediate 1 obtained in the previous step under ice bath condition, tracking and detecting by TLC, quenching reaction after the reaction is finished, and performing column chromatographySeparating to obtain an intermediate 2, finally dissolving the intermediate 2 in a redistilled tetrahydrofuran solution, adding manganese dioxide, performing reflux reaction, performing TLC tracking detection, after the reaction is finished, cooling the reaction liquid to room temperature, performing suction filtration, leaching a filter cake with ethyl acetate, combining filtrates, concentrating, and performing silica gel column chromatography separation and purification on a crude product to obtain the N-benzyl-3-acryloyl indole derivative;
step four: preparing N-benzyl indole thiosemicarbazone derivatives;
dissolving thiosemicarbazide in an ethanol solution, dissolving a 3-acylindole compound in the ethanol solution, adding the solution to the solution, performing reflux reaction, tracking and detecting by TLC (thin layer chromatography), quickly placing the solution in ice water for cooling after the reaction is finished, performing suction filtration to obtain a crude product after solid is separated out, and recrystallizing the crude product by using ethanol to obtain the N-benzyl indole thiosemicarbazone derivative.
Specifically, the substituted indole in the first step is indole, 5-cyanoindole, 6-methylindole or 7-methylindole.
Specifically, the 3-formyl substituted indole in the second step is 3-formyl indole, 3-formyl-5-cyanoindole, 3-formyl-6-methylindole or 3-formyl-7-methylindole;
the substituted benzyl chloride or benzyl bromide is benzyl chloride, 4-fluorobenzyl bromide, 4-chlorobenzyl chloride, 4-bromobenzyl bromide, 4-methylbenzyl chloride or 2-chlorobenzyl chloride.
Specifically, the N-benzyl-3-formylindole compound in the third step is N-benzyl-3-formylindole, N-4-methylbenzyl-3-formylindole, N-4-chlorobenzyl-3-formylindole or N-4-bromobenzyl-3-formylindole.
Specifically, the 3-formyl indole compounds in the fourth step are 3-formyl substituted indole, N-benzyl-3-formyl substituted indole and N-benzyl-3-acryloyl indole.
The N-benzyl indole thiosemicarbazone derivative is applied as a bactericide.
The N-benzyl indole thiosemicarbazone derivative prepared by the preparation method of the N-benzyl indole thiosemicarbazone derivative is applied as a bactericide.
Compared with the prior art, the invention has the beneficial technical effects that:
the N-benzyl indole thiosemicarbazone derivative prepared by the invention has higher activity in the aspect of inhibiting plant pathogenic fungi, and has high-efficiency and low-toxicity bacteriostatic activity.
The preparation method of the invention has simple process and low cost.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 6;
FIG. 2 is a hydrogen spectrum of Compound 28;
FIG. 3 is a hydrogen spectrum of Compound 30;
FIG. 4 is an infrared spectrum of Compound 6;
FIG. 5 is an infrared spectrum of Compound 28;
fig. 6 is an infrared spectrum of compound 30.
The details of the present invention are explained in further detail below with reference to the drawings and examples.
Detailed Description
The following embodiments of the present invention are provided, and it should be noted that the present invention is not limited to the following embodiments, and all equivalent changes based on the technical solutions of the present invention are within the protection scope of the present invention.
Example 1:
preparation of N-benzyl indole thiosemicarbazone derivatives:
the method comprises the following steps: preparing 3-formyl substituted indole derivatives;
adding 0.5mL of DMDMMF into a 50mL flask, cooling to 0-5 ℃, dropwise adding phosphorus oxychloride (1 equivalent), continuously stirring at 0-5 ℃ for 20min after dropwise adding, weighing substituted indole (1 equivalent), dissolving in 1mL of DMMF, slowly dropwise adding into the reaction system, naturally returning to room temperature for reaction, and tracking and detecting by TLC; after the reaction is finished, adding a small amount of ice water under the cooling of the ice water, adjusting the pH value to be 8-9 by using a 30% NaOH aqueous solution, and carrying out reflux reaction for 2 hours. Pouring the reaction liquid into water, stirring until solidification, and recrystallizing a filter cake by using methanol to obtain the 3-formyl substituted indole derivative.
The substituted indole is indole, 5-cyanoindole, 6-methylindole or 7-methylindole.
The synthetic route is as follows:
step two: preparing N-benzyl-3-formyl indole derivatives;
adding 3-formyl substituted indole (1 equivalent) into a 50mL round-bottom flask, dissolving the 3-formyl substituted indole with 10mL redistilled dichloromethane, sequentially adding anhydrous potassium carbonate (2 equivalents) and TEBA (0.1 equivalent), stirring at room temperature for 5-10min, slowly dropping substituted benzyl chloride or substituted benzyl bromide (2 equivalents) into the reaction system, stirring at room temperature for reaction, and tracking and detecting by TLC; after the reaction is finished, filtering anhydrous potassium carbonate, and concentrating the filtrate under reduced pressure; and (3) separating and purifying by adopting column chromatography to obtain the N-benzyl-3-formyl indole derivative.
The substituted benzyl chloride or the substituted benzyl bromide is one of benzyl chloride, 4-fluorobenzyl bromide, 4-chlorobenzyl chloride, 4-bromobenzyl bromide, 4-methylbenzyl chloride and 2-chlorobenzyl chloride, and the 3-formyl substituted indole is respectively 3-formyl indole, 3-formyl-5-cyanoindole, 3-formyl-6-methylindole or 3-formyl-7-methylindole.
The following synthetic route of the N-benzyl-3-formyl indole derivative is as follows:
step three: preparing N-benzyl-3-acryloyl indole derivatives;
adding 10mL of redistilled tetrahydrofuran into a 50mL round-bottom flask, cooling to 0 ℃, then slowly adding NaH (2 equivalents), slowly adding trimethylphosphonoacetate (1.2 equivalents) into the reaction system, then dissolving N-benzyl-3-formylindole compound (1 equivalent) into 2mL redistilled tetrahydrofuran, slowly adding the N-benzyl-3-formylindole compound into the reaction system, continuing stirring for reaction, and tracking and detecting by TLC; after the reaction is finished, saturated NH is used at 0 DEG C4Cl quench the reaction and add the appropriate amountExtracting water with ethyl acetate, drying with anhydrous sodium sulfate, mixing organic phases, separating by column chromatography to obtain intermediate 1, dissolving in 10mL anhydrous tetrahydrofuran, cooling in ice bath, and sequentially adding anhydrous AlCl3(1 eq.), LiAlH4(2 equivalents), the reaction is carried out under ice-bath conditions, TLC tracking detection is carried out until the raw materials completely react, and the reaction is stopped. Dropwise adding ice water to carry out quenching reaction, carrying out suction filtration, leaching a filter cake with ethyl acetate for several times, combining filtrates, concentrating, carrying out column chromatography separation on a crude product to obtain an intermediate 2, dissolving in a redistilled tetrahydrofuran solution, adding manganese dioxide (2 equivalents), carrying out reflux reaction, carrying out TLC (thin layer chromatography) tracking detection reaction, cooling a reaction solution to room temperature, carrying out suction filtration, leaching a filter cake with ethyl acetate for several times, combining filtrates, concentrating, and carrying out column chromatography separation on the crude product to obtain the N-benzyl-3-acryloyl indole derivative.
The N-benzyl-3-formylindole compound is N-benzyl-3-formylindole, N-4-methylbenzyl-3-formylindole, N-4-chlorobenzyl-3-formylindole or N-4-bromobenzyl-3-formylindole.
The following synthetic route of the N-benzyl-3-acryloyl indole derivative is as follows:
step four: preparing N-benzyl indole thiosemicarbazone derivatives;
weighing thiosemicarbazide (1 equivalent) into a 50mL round-bottom flask, adding 2-3 mL of absolute ethyl alcohol, heating, stirring and dissolving, then dissolving N-benzyl-3-formylindole or N-benzyl-3-acryloyl indole compounds (1 equivalent) into a small amount of ethyl alcohol, slowly dripping into the reaction liquid, carrying out oil bath reflux reaction, after TLC tracking detection reaction is finished, withdrawing from the oil bath, rapidly placing in ice water for cooling, after solid is separated out, carrying out suction filtration to obtain a crude product, and recrystallizing with ethyl alcohol to obtain the N-benzyl indole thiosemicarbazone derivative.
The following synthetic routes of the N-benzyl indole thiosemicarbazone derivatives are as follows:
the physicochemical properties of compound 1 are as follows:
1) white solid, melting point 227-229 ℃, yield 74%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.58(s,1H,H-1),11.16(s,1H,-NH-),8.29(s,1H,-CH＝N-),8.21 (d,J＝8.0Hz,1H,H-4),8.00(s,1H,-NH2),7.80(d,J＝3.0Hz,1H,H-2), 7.39-7.42(m,2H),7.20(t,J＝7.5Hz,1H,H-6),7.13(t,J＝7.5Hz,1H,H-5).
the physicochemical properties of compound 2 are as follows:
1) a white solid with a melting point of 286-288 ℃ and a yield of 81%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:12.08(s,1H,H-1),11.18(s,1H,-NH-),8.78(s,1H,-CH＝N-),8.30 (s,1H,H-4),8.03(s,1H,-NH2),8.00(d,J＝2.5Hz,1H,H-2),7.83(s,1H,-NH2), 7.59(d,J＝8.5Hz,1H,H-7),7.55(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6).
the physicochemical properties of compound 3 are as follows:
1) a light yellow solid, the melting point of which is 208-209 ℃, and the yield of which is 77%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.43(s,1H,H-1),11.13(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.07 (d,J＝8.0Hz,1H,H-4),7.98(s,1H,-NH2),7.71(d,J＝2.5Hz,1H,H-2),7.36(s, 1H,-NH2),7.20(s,1H,H-7),6.69(d,J＝8.0Hz,1H,H-5),2.40(s,3H,6-CH3).
the physicochemical properties of compound 4 are as follows:
1) yellow solid, melting point of 215-216 ℃, yield of 78%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.58(s,1H,H-1),11.17(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.03 (d,J＝7.5Hz,1H,H-4),7.99(s,1H,-NH2),7.81(d,J＝2.5Hz,1H,H-2),7.37(s, 1H,-NH2),7.05(t,J＝7.5Hz,1H,H-5),6.99(d,J＝7.0Hz,1H,H-6),2.47(s,3H, 7-CH3).
the physicochemical properties of compound 5 are as follows:
1) a light yellow solid with a melting point of 193-194 ℃ and a yield of 83%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.17(s,1H,-NH-),8.29(s,1H,-CH＝N-),8.25(d,J＝8.0Hz,1H, H-4),8.02(s,1H,-NH2),7.99(s,1H,H-2),7.50(d,J＝8.5Hz,1H,H-7),7.42(s, 1H),7.30-7.33(m,2H,Ar-H),7.24-7.26(m,3H,Ar-H),7.22(t,J＝7.5Hz,1H, H-6),7.16(t,J＝8.0Hz,1H,H-5),5.44(s,2H,-CH2-).
the physicochemical properties of compound 6 are as follows:
1) a light yellow solid, the melting point of which is 211-212 ℃, and the yield of which is 80%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows: IR cm-1(KBr):3482, 3408,3047,1600,1461,1382,744,710；1H NMR(500MHz,DMSO-d6)δ:11.16 (s,1H,-NH-),8.28(s,1H,-CH＝N-),8.24(d,J＝7.5Hz,1H,H-4),8.01(s,1H, -NH2),7.96(s,1H,H-2),7.49(d,J＝8.5Hz,1H,H-7),7.41(s,1H,-NH2),7.21(t, J＝7.0Hz,1H,H-6),7.10-7.17(m,5H,Ar-H),5.37(s,2H,-CH2-),2.23(s,3H, CH3).
The physicochemical properties of compound 7 are as follows:
1) a light yellow solid, the melting point of which is 206-207 ℃, and the yield of which is 78%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.18(s,1H,-NH-),8.27-8.29(m,2H),8.04(s,1H,-NH2),7.89(s, 1H,H-2),7.52(d,J＝7.5Hz,1H,Ar-H),7.44(d,J＝8.0Hz,2H),7.34(t,J＝7.5 Hz,1H,Ar-H),7.20-7.26(m,2H,Ar-H),7.19(t,J＝7.0Hz,1H,H-5),6.82(d,J＝ 7.0Hz,1H,Ar-H),5.54(s,2H,-CH2-).
the physicochemical properties of compound 8 are as follows:
1) white solid, melting point 204-205 ℃, yield 78%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.18(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.26(d,J＝8.0Hz,1H, H-4),8.03(s,1H,-NH2),7.99(s,1H,H-2),7.49(d,J＝8.0Hz,1H,H-7),7.43(s, 1H,-NH2),7.39(d,J＝8.0Hz,2H,Ar-H),7.28(d,J＝8.5Hz,2H,Ar-H),7.22(t,J ＝7.0Hz,1H,H-6),7.16(t,J＝7.5Hz,1H,H-5),5.44(s,2H,-CH2-).
the physicochemical properties of compound 9 are as follows:
1) white solid, melting point 202-203 ℃, yield 82%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.17(s,1H,-NH-),8.29(s,1H,-CH＝N-),8.25(d,J＝7.5Hz,1H, H-4),8.02(s,1H,-NH2),7.98(s,1H,H-2),7.52(d,J＝8.5Hz,2H,Ar-H),7.48(d, J＝8.0Hz,1H,H-7),7.42(s,1H,-NH2),7.19-7.22(m,3H,Ar-H),7.16(t,J＝7.5 Hz,1H,H-5),5.42(s,2H,-CH2-).
the physicochemical properties of compound 10 are as follows:
1) white solid, melting point 207-208 ℃, yield 79%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.17(s,1H,-NH-),8.29(s,1H,-CH＝N-),8.25(d,J＝8.0Hz,1H, H-4),8.02(s,1H,-NH2),7.99(s,1H,H-2),7.52(d,J＝8.0Hz,1H,H-7),7.42(s, 1H,-NH2),7.31-7.34(m,2H,Ar-H),7.23(t,J＝7.0Hz,1H,H-6),7.13-7.16(m, 3H,Ar-H),5.42(s,2H,-CH2-).
the physicochemical properties of compound 11 are as follows:
1) white solid with melting point of 237-238 ℃ and yield of 81%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.19(s,1H,-NH-),8.81(s,1H,-CH＝N-),8.30(s,1H,H-4),8.18 (s,1H,H-2),8.06(s,1H,-NH2),7.87(s,1H,-NH2),7.73(d,J＝8.5Hz,1H,H-7), 7.58(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6),7.31-7.34(m,2H,Ar-H),7.26-7.28(m, 3H,Ar-H),5.50(s,2H,-CH2-).
the physicochemical properties of compound 12 are as follows:
1) white solid with melting point of 238-239 ℃ and yield of 90%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.18(s,1H,-NH-),8.80(s,1H,-CH＝N-),8.28(s,1H,H-4),8.15 (s,1H,H-2),8.05(s,1H,-NH2),7.85(s,1H,-NH2),7.71(d,J＝8.5Hz,1H,H-7), 7.57(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6),7.18(d,J＝8.0Hz,2H,Ar-H),7.13(d,J ＝8.0Hz,2H,Ar-H),5.44(s,2H,-CH2-),2.24(s,3H,CH3).
the physicochemical properties of compound 13 are as follows:
1) a light green solid with a melting point of 243-244 ℃ and a yield of 85 percent;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and each peak isThe attribution is as follows:1H NMR(500MHz, DMSO-d6)δ:11.19(s,1H,-NH-),8.84(s,1H,-CH＝N-),8.28(s,1H,H-4),8.07 (s,1H,-NH2),8.05(s,1H,H-2),7.87(s,1H,-NH2),7.67(d,J＝8.5Hz,1H,H-7), 7.60(dd,J＝1.5Hz,J＝8.5Hz,1H,H-6),7.53(d,J＝8.0Hz,1H,Ar-H),7.36(t,J ＝7.5Hz,1H,Ar-H),7.28(t,J＝7.5Hz,1H,Ar-H),6.86(d,J＝7.0Hz,1H,Ar-H), 5.60(s,2H,-CH2-).
the physicochemical properties of compound 14 are as follows:
1) white solid with melting point of 238-239 ℃ and yield of 87%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.19(s,1H,-NH-),8.81(s,1H,-CH＝N-),8.29(s,1H,H-4),8.18 (s,1H,H-2),8.06(s,1H,-NH2),7.86(s,1H,-NH2),7.72(d,J＝9.0Hz,1H,H-7), 7.59(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6),7.40(d,J＝8.5Hz,2H,Ar-H),7.29(d,J ＝8.0Hz,2H,Ar-H),5.51(s,2H,-CH2-).
the physicochemical properties of compound 15 are as follows:
1) white solid, melting point 236-237 ℃, yield 84%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.19(s,1H,-NH-),8.81(s,1H,-CH＝N-),8.29(s,1H,H-4),8.18 (s,1H,H-2),8.06(s,1H,-NH2),7.86(s,1H,-NH2),7.71(d,J＝8.5Hz,1H,H-7), 7.59(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6),7.53(d,J＝8.5Hz,2H,Ar-H),7.23(d,J ＝8.5Hz,2H,Ar-H),5.49(s,2H,-CH2-).
the physicochemical properties of compound 16 are as follows:
1) white solid, melting point 241-243 ℃, yield 86%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.19(s,1H,-NH-),8.81(s,1H,-CH＝N-),8.29(s,1H,H-4),8.18 (s,1H,H-2),8.06(s,1H,-NH2),7.86(s,1H,-NH2),7.75(d,J＝8.5Hz,1H,H-7), 7.59(dd,J＝1.0Hz,J＝8.5Hz,1H,H-6),7.33-7.36(m,2H,Ar-H),7.18(t,J＝8.5 Hz,2H,Ar-H),5.49(s,2H,-CH2-).
the physicochemical properties of compound 17 are as follows:
1) white solid, melting point 223-224 ℃, yield 87%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.15(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.12(d,J＝8.0Hz,1H, H-4),8.01(s,1H,-NH2),7.88(s,1H,H-2),7.40(s,1H,-NH2),7.29-7.33(m,3H, Ar-H),7.22-7.27(m,3H,Ar-H),6.99(d,J＝8.0Hz,1H,H-5),5.39(s,2H,-CH2-), 2.38(s,3H,CH3).
the physicochemical properties of compound 18 are as follows:
1) white solid with a melting point of 222-224 ℃ and a yield of 88%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.14(s,1H,-NH-),8.25(s,1H,-CH＝N-),8.10(d,J＝8.0Hz,1H, H-4),8.00(s,1H,-NH2),7.85(s,1H,H-2),7.39(s,1H,-NH2),7.28(s,1H,H-7), 7.10-7.14(m,4H,Ar-H),6.98(d,J＝8.0Hz,1H,H-5),5.33(s,2H,-CH2-),2.38(s, 3H,6-CH3),2.24(s,3H,CH3).
the physicochemical properties of compound 19 are as follows:
1) white solid, melting point of 216-217 ℃, yield of 90%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.16(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.16(d,J＝8.5Hz,1H, H-4),8.02(s,1H,-NH2),7.79(s,1H,H-2),7.53(d,J＝7.5Hz,1H,Ar-H),7.42(s, 1H,-NH2),7.34(t,J＝8.5Hz,1H,Ar-H),7.23-7.25(m,2H,Ar-H),7.02(d,J＝8.0 Hz,1H,H-5),6.74(d,J＝7.0Hz,1H,Ar-H),5.49(s,2H,-CH2-),2.38(s,3H, 6-CH3).
the physicochemical properties of compound 20 are as follows:
1) a light pink solid with a melting point of 214-216 ℃ and a yield of 81%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.15(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.12(d,J＝8.5Hz,1H, H-4),8.01(s,1H,-NH2),7.89(s,1H,H-2),7.37-7.40(m,3H),7.28(s,1H,H-7), 7.25(d,J＝8.5Hz,2H,Ar-H),6.99(d,J＝8.0Hz,1H,H-5),5.40(s,2H,-CH2-), 2.38(s,3H,6-CH3).
the physicochemical properties of compound 21 are characterized as follows:
1) white solid, melting point 225-226 ℃, yield 91%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.14(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.11(d,J＝8.0Hz,1H, H-4),7.99(s,1H,-NH2),7.88(s,1H,H-2),7.52(d,J＝8.5Hz,2H,Ar-H),7.39(s, 1H,-NH2),7.27(s,1H,H-7),7.18(d,J＝8.5Hz,2H,Ar-H),6.99(d,J＝8.0Hz, 1H,H-5),5.38(s,2H,-CH2-),2.38(s,3H,6-CH3).
the physicochemical properties of compound 22 are as follows:
1) white solid, melting point 220-222 ℃, yield 86%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.14(s,1H,-NH-),8.26(s,1H,-CH＝N-),8.11(d,J＝8.5Hz,1H, H-4),7.99(s,1H,-NH2),7.88(s,1H,H-2),7.39(s,1H,-NH2),7.28-7.31(m,3H, Ar-H),7.16(t,J＝9.0Hz,2H,Ar-H),6.99(d,J＝8.0Hz,1H,H-5),5.38(s,2H, -CH2-),2.39(s,3H,6-CH3).
the physicochemical properties of compound 23 are as follows:
1) white solid, melting point 206-208 ℃, yield 75%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.17(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.14(d,J＝7.5Hz,1H, H-4),8.02(s,1H,-NH2),7.90(s,1H,H-2),7.41(s,1H,-NH2),7.32(t,J＝7.5Hz, 2H,Ar-H),7.25(t,J＝7.0Hz,1H,Ar-H),7.05(t,J＝7.5Hz,1H,H-5),6.92(d,J＝ 7.0Hz,3H,Ar-H),5.66(s,2H,-CH2-),2.43(s,3H,7-CH3).
the physicochemical properties of compound 24 are as follows:
1) white solid, the melting point is 214-215 ℃, and the yield is 84%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.17(s,1H,-NH-),8.29(s,1H,-CH＝N-),8.13(d,J＝7.5Hz,1H, H-4),8.02(s,1H,-NH2),7.88(s,1H,H-2),7.41(s,1H,-NH2),7.11(d,J＝8.0Hz, 2H,Ar-H),7.05(t,J＝7.0Hz,1H,H-5),6.91(d,J＝7.0Hz,1H,H-6),6.81(d,J＝ 7.5Hz,2H,Ar-H),5.60(s,2H,-CH2-),2.44(s,3H,6-CH3),2.24(s,3H,CH3).
the physicochemical properties of compound 25 are as follows:
1) white solid, the melting point of which is 263-265 ℃, and the yield of which is 82%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.18(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.18(d,J＝7.5Hz,1H, H-4),8.04(s,1H,-NH2),7.88(s,1H,H-2),7.55(d,J＝7.5Hz,1H,Ar-H),7.43(s, 1H,-NH2),7.32(t,J＝7.5Hz,1H,Ar-H),7.20(t,J＝7.5Hz,1H,Ar-H),7.08(t,J ＝7.5Hz,1H,H-5),6.93(d,J＝7.0Hz,1H,H-6),6.22(d,J＝7.5Hz,1H,Ar-H), 5.71(s,2H,-CH2-),2.34(s,3H,7-CH3).
the physicochemical properties of compound 26 are as follows:
1) white solid, melting point 209-210 ℃, yield 84%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.16(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.13(d,J＝8.0Hz,1H, H-4),8.01(s,1H,-NH2),7.89(s,1H,H-2),7.36-7.40(m,3H),7.06(t,J＝7.5Hz, 1H,H-5),6.91-6.94(m,3H,Ar-H),5.65(s,2H,-CH2-),2.42(s,3H,7-CH3).
the physicochemical properties of compound 27 are as follows:
1) white solid, the melting point is 201-203 ℃, and the yield is 85%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.16(s,1H,-NH-),8.30(s,1H,-CH＝N-),8.14(d,J＝7.5Hz,1H, H-4),8.01(s,1H,-NH2),7.89(s,1H,H-2),7.52(d,J＝8.5Hz,2H,Ar-H),7.41(s, 1H,-NH2),7.06(t,J＝7.5Hz,1H,H-5),6.93(d,J＝7.5Hz,1H,H-6),6.87(d,J＝ 8.5Hz,2H,Ar-H),5.63(s,2H,-CH2-),2.42(s,3H,7-CH3).
the physicochemical properties of compound 28 are as follows:
1) a light green solid, the melting point is 207-208 ℃, and the yield is 83%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows: IR cm-1(KBr):3428, 3338,3049,1620,749,698；1H NMR(500MHz,DMSO-d6)δ:11.17(s,1H, -NH-),8.30(s,1H,-CH＝N-),8.14(d,J＝8.0Hz,1H,H-4),8.02(s,1H,-NH2), 7.89(s,1H,H-2),7.41(s,1H,-NH2),7.16(t,J＝9.0Hz,2H,Ar-H),7.06(t,J＝7.5 Hz,1H,H-5),6.94-6.97(m,2H,Ar-H),6.93(d,J＝7.5Hz,1H,H-6),5.64(s,2H, -CH2-),2.44(s,3H,7-CH3).
The physicochemical properties of compound 29 are as follows:
1) pale yellow solid, yield 38%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.22(s,1H,-NH-),8.01(s,1H),7.89-7.90(m,2H),7.87(d,J＝ 8.0Hz,1H),7.53(d,J＝8.0Hz,2H),7.30-7.33(m,2H),7.24-7.27(m,3H), 7.16-7.20(m,3H),6.80(dd,J＝9.5Hz,J＝16.5Hz,1H),5.44(s,2H,-CH2-).
the physicochemical properties of compound 30 are as follows:
1) pale yellow solid, yield 30%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows: IR cm-1(KBr):3475, 3357,3014,1618,1452,1370,746,696；1H NMR(500MHz,DMSO-d6)δ: 11.23(s,1H,-NH-),8.03(s,1H,-NH2),7.90(d,J＝10.0Hz,2H),7.86(d,J＝7.5 Hz,1H),7.54(s,1H,-NH2),7.52(d,J＝8.0Hz,1H),7.18-7.21(m,2H),7.15-7.16 (m,3H),7.13(d,J＝8.0Hz,2H),6.79(dd,J＝9.5Hz,J＝16.0Hz,1H),5.38(s, 2H,-CH2-),2.24(s,3H,CH3).
The physicochemical properties of compound 31 are as follows:
1) yellow solid, yield 62%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.23(s,1H,-NH-),8.02(s,1H,-NH2),7.89-7.91(m,2H),7.87(d, J＝7.5Hz,1H),7.53(s,1H,-NH2),7.51(d,J＝8.0Hz,1H),7.39(d,J＝8.5Hz, 2H),7.27(d,J＝8.5Hz,2H),7.22(m,3H),6.80(dd,J＝9.5Hz,J＝16.0Hz,1H), 5.45(s,2H,-CH2-).
the physicochemical properties of compound 32 are as follows:
1) pale yellow solid, yield 65%;
2) the nuclear magnetic resonance spectrogram characteristics of the compound are as follows:
deuterated DMSO is used as a solvent, TMS is used as an internal standard, and the attribution of each peak is as follows:1H NMR(500MHz, DMSO-d6)δ:11.24(s,1H,-NH-),8.04(s,1H,-NH2),7.88-7.92(m,2H),7.87(d, J＝7.5Hz,1H),7.53-7.55(m,2H),7.51(d,J＝10.5Hz,2H),7.18-7.22(m,4H), 7.17(d,J＝7.5Hz,1H),6.80(dd,J＝9.0Hz,J＝16.0Hz,1H),5.43(s,2H,-CH2-).
example 2: bacteriostatic biological test experiment:
1. pathogenic bacteria to be tested: wheat scab (Fusarium graminearum Siehw), tomato Botrytis cinerea (Bortrytis cinerea Pers), tobacco brown spot (Alternariaalterna Fries), Curvularia zeae (Curvularia Walk), apple rot (Valsalami et Yamada), potato stem rot (Fusarium coerulatum Mart), from the institute of pesticide, northwest university of agriculture and forestry, science and technology.
2. Sample and reagent:
the samples were: 97% carbendazim original drug, 1-32 of the compound prepared in example 1, DMSO, acetone (solvent, ddokong chemical limited, analytical pure) and distilled water.
3. Determination of bacteriostatic activity of compound 1-32 under 100mg/mL
The operation method comprises the following steps:
weighing 1-32 (4.5mg) of a required compound in a sterilized test tube with a plug scale, adding 200mL of DMSO (dimethyl sulfoxide) in the test tube for dissolving, then adding acetone to a constant volume of 2mL, adding the prepared liquid medicine into 45mL of sterilized culture medium respectively, mixing uniformly, preparing 100mg/mL of toxic culture medium respectively, and taking acetone (the content of DMSO is 10%) as a blank control. Filling 15mL of culture medium tools in each dish into test tubes for constant volume, pouring the culture medium into the dishes respectively, treating 3 dishes each, cooling to prepare a flat culture medium, beating the cultured pathogen flat plate into a culture medium circular dish with hyphae along the edge by using a puncher with the inner diameter of 4mm, inversely and horizontally placing the hyphae circular dish on a corresponding medicine-containing culture medium by using an inoculation needle for aseptic manipulation, placing the culture dishes in a constant-temperature incubator at the temperature of 28 +/-1 ℃ for culture, investigating the expansion diameter of each treated bacterial dish after 96 hours, measuring the diameter of a bacterial colony by using a cross method, and recording and calculating the bacteriostasis rate of the compound according to the following formula.
TABLE 1 bacteriostatic activity of N-benzyl indole thiosemicarbazone derivatives 1-32 of the present invention
And (4) conclusion:
the result shows that the partial N-benzyl indole thiosemicarbazone derivatives (5-10) have higher bacteriostatic activity on apple rot germs, and the bacteriostatic activity of the partial derivatives (5-7) on corn curvularia and tobacco brown spot germs is higher than that of carbendazim.
Claims (4)
1. The N-benzyl indole thiosemicarbazone derivative is characterized by having a general formula shown as the following formula:
the N-benzyl indole thiosemicarbazone derivative has one of the following structures:
(29)n＝1，R1＝H，R2＝CH2-Ph；
(30)n＝1，R1＝H，R2＝CH2-(4-CH3)Ph；
(31)n＝1，R1＝H，R2＝CH2-(4-Cl)Ph；
(32)n＝1，R1＝H，R2＝CH2-(4-Br)Ph。
2.a process for the preparation of N-benzylindole thiosemicarbazone derivatives according to claim 1, comprising the steps of:
step C1: preparing N-benzyl-3-acryloyl indole derivatives;
dissolving NaH in redistilled tetrahydrofuran solution, sequentially adding trimethylphosphonoacetate and N-benzyl-3-formylindole, N-4-methylbenzyl-3-formylindole, N-4-chlorobenzyl-3-formylindole or N-4-bromobenzyl-3-formylindole, continuously stirring for reaction, tracking and detecting by TLC (thin layer chromatography), quenching the reaction after the reaction is finished, separating by column chromatography to obtain an intermediate 1, and taking A1Cl3Dissolving in redistilled tetrahydrofuran solution, sequentially adding LiAlH4Reacting with the intermediate 1 obtained in the previous step under ice bath conditions, performing TLC tracking detection, after the reaction is finished, quenching the reaction, performing column chromatography separation to obtain an intermediate 2, finally dissolving the intermediate 2 in a redistilled tetrahydrofuran solution, adding manganese dioxide, performing reflux reaction, performing TLC tracking detection, after the reaction is finished, cooling the reaction solution to room temperature, performing suction filtration, leaching a filter cake with ethyl acetate, combining the filtrate, concentrating, and performing silica gel column chromatography separation and purification on a crude product to obtain the N-benzyl-3-acryloyl indole derivative;
wherein, the intermediate 1 is
Intermediate 2 is
The N-benzyl-3-acryloyl indole derivative is
Step C2: preparing N-benzyl indole thiosemicarbazone derivatives;
dissolving thiosemicarbazide in an ethanol solution, dissolving the N-benzyl-3-acryloyl indole derivatives in the ethanol solution, adding the solution, performing reflux reaction, performing TLC (thin layer chromatography) tracking detection, quickly placing the solution in ice water for cooling after the reaction is finished, performing suction filtration to obtain a crude product after solid is separated out, and recrystallizing the crude product with ethanol to obtain the N-benzyl indole thiosemicarbazone derivatives.
3. Use of the N-benzylindol thiosemicarbazone derivative according to claim 1 for the preparation of fungicides.
4. The use of the N-benzylindole thiosemicarbazone derivatives prepared by the process for the preparation of N-benzylindole thiosemicarbazone derivatives as claimed in claim 2 for the preparation of fungicides.
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