CN114057738A - Synthesis method of chloroindole hydrazide - Google Patents
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Abstract
The invention relates to a synthesis method of chloroindole hydrazide, belonging to the technical field of pesticides. The preparation method comprises the following steps: (1) uniformly mixing a compound shown in a formula (I), a solvent I, acetonitrile and a catalyst I, and then adding a hydrogen source for reaction; after the reaction is finished, treating to obtain a compound shown in a formula (II); (2) mixing a compound shown in a formula (II), 4-chlorphenyl) methylene hydrazine, a solvent II and a catalyst II for reaction, and carrying out post-treatment after the reaction is finished to obtain chloroindole hydrazide; the invention provides a new synthetic route, which is characterized in that tryptophan or ester thereof is catalytically hydrogenated and cyclized with acetonitrile, and then reacted with (4-chlorphenyl) methylene hydrazine to obtain chloroindole hydrazide in two steps. Compared with the prior art, the preparation method has the advantages of short synthesis steps, high reaction yield, no use of reagents with high toxicity, strong corrosivity and strong irritation, and convenience for realizing industrial production.
Description
Technical Field
The invention relates to the technical field of pesticides, and particularly relates to a synthesis method of chloroindole hydrazide.
Background
The beta-carboline alkaloid is widely existed in natural products and fermentation products, has various biological activities, and is used as a lead compound in the fields of medicines and pesticides. The Wang Qingmin project group of south China university uses carboline alkaloid as a lead compound to synthesize and prepare a series of derivatives, and the tetrahydro carboline hydrazide compound is found to have better activity. The chlorine indole hydrazide is developed on the basis of the early work of the Wang Qingmin project group by the cooperation of Jingbo agricultural chemistry and the southern Kao university.
Chloroindole hydrazide, chinese name: n' - (4-chlorobenzylidene) -1-methyl-1,2,3,4-tetrahydro- β -carboline-3-carbohydrazide; english name: n' - (4-chlorobenzylidene) -1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carbohydrazide. Chloroindole hydrazides have two chiral carbons and a C ═ C double bond, four chiral isomers and a pair of cis and trans isomers, each of which is active. A paper J.Agric.food chem.2014,62, 9987-. Patent CN104744460B discloses a plurality of synthetic routes, which can use one or more of toxic, harmful, corrosive, irritating, flammable and explosive hazardous chemicals such as aldehyde, sulfuric acid, acyl chloride, thionyl chloride, hydrazine hydrate, lithium aluminum hydride, sodium borohydride and the like, and also has the problems of long steps, low yield and difficult industrial scale-up production.
Disclosure of Invention
Aiming at the defects of long synthesis route of the chloroindole hydrazide, high toxicity, strong corrosivity, strong irritation and the like of a used reagent in the prior art, the invention provides a synthesis method of the chloroindole hydrazide to solve the problems.
The technical scheme of the invention is as follows:
a synthetic method of chloroindole hydrazide comprises the following synthetic route:
wherein R is H or C1～C4Alkyl groups of (a);
the preparation method comprises the following steps:
(1) uniformly mixing a compound shown in a formula (I), a solvent I, acetonitrile and a catalyst I, adding a hydrogen source, and starting to react; after the reaction is finished, treating to obtain a compound shown in a formula (II);
(2) mixing a compound shown in a formula (II), 4-chlorphenyl) methylene hydrazine, a solvent II and a catalyst II for reaction, and carrying out post-treatment after the reaction is finished to obtain chloroindole hydrazide;
or mixing the compound of the formula (II), the (4-chlorphenyl) methylene hydrazine, the solvent II and the condensing agent for reaction, and carrying out post-treatment after the reaction is finished to obtain the chloroindole hydrazide.
Preferably, in the step (1), the feeding molar ratio of the compound of the formula (I) to acetonitrile is 1: 1-100.
Preferably, in the step (1), the catalyst I is selected from palladium-based, platinum-based and nickel-based catalysts.
Preferably, in the step (1), the catalyst I is selected from palladium carbon and platinum carbon.
Preferably, in the step (1), the hydrogen source is selected from hydrogen gas or formic acid.
Preferably, in the step (1), the solvent i is at least one selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid and caproic acid.
Preferably, in the step (1), the solvent I is at least one selected from formic acid, acetic acid and propionic acid.
Preferably, in the step (1), the amount of the solvent I is 1-40 ml/g based on the weight of the compound of the formula (I).
Preferably, in the step (2), the feeding molar ratio of the compound of the formula (II) to the (4-chlorophenyl) methylene hydrazine is 1: 0.9-1.5.
Preferably, in the step (2), the condensing agent is selected from DCC, DIC, EDCI, HATU, HBTU, TATU, SOCl2、POCl3Or PCl5。
Preferably, in the step (2), the catalyst II is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium isopropoxide, potassium isopropoxide, sodium butoxide, potassium butoxide, sodium isobutoxide, potassium tert-butoxide, methyllithium, ethyllithium, propyllithium, isopropyllithium, butyllithium, isobutyllithium, tert-butyllithium or lithium diisopropylamide.
Preferably, in the step (2), the catalyst II is selected from sodium hydride, sodium methoxide, sodium ethoxide or potassium ethoxide.
Preferably, in the step (2), the solvent II is at least one selected from N, N-dimethylformamide, N-dimethylacetamide, acetonitrile, propionitrile, toluene, ethylbenzene, xylene, dichloromethane, dichloroethane, chloroform, chlorobenzene, methanol, ethanol, propanol, isopropanol, butanol, isobutanol and sec-butanol.
Preferably, in the step (2), the solvent II is at least one selected from methanol, ethanol, toluene and N, N-dimethylformamide.
Preferably, the solvent II is used in an amount of 3 to 30ml/g based on the weight of the compound of formula (II).
The invention has the beneficial effects that:
the invention provides a new synthetic route, which is characterized in that tryptophan or ester thereof is catalytically hydrogenated and cyclized with acetonitrile, and then reacted with (4-chlorphenyl) methylene hydrazine to obtain chloroindole hydrazide in two steps. Compared with the prior art, the preparation method has the advantages of short synthesis steps, high reaction yield, no use of reagents with high toxicity, strong corrosivity and strong irritation, and convenience for realizing industrial production.
Drawings
In order to more clearly illustrate the embodiments or technical solutions in the prior art of the present invention, the drawings used in the description of the embodiments or prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained based on these drawings without creative efforts.
FIG. 1 is an HPLC chromatogram of methyl 1-methyl-1,2,3,4-tetrahydro- β -carboline-3-carboxylate prepared in example 1 of the present invention.
FIG. 2 is a chiral HPLC chromatogram of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid methyl ester prepared in example 1 of the present invention.
FIG. 3 is a MS spectrum of 1-methyl-1,2,3,4-tetrahydro- β -carboline-3-carboxylic acid methyl ester prepared in example 1 of the present invention.
FIG. 4 shows the preparation of methyl 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylate prepared in example 1 of the present invention1HNMR spectrogram.
FIG. 5 is an HPLC chromatogram of chloroindole hydrazide prepared in example 1 of the present invention.
FIG. 6 is a chiral HPLC chromatogram of chloroindole hydrazide prepared in example 1 of the present invention.
FIG. 7 is a MS spectrum of chloroindole hydrazide prepared in example 1 of the present invention.
FIG. 8 is a graphic representation of chloroindole hydrazide prepared according to example 1 of the present invention1HNMR spectrogram.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the technical solution in the embodiment of the present invention will be clearly and completely described below with reference to the drawings in the embodiment of the present invention, and it is obvious that the described embodiment is only a part of the embodiment of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Synthesis of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-methyl formate
21.8g (0.10mol,1.0eq) of tryptophan methyl ester was dissolved in 200mL of glacial acetic acid, and then 6.2g (0.15mol,1.5eq) of acetonitrile and 1.1g of 10% palladium on carbon were added, and nitrogen gas was introduced to replace air for 3 times, hydrogen gas was further introduced to replace air for 3 times, and hydrogen gas was introduced at room temperature to react for 12 hours. Filtering to remove the catalyst, decompressing and evaporating the solvent, adding 200mL of water, adjusting the pH value to be alkalescent by using ammonia water, extracting three times by using dichloromethane, 200mL each time, drying an organic phase by using anhydrous magnesium sulfate, evaporating the solvent to obtain a crude product, and recrystallizing hydrogen chloride methanol to obtain a white solid product, namely 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-methyl formate hydrochloride. Weight: 22.1 g; chemical purity: 98.5 percent; chiral purity: 51.6%/48.3% (RR/SS); yield: 78.6 percent.
MS[M+H]+:245.12.
1HNMR(400MHz,DMSO-d6)δ11.43(s,1H,-NH-),10.51(brs,1H,-NH-·HCl),10.09(brs,1H,-NH-·HCl),7.48(d,J＝7.8Hz,1H,Ar-H),7.38(d,J＝8.1Hz,1H,Ar-H),7.13(t,J＝7.0Hz,1H,Ar-H),7.03(t,J＝6.9Hz,1H,Ar-H),4.75(q,J＝6.8Hz,1H,-CHCH3),4.62(dd,J＝11.8,5.0Hz,1H,-NHCHCO-),3.86(s,3H,-OCH3),3.29(dd,J＝15.8,3.8Hz,1H,-CH2-),3.07(ddd,J＝15.8,11.9,2.4Hz,1H,-CH2-),1.75(d,J＝6.7Hz,3H,-CHCH3).
Synthesis of chloroindole hydrazide
28.1g (0.10mol,1.0eq) of methyl 1-methyl-1,2,3,4-tetrahydro- β -carboline-3-carboxylate hydrochloride and 17.0g (0.11mol,1.1eq) of (4-chlorophenyl) methylene hydrazine were added to 200mL of methanol, and then 90g (0.50mol,5.0eq) of 30 wt% sodium methoxide solution in methanol was added, followed by heating and refluxing for 5 hours. Slowly cooling to 0-5 ℃, filtering, and leaching the white-like solid product chloroindole hydrazide of the filter cake with methanol. Weight: 33.6 g; chemical purity: 98.3 percent; chiral purity: 38.9%/61.0% (RR/SS); yield: 91.7 percent.
MS[M+H]+:367.13/369.12；[2M+H]+:733.25/735.25；[2M+Na]+:755.23/757.23.
1HNMR(400MHz,DMSO-d6)δ11.52&11.40(s,1H,-CONHN＝),10.82&10.80(s,1H,-NH-),8.34&8.05(s,1H,-CH＝N-),7.79–7.58(m,2H,Ar-H),7.56–7.25(m,4H,Ar-H),7.08–6.89(m,2H,Ar-H),4.48&3.62(dd,J＝11.1,4.2Hz,1H,-NHCHCO-),4.15(dd,J＝13.9,7.1Hz,1H,-CHCH3),2.99–2.88(m,1H,-CH2-),2.77–2.57(m,1H,-CH2-),2.36&1.99(brs,1H,-NHCHCO-),1.46&1.45(d,J＝6.8,3H,-CHCH3).
Example 2
Synthesis of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-ethyl formate
23.2g (0.10mol,1.0eq) of the tryptophan ester ethyl ester was dissolved in 50mL of propionic acid, then 82g (2.0mol,20eq.) of acetonitrile and 1.2g of 10 wt.% platinum carbon were added, air was replaced with nitrogen for 3 times, then nitrogen was replaced with hydrogen for 3 times, and hydrogen was introduced to react at 60 ℃ for 6 hours under 1.0 MPa. Cooling to room temperature, filtering to remove the catalyst, decompressing and evaporating the solvent, adding 200mL of water, adjusting the pH value of the reaction solution to be alkalescent by using an aqueous solution of sodium hydroxide, filtering to obtain a crude product, and recrystallizing by using ethanol to obtain a white solid product, namely ethyl 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-formate. Weight: 18.7 g; purity: 97.1 percent; chiral purity: 51.2%/48.8% (RR/SS); yield: 72.5 percent.
Synthesis of chloroindole hydrazide
25.8g (0.10mol,1.0eq) of ethyl 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylate and 15.5g (0.10mol,1.0eq) of (4-chlorophenyl) methylene hydrazine are added into 150mL of ethanol, and then 25.2g (0.30mol,3.0eq) of potassium ethoxide are added for heating reflux reaction for 2 hours. Slowly cooling to 10-20 ℃, filtering, and leaching the white-like solid product chloroindole hydrazide of the filter cake with ethanol. Weight: 32.7 g; chemical purity: 97.7 percent; chiral purity: 35.4%/64.6% (RR/SS); yield: 89.2 percent.
Example 3
Synthesis of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-isopropyl formate
49.2g (0.20mol,1.0eq) of isopropyl tryptophan was added to 150mL of formic acid, then 410g (10mol,50eq) of acetonitrile was added, and finally 5.0g of 20 wt.% palladium hydroxide on carbon was added and the reaction was carried out under reflux for 4 hours. Cooling to room temperature, filtering to remove the catalyst, decompressing to dry the solvent, adding 500mL of water, adjusting the pH value of the reaction solution to be alkalescent by using a potassium carbonate aqueous solution, filtering to obtain a crude product, and recrystallizing isopropanol to obtain a white solid product, namely 1-methyl-2, 3,4, 9-tetrahydropyrido [3,4-b ] indole-3-isopropyl formate. Weight: 37.8 g; purity: 97.1 percent; chiral purity: 50.9%/49.1% (RR/SS); yield: 69.5 percent.
Synthesis of chloroindole hydrazide
54.4g (0.20mol,1.0eq) of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid isopropyl ester and 29.4g (0.19mol,0.95eq) of (4-chlorophenyl) methylene hydrazine are added into 350mL of toluene, and then 20g (0.50mol,2.5eq) of sodium hydride with the content of 60 percent is added for heating reflux reaction for 8 hours. Slowly cooling to room temperature, filtering, leaching filter cakes with toluene to obtain a white-like solid product, namely the chloroindole hydrazide. Weight: 64.3 g; chemical purity: 98.0 percent; chiral purity: 32.7%/67.3% (RR/SS) yield: 87.6 percent.
Example 4
Synthesis of 1-methyl-1,2,3, 4-tetrahydro-beta-carboline-3-formic acid
40.8g (0.20mol,1.0eq) of tryptophan was added to 80mL of acetic acid, followed by 574g (14mol,70eq) of acetonitrile, followed by 4.0g of Raney nickel, air was replaced with nitrogen for 3 times, nitrogen was replaced with hydrogen for 3 times, and hydrogen was introduced to react at 100 ℃ under 2.0MPa for 8 hours. Cooling to room temperature, filtering to remove the catalyst, decompressing to dry the solvent, adding 400mL of water, adjusting the pH value to 6-7 with a potassium bicarbonate water solution, filtering to obtain a crude product, and recrystallizing with ethanol to obtain a white solid product, namely 1-methyl-2, 3,4, 9-tetrahydropyrido [3,4-b ] indole-3-formic acid. Weight: 30.5 g; purity: 98.6 percent; chiral purity: 51.5%/48.4% (RR/SS); yield: 66.2 percent.
Synthesis of chloroindole hydrazide
46.0g (0.20mol,1.0eq) of 1-methyl-1,2,3,4-tetrahydro- β -carboline-3-carboxylic acid and 3.09g (0.20mol,0.95eq) of (4-chlorophenyl) methylene hydrazine were added to 200mL of DMF, followed by 34.2g (0.22mol,1.1eq) of EDCI and 29.7g (0.22mol,1.1eq) of HOBt, and the reaction was stirred at room temperature for 10 hours. After the reaction is finished, H is dropwise added into the reaction system2And (3) continuously stirring the mixture for 1 hour, filtering the mixture, washing a filter cake by using water to obtain a crude product, and leaching the crude product by using isopropanol to obtain a white-like solid product, namely the chloroindole hydrazide. Weight: 59.6 g; chemical purity: 98.8 percent; chiral purity: 22.5%/77.4% (RR/SS) yield: 81.3 percent.
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. The synthesis method of the chloroindole hydrazide is characterized in that the synthesis route is as follows:
wherein R is H or C1～C4Alkyl groups of (a);
the preparation method comprises the following steps:
(1) uniformly mixing a compound shown in a formula (I), a solvent I, acetonitrile and a catalyst I, adding a hydrogen source, and starting to react; after the reaction is finished, treating to obtain a compound shown in a formula (II);
(2) mixing a compound shown in a formula (II), 4-chlorphenyl) methylene hydrazine, a solvent II and a catalyst II for reaction, and carrying out post-treatment after the reaction is finished to obtain chloroindole hydrazide;
or mixing the compound of the formula (II), the (4-chlorphenyl) methylene hydrazine, the solvent II and the condensing agent for reaction, and carrying out post-treatment after the reaction is finished to obtain the chloroindole hydrazide.
2. The synthesis method of claim 1, wherein in the step (1), the feeding molar ratio of the compound of formula (I) to acetonitrile is 1: 1-100.
3. The synthesis method according to claim 1, wherein in the step (1), the catalyst I is selected from palladium-based, platinum-based and nickel-based catalysts.
4. The synthesis method according to claim 1, wherein in the step (1), the catalyst I is selected from palladium carbon and platinum carbon.
5. The synthesis method according to claim 1, wherein in the step (1), the hydrogen source is selected from hydrogen gas or formic acid.
6. The method according to claim 1, wherein in the step (1), the solvent I is at least one selected from the group consisting of formic acid, acetic acid, propionic acid, butyric acid, valeric acid and caproic acid.
7. The synthesis method according to claim 1, wherein in the step (1), the solvent I is used in an amount of 1 to 40ml/g based on the weight of the compound of formula (I).
8. The synthesis method according to claim 1, wherein in the step (2), the feeding molar ratio of the compound of the formula (II) to the (4-chlorophenyl) methylene hydrazine is 1: 0.9-1.5.
9. The method of claim 1, wherein in step (2), the condensing agent is selected from the group consisting of DCC, DIC, EDCI, HATU, HBTU, TATU, SOCl2、POCl3Or PCl5。
10. The method of claim 1, wherein in step (2), the catalyst II is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium isopropoxide, potassium isopropoxide, sodium butoxide, potassium butoxide, sodium isobutoxide, potassium tert-butoxide, methyllithium, ethyllithium, propyllithium, isopropyllithium, butyllithium, isobutyllithium, tert-butyllithium, or lithium diisopropylamide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023213174A1 (en) * | 2022-05-06 | 2023-11-09 | 山东京博农化科技股份有限公司 | Polymorph of chloroindole hydrazide, preparation method therefor and formulation processing technology |
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| CN109134460A (en) * | 2018-08-02 | 2019-01-04 | 南开大学 | A kind of synthetic method of B-carboline class compound |
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| CN1671706A (en) * | 2002-07-31 | 2005-09-21 | 利利艾科斯有限公司 | Modified pictet-spengler reaction and products prepared therefrom |
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| CN104744460A (en) * | 2013-12-30 | 2015-07-01 | 南开大学 | B-carboline, dihydro-B-carboline and tetrahydro-B-carboline alkaloid derivative as well as preparation method and application in aspects of plant virus prevention and cure, sterilization and insecticide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023213174A1 (en) * | 2022-05-06 | 2023-11-09 | 山东京博农化科技股份有限公司 | Polymorph of chloroindole hydrazide, preparation method therefor and formulation processing technology |
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