CN108164469B - Method for preparing triketone compound - Google Patents
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- CN108164469B CN108164469B CN201611115010.5A CN201611115010A CN108164469B CN 108164469 B CN108164469 B CN 108164469B CN 201611115010 A CN201611115010 A CN 201611115010A CN 108164469 B CN108164469 B CN 108164469B
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Abstract
The invention relates to the field of pesticide preparation, and discloses a method for preparing a triketone compound, wherein the triketone compound has a structure shown in a formula (1), and the method comprises the following steps: (1) under the alkaline condition, in the presence of a first catalyst, reacting a compound shown as a formula (2), 1, 3-cyclohexanedione and CO to obtain a product shown as a formula (3); (2) under the rearrangement reaction condition, the product shown in the formula (3) is contacted with a second catalyst and an alkaline substance to obtain the triketone compound shown in the formula (1). The method of the invention can obtain the triketone compound with low cost and high yield. Furthermore, the purity of the triketone compound obtained by the method of the present invention is high.
Description
Technical Field
The invention relates to the field of pesticide preparation, and in particular relates to a method for preparing triketone compounds.
Background
P-hydroxyphenylpyruvate dioxygenase (4-HPPD) is a target of action of new herbicides found in the 80's of the 20 th century, which is widely present in various aerobic organisms. The enzyme is a divalent iron-containing dioxygenase dependent on alpha-keto acids, which is capable of catalytically converting p-hydroxyphenylpyruvate into homogentisic acid. The action mechanism of the 4-HPPD herbicide is to inhibit the process of converting p-hydroxyphenylpyruvic acid into homogentisic acid in plants, the homogentisic acid in the plants can be further biocatalytically converted into plastoquinone and tocopherol, the plastoquinone and the tocopherol are substances required for electron chain transfer in plant photosynthesis, and if the 4-HPPD in the plants is inhibited, the synthesis of the homogentisic acid is hindered, and the electron chain transfer for photosynthesis in the plants is influenced, so that the plants are whitened and die.
The design and synthesis of 4-HPPD inhibitors containing novel structures are one of the hot areas of pesticide chemistry research in recent years. To date, more than 5 different structural classes of 4-HPPD inhibitors have been discovered, mainly triketones, pyrazoles, isoxazoles, diketocyanides and benzophenones. The herbicide developed by taking 4-HPPD as a target has a series of advantages of high efficiency, low toxicity, environmental friendliness, safety to succeeding crops and the like. Therefore, the 4-HPPD herbicide is a herbicide with great research value and development prospect, and more pesticide companies are attracted to be put into the research and development of the 4-HPPD herbicide. The commercially available triketone 4-HPPD inhibitors have various varieties, all of which contain a benzene ring structure in the molecule, such as mesotrione, sulcotrione and the like, wherein the mesotrione has the best weed removal effect and high safety.
According to the research on a 4-HPPD herbicide system, CN104557739A designs and synthesizes a novel triketone 4-HPPD compound containing a quinazolinedione structure. Specifically discloses a triketone compound which is obtained by contacting a compound with a structure shown in a formula (II) with a catalyst under the rearrangement reaction condition in the presence of alkali and a solvent. However, the compounds of the structure represented by formula (II) in this prior art process are commercially expensive; when the synthesis is carried out autonomously, the defects of complex process route and low yield exist.
In view of the above, there is a need in the art to find a method for obtaining triketones at low cost and in high yield.
Disclosure of Invention
The object of the present invention is to overcome the disadvantages of the prior art and to provide a novel process for obtaining triketones at low cost and in high yield and purity.
In order to achieve the above object, the present invention provides, in a first aspect, a process for producing a triketone compound having a structure represented by formula (1), wherein R is1、R2And R3Each independently selected from H, C1-6The method comprising:
(1) under the alkaline condition, in the presence of a first catalyst, reacting a compound shown as a formula (2), 1, 3-cyclohexanedione and CO to obtain a product shown as a formula (3);
(2) under the rearrangement reaction condition, the product shown in the formula (3) is contacted with a second catalyst and an alkaline substance to obtain the triketone compound shown in the formula (1).
In a second aspect, the present invention provides a method for preparing a triketone compound having a structure represented by formula (1), wherein R is1、R2And R3Each independently selected from H, C1-6The method comprising:
(1) cyanating the compound represented by the formula (2) to obtain a compound represented by the formula (4);
(2) carboxylating the compound shown in the formula (4) to obtain a compound shown in a formula (5);
(3) performing acyl chlorination on the compound shown in the formula (5) to obtain a compound shown in a formula (6);
(4) esterifying the compound shown in the formula (6) to obtain a compound shown in a formula (3); and
(5) under the rearrangement reaction condition, the compound shown in the formula (3) is contacted with a second catalyst and a basic substance to obtain the triketone compound shown in the formula (1).
The method of the invention can obtain the triketone compound with low cost and high yield. Furthermore, the purity of the triketone compound obtained by the method of the present invention is high.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a synthetic scheme for the preparation of compounds of formula (5) according to a preferred embodiment.
FIG. 2 is a synthetic scheme for the preparation of triketones of formula (1) according to a preferred embodiment.
FIG. 3 is a synthetic scheme for the preparation of triketones according to formula (1) according to another preferred embodiment.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In the present invention, unless otherwise specified, "first" and "second" in the first contact reaction, the second contact reaction, the first catalyst, the second catalyst, and the like do not indicate a sequential order, but merely for the purpose of distinction. Those skilled in the art should not be construed as limitations on the scope of the invention.
In a first aspect, the present invention provides a method for preparing a triketone compound having a structure represented by formula (1), wherein R is1、R2And R3Each independently selected from H, C1-6The method comprising:
(1) under the alkaline condition, in the presence of a first catalyst, reacting a compound shown as a formula (2), 1, 3-cyclohexanedione and CO to obtain a product shown as a formula (3);
(2) under the rearrangement reaction condition, the product shown in the formula (3) is contacted with a second catalyst and an alkaline substance to obtain the triketone compound shown in the formula (1).
Preferably, in the present invention, R1、R2And R3Each independently selected from H, C1-3Alkyl groups of (a); more preferably, R1、R2And R3Each independently selected from H, methyl, ethyl, n-propyl and isopropyl, and R1、R2And R3Not H at the same time.
The first catalyst is a catalyst capable of catalyzing a carbonylation reaction.
The second catalyst is a catalyst capable of catalyzing the rearrangement reaction of the product represented by the formula (3).
Preferably, in the step (1), the first catalyst contains a component A and a component B, wherein the component A is palladium and/or palladium chloride; the component B is a ligand selected from bis (2-diphenylphosphinophenyl) ether and/or 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.
Preferably, in the first catalyst, the molar ratio of the amount of the component A calculated as palladium element to the content of the component B is 1: (1-2); more preferably, the molar ratio of the amount of the component A calculated by palladium element to the content of the component B is 1: (1.05-1.4).
The inventors of the present invention found that, in the first catalyst, the component a is palladium and/or palladium chloride; and the component B is a ligand selected from bis (2-diphenylphosphinophenyl) ether and/or 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene; the molar ratio of the amount of the component A calculated by palladium element to the content of the component B is 1: (1.05-1.4), the purity and yield of the triketone compound obtained by using the first catalyst are high.
Preferably, in the step (1), the conditions for reacting the compound represented by the formula (2) with 1, 3-cyclohexanedione include: the reaction temperature is 30-100 ℃, the reaction time is 0.2-48h, and the reaction pressure is 0.1-2.5 MPa.
The inventors of the present invention have found that the purity of the product of the present invention can be increased when the pressure at which the compound represented by the formula (2) is reacted with 1, 3-cyclohexanedione is 0.6 to 2.5 MPa.
Preferably, in step (1), the compound represented by the formula (2) is used in a molar ratio to the first catalyst based on the noble metal element contained therein of 1: (0.05-0.15).
Preferably, in step (1), the basic conditions are formed by a substance selected from triethylamine and/or sodium bicarbonate.
Preferably, in step (1), the reaction is carried out in the presence of a phase transfer catalyst; more preferably, the phase transfer catalyst is tetrabutylammonium bromide.
Preferably, in the step (2), the second catalyst is at least one selected from the group consisting of sodium cyanide, potassium cyanide, acetone cyanohydrin, trimethylcyanosilane, 1,2, 4-triazole and benzo 1,2, 4-triazole.
Preferably, in the step (2), the basic substance is at least one selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and pyridine.
Preferably, in the step (2), the conditions for contacting the product represented by the formula (3) with the second catalyst and the basic substance include: the contact temperature is 5-50 ℃; the contact time is 5-30 h.
In a second aspect, the present invention provides a method for preparing a triketone compound having a structure represented by formula (1), wherein R is1、R2And R3Each independently selected from H, C1-6The method comprising:
(1) cyanating the compound represented by the formula (2) to obtain a compound represented by the formula (4);
(2) carboxylating the compound shown in the formula (4) to obtain a compound shown in a formula (5);
(3) performing acyl chlorination on the compound shown in the formula (5) to obtain a compound shown in a formula (6);
(4) esterifying the compound shown in the formula (6) to obtain a compound shown in a formula (3); and
(5) under the rearrangement reaction condition, the compound shown in the formula (3) is contacted with a second catalyst and a basic substance to obtain the triketone compound shown in the formula (1).
Preferably, in step (1), the conditions under which the cyanation is carried out include: the reaction is carried out for 3 to 48 hours under reflux in the presence of a cyanation catalyst.
In the step (1), the specific procedure for cyanating the compound represented by the formula (2) may include: contacting a compound represented by formula (2) with a cyano donor. The cyano donor may be, for example, cuprous cyanide.
Preferably, in step (2), the carboxylation is carried out under conditions including: the reaction is carried out for 2 to 30 hours under reflux in the presence of a carboxylation catalyst.
In the step (2), the concrete operation of subjecting the compound represented by the formula (4) to carboxylation may include: contacting a compound represented by formula (4) with a carboxyl donor. The carboxyl donor may be, for example: acetic acid, formic acid, and the like.
Preferably, in step (3), the conditions under which the acyl chlorination is carried out include: in the presence of acyl chloride reagent, the reaction temperature is 0-80 ℃, and the reaction time is 0.5-24 h.
In the step (3), the specific operation of subjecting the compound represented by the formula (5) to acid chlorination may include: the compound represented by the formula (5) is subjected to a contact reaction with an acid chloride at 0 to 25 ℃ in the presence of, for example, methylene chloride as a solvent, and then DMF is added to the system and the temperature is raised to reflux the reaction. The acid chloride may be, for example, thionyl chloride.
Preferably, in step (4), the esterification is carried out under conditions comprising: the reaction temperature is 10 ℃ below zero to 25 ℃ above zero, and the reaction time is 0.2-12 h.
In the step (4), the specific operation of esterifying the compound represented by the formula (6) may include: the compound shown as the formula (6) and 1, 3-cyclohexanedione are subjected to contact reaction in the presence of a solvent (such as DCM) under basic conditions.
Preferably, in the step (5), the second catalyst is at least one selected from the group consisting of sodium cyanide, potassium cyanide, acetone cyanohydrin, trimethylcyanosilane, 1,2, 4-triazole and benzo 1,2, 4-triazole.
Preferably, in the step (5), the basic substance is at least one selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and pyridine.
Preferably, in the step (5), the conditions for contacting the compound represented by the formula (3) with the second catalyst and the basic substance include: the contact temperature is 5-50 ℃; the contact time is 5-30 h.
In the first and second aspects of the present invention, the compound represented by the formula (2) may be obtained commercially or synthesized by a synthesis method of the prior art.
The compound represented by the formula (2) may be a compound (R) represented by the formula (7)3As defined above) is prepared, in particular: in an alkaline environment formed by alkaline substances such as pyridine, a compound shown as a formula (7) and C1-6And a second contact reaction is carried out between the product obtained after the contact reaction and dimethyl sulfate in an alkaline environment formed by alkaline substances such as potassium carbonate. The conditions of the first contact reaction may include: the temperature is 50-150 ℃ and the time is 4-48 h. The conditions of the second contact reaction may include: the temperature is 20-80 ℃ and the time is 2-48 h.
The compound represented by the formula (4) may be a compound (R) represented by the formula (8)3As defined above) is prepared, in particular: in an alkaline environment formed by alkaline substances such as pyridine, a compound shown as a formula (8) and C1-6And (3) performing a third contact reaction on the phenyl isocyanate substituted or unsubstituted by at least one substituent in the alkyl group, and performing a fourth contact reaction on the product obtained after the contact reaction and dimethyl sulfate in an alkaline environment formed by alkaline substances such as potassium carbonate. The conditions of the third contact reaction may include: the temperature is 50-150 ℃ and the time is 4-48 h. The conditions of the fourth contact reaction may include: the temperature is 20-80 ℃ and the time is 2-48 h.
In the present invention, the compound represented by the formula (8) may be obtained by cyanating a compound represented by the formula (7), specifically: subjecting the compound represented by the formula (7) to a fifth contact reaction with a cyano donor such as cuprous cyanide in the presence of a solvent, wherein the conditions of the fifth contact reaction may include: the temperature is the reflux reaction temperature, and the time is 4-48 h.
The compound shown in the formula (7) can be prepared from a compound shown in a formula (9), and specifically: the sixth contact reaction of the compound represented by the formula (9) with bromine in the presence of an organic solvent such as carbon tetrachloride may be carried out under conditions including: the temperature is 0-50 deg.C, and the time is 3-400 min.
According to a preferred embodiment, the compound of formula (5) according to the invention can be prepared by the synthetic route shown in fig. 1, in particular comprising the following steps:
(1) subjecting the compound shown in the formula (5-1) and potassium permanganate to seventh contact reaction under an alkaline environment formed by alkaline substances such as potassium hydroxide and the like, and then placing the obtained product in an acidic environment to obtain the compound shown in the formula (5-2), wherein the seventh contact reaction conditions comprise: the temperature is 50-150 ℃, and the time is 1-10 h;
(2) subjecting the compound shown in the formula (5-2) and thionyl chloride to eighth contact reaction in the presence of an organic solvent such as dichloromethane to obtain a compound shown in the formula (5-3), wherein the conditions of the eighth contact reaction comprise: the temperature is the reflux reaction temperature, and the time is 1-18 h;
(3) subjecting the compound shown in the formula (5-3) and a palladium carbon catalyst to ninth contact reaction in the presence of an organic solvent such as methanol to obtain a compound shown in the formula (5-4), wherein the ninth contact reaction conditions comprise: the temperature is 0-80 ℃, and the time is 4-48 h;
(4) reacting a compound represented by the formula (5-4) with C in the presence of a basic substance such as pyridine1-6A tenth contact reaction of phenyl isocyanate substituted or unsubstituted with at least one substituent in the alkyl group of (a), and an eleventh contact reaction of the product obtained after the contact reaction with methyl iodide in an alkaline environment formed by an alkaline substance such as potassium carbonate, to obtain a compound represented by formula (5-5); the tenth contact reactionThe conditions of (a) may include: the temperature is 50-150 ℃, and the time is 4-48 h; the conditions of the eleventh contact reaction may include: the temperature is 10-80 ℃, and the time is 2-48 h; and
(5) a twelfth contact reaction of the compound represented by the formula (5-5) with a carboxyl group donor such as acetic acid in the presence of a solvent such as water and in the presence of an acidic substance such as concentrated sulfuric acid; obtaining a compound shown as a formula (5); the conditions of the twelfth contact reaction may include: the temperature is 60-200 ℃, and the time is 2-48 h.
According to another preferred embodiment, the triketones of the invention are prepared by the synthetic route shown in fig. 2, in particular comprising the following steps:
(1) and (2) carrying out sixth contact reaction on the compound shown in the formula (9) and bromine in the presence of an organic solvent such as carbon tetrachloride to obtain the compound shown in the formula (7), wherein the conditions of the sixth contact reaction can comprise: the temperature is 0-50 deg.C, and the time is 3-400 min;
(2) in an alkaline environment formed by alkaline substances such as pyridine, a compound shown as a formula (7) and C1-6The phenyl isocyanate substituted or unsubstituted by at least one substituent in the alkyl group(s) of (a) is subjected to a first contact reaction, and the product obtained after the contact reaction and dimethyl sulfate are subjected to a second contact reaction in an alkaline environment formed by an alkaline substance such as potassium carbonate, so as to obtain a compound represented by formula (2); the conditions of the first contact reaction may include: the temperature is 50-150 ℃ and the time is 4-48 h. The conditions of the second contact reaction may include: the temperature is 20-80 ℃, and the time is 2-48 h;
(3) under the alkaline condition, in the presence of a first catalyst, reacting a compound shown as a formula (2), 1, 3-cyclohexanedione and CO to obtain a product shown as a formula (3); and
(4) under the rearrangement reaction condition, the product shown in the formula (3) is contacted with a second catalyst and an alkaline substance to obtain the triketone compound shown in the formula (1).
According to a third preferred embodiment, the triketones of the invention are prepared by the synthetic route shown in fig. 3, in particular comprising the following steps:
(1) and (2) carrying out sixth contact reaction on the compound shown in the formula (9) and bromine in the presence of an organic solvent such as carbon tetrachloride to obtain the compound shown in the formula (7), wherein the conditions of the sixth contact reaction can comprise: the temperature is 0-50 deg.C, and the time is 3-400 min;
(2) in an alkaline environment formed by alkaline substances such as pyridine, a compound shown as a formula (7) and C1-6The phenyl isocyanate substituted or unsubstituted by at least one substituent in the alkyl group(s) of (a) is subjected to a first contact reaction, and the product obtained after the contact reaction and dimethyl sulfate are subjected to a second contact reaction in an alkaline environment formed by an alkaline substance such as potassium carbonate, so as to obtain a compound represented by formula (2); the conditions of the first contact reaction may include: the temperature is 50-150 ℃ and the time is 4-48 h. The conditions of the second contact reaction may include: the temperature is 20-80 ℃, and the time is 2-48 h;
(3) cyanating the compound represented by the formula (2) to obtain a compound represented by the formula (4);
(4) carboxylating the compound shown in the formula (4) to obtain a compound shown in a formula (5);
(5) performing acyl chlorination on the compound shown in the formula (5) to obtain a compound shown in a formula (6);
(6) esterifying the compound shown in the formula (6) to obtain a compound shown in a formula (3); and
(5) under the rearrangement reaction condition, the compound shown in the formula (3) is contacted with a second catalyst and a basic substance to obtain the triketone compound shown in the formula (1).
The reaction according to the first and second aspects of the present invention may be carried out by subjecting the resulting product to a post-treatment by various post-treatment methods conventionally used in the art. Methods of such post-processing include, but are not limited to: extraction, recrystallization, washing, drying, filtration and the like. The present invention is not described in detail herein, and the post-processing methods mentioned in the embodiments are only for illustrative purposes, and do not indicate that they are necessary operations, and those skilled in the art may substitute other conventional methods.
The present invention will be described in detail below by way of examples and preparation examples.
In the following examples and preparations, various raw materials used were commercially available without specific description.
Preparation example 1: a compound represented by the formula (5) wherein R is3Is H, R1And R2Is methyl
1. Adding water (500mL) into a 1000mL four-neck flask, starting stirring, cooling the system to 5 ℃ by using brine ice, slowly adding potassium hydroxide (553mmol) into the 100mL four-neck flask, removing the brine ice after the addition is finished, slowly adding 2, 4-dimethyl nitrobenzene (3311mmol) dropwise, and heating the reaction system to 90 ℃ after the dropwise addition is finished. After the reaction system is heated to 90 ℃, potassium permanganate (1659mmol) is added into the four-neck flask in 0.5h in batches, after the addition is finished, the reaction system is kept at 90 ℃ for 3h, and the reaction is tracked by HPLC. After the reaction was complete, the filter cake was filtered hot and washed with 500mL of hot water (70 ℃). The filtrate was cooled to 5 ℃ and concentrated hydrochloric acid (36 wt%, 100mL) was slowly added dropwise thereto. Filtering, leaching the filter cake with 500mL of water, and drying the filter cake to obtain a white solid with the purity of 97.8% and the yield of 80%.
2. Adding dichloromethane (500mL) and a product (237mmol) obtained in the step 1 into a 1L four-neck flask, after the addition is finished, cooling the temperature of a reaction system to 5 ℃ by using brine ice, then starting to slowly dropwise add thionyl chloride (1422mmol), continuing to stir for 10min after the thionyl chloride is dropwise added, then slowly dropwise adding DMF (23.7mmol), stirring for 30min after the dropwise addition is finished, then slowly heating the reaction system to reflux and preserving heat for 6h, and tracking the reaction by using HPLC. After the reaction is finished, the reaction system is cooled to 25 ℃ and then decompressed for desolventizing. The reaction solution after desolventizing was dissolved with 250mL of methylene chloride and quickly added dropwise to a 0 ℃ methanol (500mL) solution. After the addition was complete, stirring was continued for 10min and the reaction was monitored by HPLC. After the reaction, desolventizing, adding 200mL of water and 600mL of ethyl acetate into the reaction solution after desolventizing, stirring and demixing. Then, 200mL of water was added to the organic phase, sodium bicarbonate was added thereto to adjust the pH to neutral, the mixture was allowed to stand for delamination, and the organic phase was dried over anhydrous sodium sulfate and desolventized to obtain a white solid with a purity of 98.5% and a yield of 85%.
3. Methanol (400mL), the product from step 2 (167.2mmol) was added to a 1000mL single neck bottle. Stirring was turned on and palladium on carbon (10 wt%) was added to the single-neck flask. After the exhaust, hydrogen gas is introduced to slowly raise the temperature of the reaction system to 45 ℃ and keep the temperature overnight, and the reaction is followed by HPLC. After the reaction was completed, the reaction solution was filtered while it was hot, and the filter cake was washed with hot methanol (50 ℃ C.) and filtered. And (3) desolventizing the filtrate, adding 600mL of ethyl acetate and 200mL of saturated saline solution when methanol is removed to 1/3, stirring, standing for layering, drying an organic phase by using anhydrous sodium sulfate, and desolventizing to obtain a white solid with the purity of 97.8% and the yield of 95.4%.
4. Pyridine (250mL) and the product obtained in step 3 (144mmol) were added to a 500mL four-necked flask, stirring was turned on, 2, 6-dimethylphenyl isocyanate (179mmol) was added, and after the addition, the reaction was warmed to 100 ℃ overnight and followed by HPLC. After the reaction is finished, pouring the reaction solution into 1L of water while the reaction solution is hot, stirring for 30min, filtering, washing a filter cake twice by using 100mL of isopropyl ether, drying the obtained solid, adding the obtained solid (103.6mmol), DMF (350mLl) and potassium carbonate (124mmol) into a 500mL single-neck bottle, starting stirring after the addition is finished, heating the reaction system to 45 ℃ and preserving heat for 30min, and then beginning to dropwise add dimethyl sulfate (412 mmol). After the dropwise addition, stirring and heat preservation are continued for 24h, and the reaction is followed by HPLC. After the reaction is finished, pouring the reaction system into 500mL of ice water, stirring for 30min, filtering, washing a filter cake with 200mL of isopropyl ether, and drying the filter cake to obtain a white solid with the purity of 97.5% and the yield of 60%.
5. Water (89mL), glacial acetic acid (120mL) and the product (59mmol) obtained in step 4 were added to a 500mL four-necked flask, stirring was started, concentrated sulfuric acid (120mL) was slowly added dropwise, after the addition was completed, the reaction was warmed to reflux and kept at temperature for 6h, and the reaction was followed by HPLC. And after the reaction is finished, pouring the hot reaction liquid into 500mL of ice-water mixture, stirring for 30min, filtering, washing a filter cake twice by using 200mL of isopropyl ether, and drying the obtained solid to obtain a white solid with the purity of 97.5% and the yield of 90%.
Preparation example 2: preparing a compound of formula (2), and R1And R2Is methyl, R3Is H
1. Carbon tetrachloride (100mL) and methyl 2-aminobenzoate (149mmol) were added to a 250mL four-necked flask, stirring was turned on, bromine (156.45mmol) was added dropwise, and after the addition was complete, a sample was taken and the reaction was followed by HPLC. And filtering the reaction solution after the reaction is finished, leaching a filter cake by using 200mL of isopropyl ether, and drying to obtain a yellow solid with the purity of 96.5% and the yield of 90%.
2. Pyridine (250mL) and the product obtained in step 1 (144mmol) were added to a 500mL four-necked flask, stirring was turned on, 2, 6-dimethylphenyl isocyanate (179mmol) was added, and after the addition, the reaction was warmed to 100 ℃ overnight and followed by HPLC. After the reaction is finished, pouring the reaction solution into 1L of water while the reaction solution is hot, stirring for 30min, filtering, washing a filter cake twice by using 100mL of isopropyl ether, and drying the obtained solid. Then the solid obtained (116mmol), DMF (400mL) and potassium carbonate (139mmol) were added to a 1L single-neck flask, after the addition was complete, stirring was turned on, the reaction was heated to 45 ℃ and held for 30min, after holding for 30min, dimethyl sulfate (464mmol) was added slowly dropwise. After the dropwise addition, stirring and heat preservation are continued for 24h, and the reaction is followed by HPLC. After the reaction is finished, pouring the reaction system into 1L of ice water, stirring for 30min, filtering, washing a filter cake with 200mL of isopropyl ether, and drying the filter cake to obtain the product with the purity of 96.8% and the yield of 72%.
Preparation example 3: preparing a compound of formula (4), and R1And R2Is methyl, R3Is H
DMF (300mL), methyl 2-amino-5-bromobenzoate (130.4mmol) was added to a 1000mL one-neck flask, stirring was turned on, and cuprous cyanide (2260.8mmol) was added. After the addition was complete, the reaction was warmed to reflux and held overnight and the reaction was followed by HPLC. After the reaction is finished, the reaction solution is cooled to 25 ℃, then 500mL of water is added into the reaction solution and stirred for 30min, then 300mL of ethyl acetate is added into the reaction solution, the mixture is filtered after the stirring is finished, the filtrate is kept stand and layered, the water phase is extracted for three times by 600mL of ethyl acetate, the organic phase is dried by anhydrous sodium sulfate and exsolution is carried out, and then white solid with the purity of 95.6 percent and the yield of 90 percent is obtained.
2. Pyridine (167mL) and the product obtained in step 1 (113.6mmol) were added to a 500mL four-necked flask, stirring was turned on, 2, 6-dimethylphenyl isocyanate (126.32mmol) was added, and after the addition, the reaction was warmed to 100 ℃ overnight and followed by HPLC. After the reaction is finished, pouring the reaction solution into 1L of water while the reaction solution is hot, stirring for 30min, filtering, washing a filter cake twice by using 100mL of isopropyl ether, and drying the obtained solid. Then adding the obtained solid (83mmol), DMF (260mL) and potassium carbonate (99.6mmol) into a 500mL single-neck bottle, starting stirring after the addition is finished, heating the reaction system to 45 ℃, preserving heat for 30min, then slowly dropwise adding dimethyl sulfate (332mmol), continuing stirring and preserving heat for 24 hours after the dropwise adding is finished, and tracking the reaction by HPLC. And after the reaction is finished, pouring the reaction system into 500mL of ice water, stirring for 30min, filtering, washing a filter cake with 100mL of isopropyl ether, and drying the filter cake to obtain the product with the purity of 97% and the yield of 72%.
Preparation example 4: preparing a compound of formula (2), and R1And R3Is methyl, R2Is H
This preparation was prepared in a similar manner to preparation 2, except that in this preparation, an equimolar amount of methyl 2-amino-6-methylbenzoate was used instead of methyl 2-aminobenzoate and an equimolar amount of 2-methylphenyl isocyanate was used instead of 2, 6-dimethylphenyl isocyanate in preparation 2. The rest of the process was the same as in preparation example 2 to obtain a product with a purity of 96.5% and a yield of 73%.
Example 1: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3Is H, R1And R2Is methyl
6-bromo-3- (2, 6-dimethylphenyl) -1-methyl quinazoline-2, 4(1H,3H) -dione (0.1mol), 1, 3-cyclohexanedione (0.12mol), palladium chloride (10mmol), bis (2-diphenylphosphinophenyl) ether (11mmol), triethylamine (0.35mol) and tetrabutylammonium chloride (0.12mol) were added to dioxane (400mL), and then carbon monoxide was introduced into the reaction system under a pressure of 2MPa, and the mixture was heated to 60 ℃ for reaction for 5 hours. After the reaction, filtering, adding water into the filtrate, extracting with ethyl acetate, washing the organic phase with 25 wt% hydrochloric acid to neutrality, drying the organic phase, and concentrating to obtain the crude compound. The crude product was used in the next reaction without purification.
40g of the crude product are added to acetonitrile (400mL), and triethylamine (0.15mol) and acetone cyanohydrin (0.01mol) are added with stirring. The reaction system was stirred at 30 ℃ for 15 hours. After completion of the reaction, the reaction mixture was stirred and acidified to pH 1 with 25 wt% hydrochloric acid. The obtained solid is filtered, washed by water and recrystallized by methanol to obtain light yellow solid 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methyl quinazoline-2, 4(1H,3H) -diketone with the purity of 99.8 percent and the yield of 96.0 percent.
Example 2: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3Is H, R1And R2Is methyl
6-bromo-3- (2, 6-dimethylphenyl) -1-methylquinazoline-2, 4(1H,3H) -dione (0.1mol), 1, 3-cyclohexanedione (0.12mol), palladium chloride (10mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (12mmol), triethylamine (0.35mol) and tetrabutylammonium chloride (0.12mol) were added to dioxane (400mL), and then carbon monoxide was introduced into the reaction system under a pressure of 1.6MPa and heated to 80 ℃ to react for 4 hours. After the reaction, filtering, adding water into the filtrate, extracting with ethyl acetate, washing the organic phase with 25 wt% hydrochloric acid to neutrality, drying the organic phase, and concentrating to obtain the crude compound. The crude product was used in the next reaction without purification.
The crude product was added to acetonitrile (400mL), and triethylamine (0.15mol), acetone cyanohydrin (0.01mol) were added with stirring. The reaction system was stirred at 30 ℃ for 15 hours. After completion of the reaction, the reaction mixture was stirred and acidified to pH 1 with 25 wt% hydrochloric acid. The obtained solid is filtered, washed by water and recrystallized by methanol to obtain light yellow solid 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methyl quinazoline-2, 4(1H,3H) -diketone with the purity of 99.5 percent and the yield of 96.0 percent.
Example 3: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3And R1Is methyl, R2Is H
5-methyl-6-bromo-3- (2-methylphenyl) -1-methyl quinazoline-2, 4(1H,3H) -diketone (0.1mol), 1, 3-cyclohexanedione (0.12mol), palladium chloride (10mmol), bis (2-diphenylphosphinophenyl) ether (14mmol), triethylamine (0.35mol) and tetrabutylammonium chloride (0.12mol) are added into dioxane (400mL), then carbon monoxide is introduced into the reaction system, the pressure is controlled to be 1.2MPa, and the reaction system is heated to 60 ℃ for reaction for 5 hours. After the reaction, filtering, adding water into the filtrate, extracting with ethyl acetate, washing the organic phase with 25 wt% hydrochloric acid to neutrality, drying the organic phase, and concentrating to obtain a crude product. The crude product was used in the next reaction without purification.
The crude product was added to acetonitrile (400mL), and triethylamine (0.15mol), acetone cyanohydrin (0.01mol) were added with stirring. The reaction system was stirred at 30 ℃ for 15 hours. After completion of the reaction, the reaction mixture was stirred and acidified to pH 1 with 25 wt% hydrochloric acid. The obtained solid is filtered, washed by water and recrystallized by methanol to obtain light yellow solid 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methyl quinazoline-2, 4(1H,3H) -diketone with the purity of 98.7 percent and the yield of 72 percent.
Example 4: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3Is H, R1And R2Is methyl
This example was carried out in the same manner as in example 1, except that in this example, carbon monoxide was introduced into the reaction system under a controlled pressure of 0.3MPa, and the rest was the same as in example 1.
As a result, 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methylquinazoline-2, 4(1H,3H) -dione was obtained in a purity of 67.6% and a yield of 96.0%.
Example 5: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3Is H, R1And R2Is methyl
This example was carried out in the same manner as in example 1, except that in this example, bis (2-diphenylphosphinophenyl) ether was used in an amount of 25mmol, and the remainder was the same as in example 1.
As a result, 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methylquinazoline-2, 4(1H,3H) -dione was obtained in a purity of 90.69% and a yield of 89.6%.
Example 6: preparing triketone compound shown in formula (1) according to reaction formula shown in figure 2, R3Is H, R1And R2Is methyl
This example was carried out in the same manner as in example 1, except that an equimolar amount of PdCl was used in this example2(PPh3)2The palladium chloride in example 1 was replaced, and the rest was the same as in example 1.
As a result, 3- (2, 6-dimethylphenyl) -6- (2-hydroxy-6-oxocyclohex-1-enecarboxy) -1-methylquinazoline-2, 4(1H,3H) -dione was obtained in a purity of 90.69% and a yield of 68.9%.
Example 7: the triketone compound of formula (1), R, was prepared according to the reaction scheme shown in FIG. 33Is H, R1And R2Is methyl
1. DMF (300mL) and bromide (83.6mmol) were added to a 1000mL single-neck flask, and the flask was stirred and weighed out cuprous cyanide (167.1mmol) was added. After the addition was complete, the reaction was warmed to reflux and held overnight and the reaction was followed by HPLC. After the reaction is finished, the reaction solution is cooled to 25 ℃, then 500mL of water is added into the reaction solution, the mixture is stirred for 30 minutes, then 300mL of ethyl acetate is added into the mixture, the mixture is filtered after the stirring is finished, the filtrate is kept stand for layering, the water phase of the filtrate is extracted for three times by 600mL of ethyl acetate, the organic phase is dried by anhydrous sodium sulfate, and the white solid is obtained after exsolution, the purity is 96.4%, and the yield is 90%.
2. Glacial acetic acid (150mL), water (620mL), trifluoromethanesulfonic acid (37mL) and the cyano compound (146.6mmol) obtained in step 1 were added to a 1000mL four-necked flask, stirring was started, the reaction system was cooled to about 10 ℃ with brine ice, concentrated sulfuric acid (500mL) was slowly added dropwise, after the addition of concentrated sulfuric acid was completed, the reaction system was slowly heated to reflux and kept at temperature overnight, and the reaction was followed by HPLC. After the reaction, the reaction system was cooled, and the reaction solution was poured into 1L of ice water, stirred for 30min, and filtered. Washing the filter cake with 200mL of isopropyl ether, and drying to obtain a gray solid with the purity of 97.8% and the yield of 70%.
3. Adding the product (77mmol) obtained in the step 2 and dichloromethane (300mL) into a 500mL four-neck flask, cooling the reaction system to about 5 ℃, starting to dropwise add thionyl chloride (231mmol), and continuing to stir for 10min after the dropwise addition. Then, DMF (4mmol) was added dropwise, stirring was continued for 30min after the addition was completed, the reaction system was heated to reflux and kept warm for 6 hours, and the reaction was followed by HPLC. After the reaction is finished, the reaction system is cooled to 25 ℃ and desolventized to obtain the brown solid with the purity of 98.9 percent and the yield of 100 percent.
4. Adding 1, 3-cyclohexanedione (85mmol) and DCM (200mL) into a 500mL single-neck bottle, cooling the reaction system to 0 ℃ with cold saline, dropwise adding triethylamine (155mmol), continuing to stir at low temperature for 1h after the dropwise addition is finished, then dropwise adding the acyl chloride (77mmol) containing 50mL of dichloromethane prepared in the step 3 into the low-temperature reaction system, controlling the dropwise addition time within 10min, continuing to stir at low temperature for 30min after the dropwise addition is finished, and tracking the reaction by HPLC. After completion of the reaction, the reaction system was washed with 2mol/L hydrochloric acid (30 mL. times.2), 5 wt% sodium carbonate solution (60 mL. times.2), and finally with saturated brine (30 mL). The obtained organic layer was dried over anhydrous sodium sulfate and desolventized to obtain a white solid with a purity of 97.85% and a yield of 76%.
5. And (3) sequentially adding the product (48mmol) obtained in the step (4) and 200mL of acetonitrile into a 1000mL four-neck flask, starting stirring, sequentially adding triethylamine (72mmol) and acetone cyanohydrin (0.48mmol) into the reaction system, heating the reaction system to 30 ℃ under the protection of nitrogen after the addition is finished, preserving the temperature for 12h, and tracking the reaction by using HPLC. And (2) after the reaction is finished, carrying out decompression desolventizing at 40 ℃, adding 250mL of water at 40 ℃ into acetonitrile after the acetonitrile is dried, starting stirring, adding triethylamine (100mmol) into the water, preserving the temperature of the reaction system at 40 ℃ for 30min after the dropwise addition is finished, filtering the reaction solution, cooling the obtained filtrate to 5 ℃, and adding 2mol/L hydrochloric acid into the filtrate while stirring to adjust the pH value to 1. The obtained solid was filtered, washed with water, and recrystallized from methanol to obtain a pale yellow solid with a purity of 98.9% and a yield of 70%.
From the above results, it can be seen that the method of the present invention enables to obtain triketones at low cost and in high yield. Furthermore, the purity of the triketone compound obtained by the method of the present invention is high.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (8)
1. A method for preparing triketone compound with a structure shown as formula (1), wherein R1、R2And R3Each independently selected from H, C1-6The method comprising:
(1) under the alkaline condition, in the presence of a first catalyst, reacting a compound shown as a formula (2), 1, 3-cyclohexanedione and CO to obtain a product shown as a formula (3);
(2) under the rearrangement reaction condition, the product shown in the formula (3) is contacted with a second catalyst and an alkaline substance to obtain a triketone compound shown in the formula (1);
wherein, in the step (1), the conditions for reacting the compound represented by the formula (2) with 1, 3-cyclohexanedione include: the reaction temperature is 30-100 ℃, the reaction time is 0.2-48h, and the reaction pressure is 1.2-2.5 Mpa;
the first catalyst contains a component A and a component B, wherein the component A is palladium chloride; the component B is a ligand selected from bis (2-diphenylphosphinophenyl) ether and/or 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; the second catalyst is acetone cyanohydrin.
2. The method according to claim 1, wherein in the first catalyst, the molar ratio of the amount of the component A calculated as palladium element to the content of the component B is 1: (1-2).
3. The method according to claim 1, wherein in the first catalyst, the molar ratio of the amount of the component A calculated as palladium element to the content of the component B is 1: (1.05-1.4).
4. A process according to any one of claims 1 to 3, wherein in step (1) the basic conditions are formed by a substance selected from triethylamine and/or sodium bicarbonate.
5. The process according to any one of claims 1 to 3, wherein, in step (1), the reaction is carried out in the presence of a phase transfer catalyst.
6. The process of claim 5, wherein the phase transfer catalyst is tetrabutylammonium bromide.
7. The method according to any one of claims 1 to 3, wherein, in step (2), the basic substance is selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine and pyridine.
8. The method according to any one of claims 1 to 3, wherein the conditions under which the product represented by formula (3) is contacted with the second catalyst and the basic substance in step (2) include: the contact temperature is 5-50 ℃; the contact time is 5-30 h.
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| Da-Wei Wang et al..Synthesis and Herbicidal Evaluation of Triketone-Containing Quinazoline-2,4-diones.《Journal of Agricultural and Food Chemistry》.2014,第62卷第11792页Scheme 2，Supporting information第S45-S50页. * |
| Intermolecular trapping of acylpalladium and related acylmetal derivatives with active C-H compounds;Ei-ichi Negishi et al.;《Journal of Molecular Catalysis A: Chemical》;19990708;第143卷(第1-3期);第280页Scheme 1，第282页第3.2.1小节 * |
| Synthesis and Herbicidal Evaluation of Triketone-Containing Quinazoline-2,4-diones;Da-Wei Wang et al.;《Journal of Agricultural and Food Chemistry》;20141118;第62卷;第11792页Scheme 2，Supporting information第S45-S50页 * |
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