Preparation method of 3-isochromone

Abstract

The invention provides a preparation method of 3-isochromone, and relates to the technical field of organic synthesis. Specifically, methyl phenylacetate and N, N-dimethylformamide are used as raw materials, and 3-isochromone is prepared through a Vilsmeier-Haack reaction; preferably, the methyl phenylacetate, the N, N-dimethylformamide and the phosphorus oxychloride are mixed, a Vilsmeier-Haack reaction is carried out, then an intramolecular condensation reaction is carried out, and the 3-isochromone is prepared. The method has the advantages of simple and easily available starting materials, short reaction steps and no use of highly toxic chemicals, provides a new route for expanding the synthesis method of 3-isochromone, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of 3-iso-chromone. BACKGROUND

[0002] 3-iso-chromone fungicides have the characteristics of broad spectrum, high efficiency and systemicity, and have been widely used in the world. Its application has been almost 30 years, and it is safe and stable. 3-iso-chromone (3-Isochromanone, CAS 4385-35-7) plays an important role in the production of pharmaceuticals and agricultural chemicals, so it has attracted many chemical workers to explore its preparation method.

[0003] Patent WO9910335 discloses two synthetic routes of 3-iso-chromone prepared from dimethylbenzene. One is to introduce a chlorine atom in the single methyl group of o-dimethylbenzene, and then to obtain a cyanomethyl group connected to the phenyl group through a nucleophilic substitution reaction, and then to introduce a chlorine atom in the other methyl group of o-dimethylbenzene, and then to realize intramolecular nucleophilic substitution of the cyanomethyl group and chloro atom and ring-closing reaction to obtain 3-iso-chromone; the second is to obtain a cyanomethyl group and a hydroxymethyl group through a series of nucleophilic substitution reactions at the two methyl groups of o-dimethylbenzene, to hydrolyze the cyano group into a carboxymethyl group, and then to obtain 3-iso-chromone through intramolecular esterification reaction. However, the above two synthetic routes have many reaction steps and long production cycle.

[0004] Patent WO2001025206 discloses a method for preparing 3-iso-chromone from 2-indanone through oxidation reaction. However, the oxidant has safety hazards, and the raw material conversion is not complete. Further, patent CN201610348233.X discloses a synthesis method of iso-chromone compounds, which reacts and separates iso-chroman or its derivative having a specific structural formula, double nuclear copper salicylate complex and chloro salt to obtain an iso-chromone compound. However, the copper catalyst oxidation method used by it is still in the milligram level research stage, and cannot be popularized and applied.

[0005] Patent CN202410003466.0 discloses a preparation method of 3-iso-chromone, which mixes benzeneacetic acid, polyformaldehyde and a phase transfer catalyst, and then passes into hydrogen chloride gas, and then adds the catalyst in batches, mixes and reacts to obtain 3-iso-chromone.

[0006] Therefore, the present application is proposed. SUMMARY

[0007] The application aims to provide a preparation method of 3-isochromone, expand and provide a brand new synthesis route of 3-isochromone; meanwhile, the Vilsmeier-Haack reaction refers to that aromatic compounds react with disubstituted formamide under the action of phosphorus oxychloride to generate formylated products on the aromatic ring, and the reaction plays an increasingly important application in organic synthesis, and the application aims to provide a method for preparing 3-isochromone by the Vilsmeier-Haack reaction.

[0008] In order to achieve the above-mentioned purpose of the application, the following technical solutions are adopted: The application discloses a preparation method of 3-isochromone, comprising the following steps: taking methyl phenylacetate and N,N-dimethylformamide as raw materials, and preparing 3-isochromone by a Vilsmeier-Haack reaction.

[0009] Preferably, the preparation method comprises the following steps: S1, mixing methyl phenylacetate, N,N-dimethylformamide and phosphorus oxychloride, and preparing an intermediate shown in a structural formula (I) by a Vilsmeier-Haack reaction; S2, performing intramolecular condensation reaction on the intermediate to obtain 3-isochromone; (I).

[0010] More preferably, the preparation method of the methyl phenylacetate comprises the following steps: mixing phenylacetic acid and methanol, adding concentrated sulfuric acid and performing a reflux reaction; after the reaction is completed, removing methanol under reduced pressure; then mixing with ethyl acetate and deionized water and performing liquid separation to obtain an organic phase; and after washing and drying, the methyl phenylacetate is obtained.

[0011] Preferably, the use amount ratio of the methyl phenylacetate and the N,N-dimethylformamide is 1: (4-6) g / mL.

[0012] More preferably, the mass ratio of the methyl phenylacetate and the phosphorus oxychloride in the step S1 is 1: (1-1.6).

[0013] Preferably, the temperature of the Vilsmeier-Haack reaction is 95-100 DEG C, and the time length is 1.6-2.5 h.

[0014] More preferably, the intermediate is obtained after the Vilsmeier-Haack reaction through post-treatment; The post-treatment comprises the following steps: cooling the reaction solution to 10 DEG C, adding deionized water and adjusting the pH to 5, then adding ethyl acetate and performing extraction, and separating to obtain an organic phase; and after washing, drying and purifying the organic phase, the intermediate is obtained.

[0015] Further preferably, the purification is performed by a silica gel column, and the mobile phase comprises heptane and ethyl acetate in a volume ratio of 8-12:1.

[0016] More preferably, the intramolecular condensation reaction comprises: S2-1, dissolving the intermediate in tetrahydrofuran, adding sodium borohydride under a protective gas environment at 0-10℃, and stirring for 1.6-2.6h; S2-2, adjusting the pH of the reaction system to 2, stirring for 2.6-3.6h under a protective gas environment at 0-10℃; S2-3, after the reaction is completed, first removing tetrahydrofuran under reduced pressure, and then extracting with ethyl acetate to obtain an organic phase; drying the organic phase with anhydrous sodium sulfate, and then concentrating to a volume of ≤15mL; adding heptane to the concentrated solution to crystallize, washing with heptane, and then vacuum drying to obtain 3-isoflavone.

[0017] Further preferably, the mass ratio of the intermediate to the sodium borohydride is 5:(0.25-0.45).

[0018] Further preferably, the usage ratio of the intermediate to the tetrahydrofuran is 1:(8-16) g / mL.

[0019] Compared with the prior art, the present application has the following advantages: The present application provides a synthetic process route for preparing 3-isoflavone from phenylacetic acid and N,N-dimethylformamide as starting materials via a Wielshmiier-Hack reaction. Compared with the existing synthetic process, the present application has the following advantages: simple and readily available starting materials, short reaction steps, and no use of toxic chemicals, etc., and the synthesized 3-isoflavone can be used in the fields of pesticides, medicines, materials, etc. DETAILED DESCRIPTION

[0020] The technical solutions of the present application will be described clearly and completely below in conjunction with specific embodiments, but those skilled in the art will understand that the following described embodiments are part of the embodiments of the present application, rather than all the embodiments, and are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without making creative efforts are within the scope of protection of the present application. The specific conditions are not specified in the embodiments, and are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, and are all conventional products that can be purchased on the market. In addition, the terms "first", "second", "third" are only used for description purposes, and cannot be understood as indicating or implying relative importance.

[0021] The application provides a preparation method of 3-isochromone, which mainly comprises the following steps: using methyl phenylacetate and N,N-dimethylformamide as raw materials, and preparing 3-isochromone through a Vilsmeier-Haack reaction.

[0022] It is worth noting that the Vilsmeier-Haack reaction is used in the application, but the application is not limited to the Vilsmeier-Haack reaction; the preparation method defined in the application is open, and in addition to the Vilsmeier-Haack reaction, other necessary reaction processes are also included; meanwhile, the raw materials used in the application are not limited to methyl phenylacetate and N,N-dimethylformamide.

[0023] As a preferred embodiment, the preparation method specifically comprises the following steps: S1, mixing methyl phenylacetate, N,N-dimethylformamide and phosphorus oxychloride, and preparing an intermediate with the structure of through a Vilsmeier-Haack reaction; S2, performing intramolecular condensation reaction on the intermediate to obtain 3-isochromone.

[0024] As a more preferred embodiment, the methyl phenylacetate can be purchased on the market or prepared through an esterification reaction; for example, the methyl phenylacetate is prepared through an esterification reaction of phenylacetic acid and methanol, and the characteristics of the esterification reaction can be implemented through a conventional manner in the field.

[0025] As an optional embodiment, the preparation method of the methyl phenylacetate comprises the following steps: mixing phenylacetic acid and methanol, adding concentrated sulfuric acid and performing a reflux reaction; after the reaction is completed, methanol is removed through reduced pressure concentration; then mixed solvents are added to perform liquid separation, and the organic phase is obtained, and the methyl phenylacetate is obtained after washing and drying; wherein the mixed solvents comprise ethyl acetate and deionized water.

[0026] For step S1, the following more preferred characteristics exist: As a more preferred embodiment, the use amount ratio of the methyl phenylacetate and the N,N-dimethylformamide is 1: (4-6) g / mL or kg / L; and the mass ratio of the methyl phenylacetate and the phosphorus oxychloride is 1: (1-1.6).

[0027] As a more preferred embodiment, the temperature of the Vilsmeier-Haack reaction is 95-100 DEG C, and the time length is 1.6-2.5 h.

[0028] ​As a more preferred embodiment, after the Vilsmeier-Haack reaction is completed and the reaction solution is cooled to 10°C, deionized water is added to the reaction solution, the pH is adjusted to 5, and then ethyl acetate is added and extracted, and the organic phase is separated; the organic phase is washed, dried, and purified to obtain the intermediate; wherein the purification is performed by a silica gel column, and the mobile phase comprises heptane and ethyl acetate in a volume ratio of 8-12:1.

[0029] As a further preferred embodiment, the volume ratio of the deionized water to the reaction solution is 10: (5-8).

[0030] As a further preferred embodiment, the adjustment of the pH is performed by a sodium carbonate solution with a concentration of 8wt.%-15wt.%.

[0031] For step S2, there are also the following more preferred features: As a more preferred embodiment, the intramolecular condensation reaction comprises the following steps: S2-1, dissolving the intermediate in tetrahydrofuran, adding sodium borohydride at 0°C-10°C in a protective gas environment, and stirring for 1.6h-2.6h; S2-2, adjusting the pH of the reaction system to 2, stirring at 0°C-10°C in a protective gas environment for 2.6h-3.6h; S2-3, after the reaction is completed, first removing tetrahydrofuran under reduced pressure, and then extracting with ethyl acetate to obtain an organic phase; the organic phase is dried with anhydrous sodium sulfate, and then concentrated to a volume of ≤15mL; heptane is added to the concentrated solution for crystallization, and then washed with heptane, and vacuum dried to obtain 3-isoflavone.

[0032] As a further preferred embodiment, the mass ratio of the intermediate to the sodium borohydride is 5: (0.25-0.45).

[0033] As a further preferred embodiment, the usage ratio of the intermediate to the tetrahydrofuran is 1: (8-16) in g / mL or kg / L.

[0034] As a further preferred embodiment, the adjustment of the pH is performed by a hydrochloric acid solution with a concentration of 4mol / L-8mol / L.

[0035] Example 1 (1) 100 g of phenylacetic acid was added to 500 mL of methanol, 10 mL of concentrated sulfuric acid was added dropwise, and heated to reflux for 8 h. The methanol was removed by concentration under reduced pressure. Then 600 mL of ethyl acetate and 500 mL of water were added, stirred to mix well, and allowed to stand to separate into organic and aqueous phases. The organic phase was washed with 100 mL of 5% sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain 99 g of methyl phenylacetate with a yield of 90%.

[0036] The hydrogen nuclear magnetic resonance hydrogen spectrum was detected at 400 MHz with DMSO as the solvent to obtain the following results: δ = 7.37-7.30 (m, 2H), δ = 7.26 (dd, J = 10.1, 4.4 Hz, 3H), δ = 3.68 (s, 2H), δ = 3.62 (s, 3H).

[0037] (2) 100 g of methyl phenylacetate was dissolved in 500 mL of dry N,N-dimethylformamide under nitrogen protection, and the temperature was controlled at 98°C. 112.6 g of phosphorus oxychloride was added dropwise, and the temperature was maintained for two hours after the addition was completed.

[0038] The reaction solution was slowly poured into 1 L of cold water at 10°C, the pH was adjusted to 5 with 10 wt.% sodium carbonate solution, and 600 mL of ethyl acetate was used for extraction to obtain an ethyl acetate phase. The ethyl acetate phase was washed with water four times, each time with 300 mL of water, and then the washed ethyl acetate phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain 108 g of crude oil. The crude oil was purified by silica gel column separation, the mobile phase was heptane and ethyl acetate with a volume ratio of 10:1, and 5.9 g of oily intermediate was obtained with a yield of 5%.

[0039] The hydrogen nuclear magnetic resonance hydrogen spectrum was detected at 400 MHz with DMSO as the solvent to obtain the following results: δ = 10.10 (s, 1H), δ = 7.94 (dd, J = 7.5, 1.4 Hz, 1H), δ = 7.65 (td, J = 7.5, 1.5 Hz, 1H), δ = 7.57 (dt, J = 7.5, 3.7 Hz, 1H), δ = 7.42 (d, J = 7.6 Hz, 1H), δ = 4.09 (s, 2H), δ = 3.60 (s, 3H).

[0040] (3) 5 g of the oily intermediate was dissolved in 50 mL of tetrahydrofuran under nitrogen protection, and 0.32 g of sodium borohydride was added in three batches at a temperature of 8°C. The temperature was controlled and stirred for 2 hours. The pH was adjusted to 2 with 6 mol / L hydrochloric acid at a temperature of 8°C, and stirred for 3 hours.

[0041] After the reaction, remove the tetrahydrofuran under reduced pressure, then add 100 mL of ethyl acetate to extract, dry with anhydrous sodium sulfate, and then concentrate to 10 mL under reduced pressure; add the concentrated solution dropwise to 50 mL of heptane under stirring to crystallize, filter, rinse with 10 mL of heptane, obtain the wet product, and dry under vacuum at 30°C to obtain 2.9 grams, with a yield of 70%.

[0042] The hydrogen nuclear magnetic resonance hydrogen spectrum is detected at 400 MHz with DMSO as the solvent to obtain the following results: δ = 7.57 ~ 7.10 (m, 4H), δ = 5.36 (s, 2H), δ = 3.81 (s, 2H).

[0043] Examples 2-4: Repeat Example 1 to detect the yield of steps (2), (3) through repeated experiments.

[0044] Example 5: substantially the same as Example 1, with the only difference being that: the reaction temperature in step (2) is changed from 98°C to 95°C; the reaction temperature in step (3) is changed from 8°C to 0°C.

[0045] Example 6: substantially the same as Example 1, with the only difference being that: the reaction temperature in step (2) is changed from 98°C to 100°C; the reaction temperature in step (3) is changed from 8°C to 10°C.

[0046] The yield of steps (2), (3) of each example is described in Table 1 below.

[0047] Table 1

[0048] As can be seen from Table 1 above, the preparation process of the present application has stable yield, and the raw materials are economical, the reaction process is simplified, and no toxic chemicals are used, which has good application prospect and popularization.

[0049] Although the present application has been illustrated and described with specific embodiments, it should be realized that the above examples are only used to illustrate the technical solutions of the present application, and are not limiting; those skilled in the art should understand that the technical solutions described in the above examples can be modified, or some or all of the technical features can be replaced with equivalents without departing from the spirit and scope of the present application; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the examples of the present application; therefore, this means that all these replacements and modifications within the scope of the present application are included in the appended claims.

Claims

1. A process for the preparation of 3-isochromones, characterized in that, The application relates to a preparation method of 3-isochromone. The application relates to a preparation method of 3-isochromone.

2. The method for preparing 3-isochromone according to claim 1, characterized in that, S1, mixing methyl phenylacetate, N,N-dimethylformamide and phosphorus oxychloride to prepare an intermediate shown in a structural formula (I) through a Vilsmeier-Haack reaction; S2, carrying out intramolecular condensation reaction on the intermediate to obtain 3-isochromone; The preparation method of the methyl phenylacetate comprises the following steps: （I）。 3. The process for the preparation of 3-isochromones according to claim 2, characterized in that, The methyl phenylacetate is obtained by mixing phenylacetic acid and methanol, adding concentrated sulfuric acid and carrying out reflux reaction; after the reaction is completed, methanol is removed through concentration under reduced pressure; then the mixture is mixed with ethyl acetate and deionized water and is subjected to liquid separation to obtain an organic phase; and the organic phase is washed and dried to obtain the methyl phenylacetate. The mass ratio of the methyl phenylacetate to the N,N-dimethylformamide is 1: (4-6) g / mL.

4. The method for preparing 3-isochromone according to claim 2, characterized in that, And / or, the mass ratio of the methyl phenylacetate to the phosphorus oxychloride is 1: (1-1.6) in step S1. The Vilsmeier-Haack reaction is carried out at a temperature of 95-100 DEG C for 1.6-2.5 h.

5. The method for preparing 3-isochromone according to claim 1, characterized in that, The intermediate is obtained through post-treatment after the Vilsmeier-Haack reaction; 6. The method for preparing 3-isochromone according to claim 2, characterized in that, The post-treatment comprises the following steps: cooling the reaction solution to 10 DEG C, adding deionized water and adjusting the pH to 5, then adding ethyl acetate and carrying out extraction, and separating to obtain an organic phase; and the organic phase is washed, dried and purified to obtain the intermediate. The purification is carried out through a silica gel column, and the mobile phase comprises heptane and ethyl acetate, and the volume ratio is 8-12:

1.

7. The method for preparing 3-isochromone according to claim 6, characterized in that, The intramolecular condensation reaction comprises the following steps:

8. The method for preparing 3-isochromone according to claim 2, characterized in that, S2-1, dissolving the intermediate in tetrahydrofuran, adding sodium borohydride under the protection of an inert gas at 0-10 DEG C, and stirring for 1.6-2.6 h; S2-2, adjusting the pH of the reaction system to 2, stirring under the protection of an inert gas at 0-10 DEG C for 2.6-3.6 h; S2-3, after the reaction is completed, removing tetrahydrofuran through concentration under reduced pressure, then extracting with ethyl acetate to obtain an organic phase; the organic phase is dried through anhydrous sodium sulfate, and then concentrated to a volume of less than or equal to 15 mL; heptane is added to the concentrated solution for crystallization, and then the 3-isochromone is obtained through washing with heptane and vacuum drying. The mass ratio of the intermediate to the sodium borohydride is 5: (0.25-0.45).

9. The method of claim 8, wherein the 3-isochromones are prepared by the reaction of a compound of formula (VII) with a compound of formula (VIII) ###00006### (VII) (VIII) in the presence of a base. The mass ratio of the intermediate to the tetrahydrofuran is 1: (8-16) g / mL.

10. The method of claim 8, wherein the 3-isochromone is prepared by the process of claim 1. ​

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