WO2017100985A1

WO2017100985A1 - Preparation method for 2,2-dihalo-1,3-dicarbonyl derivatives

Info

Publication number: WO2017100985A1
Application number: PCT/CN2015/097321
Authority: WO
Inventors: 邹建平; 周少方; 张国玉; 张令
Original assignee: 苏州大学张家港工业技术研究院
Priority date: 2015-12-14
Filing date: 2015-12-14
Publication date: 2017-06-22

Abstract

Disclosed is a method for preparing 2,2-dihalo-1,3-dicarbonyl derivatives. The method is applicable in a broad range of 1,3-dicarbonyl derivatives, which have various types of readily available raw materials. The method is utilized to produce various types of products, not only can be used directly, but also can be used for further reactions. The method has mild reaction conditions, simple operations and post-processing process, short reaction time, high yield, and reduced pollution and is suitable for industrialized production.

Description

Title: Preparation of a 2,2-di-g-1,3-dicarbonyl derivative

[0001] The present invention relates to the technical field of preparation of organic compounds, and in particular to a method for preparing a 2,2-dihalo-1,3-dicarbonyl derivative.

Background technique

[0002] 2,2-Dichloro-1,3-dicarbonyl derivatives are an important class of pharmaceutical and pesticide intermediates. Sun has published a process for the preparation of 2-chloro-1,3-benzenediol from 2,2-dichloro-1,3-cyclohexanedione. 2-Chloro-1,3-benzenediol is an important pharmaceutical and dye intermediate widely used in the synthesis of pharmaceuticals, pesticides and dyes. Its technical route is as follows:

[0003]

[0004] 1,3-cycloheptanedione can be prepared from 2,2-dichlorocycloheptane-1,3-dione, which is an important pharmaceutical intermediate.

(See: Acton, N.; Bros si, A.; Newton, D. L.; Sporn, M. B. J. Med. Chem., 1980, 23, 805-809). Its technical route is as follows:

[0005]

[0006] Tippe discloses a kind of 2,2-dichloro-4-(2,4-dichlorophenoxy)-1-phenyl-1,3-butanedione (1)

Process for the preparation of 2,2-bis(4-bromoanilino)-4-(2,4-dichlorophenoxy)-1-phenyl-1,3-butanedione (2), Compounds 1 and 2 Rhizoctonia solani, Fusarium oxysporum, and Phytophthora infestans have certain inhibitory effects; The route is as follows:

[] 0 /... ,.

From the 2,2-dichloro-1,3-dicarbonyl derivative, a compound 3, 5-phenyl-3-amino 1,2,4-triazole (compound 4) which can be used for the synthesis of a drug can be synthesized. The drug molecule compound 5 for treating Parkinson's disease; 2,2-dibromo-1,3-dicarbonyl derivative is also an important class of bromine reagent.

The synthetic methods for the disclosed 2,2-dichloro-1,3-dicarbonyl derivatives are mainly as follows:

[0009] The 2,2-dichloro-1,3-dicarbonyl compound is prepared by using the KCIO ₃ /NaHSO ₃ /ZnSO ₄ system, which has the disadvantages of narrow application range, high risk of operation, and large material loss. A method for preparing a 2,2-dichloro-1,3-dicarbonyl derivative using PhICl ₂ as a chlorinating reagent, which has a disadvantage that the substrate is difficult to obtain, the operation process is dangerous, and the chlorinating reagent is expensive. [0010] The synthetic methods for the disclosed 2,2-dibromo-1,3-dicarbonyl derivatives are mainly as follows:

[0011] A 2,2-dibromo-1,3-dicarbonyl derivative was prepared by a grinding method, and the method disclosed the results of three 2,2-dibromo-1,3-dicarbonyl derivatives, Insufficient application range, difficulty in amplification, etc.; Preparation of 2,2-dibromo-1,3-dicarbonyl derivative by using 0 _XOne /NH ₄ Br, the method is only applicable to 5 2,2-dibromo- The 1,3-dicarbonyl derivative has the disadvantages of a narrow application range of the substrate, a high risk of operation, and difficulty in amplification.

technical problem

[0012] The dihalogenation technology of the disclosed 1,3-dicarbonyl derivatives has difficulty in obtaining substrates, narrow application range of substrates, harsh reaction conditions, expensive halogenated reagents, high production cost, high pollution, and inconvenient operation. The scale of the reaction is difficult to enlarge. Therefore, it is important to find a method that meets the requirements of green chemistry, has mild reaction conditions, is universally suitable, and is suitable for large-scale production.

Problem solution

Technical solution

[0013] An object of the present invention is to provide a process for preparing a 2,2-dihalo-1,3-dicarbonyl derivative which has a simple source of raw materials, high yield, mild reaction conditions and good universality. advantage.

[0014] In order to achieve the above object, the technical solution adopted by the present invention is: a dihalogenation method of a 1,3-dicarbonyl derivative, comprising the steps of: 1,3-dicarbonyl derivative, sodium sulphate The manganese acetate and the copper catalyst are added to the solvent and reacted at 30 to 90 ° C to obtain a 2,2-di-1,3-dicarbonyl derivative;

[0015] The 1,3-dicarbonyl derivative is represented by the following chemical structural formula:

[0016]

Wherein R 2 is selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group or an alkoxy group; and R 2 is selected from the group consisting of: an alkyl group, an aryl group

One of a heteroaryl group or an alkoxy group;

[0018] the sodium salt is sodium bromide or sodium chloride;

[0019] The copper catalyst has the chemical formula CuX _n , wherein X is C1 or Br;

[0020] the solvent is selected from the group consisting of: methanol, ethanol, ethylene glycol, acetonitrile, acetic acid, propionic acid, dimethylformamide One.

[0021] The 2,2-di-1,3-dicarbonyl derivative is represented by the following chemical structural formula:

[0023] In the above technical solution, the 1,3-dicarbonyl derivative is selected from the group consisting of ethyl benzoate, ethyl (4-methylbenzoyl)acetate, and (4-methoxybenzoyl) Ethyl acetate, (2-methylbenzoyl) ethyl acetate, (

2-methoxybenzoyl) ethyl acetate, ethyl naphthoacetate, (4-chlorobenzoyl) ethyl acetate, (4-bromobenzoyl) ethyl acetate, (4-nitrobenzene Formyl) ethyl acetate, (3-bromobenzoyl) ethyl acetate, 1,3-diphenyl-1,3-propanedione, 1-(2-furyl)-3-phenyl-1 , 3-propanedione, 1-(2-thienyl)-3-phenyl-1,

3-propanedione, 1-(2-pyrrolyl)-3-phenyl-1,3-propanedione, 1-(4-methylphenyl)-3-phenyl-1,3-propane Ketone, μ(4-methoxyphenyl)-3-phenyl-1,3-propanedione, 1-(2-methylphenyl)-3-phenyl-1,3-propanedione, 1,3-bis(2-methoxyphenyl)-1,3-propanedione, 1-phenyl-1,3-pentanedione, 1-(4-chlorophenyl)-3-phenyl -1,3-propanedione, 1-(4-bromophenyl)-3-phenyl-1,3-propanedione, ethyl 3-oxopentanoate, 1,3-pentanedione, 3 , one of 5-heptanedione and diethyl malonate.

[0024] In the above technical solution, the reaction is followed by thin layer chromatography (TLC) until it is completely finished.

[0025] The present invention uses sodium bromide or sodium chloride as a raw material, and reacts with a 1,3-dicarbonyl derivative to prepare a product; sodium hydride is used, in a molar ratio, 1,3-dicarbonyl derivative: sodium halide : Manganese acetate: The copper catalyst is 1:2: (2 to 8): (0.08-0.12); Preferably, the 1,3-dicarbonyl derivative: manganese acetate: the copper catalyst is 1:4:0.1. Taking sodium bromide, in a molar ratio, 1,3-dicarbonyl derivative: sodium halide: manganese acetate: copper catalyst is 1:2: (6~8): (0.08-0.12); preferably, 1, 3-Dicarbonyl derivative: Manganese acetate: The copper catalyst was 1:7:0.1.

[0026] In a preferred technical solution, the product is subjected to column chromatography separation and purification after the reaction is completed; column chromatography separation Purification treatment with petroleum ether / ethyl acetate as the eluent, preferably the volume ratio of petroleum ether to ethyl acetate is 20:

The preferred reaction temperature of the present invention is from 60 to 70 °C. The reaction is mild, the product yield is high, and energy waste is avoided. [0028] The reaction process of the above technical solution can be expressed as:

Advantageous effects of the invention

Beneficial effect

[0030] Due to the use of the above technical solutions, the present invention has the following advantages over the prior art:

[0031] 1. The present invention uses the 1,3-dicarbonyl derivative and the sodium halide as the starting materials for the first time, and efficiently prepares 2,2-dihalo-1 in air in the presence of manganese acetate and a copper catalyst. 3-dicarbonyl derivative; easy to obtain raw materials, many kinds of products, the prepared product can be used directly, can also be used as an intermediate for other further reactions

[0032] 2. The invention has simple raw materials, does not need various compounding reagents required by the prior art, has small reagent dosage, good selectivity, low cost, and avoids the application of existing toxic compounds and reduces pollution environment; A small amount of catalyst can efficiently obtain the product, which not only simplifies the purification process of the product, but also reduces the generation of waste. Moreover, manganese acetate and copper catalyst can be recycled, avoiding waste of raw materials, and has positive practical significance for industrial applications.

[0033] 3. The preparation method of the present invention has simple reaction conditions, does not require a complicated atmosphere environment of the prior art, and can efficiently obtain a product by reacting in air, and the post-treatment is very simple, and column chromatography can be performed, thereby avoiding the existing reaction. The risk factors in the process are conducive to chemical synthesis and safe production, and to ensure the safety of life and property. [0034] 4. In the method of the present invention, the reaction is carried out in air, the reaction conditions are mild, the pollution is small, and the reaction time is short, and is particularly suitable for various 1,3-dicarbonyl derivatives, and the yield of the target product. High, easy to handle and post-process, suitable for industrial production. Embodiments of the invention

[0035] The present invention will be further described below in conjunction with the embodiments:

Example 1: Synthesis of 2,2-dibromobenzoylacetate

[0037] Taking ethyl benzoylacetate and sodium bromide as raw materials, the reaction steps are as follows:

[0038] Ethyl benzoylacetate (0.192 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (1.89 g) were added to the reaction flask. , 7

Methyl) and methanol (10 ml), 30 ° C reaction; TLC followed the reaction until the end; the crude product obtained after the end of the reaction was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 79%). The analytical data of the product are as follows: ΉΝΜΙ (400 ΜΗζ, CDC1 ₃ ): δ 8.22 - 7.80 (m, 2H), 7.65 - 7.54 (m, 1H), 7.50 - 7.37 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.13 (t, /= 7.1 Hz, 3H).

Example 2: Synthesis of 2,2-dichlorobenzoylacetic acid ethyl acetate

[0040] Taking ethyl benzoylacetate and sodium chloride as raw materials, the reaction steps are as follows:

[0041] Ethyl benzoylacetate (0.192 g, 1 mmol), sodium chloride (0.116 g, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol), manganese acetate (1.89 g) were added to the reaction flask. , 7

Methyl) and ethanol (10 ml), 40 ° C; TLC followed the reaction until the end; the crude product obtained after the end of the reaction was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 81%). The analytical data of the product is as follows: ΉΝΜΙ (400 ΜΗζ,

CDC1 ₃ ): δ 8.42 - 7.80 (m, 2H), 7.67 - 7.54 (m, 1H), 7.50 - 7.37 (m, 2H), 4.28 (q, J =

7.1 Hz, 2H), 1.13 (t, /= 7.1 Hz, 3H).

Example 3: Synthesis of 2,2-dibromo(4-methylbenzoyl)acetic acid ethyl acetate

[0043] Taking (4-methylbenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0044] (4-methylbenzoyl) ethyl acetate (0.206 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), cuprous iodide (0.020 g, 0.1 mmol), acetic acid Manganese (1.89 g, 7 mmol) and acetonitrile (10 ml), 50. C reaction; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield: 77%). The analytical data for the product are as follows: Ή ΝΜΚ (400 ΜΗζ, .θα ₃ ): (5 7.91 (d, / = 8.4 Hz, 2H), 7.24 (d, /= 8.2 Hz, 2H), 4.29 (q, /= 7.1 Hz, 2H), 2.42 (s, 3H), 1.16 (t, / = 7.1 Hz, 3H).

Example 4: Synthesis of 2,2-dibromo(4-methoxybenzoyl)acetic acid ethyl acetate

[0046] Taking (4-methoxybenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0047] (4-methoxybenzoyl) ethyl acetate (0.222 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), copper chloride (0.013 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), 60. C reaction; TLC followed the reaction until the end; the crude product obtained after the reaction was purified by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield 81%). The analytical data of the product are as follows: Ή ΝΜΚ (400 ΜΗζ, .θα ₃ ): (5 8.12 - 7.90 (m, 2H), 6.91 (d, / = 9.0 Hz, 2H), 4.29 (q, / = 7.1 Hz, 2H ), 3.87 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).

Example 5: Synthesis of 2,2-dibromo(2-methylbenzoyl)acetic acid ethyl acetate

[0049] Taking (2-methylbenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0050] Add (2-methylbenzoyl) ethyl acetate (0.206 g, 1) to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), copper chloride (0.013 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and propionic acid (10 ml), 70 ° C reaction; TLC tracking reaction The crude product obtained after the completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield: 76%). The analytical data for the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): ό 7.79 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 4.26 (q, / = 7.1 Hz, 2H), 2.46 (s, 3H), 1.15 (t, / = 7.1 Hz, 3H).

Example 6: Synthesis of 2,2-dibromo(2-methoxybenzoyl)acetic acid ethyl acetate

[0052] Taking (2-methoxybenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0053] (2-Methoxybenzoyl) ethyl acetate (0.222 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), cuprous iodide (0.020 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and dimethylformamide (10 ml), reaction at 80 ° C ; TLC tracking response straight The crude product obtained after completion of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the objective product (yield: 82%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 3): δ 7.95 (dd, /= 7.9, 1.7 Hz, 1H), 7.64 - 7.48 (m, 1H), 7.15 - 7.03 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.26 (q, /= 7.1 Hz, 2H), 3.81 (s, 3H), 1.21 (t, /= 7.1 Hz, 3H).

Example 7: Synthesis of 2,2-dibromonaphthoylacetate

[0055] Taking ethyl naphthoylacetate and sodium bromide as raw materials, the reaction steps are as follows:

[0056] Ethyl naphthoylacetate (0.242 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous iodide (0.020 g, 0.1 mmol), manganese acetate (1.89 g) were added to the reaction flask. , 7 mmol) and dimethylformamide (10 ml), reaction at 90 ° C; TLC followed the reaction until the end; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) ), the target product was obtained (yield 84%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): δ 8.20 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.59 - 7.53 (m, 1H), 7.46 (t, /= 7.8 Hz, 1H), 4.21 (q, / = 7.1 Hz, 2H), 1.01 (t, J = 7.1 Hz, 3H).

Example 8: Synthesis of 2,2-dibromo(4-chlorobenzoyl)acetic acid ethyl acetate

[0058] Taking (4-chlorobenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0059] (4-chlorobenzoyl) ethyl acetate (0.226 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), copper bromide (0.022 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), 30. C reaction; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield: 77%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): ό 7.95 (d, / = 8.6 Hz, 2H), 7.41 (d, /= 8.6 Hz, 2H), 4.28 (q, /= 7.1 Hz, 2H), 1.16 (t, / = 7.1 Hz, 3H).

Example 9: Synthesis of 2,2-dibromo(4-bromobenzoyl)acetic acid ethyl acetate

[0061] Taking (4-bromobenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0062] (4-Bromobenzoyl) ethyl acetate (0.269 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), copper bromide (0.022 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), 40. C reaction; TLC tracks the reaction until it is completely over The crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield: 73%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): ό 7.88 (d, / = 8.7 Hz, 2H), 7.60 (d, / = 8.7 Hz, 2H), 4.30 (q, / = 7.1 Hz, 2H), 1.18 (t, / = 7.1 Hz, 3H).

Example 10: Synthesis of 2,2-dibromo(4-nitrobenzoyl)acetic acid ethyl acetate

[0064] Taking (4-nitrobenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0065] (4-Nitrobenzoyl) ethyl acetate (0.237 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), copper iodide (0.064 g, 0.2 mmol), manganese acetate (1.89 g, 7 mmol) and ethanol (10 ml), 60. C reaction; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the objective product (yield 65%). The analytical data of the product are as follows: 'HNMR (400 MHz, CDC1 ₃ ): ό 8.34 - 8.28 (m, 2H), 8.25 - 8.16 (m, 2H), 4.33 (q, / = 7.1 Hz, 2H), 1.21 (t , / = 7.1 Hz, 3H).

Example 11: Synthesis of 2,2-dibromo(3-bromobenzoyl)acetic acid ethyl acetate

[0067] Taking (3-bromobenzoyl) ethyl acetate and sodium bromide as raw materials, the reaction steps are as follows:

[0068] Ethyl (3-bromobenzoyl)acetate (0.269 g, 1) was added to the reaction flask.

Methyl), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (1.62 g, 6 mmol) and ethanol (10 ml), 60. C reaction; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the objective product (yield 65%). The analytical data of the product are as follows: Ή ΝΜΚ (400 ΜΗζ, θα ₃ ): (5 8.16 (s, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.71 (d, / = 8.0 Hz, 1H), 7.33 (t, / = 8.0 Hz, 1H), 4.31 (q, / = 7.1 Hz, 2H), 1.19 (t, / = 7.1 Hz, 2H).

Example 12: Synthesis of 2,2-dibromo-1,3-diphenyl-1,3-propanedione

[0070] Taking 1,3-diphenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0071] 1,3-diphenyl-1,3-propanedione (0.224 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum Ether = 1:20), the desired product was obtained (yield: 74%). The analytical data of the product are as follows: 3⁄4 NMR (400 MHz, CDC1 ₃ ): (58.06 - 7.82 (m, 4H), 7.52 - 7.46 (m, 2H), 7.41 - 7.31 (m, 4H).

Example 13: Synthesis of 2,2-dichloro-1,3-diphenyl-1,3-propanedione

[0073] Taking 1,3-diphenyl-1,3-propanedione and sodium chloride as raw materials, the reaction steps are as follows:

[0074] 1,3-diphenyl-1,3-propanedione (0.224 g, 1 mmol) and sodium chloride (0.116 g) were added to the reaction flask.

, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol), manganese acetate (0.81 g, 3 mmol) and ethanol (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; The crude product was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to afford product (yield: 73%). The analytical data of the product are as follows: 3⁄4 NMR (400 MHz, CDC1 ₃ ): (58.06 - 7.82 (m, 4H), 7.52 - 7.46 (m, 2H), 7.41 - 7.31 (m, 4H).

Example 14 Synthesis of 1-(2-furyl)-2,2-dibromo-3-phenyl-1,3-propanedione

[0076] Taking 1-(2-furyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0077] 1-(2-furyl)-3-phenyl-1,3-propanedione (0.214 g, 1 mmol), sodium bromide was added to the reaction flask.

(0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; The crude product obtained after the separation was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 74%). The analytical data of the product are as follows: ΉΝΜΙ (400 ΜΗζ, CDC1 ₃ ): (58.85-8.50 (m, 2H), 7.88 -7.50 (m, 5H), 7.33 -7.30 (m, 1H)=

Example 15 Synthesis of l-(2-furyl)-2,2-dichloro-3-phenyl-1,3-propanedione

[0079] Taking 1-(2-furyl)-3-phenyl-1,3-propanedione and sodium chloride as raw materials, the reaction steps are as follows:

[0080] 1-(2-furyl)-3-phenyl-1,3-propanedione (0.214 g, 1 mmol), sodium chloride was added to the reaction flask.

(0.116 g, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol), manganese acetate (1.08 g, 4 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; The obtained crude product was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to afford product (yield: 85%). The analytical data of the product are as follows: 'HNMR (400 MHz, CDC1 ₃ ): (58.85_8.50 (m, 2H), 7.88 - 7.50 (m, 5H), 7.33 - 7.30 (m, 1H).

Example 16: Synthesis of l-(2-thienyl)-2,2-dibromo-3-phenyl-1,3-propanedione

[0082] With 1-(2-thienyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0083] 1-(2-Thienyl)-3-phenyl-1,3-propanedione (0.230 g, 1 mmol), sodium bromide was added to the reaction flask. (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (2.16 g, 8 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; The crude product obtained after the separation was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 80%). The analytical data of the product is as follows: ΉΝΜΙ (400 ΜΗζ,

CDC1 ₃ ): (58.15-7.90 (m, 4H), 7.88 -7.50 (m, 3H), 7.33 - 7.20 (m, 1H).

Example 17: Synthesis of l-(2-pyrrolyl)-2,2-dibromo-3-phenyl-1,3-propanedione

[0085] Taking 1-(2-pyrrolyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0086] 1-(2-pyrrolyl)-3-phenyl-1,3-propanedione (0.213 g, 1 mmol), sodium bromide was added to the reaction flask.

1:20), the target product was obtained (yield 78%). The analytical data of the product are as follows: ΉΝΜΙ (400 ΜΗζ, CDC1 ₃ ): (510.80 (s, 1H), 8.21-8.00 (m, 3H), 7.74 - 7.48 (m, 3H), 7.35-7.00 (m, 2H).

Example 18: Synthesis of 2,2-dibromo-1-(4-methoxyphenyl)-3-phenyl-1,3-propanedione

[0088] 1-(4-methoxyphenyl)-3-phenyl-1,3-propanedione, sodium bromide as a raw material, the reaction steps are as follows

[0089] 1-(4-Methoxyphenyl)-3-phenyl-1,3-propanedione (0.254 g, 1 mmol), sodium bromide (0.206 g, 2 mmol) was added to the reaction flask. , copper bromide (0.014 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and dimethylformamide (10 ml), reacted at 70 ° C; TLC followed the reaction until it was completely finished; The crude product was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to afford product (yield: 85%). The analytical data of the product are as follows: NMR NMR (400 MHz, CDC1 ₃ ): 07.97 - 7.87 (m, 4H), 7.46 (t, / = 7.4 Hz, 1H), 7.33 (t, /= 7.9 Hz, 2H), 6.83 - 6.67 (m, 2H), 3.78 (s, 3H).

Example 19: Synthesis of 2,2-dibromo-1-(2-methylphenyl)-3-phenyl-1,3-propanedione

[0091] 1-(2-methylphenyl)-3-phenyl-1,3-propanedione, sodium bromide was used as a raw material, and the reaction steps were as follows: [0092] 1-(1) was added to the reaction flask. 2-methylphenyl)-3-phenyl-1,3-propanedione (0.238 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol) , manganese acetate (1.89 g, 7 mmol) and dimethylformamide (10 ml), 70 ° C reaction; TLC tracking reaction until the end; The crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield: 88%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): ό 7.97 - 7.93 (m, 2H), 7.78 (d, / = 7.1 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.41 - 7.32 (m, 3H), 7.24 (d, J = 7.7 Hz, 1H), 7.13 (t, / = 8.0 Hz, 1H), 2.50 (s, 3H).

Example 20: Synthesis of 2,2-bromo-1,3-bis(2-methoxyphenyl)-1,3-propanedione

[0094] using 1,3-bis(2-methoxyphenyl)-1,3-propanedione, sodium bromide as a raw material, the reaction steps are as follows: Add 1,3-bis (2) in the reaction flask -Methoxyphenyl)-1,3-propanedione (0.284 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate (1.89) g, 7 mmol) and dimethylformamide (10 ml), reaction at 70 ° C; TLC followed the reaction until the end; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1: 20), the target product was obtained (yield 89%). The analytical data of the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): ό 7.98 (dd, J = 7.9, 1.7 Hz, 2H), 7.48 - 7.38 (m, 2H), 7.00 (t, J = 7.9 Hz, 2H ), 6.79 (d, J = 8.3 Hz, 2H), 3.57 (s, 6H).

Example 21: Synthesis of 2,2-dibromo-1-phenyl-1,3-pentanedione

[0096] Taking 1-phenyl-1,3-pentanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0097] 1-phenyl-1,3-pentanedione (0.176 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol) were added to the reaction flask. , manganese acetate (1.89 g, 7

Methyl) and acetic acid (10 ml), 60 ° C; TLC followed the reaction until the end; the crude product obtained after the end of the reaction was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 78%). The analytical data of the product are as follows: Ή ΝΜΙ (400 ΜΗζ, CDC1 ₃ ): δ 8.09 - 7.95 (m, 2H), 7.61 - 7.55 (m, 1H), 7.45 (t, /= 7.9 Hz, 2H), 2.82 (q , J = 7.2 Hz, 2H), 1.16 (t, / = 7.2 Hz, 3H).

Example 22: Synthesis of 2,2-dibromo-1-(4-chlorophenyl)-3-phenyl-1,3-propanedione

[0099] Taking 1-(4-chlorophenyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows: [0100] Add 1- (4) to the reaction flask -Chlorophenyl)-3-phenyl-1,3-propanedione (0.256 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), acetic acid Manganese (1.89 g, 7 mmol) and acetonitrile (10 ml) were reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20), the target product was obtained (yield 76%). The analytical data for the product are as follows: Ή ΝΜΙ (400 ΜΗζ, CDC1 ₃ ): (57.95 (d, / = 7.5 Hz, 2H), 7.89 (d, / = 8.7 Hz, 2H), 7.52 (t, /= 7.4 Hz, 1H), 7.38 (t, / = 7.8 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H).

Example Twenty-three: Synthesis of 2,2-dibromo-1-(4-bromophenyl)-3-phenyl-1,3-propanedione

Taking 1-(4-bromophenyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows: [0103] Add 1- (4) to the reaction flask -Bromophenyl)-3-phenyl-1,3-propanedione (0.301 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), acetic acid Manganese (1.89 g, 7 mmol) and acetonitrile (10 ml) were reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether =

1:20), the target product was obtained (yield 80%). The analytical data of the product are as follows: Ή ΝΜΙ (400 ΜΗζ, CDC1 ₃ ): δ 7.99 - 7.92 (m, 2H), 7.86 - 7.75 (m, 2H), 7.56 - 7.47 (m, 3H), 7.38 (t, J = 7.8 Hz, 2H).

Example twenty-four: Synthesis of ethyl 2,2-dibromo-3-oxopentanoate

[0105] Taking ethyl 3-oxopentanoate and sodium bromide as raw materials, the reaction steps are as follows:

[0106] Ethyl 3-oxopentanoate (0.144 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate ( 1.89 g, 7

1:20), the target product was obtained (yield 64%). The analytical data for the product are as follows: Ή ΝΜΙ (400 ΜΗζ, CDC1 ₃ ): (54.35 (q, / = 7.1 Hz, 2H), 2.94 (q, / = 7.2 Hz, 2H), 1.33 (t, /= 7.1 Hz, 3H), 1.21 (t, / = 7.2 Hz, 3H).

Example 25: Synthesis of 2,2-dichloro-3-oxopentanoate

[0108] Taking ethyl 3-oxopentanoate and sodium chloride as raw materials, the reaction steps are as follows:

[0109] Ethyl 3-oxopentanoate (0.144 g, 1 mmol), sodium chloride (0.116 g, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol), manganese acetate ( 1.08 g, 4

1:20), the target product was obtained (yield 74%). The analytical data of the product is as follows: Ή ΝΜΙ (400 ΜΗζ, CDC1 ₃ ): (54.35 (q, / = 7.1 Hz, 2H), 2.94 (q, / = 7.2 Hz, 2H), 1.33 (t, /= 7.1 Hz, 3H),

1.21 (t, / = 7.2 Hz, 3H).

Example Twenty-six: Synthesis of 3,3-dibromo-1,3-pentanedione

[0111] Taking 1,3-pentanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0112] 1,3-pentanedione (0.100 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate were added to the reaction flask. (1.89 g, 7 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) , the target product was obtained (yield 68%). The analytical data of the product are as follows: NMR NMR (400 MHz, CDC1 ₃ ): δ 2.60 (s, 6H).

Example 27: Synthesis of 4,4-dibromo-3,5-heptanedione

[0114] Taking 3,5-heptanedione and sodium bromide as raw materials, the reaction steps are as follows:

[0115] 3,5-heptanedione (0.128 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol), manganese acetate were added to the reaction flask. (1.89 g, 7 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) , the target product was obtained (yield 65%). The analytical data for the product are as follows: NMR NMR (400 MHz, CDC1 ₃ ): 52.15 (q, /= 7.2 Hz, 4H), 1.23 (t, / = 7.2 Hz, 6H).

Example 28: Synthesis of 4,4-dichloro-3,5-heptanedione

[0117] Taking 3,5-heptanedione and sodium chloride as raw materials, the reaction steps are as follows:

[0118] 3,5-heptanedione (0.128 g, 1 mmol), sodium chloride (0.116 g, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol), manganese acetate were added to the reaction flask. (1.08 g, 4 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) , the target product was obtained (yield 71%). The analytical data for the product are as follows: NMR NMR (400 MHz, CDC1 ₃ ): 52.15 (q, /= 7.2 Hz, 4H), 1.23 (t, / = 7.2 Hz, 6H).

Example 29: Synthesis of diethyl 2,2-dibromomalonate

[0120] Taking diethyl malonate and sodium bromide as raw materials, the reaction steps are as follows:

[0121] Diethyl malonate (0.160 g, 1 mmol), sodium bromide (0.206 g, 2 mmol) was added to the reaction flask. , copper bromide (0.014 g, 0.1 mmol), manganese acetate (1.89 g, 7 mmol) and acetic acid (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the crude product obtained after the reaction was completed Column chromatography (ethyl acetate: petroleum ether = 1:20) gave the desired product (yield: 74%). The analytical data for the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): δ 4.75 (q, / = 7.3 Hz, 4H), 1.63 (t, / = 7.3 Hz, 6H).

Example 30: Synthesis of diethyl 2,2-dichloromalonate

[0123] Taking diethyl malonate and sodium chloride as raw materials, the reaction steps are as follows:

[0124] Diethyl malonate (0.160 g, 1 mmol), sodium chloride (0.116 g, 2 mmol), cuprous chloride (0.010 g, 0.1 mmol) manganese acetate (1.08 g, 4 mmol) and acetic acid (10 ml), 60 ° C reaction; TLC followed the reaction until the end; the crude product obtained after the end of the reaction was separated by column chromatography (ethyl acetate: petroleum ether = 1:20) to give the desired product (yield 72%). The analytical data for the product are as follows: Ή NMR (400 MHz, CDC1 ₃ ): δ 4.75 (q, / = 7.3 Hz, 4H), 1.63 (t, / = 7.3 Hz, 6H).

Example 31: Synthesis of 2,2-dibromo-1-(4-methylphenyl)-3-phenyl-1,3-propanedione

Taking 1-(4-methylphenyl)-3-phenyl-1,3-propanedione and sodium bromide as raw materials, the reaction steps are as follows: [0127] 1-(1) is added to the reaction flask. 4-methylphenyl)-3-phenyl-1,3-propanedione (0.238 g, 1 mmol), sodium bromide (0.206 g, 2 mmol), cuprous bromide (0.014 g, 0.1 mmol) , manganese acetate (1.89 g, 7 mmol) and ethanol (10 ml), react at 60 ° C; TLC followed the reaction until the end; distill off the solvent, the residue was extracted twice with ethyl acetate, and the residue remained after extraction The next experiment was carried out; the combined ethyl acetate extracts were combined, and ethyl acetate was evaporated to give the crude product, which was purified by column chromatography (ethyl acetate: petroleum ether = 1:20) %). The analytical data for the product are as follows: Ή ΝΜΙ (400 MHz, CDC1 3): δ 7.92 (d, / = 7.5 Hz, 2H), 7.83 (d, / = 8.3 Hz, 2H), 7.43 (t, /= 7.4 Hz, 1H), 7.30 (t, /= 7.8 Hz, 2H), 7.10 (d, / = 8.2 Hz, 2H), 2.28 (s, 3H).

Example 32: Synthesis of 2,2-dibromo-1-(4-methylphenyl)-3-phenyl-1,3-propanedione

[0129] In the thirty-first reaction step of the embodiment

(3)

1-(4-methylphenyl)-3-phenyl-1,3-propanedione (0.238 g, 1 mmol) and sodium bromide (0.206 g) were added to the residue obtained after extraction. , 2 mmol), manganese acetate (0.54 g, 2 mmol) and B Alcohol (10 ml), reacted at 60 ° C; TLC followed the reaction until it was completely finished; the solvent was evaporated, the residue was extracted twice with ethyl acetate, and the residue remaining after extraction was used for the next experiment; The ester extract was evaporated to give the title compound (yield: ethyl acetate: petroleum ether = 1:20).

The catalyst bromide in the reaction of the present invention and the manganese acetate which is not consumed in the reaction can be further utilized by the second reaction, and the subsequent reaction does not require the addition of the catalyst copper bromide, as long as the appropriate amount of manganese acetate is added, plus Other reactants and solvents can be used, so that resources can be reused to save resources and reduce pollution.

Claims

Claim

[Claim 1] A method for producing a 2,2-disubstituted-1,3-dicarbonyl derivative, which comprises the steps of: 1,3-dicarbonyl derivative, sodium chloride, manganese acetate And a copper catalyst is added to the solvent and reacted at 30 to 90 ° C to obtain a 2,2-di-1,3-dicarbonyl derivative; the 1,3-dicarbonyl derivative is as defined in the following chemical structure Show:

Wherein R ^{1 is} selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group or an alkoxy group; and R ^{2 is} selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group or an alkoxy group;

The copper catalyst has the chemical formula CuX _n , wherein X is C1 or Br; n is 1 or 2; the solvent is selected from the group consisting of: methanol, ethanol, ethylene glycol, acetonitrile, acetic acid, propionic acid, dimethylformamide a kind

The 2,2-di-1,3-dicarbonyl derivative is represented by the following chemical formula:

[Claim 2] The method for producing a 2,2-disubstituted-1,3-dicarbonyl derivative according to Claim 1, characterized by: 1,3-dicarbonyl derivative: sodium chloride in a molar ratio : Manganese acetate: copper catalyst is 1:2: (

2~8 0.08~0.12

[Claim 3] The method for producing a 2,2-dihalo-1,3-dicarbonyl derivative according to claim 2, wherein: 1,3-dicarbonyl derivative: manganese acetate in a molar ratio : The copper catalyst was 1:4:0.1.

[Claim 4] The method for producing a 2,2-disubstituted-1,3-dicarbonyl derivative according to claim 1, wherein the 1,3-dicarbonyl derivative is selected from benzoylacetic acid Ethyl acetate, (4-methylbenzoyl) ethyl acetate, (4-methoxybenzoyl) ethyl acetate, (2-methylbenzoyl)acetic acid Ethyl acetate, (2-methoxybenzoyl) ethyl acetate, ethyl naphthoacetate, (4-chlorobenzoyl) ethyl acetate, (4-bromobenzoyl) ethyl acetate, (4 -nitrobenzoyl) ethyl acetate, (3-bromobenzoyl) ethyl acetate, 1,3-diphenyl-1,3-propanedione, 1-(2-furyl)-3- Phenyl-1,3-propanedione, 1-(2-thienyl)-3-phenyl-1,3-propanedione, 1-(2-pyrrolyl)-3-phenyl-1,3 -propylenedione, 1-(4-methylphenyl)-3-phenyl-1,3-propanedione, 1-(4-methoxyphenyl)-3-phenyl-1,3- Propanedione, 1-(2-methylphenyl)-3-phenyl-1,3-propanedione, 1,3-bis(2-methoxyphenyl)-1,3-propanedione , 1-phenyl-1,3-pentanedione, 1-(4-chlorophenyl)-3-phenyl-1,3-propanedione, 1-(4-bromophenyl)-3-benzene One of 1,3-propanedione, ethyl 3-oxopentanoate, 1,3-pentanedione, 3,5-heptanedione, and diethyl malonate.

[Claim 5] The method for producing a 2,2-di-1,3-dicarbonyl derivative according to claim 1, wherein: the reaction is carried out in the air; the reaction is traced by thin layer chromatography until completely After the end of the reaction, the product is subjected to column chromatography separation and purification treatment.

[Claim 6] A method for producing a 2,2-disubstituted-1,3-dicarbonyl derivative, which comprises the steps of: 1,3-dicarbonyl derivative, sodium bromide, manganese acetate And a copper catalyst is added to the solvent and reacted at 30 to 90 ° C to obtain a 2,2-di-1,3-dicarbonyl derivative; in a molar ratio, a 1,3-dicarbonyl derivative: sodium bromide: Manganese acetate: copper catalyst is 1:2: (6~8):

(0.08~0.12);

The 1,3-dicarbonyl derivative is represented by the following chemical structural formula:

§ ,

The 2,2-di-1,3-dicarbonyl derivative is represented by the following chemical formula: The method for producing a 2,2-dihalo-1,3-dicarbonyl derivative according to claim 6, wherein the 1,3-dicarbonyl derivative is selected from the group consisting of ethyl benzoate, 4-methylbenzoyl) ethyl acetate, (4-methoxybenzoyl) ethyl acetate, (2-methylbenzoyl) ethyl acetate, (2-methoxybenzoyl)acetic acid Ethyl acetate, ethyl naphthoacetate, ethyl (4-chlorobenzoyl)acetate, ethyl (4-bromobenzoyl)acetate, ethyl (4-nitrobenzoyl)acetate, (3- Bromobenzoyl) ethyl acetate, 1,3-diphenyl-1,3-propanedione, 1-(2-furyl)-3-phenyl-1,3-propanedione, 1-( 2-thienyl)-3-phenyl-1,3-propanedione, 1-(2-pyrrolyl)-3-phenyl-1,3-propanedione, 1-(4-methylphenyl )-3-phenyl-1,3-propanedione, 1-(4-methoxyphenyl)-3-phenyl-1,3-propanedione, 1-(2-methylphenyl) -3-phenyl-1,3-propanedione, 1,3-bis(2-methoxyphenyl)-1,3-propanedione, 1-phenyl-1,3-pentanedione, 1-(4-Chlorophenyl)-3-phenyl-1,3-propanedione, 1-(4-bromophenyl)-3-phenyl-1,3-propanedione, 3-oxo Ethyl valerate, 1,3 One of pentanedione, 3,5-heptanedione, and diethyl malonate.

The process for producing a 2,2-dihalo-1,3-dicarbonyl derivative according to claim 6, wherein: the reaction is carried out in air; the reaction is traced by thin layer chromatography until it is completely finished; The product is then subjected to column chromatography separation and purification.

The method for producing a 2,2-dihalo-1,3-dicarbonyl derivative according to claim 6, wherein: 1,3-dicarbonyl derivative: manganese acetate: copper catalyst is 1 in terms of molar ratio :7:0.1.

The process for producing a 2,2-dihalo-1,3-dicarbonyl derivative according to claim 6, wherein the reaction temperature is 60 to 70 °C.