Preparation method of 5-chloroindanone

Abstract

The invention discloses a preparation method of 5-chloroindanone, and belongs to the technical field of chemical material preparation. The preparation method comprises the following steps: taking 2-bromo-4-chlorobenzaldehyde as a raw material and reacting with acrylate under the action of DABCO to generate an intermediate; and performing cyclization reaction under the action of a palladium catalyst and alkali to generate the 5-chloroindanone. According to the invention, the ionic liquid catalyst is added to cooperate with the DABCO to carry out Baylis-Hillman reaction, so that the dosage of the DABCO is reduced, and the yield is improved; through the positioning cyclization reaction of bromine on a benzene ring and olefin, the generation of isomers is greatly reduced, the isomers and a large amount of waste acid and wastewater caused by Friedel-Crafts cyclization reaction are avoided, and an effective new path is provided for the preparation of 5-chloroindanone.

Description

Technical Field

[0001] The invention relates to a method for preparing 5-chloroindanone, and belongs to the technical field of chemical material preparation. Background Art

[0002] 5-Chloroindanone is an important organic synthesis intermediate with a wide range of applications. Pharmaceutical field: 5-Chloroindanone has important applications in the pharmaceutical field and can be used to prepare a variety of new drugs, such as anti-tumor drugs, anti-inflammatory drugs, cardiovascular drugs, etc. With the aging of the population and changes in the disease spectrum, the demand in the pharmaceutical market will continue to grow, providing huge market opportunities for the development of 5-chloroindanone. Pesticide field: 5-Chloroindanone can be used to prepare high-efficiency, low-toxic, and low-residue pesticides, such as insecticides, fungicides, herbicides, etc. Dyes and liquid crystal materials: 5-Chloroindanone also has broad application prospects in the fields of dyes and liquid crystal materials.

[0003] For this product, after literature search of the prior art, the current synthesis methods of 5-chloroindanone are as follows:

[0004] A. Patents [CN113087609A; CN115974664A] report that 5-chloroindanone is produced by cyclization reaction using 1-(4-chlorophenyl)-2-propene-1-one as a raw material.

[0005] B. Patents and literature [CN108329197A; CN107673956A; CN104910001A; CN108329197A; Journal of Chemical Research, Miniprint, 1996, 1, 301] report that m-chlorophenylpropionyl chloride is used as a raw material to undergo a Friedel-Crafts cyclization reaction to generate 5-chloroindanone.

[0006] C. Literature [Synthetic Communications, 2016, 46, 1747; Chinese Journal of Chemistry, 2017, 35, 1391] reported that 5-chloro-2,3-dihydro-1H-indene-1-ol was used as a raw material for oxidation reaction to generate 5-chloroindanone.

[0007] D. Literature and patents [CN109293488A; CN106588612A; Asian Journal of Chemistry, 2012, 24, 1413] reported that 5-chloroindanone was generated by a two-step Friedel-Crafts reaction using chlorobenzene and 3-chloropropionyl chloride as raw materials.

[0008] The above routes use olefin cyclization or Friedel-Crafts reaction, but the reaction localization efficiency is low and there are a large number of isomers. In view of the shortcomings of the above routes, it is necessary to study their synthesis methods to meet the growing market demand. Summary of the invention

[0009] The technical problem to be solved by the present invention is to provide a method for preparing 5-chloroindanone. The method provided by the present invention uses 2-bromo-4-chlorobenzaldehyde as a raw material and acrylate under the action of DABCO and an ionic liquid catalyst to generate an intermediate; then, under the action of a palladium catalyst and a base, the olefin and the bromine on the benzene ring undergo a site-specific cyclization reaction, and a decarboxylation reaction is simultaneously performed to generate 5-chloroindanone, thereby greatly reducing the generation of isomers, improving the yield of the product, and avoiding the generation of a large amount of waste acid and wastewater by the Friedel-Crafts reaction.

[0010] The objective of the present invention is achieved through the following technical solutions, and the reaction equation is expressed as follows:

[0011] The steps include:

[0012] A. mixing 2-bromo-4-chlorobenzaldehyde, acrylate, DABCO and an ionic liquid catalyst in a solvent to generate an intermediate;

[0013] B. The intermediate, palladium catalyst, tri-tert-butylphosphine tetrafluoroborate, NaBARF and base are mixed in an organic solvent and reacted at elevated temperature to generate 5-chloroindanone.

[0014] Furthermore, in step A of the above technical solution, the acrylate is selected from methyl acrylate or ethyl acrylate.

[0015] Furthermore, in step A of the above technical solution, the solvent is triethanolamine.

[0016] Furthermore, in step A of the above technical solution, the ionic liquid catalyst is selected from 1-butyl-3-methylimidazolium tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate.

[0017] Furthermore, in step A of the above technical solution, the molar ratio of 2-bromo-4-chlorobenzaldehyde, acrylate, DABCO and ionic liquid catalyst is 1:1-1.3:0.2-0.4:0.05-0.1.

[0018] Furthermore, in step B of the above technical solution, the palladium catalyst is palladium acetate.

[0019] Furthermore, in step B of the above technical solution, the base is potassium phosphate.

[0020] Furthermore, in step B of the above technical solution, the organic solvent is selected from DMF, DMAc or sulfolane.

[0021] Furthermore, in step B of the above technical solution, the temperature rising reaction condition is 100-140°C.

[0022] Furthermore, in step B of the above technical scheme, the molar ratio of the intermediate, palladium catalyst, tri-tert-butylphosphine-tetrafluoroborate, NaBARF (sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) and base is 1: 0.01-0.03: 0.02-0.04: 0.03-0.05: 2-3. Beneficial effects of the present invention:

[0023] A. The present invention uses benzene 2-bromo-4-chlorobenzaldehyde and acrylate to carry out Baylis-Hillman reaction, adds ionic liquid catalyst to coordinate DABCO reaction, reduces the amount of DABCO used, and improves the yield; at the same time, triethanolamine is used as a solvent to improve the reaction rate.

[0024] B. The cyclization reaction of the present invention adds a phosphine ligand to improve the efficiency of the site-directed cyclization reaction catalyzed by palladium acetate. It avoids the use of isomers and a large amount of waste acid and waste water caused by the Friedel-Crafts cyclization reaction. It provides a route reference for the synthesis of such compounds. Specific embodiments

[0025] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0026] Example 1

[0027]

[0028] Under nitrogen protection, 21.9 g (0.1 mol) of 2-bromo-4-chlorobenzaldehyde, 10.3 g (0.12 mol) of methyl acrylate, 3.4 g (0.03 mol) of DABCO and 1.8 g (0.008 mol) of 1-butyl-3-methylimidazolium tetrafluoroborate catalyst were mixed in 100 ml of triethanolamine and reacted at room temperature for 4 hours. Subsequently, 100 ml of diisopropyl ether was added to dilute the mixture, and then 5% hydrochloric acid was added to adjust the pH to 6-7. The layers were separated, and the aqueous layer was extracted once with 100 ml of diisopropyl ether. The organic layers were combined and concentrated, and the crude product was purified by petroleum ether / diisopropyl ether (v / v=5 / 1) column chromatography to obtain 26.9 g of an intermediate with a yield of 88% and an HPLC yield of 99.2%. 1 HNMR (400MHz, CDCl3): 7.56(d,1H),7.42(d,1H),7.16(s,1H),6.37(s,1H),5.86(s,1H),5.55(s,1H),3.82(s,3H),2.71(s,1H).

[0029] Comparative Example 2

[0030] Under nitrogen protection, 21.9 g (0.1 mol) of 2-bromo-4-chlorobenzaldehyde, 10.3 g (0.12 mol) of methyl acrylate and 3.4 g (0.03 mol) of DABCO catalyst were mixed in 100 ml of triethanolamine and reacted at room temperature for 6 hours. Subsequently, 100 mL of diisopropyl ether was added for dilution, and then hydrochloric acid (2%) was added to adjust the pH to 6-7. The layers were separated, and the aqueous layer was extracted once more with 100 mL of diisopropyl ether. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of petroleum ether / diisopropyl ether (v / v=5 / 1) to obtain an intermediate of 22.9 g with a yield of 75% and an HPLC yield of 99.0%.

[0031] Example 3

[0032]

[0033] Under nitrogen protection, the intermediate 15.3g (0.05mol), palladium acetate 0.14g (0.6mmol), t-Bu3P-HBF4 (0.44g, 1.5mmol), NaBARF (1.2g) and potassium phosphate 26.5g (0.125mol) were mixed in 200mLDMAc, heated to 100-105℃, reacted for 1 hour, cooled to room temperature, filtered, concentrated to 30mL, added 100mL ethyl acetate and 50mL water, separated, the organic layer was concentrated, and the crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v=1 / 10) as the eluent to obtain 6.8g of the target product 5-chloroindanone with a yield of 82% and HPLC 99.1%. 1HNMR(400MHz, CDCl3):7.70(d,1H),7.48(s,1H),7.36(d,1H),3.22-3.09(m,2H),2.78-2.68(m,2H).

[0034] Example 4

[0035] Under nitrogen protection, 15.3 g (0.05 mol) of the intermediate, 0.34 g (1.5 mmol) of palladium acetate and 26.5 g (0.125 mol) of potassium phosphate were mixed in 200 mL of DMAc, heated to 135-140 ° C, reacted for 3 hours, cooled to room temperature, filtered, concentrated to 30 mL, added with 100 mL of ethyl acetate and 50 mL of water, separated, and the organic layer was concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 10) to obtain 5.7 g of the target product 5-chloroindanone with a yield of 68% and an HPLC yield of 99.1%.

[0036] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 5-chloroindanone, characterized in that: The steps include: A. mixing 2-bromo-4-chlorobenzaldehyde, acrylate, DABCO and an ionic liquid catalyst in a solvent to generate an intermediate; B. The intermediate, palladium catalyst, tri-tert-butylphosphine tetrafluoroborate, NaBARF and base are mixed in a solvent and reacted at elevated temperature to generate 5-chloroindanone.

2. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step A, the acrylate is selected from methyl acrylate or ethyl acrylate.

3. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step A, the solvent is triethanolamine.

4. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step A, the ionic liquid catalyst is selected from 1-butyl-3-methylimidazolium tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate.

5. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step A, the molar ratio of 2-bromo-4-chlorobenzaldehyde, acrylate, DABCO and ionic liquid catalyst is 1:1-1.3:0.2-0.4:0.05-0.

1.

6. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step B, the palladium catalyst is palladium acetate; the base is potassium phosphate; and the organic solvent is selected from DMF, DMAc or sulfolane.

7. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step B, the temperature of the reaction is 100-110°C.

8. The method for preparing 5-chloroindanone according to claim 1, characterized in that: In step B, the molar ratio of the intermediate, palladium catalyst, tri-tert-butylphosphine-tetrafluoroborate, NaBARF and base is 1: 0.01-0.03: 0.02-0.04: 0.03-0.05: 2-3.

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