A preparation method of 5-chloroindanone

Abstract

The present invention discloses a method for preparing 5-chloroindanone, and belongs to the technical field of chemical material preparation. The present invention uses 2-bromo-4-chlorobenzaldehyde as a raw material and acrylate under the action of DABCO to generate an intermediate; then, a cyclization reaction is performed under the action of a palladium catalyst and a base to generate 5-chloroindanone. The present invention adds an ionic liquid catalyst to cooperate with DABCO to perform a Baylis-Hillman reaction, thereby reducing the amount of DABCO used and improving the yield; through the bromine on the benzene ring and the olefin positional cyclization reaction, the generation of isomers is greatly reduced, while avoiding the isomers caused by the Friedel-Crafts cyclization reaction and a large amount of waste acid and wastewater, providing an effective new path for the preparation of 5-chloroindanone.

Description

Technical Field

[0001] The invention relates to a preparation method of 5-chloroindanone, belonging 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-toxicity, and low-residue pesticides, such as insecticides, fungicides, and herbicides. Dyes and liquid crystal materials: 5-Chloroindanone also has broad application prospects in fields such as dyes and liquid crystal materials.

[0003] Regarding this product, after searching the literature on the existing technologies, the following methods are currently available for the synthesis of 5-chloroindanone:

[0004] A. Patents [CN113087609A; CN115974664A] report that 5-chloroindanone is produced by cyclization reaction using 1-(4-chlorophenyl)-2-propen-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 raw material for oxidation reaction to produce 5-chloroindanone.

[0007] D. Literature and patents [CN109293488A; CN106588612A; Asian Journal of Chemistry, 2012, 24, 1413] report that 5-chloroindanone is produced 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 location efficiency is low and a large number of isomers exist. 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-directed cyclization reaction, and a decarboxylation reaction is simultaneously carried out 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 acrylic acid ester 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 the 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-raising reaction condition is 100-140°C.

[0022] Furthermore, in step B of the above technical solution, 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 the Baylis-Hillman reaction, adds an ionic liquid catalyst to coordinate the DABCO reaction, reduces the amount of DABCO used, and improves the yield; At the same time, triethanolamine is used as a solvent to increase the reaction rate.

[0024] B. The addition of a phosphine ligand to the cyclization reaction of the present invention improves the efficiency of the palladium acetate-catalyzed site-directed cyclization reaction. This avoids the isomerization and large amounts of waste acid and wastewater caused by the Friedel-Crafts cyclization reaction. This provides a reference route 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 such modifications or substitutions shall be within the scope of the present invention. Any person skilled in the art who can easily conceive of changes or substitutions within the technical scope disclosed in the present invention shall be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be based on the scope of protection described in the claims.

[0026] Example 1

[0027]

[0028] Under nitrogen, 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 column chromatography on petroleum ether / diisopropyl ether (v / v = 5 / 1) to obtain 26.9 g of the intermediate with a yield of 88% and an HPLC index 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, 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. The mixture was then diluted with 100 mL of diisopropyl ether and the pH was adjusted to 6-7 by adding hydrochloric acid (2%). 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, and the crude product was purified by column chromatography using petroleum ether / diisopropyl ether (v / v = 5 / 1) as eluent to obtain 22.9 g of the intermediate with a yield of 75% and an HPLC yield of 99.0%.

[0031] Example 3

[0032]

[0033] Under nitrogen protection, 15.3 g (0.05 mol) of the intermediate, 0.14 g (0.6 mmol) of palladium acetate, 0.44 g (1.5 mmol) of t-Bu3P-HBF4, NaBARF (1.2 g) and 26.5 g (0.125 mol) of potassium phosphate were mixed in 200 mL of DMAc, heated to 100-105°C, reacted for 1 hour, cooled to room temperature, filtered, concentrated to 30 mL, and 100 mL of ethyl acetate and 50 mL of water were added. The layers were separated and the organic layer was concentrated. The crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v = 1 / 10) as the eluent to give 6.8 g of the target product 5-chloroindanone in a yield of 82% and an HPLC purity of 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, 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, and concentrated to 30 mL. 100 mL of ethyl acetate and 50 mL of water were added, the layers were separated, and the organic layer was concentrated. The crude product was purified by column chromatography with ethyl acetate / n-hexane (v / v = 1 / 10) as the eluent to obtain 5.7 g of the target product, 5-chloroindanone, in a yield of 68%, and an HPLC index of 99.1%.

[0036] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection 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 triethanolamine to generate an intermediate; the ionic liquid catalyst is selected from 1-butyl-3-methylimidazolium tetrafluoroborate or 1-butyl-3-methylimidazolium hexafluorophosphate; B. Mixing the intermediate, palladium catalyst, tri-tert-butylphosphine tetrafluoroborate, NaBARF and base in a solvent, and reacting them at elevated temperature to generate 5-chloroindanone; the elevated temperature is 100-110°C.

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

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

1.

4. The method for preparing 5-chloroindanone according to claim 1, wherein: 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.

5. The method for preparing 5-chloroindanone according to claim 1, wherein: 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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