JP2023055056A - Method for producing cyclopropyl bromide - Google Patents

Abstract

To provide a method for producing cyclopropyl bromide with low toxicity and a low risk of explosion, and at low cost.SOLUTION: Cyclopropyl bromide is prepared by a production method including a chemical reaction of: cyclopropanecarboxylic acid or a potassium salt thereof; a Bronsted base having potassium such as potassium hydroxide, potassium carbonate, potassium bicarbonate, tripotassium phosphate and dipotassium hydrogenphosphate; and a brominating agent such as N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.SELECTED DRAWING: None

Description

The present invention relates to a method for producing cyclopropyl bromide. More particularly, the present invention relates to a process for producing cyclopropyl bromide using synthetic raw materials that are less toxic, less explosive, and less expensive.

Cyclopropyl bromide is useful as a starting material for organic synthesis to produce cyclopropylmagnesium bromide, a Grignard reagent, cyclopropylboronic acid, ciprofloxacin, enrofloxacin, and sparfloxacin. .

Various methods for producing cyclopropyl bromide have been proposed.
For example, Non-Patent Document 1 discloses that cyclopropanecarboxylic acid is combined with silver nitrate to obtain silver cyclopropanecarboxylate, which is reacted with dibromine to produce cyclopropyl bromide.

Non-Patent Document 2 discloses that cyclopropyl bromide was produced by reacting cyclopropanecarboxylic acid with dibromine using mercury oxide.

Patent Document 1 discloses that cyclopropyl bromide was produced by reacting cyclopropanecarboxylic acid with lead tetraacetate and lithium bromide.

Non-Patent Document 3 discloses that cyclopropyl bromide was produced by reacting dicyclopropyl peroxyanhydride with carbon tetrabromide.

Patent Document 2 discloses that cyclopropanecarboxylic acid is combined with carbonyldiimidazole to obtain 1-(1H-imidazol-1-yl)cyclopropanecarboxylic acid, which is reacted with bromotrichloromethane to give cyclopropyl bromide. disclosed that it was manufactured

Non-Patent Document 4 discloses that cyclopropyl bromide was produced by reacting bis(acetyloxy)(phenyl)-λ ³ -iodane with cyclopropanecarboxylic acid and potassium bromide under fluorescent irradiation. disclosed.

CN111099958A CN 104892355 A

Journal of American Chemical Society 1951, 73, 3176. Organic Synthesis 1973, 43, 9. Journal of American Chemical Society 1961, 83, 1987. Org. Process Res. Dev. 2020, 24, 1328.

An object of the present invention is to provide a method for producing cyclopropyl bromide using synthetic raw materials with low toxicity, low risk of explosion, and low cost.

The present invention includes the following forms.

[1] cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate;
a Bronsted base having potassium;
including chemically reacting with a brominating agent,
A method for producing cyclopropyl bromide.

[2] potassium cyclopropanecarboxylate;
including chemically reacting with a brominating agent,
A method for producing cyclopropyl bromide.

The production method of the present invention can safely obtain cyclopropyl bromide while avoiding the use of toxic metals.

The method for producing cyclopropyl bromide of the first form of the present invention comprises chemically reacting cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate, a Bronsted base having potassium, and a brominating agent.

The method for producing cyclopropyl bromide of the second form of the present invention comprises chemically reacting potassium cyclopropanecarboxylate with a brominating agent.

Potassium cyclopropanecarboxylate used in the present invention can be obtained, for example, by neutralizing cyclopropanecarboxylic acid with a potassium compound in an aqueous medium. The potassium compound used in the neutralization reaction may be a Bronsted base with potassium. Potassium hydroxide is particularly preferred. After the neutralization reaction, potassium cyclopropanecarboxylate can be taken out by a known method. For example, an organic solvent such as toluene is added to the liquid after the neutralization reaction, dehydration is performed using a Dean-Stark apparatus or the like, and the precipitate is collected by filtration.

Examples of Bronsted bases containing potassium used in the present invention include potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, tripotassium phosphate, and dipotassium hydrogen phosphate. Of these, tripotassium phosphate is preferred.

The amount of Bronsted base containing potassium to be used is preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents, still more preferably 1 to 1.5 equivalents, relative to cyclopropanecarboxylic acid. It is preferably 0 to 0.5 equivalents relative to potassium.

Brominating agents used in the present invention include, for example, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, tribromoisocyanuric acid, dibromine (Br ₂ ), dioxane bromine complexes, tetrabutylammonium tribromide, and the like. Of these, dibromine is preferred.

The amount of the brominating agent to be used is preferably 1 to 3 equivalents, more preferably 1.2 to 2.5 equivalents, still more preferably 1.5 to 2 equivalents, relative to cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate. is.

The chemical reaction may be carried out without solvent or in an organic solvent. Examples of the organic solvent used in the present invention include nitrile solvents such as acetonitrile and propanenitrile; chlorine solvents such as chlorobenzene, dichlorobenzene, and 1,1,2,2-tetrachloroethane. Of these, 1,1,2,2-tetrachloroethane is preferred.
The amount of the solvent used is preferably 0.3 to 10 L, more preferably 0.4 to 5 L, still more preferably 0.5 to 2 L, relative to 1 mol of cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate.

The chemical reaction is preferably carried out at 50-150°C, more preferably 70-120°C, even more preferably 80-100°C. The reaction time is preferably 10 minutes to 8 hours, more preferably 20 minutes to 4 hours, still more preferably 30 minutes to 2 hours.

The chemical reaction can be carried out, for example, by adding cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate, a Bronsted base containing potassium, and a brominating agent to an organic solvent at the above temperature and time. , or cyclopropanecarboxylic acid or potassium cyclopropanecarboxylate and a Bronsted base with potassium are added in an organic solvent to the above temperature, and then the brominating agent is added (dropwise) for the above time. can be done.

Next, an example of the manufacturing method of the present invention will be shown.

[Example 1]
258 mg (3 mmol) of cyclopropanecarboxylic acid, 637 mg (3 mmol) of tripotassium phosphate, and 309 μl (6 mmol) of dibromine were added to 6 ml of 1,1,2,2-tetrachloroethane and stirred at 100° C. for 4 hours while stirring. reacted.
It was then cooled to room temperature. To this, 20 ml of water, 5 ml of saturated sodium carbonate aqueous solution and 0.3 g of sodium thiosulfate were added and stirred for 10 minutes. The resulting liquid was then allowed to settle and the organic phase was removed. A 72% yield of cyclopropyl bromide was obtained in the organic phase.

[Example 2]
4.30 g (50 mmol) of cyclopropanecarboxylic acid and 10.61 g (50 mmol) of tripotassium phosphate were added to 100 ml of 1,1,2,2-tetrachloroethane and the solution was heated to 100°C. To this was added dropwise 5.16 ml (100 mmol) of dibromine over 30 minutes. After that, chemical reaction was carried out while stirring at 100° C. for 1 hour.
It was then cooled to room temperature. This liquid was added to an aqueous solution prepared by adding 26.5 g of sodium carbonate and 4.74 g of sodium thiosulfate to 150 ml of water under ice cooling, and the mixture was stirred for 10 minutes.
The resulting liquid was then allowed to settle and the organic phase was removed. A 77% yield of cyclopropyl bromide was obtained in the organic phase. Distillation of the organic phase gave 1.99 g of cyclopropyl bromide in 33% yield (97.9% purity). ¹ H NMR (400MHz, CDCl ₃ ) δ0.88-1.01 (m, 4H), 2.84-2.90 (m, 2H).

[Manufacturing example]
Under ice-cooling, 43.22 g (500 mmol) of cyclopropanecarboxylic acid was added dropwise to an aqueous solution prepared by dissolving 32.66 g (purity 85.9%, 500 mmol) of potassium hydroxide in 100 ml of water. To this, 375 ml of toluene was added and heated to 120-135°C. The resulting liquid was dehydrated for 5 hours using a Dean-Stark apparatus. After that, about 100 ml of toluene was distilled off to obtain a slurry. The slurry was suction filtered to remove solids and dried under vacuum. 61.07 g of needle-like crystals of potassium cyclopropanecarboxylate were obtained (yield 98%).

[Example 3]
12.42 g (100 mmol) of potassium cyclopropanecarboxylate obtained in the production example was mixed with 2.14 g (10 mmol) of tripotassium phosphate and 50 ml of 1,1,2,2-tetrachloroethane and heated. to 100°C. 7.88 ml of dibromine (98.1% purity, 150 mmol) was added dropwise to this liquid over 30 minutes. After that, chemical reaction was carried out while stirring at 100° C. for 1 hour.
It was then cooled to room temperature. This liquid was added to an aqueous solution prepared by adding 15.90 g of sodium carbonate and 7.11 g of sodium thiosulfate to 300 ml of water under ice cooling, and the mixture was stirred for 30 minutes.
The resulting liquid was then allowed to settle and the organic phase was removed. An 83% yield of cyclopropyl bromide was obtained in the organic phase. Distillation of the organic phase gave 7.62 g of cyclopropyl bromide in 63% yield (99.3% purity).

[Example 4]
12.42 g (100 mmol) of potassium cyclopropanecarboxylate obtained in Production Example was mixed with 50 ml of 1,1,2,2-tetrachloroethane and heated to 100°C. 10.51 ml of dibromine (98.1% purity, 200 mmol) was added dropwise to this liquid over 30 minutes. After that, chemical reaction was carried out while stirring at 100° C. for 1 hour.
It was then cooled to room temperature. This liquid was added to an aqueous solution prepared by adding 21.20 g of sodium carbonate and 9.49 g of sodium thiosulfate to 300 ml of water under ice cooling, and the mixture was stirred for 30 minutes.
The resulting liquid was then allowed to settle and the organic phase was removed. An 80% yield of cyclopropyl bromide was obtained in the organic phase.

In the production method of the present invention, relatively inexpensive potassium is used as a metal without using silver, mercury, lead, or the like. The production method of the present invention has no toxic effects on living organisms and no risk of explosion.

Claims (2)

cyclopropanecarboxylic acid or its potassium salt;
a Bronsted base having potassium;
including chemically reacting with a brominating agent,
A method for producing cyclopropyl bromide. a potassium salt of cyclopropanecarboxylic acid;
including chemically reacting with a brominating agent,
A method for producing cyclopropyl bromide.