1. A novel cyclopropyl bromine synthesis method is characterized by comprising the following two synthesis steps:

1) dibromoethylene is used as an initial raw material, and reacts with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain dibromo-cyclopropane;

2) and (3) carrying out Grignard reaction on the crude product of the dibromo-cyclopropane and Mg, and carrying out acid washing, filtering, layering and normal pressure distillation to obtain a cyclopropyl bromine finished product.

2. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that the reaction solvent in step 1) is at least one of THF, DMF, toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, ethanol, diethyl ether and ethyl acetate.

3. The novel cyclopropyl bromide synthesis method according to claim 1, wherein the molar ratio of the dibromoethylene to the diazomethane to the palladium catalyst in step 1) is 1: 1-2.0: 0.002 to 0.02.

4. The novel cyclopropyl bromine synthesis process according to claim 1, characterized in that step 1) said palladium catalyst is Pd (oAc)₂、Pd(NO₃)₂、PdSO₄、Pdcl₂、Pd(TFA)₂At least one of them.

5. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that the reaction temperature in the step 1) is-15-130 ℃, and the reaction time is 5-15 hours.

6. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that in the step 2), the molar ratio of the trans-dibromo-cyclopropane to Mg is 1: 1.0-1.5.

7. The novel cyclopropyl bromide synthesis method according to claim 1, characterized in that in the step 2), the reaction temperature is-10-80 ℃, and the reaction time is 4-20 hours.

8. The novel cyclopropyl bromine synthesis method according to claim 1, wherein the hydrolysis agent in step 2) is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid.

9. The novel cyclopropyl bromine synthesis method according to claim 1, wherein the concentration of the hydrolysis agent in the step 2) is 1-5%.

Background

The cyclopropyl bromine is mainly applied to synthesizing various drugs containing cyclopropyl such as ciprofloxacin, enrofloxacin, sparfloxacin and the like, the main synthesis method in the industry at present is to prepare the cyclopropanecarboxylic acid through decarboxylation bromination reaction with bromine in tetrachloroethane under the catalysis of mercury oxide, the method has low yield, a large amount of mercury-containing wastewater can be generated in the production process, and the environmental pollution is serious. In the prior report, bromoethylene is used as a raw material, and denitrification cyclization reaction is carried out through palladium catalysis to prepare cyclopropyl bromine.

Disclosure of Invention

Aiming at the problems, the invention provides an improved cyclopropyl bromine synthesis route, which adopts dibromoethylene as a raw material to perform denitrification and cyclization with diazomethane under the catalysis of palladium, and then prepares cyclopropyl bromine by Grignard reaction and hydrolysis debromination, and the specific mechanism and steps are as follows:

1) firstly, dibromoethylene is used as an initial raw material and reacts with diazomethane in a certain amount of solvent at a certain molar ratio and a certain reaction temperature under the action of a palladium catalyst to obtain a crude product of dibromo-cyclopropane.

2) And secondly, carrying out Grignard reaction on the crude product of the dibromo-cyclopropane and Mg, and carrying out acid washing, filtering, layering and normal-pressure distillation to obtain a cyclopropyl bromine finished product.

Further, in the above scheme, in the first step, the reaction solvent is at least one of THF, DMF, toluene, xylene, chlorobenzene, dichlorobenzene, acetonitrile, ethanol, diethyl ether, ethyl acetate;

further, in the above scheme, in the first step, the molar ratio of the vinyl bromide to the diazomethane and the palladium catalyst is 1: 1-1.5: 0.005 to 0.01;

further, in the scheme, in the first step, the reaction temperature is-15-120 ℃, and the reaction time is 5-15 h;

further, in the scheme, in the second step, the molar ratio of the trans-dibromo-cyclopropane to Mg is 1: 1.0-1.5;

further, in the scheme, in the second step, the reaction temperature is-10-80 ℃, and the reaction time is 4-20 hours;

further, in the above scheme, in the second step, the hydrolytic agent is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and nitric acid;

further, in the scheme, in the second step, the concentration of the hydrolytic agent is 1-10%.

The invention has the beneficial effects that:

1) the method avoids the use of dangerous chemicals of vinyl bromide and mercury oxide, almost has no wastewater, is environment-friendly, has high production safety, and has very high economic and social meanings.

2) The synthesis route has the advantages of mild reaction conditions, high product yield, high purity and stable quality.

The specific implementation example is as follows:

[ example 1 ] Synthesis of cyclopropyl Bromide

Firstly, 200ml of THF/diethyl ether mixed solution (mass ratio of 1: 1) is added into a 500ml four-mouth bottle under the protection of nitrogen, the temperature is reduced to-15 ℃, and then 12.6g (0.30mol) of diazomethane and 0.67g (0.003mol) of Pd (oAc) are added₂Stirring is started, 46.45g (0.25mol) of dibromoethene is slowly dropped into the mixture, the temperature is raised and the reflux is carried out after the reaction is carried out for 1.5h, the reaction is kept for 10 h-12 h, and the temperature is reduced to-5 ℃ after the TLC detection reaction is finished.

Secondly, under the protection of nitrogen, adding 120ml of THF and 6g (0.25mol) of Mg into another 500ml four-mouth bottle for Grignard initiation, then dropwise adding the reaction solution in the first step at-5-0 ℃, reacting for 1h, then heating to 40 ℃, reacting for 6h, then cooling to room temperature, slowly dropwise adding 100g of 1% diluted hydrochloric acid into the reaction mother solution, stirring for 0.5h, then standing for liquid separation, and distilling the organic phase at normal pressure to obtain 27.2g of cyclopropyl bromine; the purity is 99.8 percent, and the yield is 90 percent.

[ example 2 ] Synthesis of cyclopropyl Bromide

Firstly, adding 180ml THF into a 250ml four-mouth bottle under the protection of nitrogen, and coolingAfter a temperature of-10 ℃ was reached, 14.7g (0.35 mol) of diazomethane and 0.89g (0.004mol) of Pd (oAc)₂Starting stirring, slowly dropwise adding 65.0g (0.30mol) of dibromoethylene, reacting for 1h, heating up and refluxing, keeping the temperature for reaction for 10 h-12 h, and cooling to-10 ℃ after TLC detection reaction.

Secondly, under the protection of nitrogen, adding 120ml of THF and 9.6g (0.4mol) of Mg into another 500ml four-mouth bottle, after Grignard initiation, dropwise adding the reaction solution in the first step at 0-5 ℃, reacting for 3h, then heating to 60 ℃, reacting for 6h, then cooling to room temperature, slowly dropwise adding 100g of 1% dilute sulfuric acid into the reaction mother solution, stirring for 0.5h, then standing for liquid separation, and distilling the organic phase at normal pressure to obtain 31.95g of cyclopropyl bromine; purity 99.6%, yield 88%.

[ example 3 ] Synthesis of cyclopropyl Bromide

The first step, 150ml toluene is added into a 250ml four-mouth bottle under the protection of nitrogen, the temperature is reduced to-5 ℃, and then 12.6g (0.30mol) diazomethane and 0.67g (0.003mol) Pd (oAc) are added₂Starting stirring, slowly dropwise adding 46.47g (0.25mol) of liquid dibromoethene, reacting for 2h, heating up and refluxing, keeping the temperature for reacting for 4 h-6 h, and cooling to-5 ℃ after TLC detection reaction.

Secondly, under the protection of nitrogen, 100ml of THF and 6g (0.25mol) of Mg are added into another 500ml four-mouth bottle for Grignard initiation, then the reaction liquid in the first step is dripped at-5 ℃ for reaction for 2h, then the temperature is raised to 60 ℃ for reaction for 4h, then the temperature is lowered to room temperature, 100g of dilute hydrochloric acid with the concentration of 1 percent is slowly dripped into the reaction mother liquid, the mixture is stirred for 0.5h, then the mixture is kept stand for liquid separation, and the organic phase is distilled under normal pressure to obtain 25.7g of cyclopropyl bromide; the purity is 99.7 percent, and the yield is 85 percent.