Synthesis method of cyclopropyl alcohol

Abstract

The invention provides a synthetic method of cyclopropyl alcohol, which comprises the following steps: firstly, by taking vinyl acetate as a substrate, carrying out diazomethane catalytic cyclopropanation reaction to obtain cyclopropyl acetate; and secondly, carrying out hydrolysis reaction on the cyclopropyl acetate to obtain cyclopropyl alcohol. The synthetic method for preparing cyclopropyl alcohol has the advantages of simple process, convenient post-treatment, no obvious by-product or waste water, yield of more than 95%, and substantial cost reduction, and is more suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, relates to a pharmaceutical intermediate, and specifically relates to a method for synthesizing cyclopropyl alcohol. Background Art

[0002] Compounds with cyclopropane structural units have good biological and physiological activities, and many intermediates of biological metabolism also have derivatives with cyclopropane structures. Therefore, cyclopropane structures have important applications in drug molecule design. Among them, cyclopropylamine compounds are a class of compounds with high reactivity. They can be used as important intermediates for introducing cyclopropane structures in the synthesis of medicines and pesticides, and have broad application prospects.

[0003] At present, the synthesis of cyclopropyl alcohol compounds is mainly achieved by ring-closing olefin halides under the action of organic metal reagents. Nitropropane is used as a raw material to condense under alkaline conditions to form a nitrocyclopropane structure compound, and then a metal borohydride compound is used to reduce it to obtain an aminocyclopropane structure compound (US4085273, US4065480). This type of method has low yield, harsh reaction conditions, and poor atom economy, resulting in high costs. Summary of the invention

[0004] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing cyclopropyl alcohol to solve the technical problem that the industrial application cost of cyclopropyl alcohol in the prior art needs to be further reduced.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions to achieve the above problems:

[0006] A method for synthesizing cyclopropyl alcohol comprises the following steps: firstly, using vinyl acetate as a substrate, carrying out a cyclopropanation reaction catalyzed by diazomethane to obtain cyclopropyl acetate; and secondly, carrying out a hydrolysis reaction on the cyclopropyl acetate to obtain cyclopropyl alcohol.

[0007] The method comprises the following steps:

[0008] Step 1: In N 2 Under atmosphere, the substrate vinyl acetate is uniformly mixed with the first solvent and the cyclization catalyst and added into the reactor.

[0009] Step 2: introducing diazomethane gas into the reactor using nitrogen as carrier gas, heating to carry out cyclopropanation reaction, stopping the reaction when the reaction conversion rate is monitored to be greater than 99%, and stopping after nitrogen purging for 1 hour to obtain an organic phase containing cyclopropane product.

[0010] Step 3: The organic phase containing the cyclopropane product is distilled to obtain cyclopropyl acetate with a purity of >99.5%.

[0011] Step 4: Evenly mix the cyclopropyl acetate obtained in step 3, the second solvent, water and the hydrolysis catalyst, and then add the mixture into the reaction kettle.

[0012] Step 5, start the heating and stirring of the reactor, increase the temperature to carry out the hydrolysis reaction, and when the reaction conversion rate is monitored to be greater than 99.8%, cool down and filter to obtain the reaction solution.

[0013] Step 6: The reaction solution obtained in step 5 is subjected to solvent removal and distillation to obtain cyclopropyl alcohol with a purity of >99.5%.

[0014] The present invention also has the following technical features:

[0015] Preferably, in step 1, the cyclization catalyst is palladium chloride.

[0016] Preferably, in step 4, the hydrolysis catalyst is potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide or tetrabutylammonium hydroxide.

[0017] Preferably, in step 2, the temperature of the cyclopropanation reaction is 5 to 50°C.

[0018] Preferably, in step five, the reaction temperature of the hydrolysis reaction is 60 to 150° C., and the reaction time is 4 to 12 hours.

[0019] Preferably, in step 1, the amount of the cyclization catalyst used is 0.1% to 10wt.% of the mass of vinyl acetate.

[0020] Preferably, in step 4, the amount of the hydrolysis catalyst used is 0.1% to 10wt.% of the mass of the cyclopropyl acetate.

[0021] Preferably, in step 2, the molar ratio of diazomethane to vinyl acetate is (1-7):1.

[0022] Preferably, in step 1, the first solvent is one or a mixture of more than one of methanol, ethanol, tert-butanol and ethylene glycol.

[0023] Preferably, in step 1, the amount of the first solvent used is 0.5 to 10 times the mass of vinyl acetate.

[0024] Preferably, in step 4, the second solvent is one or a mixture of more than one of methanol, ethanol, tert-butanol and ethylene glycol.

[0025] Preferably, in step 4, the amount of the second solvent used is 0.5 to 10 times the mass of vinyl acetate.

[0026] Compared with the prior art, the present invention has the following technical effects:

[0027] The synthetic method for preparing cyclopropyl alcohol of the present invention has simple process, convenient post-treatment, no obvious by-products and waste water, and the yield can reach more than 95%, and the cost is significantly reduced, and it is more suitable for industrial large-scale production.

[0028] The specific contents of the present invention are further explained in detail below in conjunction with embodiments. DETAILED DESCRIPTION

[0029] It should be noted that all raw materials in the present invention, unless otherwise specified, are raw materials known in the art.

[0030] In the present invention, the structural formula of vinyl acetate is

[0031] In the present invention, the structural formula of cyclopropyl acetate is

[0032] In the present invention, the structural formula of cyclopropyl alcohol is

[0033] The present invention provides a method for synthesizing cyclopropyl alcohol, and the synthetic route of the method is:

[0034]

[0035] The cyclopropyl alcohol synthesized by the invention can be used as a pharmaceutical intermediate.

[0036] Specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent changes made on the basis of the technical solution of this application fall within the protection scope of the present invention.

[0037] Embodiment 1:

[0038] The present embodiment provides a method for synthesizing cyclopropyl alcohol, which is carried out according to the following steps:

[0039] At 25°C, 860g of vinyl acetate, 1000g of tetrahydrofuran and 1g of palladium chloride were stirred and mixed uniformly and then added to the reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced, and the ventilation time was maintained at 2-3h, during which the temperature of the reactor was maintained between 20-30 degrees Celsius, and the tail gas was discharged after being absorbed by acetic acid; after the reaction, the organic phase was directly evaporated to remove the solvent, and then vacuum distillation was performed to obtain 910g of cyclopropyl acetate with a gas phase purity of 99.6%; the obtained cyclopropyl acetate and 1000g of ethanol were mixed uniformly and then put into a 3L reaction autoclave, and then 45g of potassium hydroxide catalyst and 80g of water were added, stirring was turned on and the temperature was raised to 70°C for hydrolysis, and sampling and analysis after 3 hours showed a conversion rate of 99.9%, and the reaction was stopped; after separating the organic phase, vacuum distillation was performed to obtain 507g of cyclopropyl alcohol with a gas phase purity of 99.7% and a comprehensive yield of 96%.

[0040] The characterization data of the product obtained by the present invention are as follows:

[0041] 1 H NMR (400 MHz, CDCl 3 )δ4.76(s,1H),3.45-3.31(m,1H),0.62-0.46(m,4H)ppm.

[0042] 13 C NMR (101 MHz, CDCl 3 )δ42.13,7.45ppm.

[0043] It can be seen from the above characterization data that the product obtained in this example is the target compound cyclopropyl alcohol.

[0044] Embodiment 2:

[0045] The present embodiment provides a method for synthesizing cyclopropyl alcohol, which is carried out according to the following steps:

[0046] At 25°C, 860g of vinyl acetate, 1000g of tetrahydrofuran and 1g of palladium chloride were stirred and mixed uniformly and then added to the reactor; after nitrogen purging, 630g (1.5 equivalents) of diazomethane gas diluted with nitrogen was introduced, and the ventilation time was maintained at 2-3h, during which the temperature of the reactor was maintained between 20 and 30 degrees Celsius, and the tail gas was discharged after being absorbed by acetic acid; after the reaction, the organic phase was directly evaporated to remove the solvent, and then vacuum distilled to obtain 906g of cyclopropyl acetate with a gas phase purity of 99.6%; the obtained cyclopropyl acetate and 1000g of ethanol were mixed uniformly and put into a 3L reaction autoclave, and then 50g of tetrabutylammonium hydroxide catalyst and 80g of water were added, stirring was turned on and the temperature was raised to 70°C for hydrolysis, and after 3 hours, sampling and analysis showed that the conversion rate was 99.9%, and the reaction was stopped; after separating the organic phase, 510g of cyclopropyl alcohol was obtained by vacuum distillation with a gas phase purity of 99.5% and a comprehensive yield of 95%.

[0047] The characterization data of the product prepared in the present invention are substantially the same as those of Example 1, indicating that the product prepared in this example is the target compound cyclopropyl alcohol.

Claims

1. A method for synthesizing cyclopropyl alcohol, characterized in that: The method firstly uses vinyl acetate as a substrate and performs a diazomethane-catalyzed cyclopropanation reaction to obtain cyclopropyl acetate; secondly, the cyclopropyl acetate is hydrolyzed to obtain cyclopropyl alcohol.

2. The method for synthesizing cyclopropyl alcohol according to claim 1, characterized in that: The method comprises the following steps: Step 1, under N2 atmosphere, uniformly mix the substrate vinyl acetate, the first solvent and the cyclization catalyst and add them into the reactor; Step 2, diazomethane gas is introduced into the reactor using nitrogen as a carrier gas, the temperature is raised to carry out cyclopropanation reaction, and the reaction is stopped when the reaction conversion rate is monitored to be greater than 99%, and the reaction is stopped after nitrogen purging for 1 hour to obtain an organic phase containing the cyclopropane product; Step 3, the organic phase containing the cyclopropane product is distilled to obtain cyclopropyl acetate with a purity of >99.5%; Step 4, mixing the cyclopropyl acetate obtained in step 3, the second solvent, water, and the hydrolysis catalyst uniformly and adding the mixture into a reaction kettle; Step 5, start the heating and stirring of the reactor, increase the temperature to carry out the hydrolysis reaction, and when the reaction conversion rate is monitored to be greater than 99.8%, cool down and filter to obtain the reaction solution; Step 6: The reaction solution obtained in step 5 is subjected to solvent removal and distillation to obtain cyclopropyl alcohol with a purity of >99.5%.

3. The method for synthesizing cyclopropyl alcohol as claimed in claim 2, characterized in that: In step 1, the cyclization catalyst is palladium chloride.

4. The method for synthesizing cyclopropyl alcohol as claimed in claim 2, characterized in that: In step 4, the hydrolysis catalyst is potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide or tetrabutylammonium hydroxide.

5. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 2, the temperature of the cyclopropanation reaction is 5 to 50°C.

6. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 5, the reaction temperature of the hydrolysis reaction is 60-150° C., and the reaction time is 4-12 hours.

7. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 1, the amount of the cyclization catalyst is 0.1% to 10wt.% based on the mass of vinyl acetate; In step 4, the amount of the hydrolysis catalyst used is 0.1% to 10wt.% of the mass of the cyclopropyl acetate.

8. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 2, the molar ratio of diazomethane to vinyl acetate is (1-7):

1.

9. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 1, the first solvent is one or a mixture of more than one of methanol, ethanol, tert-butanol and ethylene glycol; in step 1, the amount of the first solvent is 0.5 to 10 times the mass of vinyl acetate.

10. The method for synthesizing cyclopropyl alcohol according to claim 2, characterized in that: In step 4, the second solvent is one or a mixture of more than one of methanol, ethanol, tert-butanol and ethylene glycol; in step 4, the amount of the second solvent is 0.5 to 10 times the mass of vinyl acetate.

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