Preparation method of 3-chloro-1-propanol

Abstract

The invention relates to the technical field of synthesis of medical intermediates, and discloses a preparation method of 3-chloro-1-propanol, which comprises the following steps: adding 1, 3-propylene glycol into a solvent, adding part of hydrochloric acid, and heating for reflux reaction; carrying out central control detection on the reacted solvent, and cooling to separate out a solvent layer; adding part of hydrochloric acid and the solvent into the reactant from which the solvent is separated, adding methanesulfonic acid, heating, and carrying out heat preservation reaction; carrying out central control detection on the reacted water phase sample, and cooling to separate out the solvent; mixing the solvents, heating, and dropwise adding a sodium hydroxide solution for reaction; after the reaction, sampling for central control detection, cooling and standing for layering; separating out an organic layer, washing with water, and rectifying to obtain a product. According to the method, hydrochloric acid and a solvent are added in batches, impurities in the product can be effectively reduced, the product with high yield and high purity is obtained, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a method for preparing 3-chloro-1-propanol. Background Art

[0002] 3-Chloro-1-propanol is an important intermediate in drug synthesis and can be used in the synthesis of a variety of drugs, such as the synthesis of 3-chloropropyl chloroformate, nelfinavir intermediates, and antithrombotic drug clopidogrel intermediates.

[0003] At present, there are many existing synthetic routes for 3-chloro-1-propanol, and the following ones are relatively mature and have certain industrial value: 1. Prepared by the reaction of 1,3-propylene glycol and dichlorothionyl. This method will generate more 1,3-dichloropropane and propylene sulfite impurities, affecting the purity of the product.

[0004] 2. Use bromochloropropane and react, and then react the product with methanol to obtain the product by transesterification. This method requires the use of bromochloropropane, has poor atom economy, and uses a two-step reaction, which is relatively cumbersome.

[0005] 3. CN110668918 uses hydrochloric acid and 1,3-propylene glycol in the presence of benzenesulfonic acid as the catalyst for preparation. This method has cheap raw materials and is more suitable for large-scale production. However, it also faces the problem of generating 1,3-dichloropropane and other impurities with growing carbon chains in the product. In order to prevent excessive generation of impurities, measures to control the progress of the reaction are generally adopted, and there is often a lot of residual raw materials. Although the raw materials can be recycled and reused later, the process difficulty and production time are increased. Summary of the invention

[0006] The invention aims to overcome the above problems existing in the prior art 3-chloro-1-propanol preparation method and provide a 3-chloro-1-propanol preparation method. The method of adding hydrochloric acid and a solvent in batches can effectively reduce impurities in the product, obtain a high-yield and high-purity product, and is suitable for industrial production.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 1,3-propylene glycol to a solvent, and add hydrochloric acid with a mass concentration of 25-30%, and heat to reflux for reaction; the amount of HCl added in the hydrochloric acid is 0.9-1.1 times the equivalent of 1,3-propylene glycol; (2) taking the organic phase after the reaction in step (1) for testing, and when the content of 1,3-dichloropropane is greater than 5wt%, cooling and separating the solvent layer; (3) Adding hydrochloric acid and solvent with a mass concentration of 25-30% to the reactants after the solvent is separated, and adding methanesulfonic acid, heating and then keeping the temperature to react; the amount of HCl added in the hydrochloric acid is 0.3-0.5 times the equivalent of 1,3-propylene glycol; (4) taking a sample of the aqueous phase after the reaction in step (3), detecting that the reaction of 1,3-propylene glycol is complete, stopping the reaction, cooling, and separating the solvent; (5) combining the solvents separated in step (2) and step (4), heating the solvents, and adding a sodium hydroxide solution dropwise thereto to react; sampling and testing the 1,3-dichloropropane after the reaction is complete, cooling the solvents and allowing them to stand for stratification; (6) Separating the organic layer separated in step (5), washing with water and then distilling to obtain the 3-chloro-1-propanol.

[0008] The present invention adopts a method of adding hydrochloric acid and solvent in batches, and utilizes the difference in solubility of 1,3-propylene glycol and the product in the aqueous phase and the solvent, so that the product is separated from the aqueous phase system in time during the reaction, and the continuous increase of 1,3-dichloropropane is avoided. At the same time, the present invention strictly controls the amount of hydrochloric acid added in each step. If the amount of hydrochloric acid added is too little, the raw material 1,3-propylene glycol will not react completely; if the amount of hydrochloric acid is too much, the impurity 1,3-dichloropropane is easily generated, which will affect the yield and purity of the product. In the later stage, the catalysis of methanesulfonic acid is used to reduce the reaction temperature, so that a small amount of 1,3-propylene glycol is quickly converted into a product and the generation of other by-products is reduced. Finally, a small amount of 1,3-dichloropropane generated in the reaction is partially hydrolyzed to be converted into the desired product again. The method in the present invention can make full use of the raw materials in a single batch, improve the production efficiency; the operation is relatively simple, the reaction conditions are mild, and the disadvantages of the 3-chloro-1-propanol preparation method in the prior art are overcome, and a high-yield and high-purity product can be obtained, which is suitable for industrial production.

[0009] Preferably, the solvent in step (1) and step (3) is selected from one or more of benzene, toluene and ethylene dichloride.

[0010] Preferably, the amount of solvent added in step (1) is 1.5 to 2.5 times the mass of 1,3-propylene glycol.

[0011] Preferably, in step (1), the reflux reaction temperature is 70-90° C., and the reflux reaction time is 6-9 h.

[0012] Preferably, the temperature is lowered to below 30° C. in step (2).

[0013] Preferably, the amount of solvent added in step (3) is 1 to 1.5 times the mass of 1,3-propylene glycol; and the amount of methanesulfonic acid added is 0.01 to 0.02 equivalent times the mass of 1,3-propylene glycol.

[0014] Preferably, the insulation reaction temperature in step (3) is 50-70° C., and the insulation reaction time is 4-6 h.

[0015] Preferably, the temperature is lowered to below 30° C. in step (4).

[0016] Preferably, the mass fraction of the sodium hydroxide solution added in step (5) is 4-6%, and the pH of the system is controlled between 9.1 and 9.6 after the addition of sodium hydroxide.

[0017] Preferably, in step (5), after the temperature is raised to 45-55° C., a sodium hydroxide solution is added dropwise to carry out the reaction until the pH remains unchanged.

[0018] Therefore, the present invention has the following beneficial effects: (1) By utilizing the difference in solubility between 1,3-propylene glycol and the product in the aqueous phase and the solvent, the product can be separated from the aqueous phase system in a timely manner during the reaction, thus avoiding the continuous increase of 1,3-dichloropropane; (2) Using methane sulfonic acid as a catalyst can reduce the reaction temperature, allowing a small amount of 1,3-propylene glycol to be quickly converted into products and reducing the generation of other by-products; (3) Finally, the small amount of 1,3-dichloropropane generated in the reaction is partially hydrolyzed to convert it back into the desired product, thereby improving the purity of the product. DETAILED DESCRIPTION

[0019] The present invention is further described below in conjunction with specific implementation methods.

[0020] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are conventional methods in the art.

[0021] Overall embodiment: A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 1,3-propylene glycol to a solvent, and add hydrochloric acid with a mass concentration of 25-30%, heat to 70-90°C, and reflux for 6-9 hours; the amount of HCl added in the hydrochloric acid is 0.9-1.1 times the equivalent of 1,3-propylene glycol; the amount of solvent added is 1.5-2.5 times the mass of 1,3-propylene glycol; (2) taking the organic phase after the reaction in step (1) for testing, and when the content of 1,3-dichloropropane is greater than 5%, cooling it to below 30° C. and separating the solvent layer; (3) After the solvent is separated, hydrochloric acid and solvent with a mass concentration of 25-30% are added again, and methane sulfonic acid is added, and the temperature is raised to 50-70°C for reaction for 4-6 hours; the amount of HCl added in the hydrochloric acid is 0.3-0.5 times the mass of 1,3-propylene glycol; the amount of solvent added is 1-1.5 times the mass of 1,3-propylene glycol; the amount of methane sulfonic acid added is 0.01-0.02 times the mass of 1,3-propylene glycol; (4) taking a sample of the aqueous phase after the reaction in step (3), detecting that the reaction of 1,3-propylene glycol is complete, stopping the reaction, cooling the sample to below 30° C., and separating the solvent; (5) The solvents separated in step (2) and step (4) are combined, heated to 45-55° C., and then a 4-6% by mass sodium hydroxide solution is added dropwise thereto to control the pH of the system between 9.1 and 9.6. After the pH remains unchanged, a sample is taken for testing. After the reaction of 1,3-dichloropropane is completed, the temperature is cooled to room temperature and allowed to stand for stratification; (6) Separate the organic layer separated in step (5), wash it once with water, and then distill it to obtain the 3-chloro-1-propanol.

[0022] Embodiment 1: A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 152.2 g of 1,3-propylene glycol, 300 g of toluene and 244 g of 30 wt% hydrochloric acid into a reaction flask, stir evenly, and heat to 80 °C for reflux reaction for 7 h; (2) The organic phase was taken for testing, and the 1,3-dichloropropane content was 5.7 wt%. The temperature was lowered to 29 °C, allowed to stand, and the upper solvent was separated; (3) Add 122 g of 30 wt% hydrochloric acid, 200 g of toluene, and 3.8 g of methanesulfonic acid into the flask; (4) Raise the temperature of the material to 65°C and keep the temperature for 4 hours; (5) Take a sample of the aqueous phase, check whether the reaction of 1,3-propylene glycol is complete, stop the reaction, cool to 25°C, let stand, and separate the upper solvent; (6) Combine the solvents separated in step (2) and step (5), raise the temperature to 50° C., and slowly dropwise add 5 wt % sodium hydroxide solution to maintain the pH value of the system between 9.1 and 9.5; (7) React until the pH value remains essentially unchanged, take a sample to detect whether the reaction of 1,3-dichloropropane is complete, and cool to room temperature; (8) The upper layer of material was separated, washed once with water and then distilled to obtain 179.0 g of the product with a yield of 94.6% and a purity of more than 99%.

[0023] Embodiment 2: A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 152.2 g of 1,3-propylene glycol, 230 g of benzene and 244 g of 30 wt% hydrochloric acid into a reaction flask, stir evenly, and heat to 80 °C for reflux reaction for 9 h; (2) The organic phase was taken for testing, and the 1,3-dichloropropane content was 6.3 wt%. The temperature was lowered to 28 °C, allowed to stand, and the upper solvent was separated; (3) Add 98 g of 30 wt% hydrochloric acid, 200 g of toluene, and 2.9 g of methanesulfonic acid into the flask; (4) Raise the temperature of the material to 60°C and keep the temperature for 4 hours; (5) Take a sample of the aqueous phase, check whether the reaction of 1,3-propylene glycol is complete, stop the reaction, cool to 25°C, let stand, and separate the upper solvent; (6) Combine the solvents separated in step (2) and step (5), raise the temperature to 50° C., and slowly dropwise add 5 wt % sodium hydroxide solution to maintain the pH value of the system between 9.1 and 9.5; (7) React until the pH value remains essentially unchanged, take a sample to detect whether the reaction of 1,3-dichloropropane is complete, and cool to room temperature; (8) The upper layer of material was separated, washed once with water and then distilled to obtain 183.0 g of the product with a yield of 96.8% and a purity of more than 99%.

[0024] Embodiment 3: A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 152.2 g of 1,3-propylene glycol, 350 g of toluene and 268 g of 30 wt% hydrochloric acid into a reaction flask, stir evenly, and heat to 80 °C for reflux reaction for 6 h; (2) The organic phase was taken for testing, and the 1,3-dichloropropane content was 5.1 wt%. The temperature was lowered to 28 °C, allowed to stand, and the upper solvent was separated; (3) Add 75 g of 30 wt% hydrochloric acid, 200 g of toluene, and 2.9 g of methanesulfonic acid into the flask; (4) Raise the temperature of the material to 60°C and keep the temperature for 4 hours; (5) Take a sample of the aqueous phase, check whether the reaction of 1,3-propylene glycol is complete, stop the reaction, cool to 25°C, let stand, and separate the upper solvent; (6) Combine the solvents separated in step (2) and step (5), raise the temperature to 50° C., and slowly dropwise add 5 wt % sodium hydroxide solution to maintain the pH value of the system between 9.1 and 9.5; (7) React until the pH value remains essentially unchanged, take a sample to detect whether the reaction of 1,3-dichloropropane is complete, and cool to room temperature; (8) The upper layer of material was separated, washed once with water and then distilled to obtain 184.5 g of the product with a yield of 97.6% and a purity of more than 99%.

[0025] Comparative Example 1 (without adding hydrochloric acid and solvent in batches): A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 152.2 g of 1,3-propylene glycol, 550 g of toluene and 343 g of 30 wt% hydrochloric acid into a reaction flask, stir evenly, and heat to 80 °C for reflux reaction; (2) Take a sample of the aqueous phase, check whether the reaction of 1,3-propylene glycol is complete, stop the reaction, cool to 25°C, let stand, and separate the upper solvent; (3) Heat the solvent to 50°C and slowly add 5 wt% sodium hydroxide solution to maintain the pH value of the system between 9.1 and 9.5; (4) React until the pH value remains essentially unchanged, take a sample to detect whether the reaction of 1,3-dichloropropane is complete, and cool to room temperature; (5) The upper layer was separated, washed once with water and then distilled to obtain 134.2 g of the product with a yield of 71% and a purity of 96.8%.

[0026] Comparative Example 2 (excessive amount of hydrochloric acid added in step (1)): The difference between Comparative Example 2 and Example 1 is that 300 g of 30 wt% hydrochloric acid is added in step (1), and the rest is the same as in Example 1. In Comparative Example 2, 170.9 g of the product is obtained, with a yield of 90.4% and a purity of 98.3%.

[0027] Comparative Example 3 (Changing the Type of Catalyst): The difference between Comparative Example 3 and Example 1 is that methanesulfonic acid in step (3) is replaced by 3.8 g of concentrated sulfuric acid, and the rest is the same as in Example 1. In Comparative Example 3, 165 g of product is obtained with a yield of 87.3% and a purity of 98.1%.

[0028] Comparative Example 4 (without addition of sodium hydroxide solution for hydrolysis): A method for preparing 3-chloro-1-propanol comprises the following steps: (1) Add 152.2 g of 1,3-propylene glycol, 300 g of toluene and 244 g of 30 wt% hydrochloric acid into a reaction flask, stir evenly, and heat to 80 °C for reflux reaction for 7 h; (2) The organic phase was taken for testing, and the 1,3-dichloropropane content was 5.7 wt%. The temperature was lowered to 29 °C, allowed to stand, and the upper solvent was separated; (3) Add 122 g of 30 wt% hydrochloric acid, 200 g of toluene, and 3.8 g of methanesulfonic acid into the flask; (4) Raise the temperature of the material to 65°C and keep the temperature for 4 hours; (5) Take a sample of the aqueous phase, check whether the reaction of 1,3-propylene glycol is complete, stop the reaction, cool to 25°C, let stand, and separate the upper solvent; (6) The solvents separated in step (2) and step (5) were combined, washed once with water, and then distilled to obtain 173 g of product with a yield of 91.5% and a purity of 97.8%.

[0029] It can be seen from the results of the above examples and comparative examples that the products obtained by the method of the present invention in Examples 1 to 3 have high yield and purity and low impurity content.

[0030] In Comparative Example 1, hydrochloric acid and solvent were not added in batches, and the product could not be separated from the aqueous phase system in time, resulting in a large amount of raw materials generating 1,3-dichloropropane; when the dilute alkali solution was added dropwise in the third step, 1,3-dichloropropane was difficult to be completely converted into the product or the product was reconverted into the raw material, resulting in a significant decrease in product yield and purity compared with those in the embodiment.

[0031] In Comparative Example 2, the amount of hydrochloric acid added in step (1) exceeds the scope of the present invention. Due to the excessive amount of raw materials, 1,3-dichloropropane and other impurities are generated too quickly, resulting in a decrease in product yield and purity.

[0032] In Comparative Example 3, the type of catalyst was changed. Due to its weak catalytic ability, the reaction time was greatly prolonged, more impurities were generated, and the yield and purity of the product were significantly reduced compared with those in the example.

[0033] In Comparative Example 4, the 1,3-dichloropropane in the product was not partially hydrolyzed, and the yield and purity of the product were also reduced.

[0034] Therefore, the method of the present invention can effectively reduce the generation of impurities, and can obtain high-yield and high-purity products, which is suitable for industrial production.

Claims

1. A method for preparing 3-chloro-1-propanol, characterized in that: The steps include: (1) Add 1,3-propylene glycol to a solvent, and add hydrochloric acid with a mass concentration of 25-30%, and heat to reflux for reaction; the amount of HCl added in the hydrochloric acid is 0.9-1.1 times the equivalent of 1,3-propylene glycol; (2) taking the organic phase after the reaction in step (1) for testing, and when the content of 1,3-dichloropropane is greater than 5wt%, cooling and separating the solvent layer; (3) Adding hydrochloric acid and solvent with a mass concentration of 25-30% to the reactants after the solvent is separated, and adding methanesulfonic acid, heating and then keeping the temperature to react; the amount of HCl added in the hydrochloric acid is 0.3-0.5 times the equivalent of 1,3-propylene glycol; (4) taking a sample of the aqueous phase after the reaction in step (3), detecting that the reaction of 1,3-propylene glycol is complete, stopping the reaction, cooling, and separating the solvent; (5) combining the solvents separated in step (2) and step (4), heating the solvents, and adding a sodium hydroxide solution dropwise thereto to react; sampling and testing the 1,3-dichloropropane after the reaction is complete, cooling the solvents and allowing them to stand for stratification; (6) Separating the organic layer separated in step (5), washing with water and then distilling to obtain the 3-chloro-1-propanol.

2. The preparation method according to claim 1, characterized in that: The solvent in step (1) and step (3) is selected from one or more of benzene, toluene and ethylene dichloride.

3. The preparation method according to claim 1 or 2, characterized in that: The amount of solvent added in step (1) is 1.5 to 2.5 times the mass of 1,3-propylene glycol.

4. The preparation method according to claim 1 or 2, characterized in that: In step (1), the reflux reaction temperature is 70-90° C., and the reflux reaction time is 6-9 h.

5. The preparation method according to claim 1, characterized in that: In step (2), the temperature is lowered to below 30°C.

6. The preparation method according to claim 1, characterized in that: In step (3), the amount of solvent added is 1 to 1.5 times the mass of 1,3-propylene glycol; the amount of methanesulfonic acid added is 0.01 to 0.02 equivalents of 1,3-propylene glycol.

7. The preparation method according to claim 1 or 6, characterized in that: In step (3), the reaction temperature is 50-70° C. and the reaction time is 4-6 hours.

8. The preparation method according to claim 1, characterized in that: In step (4), the temperature is lowered to below 30°C.

9. The preparation method according to claim 1, characterized in that: The mass fraction of the sodium hydroxide solution added in step (5) is 4-6%, and the pH of the system is controlled between 9.1-9.6 after the addition of sodium hydroxide.

10. The preparation method according to claim 1 or 9, characterized in that: In step (5), the temperature is raised to 45-55° C., and then sodium hydroxide solution is added dropwise to carry out the reaction until the pH value remains unchanged.