Anhydrous treatment method of N, N-dimethylamino-3-chloropropane

Abstract

The invention discloses a method for anhydrous treatment of N, N-dimethylamino-3-chloropropane, which sequentially comprises the following steps: (1) adding 1-3 parts by mass of potassium hydroxide into a bottle containing 100 parts by mass of N, N-dimethylamino-3-chloropropane, stirring for 30 minutes at room temperature, and standing to separate a lower-layer water phase so as to realize preliminary water removal; (2) adding 5-10 parts by mass of anhydrous magnesium sulfate and 0.5-2 parts by mass of potassium hydroxide, stirring and drying for 6 hours, and filtering to obtain N, N-dimethylamino-3-chloropropane of which the water content is less than or equal to 0.5%; and (3) adding 4-8 parts by mass of a 3A molecular sieve, sealing, standing and drying until the water content in the N, N-dimethylamino-3-chloropropane is less than or equal to 0.1%. According to the method, the water content in the N, N-dimethylamino-3-chloropropane can be rapidly reduced to be 0.1% or below, the material and process cost is low, materials with high dangerousness do not need to be used in the process, and the safety is good.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for treating N,N-dimethylamino-3-chloropropane without water. Background Art

[0002] N,N-dimethylamino-3-chloropropane is a raw material for preparing Grignard reagent 3,3-dimethylaminopropylmagnesium chloride, and the Grignard reaction needs to be carried out under anhydrous conditions. Effectively reducing the water content in N,N-dimethylamino-3-chloropropane is a prerequisite for preparing Grignard reagent 3,3-dimethylaminopropylmagnesium chloride.

[0003] In the prior art, there are generally three common methods for treating organic solvents without water: 1. Chemical method: removing water by reaction with a desiccant, such as anhydrous sodium sulfate, anhydrous magnesium sulfate, alkali metals, phosphorus pentoxide, etc.; 2. Physical drying: azeotropic distillation, fractional distillation, etc.; 3. Physical adsorption: molecular sieves, etc. However, these methods have the following disadvantages respectively: 1. Anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, etc. are only suitable for preliminary water removal and it is difficult to reduce the water content of the solvent below 0.1%; 2. Alkali metals and phosphorus pentoxide are expensive and dangerous; 3. Azeotropic distillation is mostly not applicable; 4. Molecular sieves are expensive and the water removal rate is slow.

[0004] N,N-dimethylamino-3-chloropropane is generally stored in the form of N,N-dimethylamino-3-chloropropane hydrochloride. After desalination, the water content is roughly above 5%. When in use, the water content needs to be reduced below 0.1%. Considering issues such as safety, production efficiency, and cost, there is no particularly good method for treating N,N-dimethylamino-3-chloropropane without water in the current technology. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for treating N,N-dimethylamino-3-chloropropane without water, which can reduce the water content in N,N-dimethylamino-3-chloropropane below 0.1% with good safety, fast water removal speed, and low cost.

[0006] The present invention is realized through the following technical solutions:

[0007] A method for treating N,N-dimethylamino-3-chloropropane without water successively includes the following steps:

[0008] (1) Add 1 - 3 parts by mass of potassium hydroxide to a bottle containing 100 parts by mass of N,N-dimethylamino-3-chloropropane, stir at room temperature for 30 minutes, and let it stand to separate the lower aqueous phase to achieve preliminary water removal;

[0009] (2) Add 5 - 10 parts by mass of anhydrous magnesium sulfate and 0.5 - 2 parts by mass of potassium hydroxide to the N,N - dimethylamino - 3 - chloropropane that has completed preliminary water removal obtained in step (1), stir and dry for 6 hours, then filter to obtain N,N - dimethylamino - 3 - chloropropane with a water content ≤ 0.5%.

[0010] (3) Add 4 - 8 parts by mass of 3A molecular sieve to the N,N - dimethylamino - 3 - chloropropane with a water content ≤ 0.5% obtained in step (2), seal it, and let it stand for drying until the water content in the N,N - dimethylamino - 3 - chloropropane ≤ 0.1%.

[0011] In the present invention, the reason for choosing such an arrangement order of the process, that is, first using 1 - 3 parts by mass of potassium hydroxide to complete preliminary water removal, then using 5 - 10 parts by mass of anhydrous magnesium sulfate and 0.5 - 2 parts by mass of potassium hydroxide for secondary water removal, and finally using 4 - 8 parts by mass of 3A molecular sieve for final water removal, is that the N,N - dimethylamino - 3 - chloropropane just after removing the hydrochloride has a large amount of water and needs to quickly remove a large amount of water. Potassium hydroxide can continuously force out the water and separate most of the water by stratification. However, through repeated experiments, it is very difficult to reduce the water content below 0.5%. Next, using anhydrous magnesium sulfate and potassium hydroxide, while potassium hydroxide forces out the water, anhydrous magnesium sulfate can quickly absorb it. Using them together can continue to reduce the water content below 0.5%. However, through repeated experiments, it is very difficult to reduce the water content below 0.2%. Therefore, finally using 3A molecular sieve for dehydration can reduce the water content below 0.1%.

[0012] In the present invention, the reason for choosing to first use 1 - 3 parts by mass of potassium hydroxide to complete preliminary water removal in step (1) is that the inventor conducted a comparative experiment on the primary water removal method, that is, choosing anhydrous magnesium sulfate and KOH for comparative experiments, and the results are shown in the following table:

[0013]

[0014] It was found in the experiment that when using anhydrous magnesium sulfate for drying, it caked and became viscous during filtration, making it difficult to filter and not conducive to operation; when using the method of primary water removal with KOH, after adding KOH and stirring to dissolve, water continued to seep out, and the water layer could be continuously separated. The effect of primary water removal was also better than directly using anhydrous magnesium sulfate, and the operation was simple. Therefore, in the primary water removal of step (1), it is preferred to use KOH for primary water removal.

[0015] Preferably, in the step (1), 1 part by mass of potassium hydroxide is added. The reason for preferably adding 1 part by mass of potassium hydroxide is that through the comparative experiment on the dosage of potassium hydroxide for primary water removal, that is, conducting comparative experiments when the dosages of potassium hydroxide are 0.5%, 1% and 3% of the total mass of N,N-dimethylamino-3-chloropropane, the inventors found the results as shown in the following table:

[0016] Project Mid-control moisture content 0.5％ 0.9％ 1％ 0.6％ 3％ 0.5％

[0017] It was found in the experiment that after adding 0.5% KOH and stirring, when it was stratified, it was found that the organic layer was relatively turbid and there was still a large amount of water that could not be removed; when the KOH was continuously added to 1%, the organic layer was clarified, and the water content was detected to be 0.6%, which had achieved the effect of primary water removal; when the KOH was continuously added to 3%, a little KOH could not be dissolved, and the water content was detected to be 0.5%. Based on this, it can be known that when selecting the dosage of potassium hydroxide for primary water removal, using 1% KOH for primary water removal is the best, so preferably 1 part by mass of potassium hydroxide is added.

[0018] In the present invention, the reason for choosing to add 5 - 10 parts by mass of anhydrous magnesium sulfate and 0.5 - 2 parts by mass of potassium hydroxide in step (2) and then stirring and drying for 6 hours is that through the comparative experiment on the drying time of anhydrous magnesium sulfate and potassium hydroxide, that is, conducting comparative experiments by selecting 6h, 8h, 10h, 12h and 14h, the inventors found the results as shown in the following table:

[0019] Project Mid-control moisture content 6h 0.1％ 8h 0.2％ 10h 0.1％ 12h 0.1％ 14h 0.1％

[0020] It was found in the experiment that after examining different drying times, it was found that drying for 6h had reached the in-process control standard. Therefore, when selecting the drying time of anhydrous magnesium sulfate and potassium hydroxide in step (2), it is preferably dried for 6h.

[0021] Preferably, in the step (3), 5 parts by mass of 3A molecular sieve is added.

[0022] Preferably, in the step (3), the time for static drying in a closed state after adding 3A molecular sieve is 12 hours. The reason for preferably setting the time for static drying in a closed state after adding 3A molecular sieve to 12 hours is that through the comparative experiment on the drying time of 3A molecular sieve, that is, conducting comparative experiments by selecting 6h, 12h and 18h, the inventors found the results as shown in the following table:

[0023] Project Moisture content 6h 0.18％ 12h 0.06％ 18h 0.05％

[0024] It was found in the experiment that after examining different drying times, it was found that drying for 12h had reached the in-process control standard. Therefore, when selecting the drying time of the molecular sieve, it is preferably dried for 12h.

[0025] In the present invention, by first using 5-10 parts by mass of anhydrous magnesium sulfate and 0.5-2 parts by mass of potassium hydroxide for secondary water removal, and then using 4-8 parts by mass of 3A molecular sieve for final water removal, the cost is greatly reduced. Because after the water is removed by potassium hydroxide, the water content is generally between 0.5% and 1%. If directly using 3A molecular sieve, the dosage is very large and the cost is very high. Through repeated experiments, a method of using anhydrous magnesium sulfate and KOH for dehydration simultaneously first is found. Thus, finally, the water removal process is simple to operate and has a low cost.

[0026] The beneficial effects of the present invention are:

[0027] The method for treating N,N-dimethylamino-3-chloropropane without water in the present invention has a clever process. By the combined use of three desiccants, namely potassium hydroxide, anhydrous magnesium sulfate and 3A molecular sieve, the water content in N,N-dimethylamino-3-chloropropane can be quickly reduced to less than 0.1%. Specifically, using the characteristic that potassium hydroxide is easily soluble in water to force out the water from N,N-dimethylamino-3-chloropropane to achieve preliminary water removal, and then using anhydrous magnesium sulfate to absorb simultaneously to reduce the water content to the greatest extent. Finally, after filtration, using 3A molecular sieve to adsorb water, the water content in N,N-dimethylamino-3-chloropropane is reduced to less than 0.1%. The whole process has a simple and controllable process, a fast water removal speed, good water removal thoroughness, low material and process costs, no need to use highly dangerous materials during the process, good safety, high economic value, strong practicability, and is worthy of promotion. Brief Description of the Drawings

[0028] The present invention will be described by way of examples with reference to the drawings, where:

[0029] Figure 1 is the process flow diagram of the present invention. Detailed Embodiments

[0030] All the features disclosed in this specification, or all the steps in the disclosed methods or processes, except for mutually exclusive features and / or steps, can be combined in any way.

[0031] Any feature disclosed in this specification (including any additional claims, abstract and drawings), unless specifically stated, can be replaced by other equivalent or features with similar purposes. That is, unless specifically stated, each feature is only an example in a series of equivalent or similar features.

[0032] Such as Figure 1As shown below, a method for treating N,N-dimethylamino-3-chloropropane without water: Add 1 part by mass of potassium hydroxide to a bottle containing 100 parts by mass of N,N-dimethylamino-3-chloropropane, stir at room temperature for 30 minutes, let it stand to separate the lower aqueous phase, then add 10 parts by mass of anhydrous magnesium sulfate and 0.5 part by mass of potassium hydroxide, stir and dry for 6 hours. After filtration, the water content of the material is detected to be less than 0.5%. Then weigh 5 parts by mass of 3A molecular sieve, seal it, and let it stand and dry for 12 h to obtain N,N-dimethylamino-3-chloropropane with a water content of less than 0.1%.

[0033] Taking the above method as the standard, 3 batches of experiments were completed. The feeding amounts were 300 g, 600 g, and 1000 g of N,N-dimethylamino-3-chloropropane respectively. The test results are shown in the following table:

[0034]

[0035] It can be seen from the data analysis that the 3 batches of products obtained by the method of the present invention all meet the quality standard that the final water content in N,N-dimethylamino-3-chloropropane ≤ 0.1%, and the quality analysis data are not very different, indicating that the process effect is very stable.

[0036] The present invention is not limited to the foregoing specific embodiments. The present invention extends to any new feature or any new combination disclosed in this specification, and any new method or process step or any new combination disclosed.

Claims

1. A method for the anhydrous treatment of N,N-dimethylamino-3-chloropropane, characterized in that, It successively includes the following steps: (1) Add 1-3 parts by mass of potassium hydroxide to a bottle containing 100 parts by mass of N,N-dimethylamino-3-chloropropane, stir at room temperature for 30 minutes, and let it stand to separate the lower aqueous phase to achieve preliminary water removal; (2) Add 5-10 parts by mass of anhydrous magnesium sulfate and 0.5-2 parts by mass of potassium hydroxide to the N,N-dimethylamino-3-chloropropane that has completed preliminary water removal obtained in step (1), stir and dry for 6 hours, and filter to obtain N,N-dimethylamino-3-chloropropane with a water content ≤ 0.5%; (3) Add 4-8 parts by mass of 3A molecular sieve to the N,N-dimethylamino-3-chloropropane with a water content ≤ 0.5% obtained in step (2), seal it, and let it stand and dry until the water content in the N,N-dimethylamino-3-chloropropane ≤ 0.1%.

2. A method for treating N,N-dimethylamino-3-chloropropane without water according to claim 1, characterized in that, In step (1), the added potassium hydroxide is 1 part by mass.

3. A method for treating N,N-dimethylamino-3-chloropropane without water according to claim 1, characterized in that, In step (3), the added 3A molecular sieve is 5 parts by mass.

4. A method for treating N,N-dimethylamino-3-chloropropane without water according to claim 1, characterized in that, In step (3), the time for standing and drying after adding 3A molecular sieve is 12 hours.

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