Method for recycling side reaction products in production of 3-amino-1-adamantanol

Abstract

The invention relates to a method for recycling a side reaction product in production of 3-amino-1-adamantanol, belonging to a technical method for recycling and utilizing a nitration side reaction product in a process of producing a medical intermediate 3-amino-1-adamantanol. In the neutralization-alkalization operation of nitration reaction mixed acid liquor in the production process of 3-amino-1-adamantanol, a segmented adjustment operation mode is adopted, a nitration reaction termination material is neutralized and adjusted to the optimal pH range of 5-7, and nitration side reaction products are separated out, separated and purified. And then carrying out pressurized (0.05-0.1 MPa) high-temperature (more than 100 DEG C) reaction on the separated nitration side reactant in a mixed water solution of strong inorganic alkali (sodium hydroxide or potassium hydroxide) and organic alkali (pyridine), so that the nitration side reactant is converted into 1, 3-adamantanediol. The target product 1, 3-adamantanediol is separated and collected through subsequent operations such as evaporation concentration, cooling crystallization, separation crystallization and the like.

Description

Technical Field

[0001] The invention relates to a method for recovering and utilizing a nitration side reaction product produced in a chemical synthesis stage during the production process of a pharmaceutical intermediate 3-amino-1-adamantanol. Background Art

[0002] 3-Amino-1-adamantanol is a derivative of adamantane. It is an indispensable fragment for the synthesis of vildagliptin, an effective drug for the treatment of type 2 diabetes, and an important pharmaceutical intermediate. At present, the large-scale production of 3-amino-1-adamantanol products at home and abroad mainly adopts the process of using 1-adamantanamine as the starting material, first nitrification reaction and then hydrolysis, but there are differences in the setting of process parameters and production process (intermittent or continuous flow).

[0003] We produce 3-amino-1-adamantanol according to our own technology (CN107325010A), also using 1-adamantanamine as the starting material, first using nitric acid-sulfuric acid mixed acid as the nitrating agent, and adopting a tubular continuous reaction method to carry out nitration, so as to convert 1-adamantanamine into a 3-amino-1-adamantanane nitration intermediate product, and then adding the nitration reaction mixture into clean water for dilution to terminate the nitration reaction, and then gradually adding an inorganic strong base (sodium hydroxide or potassium hydroxide) aqueous solution into the nitration reaction mixed acid solution (a mixture of sulfuric acid-nitric acid-nitration reaction intermediate-water) for base-catalyzed hydrolysis, so as to hydrolyze the 3-amino-1-adamantanane nitration intermediate product into the target product 3-amino-1-adamantanol. The nitration intermediate of 3-amino-1-adamantane is in a soluble state in the strong acid environment of the mixed acid solution and in the neutralization to weak alkaline solution stage. It is hydrolyzed and converted into 3-amino-1-adamantanol under strong alkaline conditions (pH>10). 3-amino-1-adamantanol has low solubility in alkaline aqueous solution. In strong alkaline aqueous solution (pH>14), 3-amino-1-adamantanol is fully precipitated in a solid state. The precipitated target product 3-amino-1-adamantanol can be separated by suction filtration or organic solvent extraction.

[0004] The method adopted by the domestic and foreign 3-amino-1-adamantanol manufacturers in the alkalization-hydrolysis reaction operation of the production process is to directly add alkali solution for neutralization and alkalization while stirring and mixing, until the nitration reaction mixed acid solution is neutralized and alkalized to strong alkalinity, so that the 3-amino-1-adamantanol product is fully precipitated. In production practice, we accidentally observed that in the alkalization process of the nitration reaction mixed acid solution, when the acidity of the material liquid is gradually reduced to the weak acid close to the neutral stage, some white solids will be precipitated in the originally homogeneous mixed acid solution, but as the material liquid begins to change from weak acid to weak alkalinity (pH 9-10), these white solids precipitated in the weak acid stage then dissolve and disappear again, and the material liquid becomes a homogeneous liquid again, until the alkalinity of the material liquid is further enhanced to more than pH 10, 3-amino-1-adamantanol precipitates begin to appear in large quantities. For this reason, we have specially conducted several special inspections during the production process, confirmed the objective existence of this phenomenon, and separated the precipitate under the weak acid for comparative detection, and determined that this precipitate is not the nitration reaction precursor of 3-amino-1-adamantanol, nor is it the target product 3-amino-1-adamantanol, but another side reaction product of 1-adamantanamine in the nitration reaction. This nitration side reaction product is not easy to transform in the hydrolysis reaction, and is precipitated under weak acid conditions, but is redissolved in alkaline liquid, so according to the current production process, it will not be extracted in the production operation of separating 3-amino-1-adamantanol, but is dissolved in the production waste alkali liquid. Due to the analytical detection method executed according to the current production, in the process of preparing the test sample, the nitration side reaction product will not be extracted by the organic solvent because it is dissolved in the alkaline water liquid, so it cannot be detected. Therefore, there is no public report about this nitration side reaction product so far.

[0005] Through further investigation, we determined that the amount of this side reaction product in the nitration reaction of 1-adamantanamine can usually reach 2% to 6% of the conversion of 1-adamantanamine. And further research found that this nitration side reaction product can be converted into another adamantane derivative 1,3-adamantanediol through corresponding chemical reaction treatment. 1,3-adamantanediol is an important organic synthesis intermediate and is widely used in the fields of medicine, pesticides and IT technology.

[0006] To this end, we have developed a specialized technical method for recovering and utilizing the nitration side reaction products in the production of the above-mentioned 3-amino-1-adamantanol. Summary of the invention

[0007] The present invention aims to provide a method for recycling side reaction products in the production of 3-amino-1-adamantanol, aiming to recover and utilize the nitration side reaction products and convert them into 1,3-adamantanediol in the process of producing the pharmaceutical intermediate 3-amino-1-adamantanol by using 1-adamantanamine as a starting material and adopting a process of first nitration and then hydrolysis.

[0008] At present, the large-scale production of 3-amino-1-adamantanol at home and abroad all uses 1-adamantanamine as the starting material, first uses nitric acid or nitric acid-sulfuric acid mixed acid as a nitrating agent to carry out nitration reaction, converts 1-adamantanamine into 3-amino-1-adamantanane nitration intermediate product, then adds clean water to dilute the mixed material after the nitration reaction to terminate the nitration reaction, and then adds inorganic strong alkali (sodium hydroxide or potassium hydroxide) aqueous solution to the nitration reaction mixed acid solution (mixed homogeneous liquid composed of sulfuric acid-nitric acid-nitration reaction intermediate-water) for neutralization-alkalization. The current production process adopts a one-time alkalization operation, that is, the strong alkali solution is added until the nitration reaction mixed acid solution is neutralized and alkalized to a strong alkalinity, so that the 3-amino-1-adamantanane nitration intermediate product is hydrolyzed and converted into the target product 3-amino-1-adamantanol. 3-amino-1-adamantanol has low solubility in the strong alkaline aqueous solution and precipitates. Then, the target product 3-amino-1-adamantanol is separated from the waste alkali liquor by mechanical separation or organic solvent extraction. As described in the previous background technology, in addition to the nitration intermediate of the target product 3-amino-1-adamantanane generated by the positive reaction, other side reactions will also occur during the nitration reaction to generate nitration side reaction impurities. However, according to the current 3-amino-1-adamantanol production process, the nitration side reaction generated by the nitration side reaction will eventually dissolve in the production waste alkali liquor and be lost along with the waste alkali liquor without being recycled.

[0009] The purpose of the present invention is achieved by the following technical scheme: the steps of recycling the nitration side reaction products in the production process of 3-amino-1-adamantanol are as follows:

[0010] 1. Recovery of nitration by-products:

[0011] In the neutralization-alkalization operation of the nitration reaction mixed acid solution in the production of 3-amino-1-adamantanol, a staged adjustment operation mode is adopted. The material is firstly neutralized with a strong alkali (sodium hydroxide or potassium hydroxide) aqueous solution to adjust the pH to a range of 5 to 7, and then allowed to stand for more than 1 hour to allow the precipitated side reaction products to fully sink, and then the nitration side reaction solid precipitate is separated from the nitration mixed acid solution.

[0012] The study found that nitration by-reaction products can be precipitated from the mixed acid solution in the pH range of 3 to 8, but the precipitation is most complete in the pH range of 5 to 7. In addition, the precipitated nitration by-reaction product particles are larger and easily sink to the bottom of the container when left stationary, making it easier to separate them.

[0013] 2. Purification of nitration by-products:

[0014] The separated nitration side reaction precipitate is filtered or centrifuged to remove most of the nitrating acid liquid, and the filter residue is washed with weakly acidic water at room temperature with a pH of 5 to 7 (adjusted with dilute sulfuric acid or hydrochloric acid) to fully remove the nitrating acid liquid, so as to obtain a relatively pure nitration side reaction product.

[0015] Studies have found that in weakly acidic water, nitrification by-products are difficult to dissolve, while the acid and inorganic salts contained in the filter residue are easily dissolved and carried out by the flushing water.

[0016] 3. Conversion reaction of nitration byproducts:

[0017] (1) Add the purified nitration side reaction product to clean water of 4 to 5 times its weight, add 25% sodium hydroxide solution or 35% potassium hydroxide solution while stirring, and dissolve the nitration side reaction product after adding the alkali solution. The amount of strong alkali solution added is 0.2 to 0.4 times of the nitration side reaction product, and its amount added is equivalent to: the amount of sodium hydroxide added is 0.05 to 0.1 times of the nitration side reaction product; the amount of potassium hydroxide added is 0.07 to 0.14 times of the nitration side reaction product.

[0018] (2) Adding a reaction promoter, pyridine, the amount of pyridine added is 0.03 to 0.05 times the amount of the nitration side reaction product.

[0019] (3) The material liquid is then heated and pressurized to (0.05 MPa to 0.1 MPa; >100° C.) and reacted for about 0.5 to 1 hour at a high temperature until all the nitration byproducts are converted into 1,3-adamantanediol.

[0020] The study found that the conversion of nitration side reactions can only be carried out at a relatively high temperature (>100°C). In order to meet this temperature condition, a pressurized reaction method is adopted. It is also found that if only inorganic bases (sodium hydroxide or potassium hydroxide) are used, the conversion reaction rate of nitration side reactions is very slow even at high temperatures, and it is difficult to fully complete. When a small amount of organic base is added, the conversion rate of nitration side reactions can be significantly increased, and the conversion can be completed. Through screening and comparison of a variety of organic bases, pyridine has the best effect, and only a small amount of addition is required to effectively promote the conversion reaction. Further research also shows that if only organic bases (such as only pyridine) are used instead of inorganic strong bases, although nitration side reactions can also be converted, it is necessary to use at least 7 times more pyridine than nitration side reactions and no water or less water is added to achieve the effect of fully converting nitration side reactions. From the perspective of economic efficiency, we choose a reaction treatment method that combines inorganic strong bases and organic bases.

[0021] 4. Separation of the reaction product 1,3-adamantanediol:

[0022] The converted material liquid is cooled, and hydrochloric acid is added while stirring to neutralize and adjust the pH to 7-8. Then the neutralized material liquid is evaporated and concentrated under normal pressure or reduced pressure until a large amount of crystals are precipitated in the material liquid. The material is cooled to 5°C-10°C, and allowed to stand for aging and crystallization for 2-3 hours.

[0023] 1,3-adamantanediol is separated from the mother liquor by suction filtration or centrifugation, and the filter residue is rinsed with an appropriate amount of cold water (5°C to 10°C) to remove impurities contained in the mother liquor.

[0024] The separated crystals are dried to remove moisture, thereby obtaining the target product 1,3-adamantanediol.

[0025] So far, there has been no public report that a nitration side reaction will occur in the process of producing the pharmaceutical intermediate 3-amino-1-adamantanol by using 1-adamantanamine as the starting material and adopting a process of nitration followed by hydrolysis. The product of this nitration side reaction will precipitate in a mixed acid solution with a pH of 3 to 8 during the hydrolysis reaction, but will dissolve again after the pH value of the material solution rises to 9 to 10. There is no public technical method for how to recover and utilize the nitration side reaction product. The present invention is the first and only public report of a method for recovering and utilizing the nitration side reaction product.

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

[0027] In the current production process of the pharmaceutical intermediate 3-amino-1-adamantanol using 1-adamantanamine as the starting material and adopting the process of nitration followed by hydrolysis, the technical method is used to separate, recover and treat the nitration side reaction products and convert them into 1,3-adamantanediol, which is equivalent to increasing the yield of the starting material 1-adamantanamine into products with higher value by 2% to 6%. DETAILED DESCRIPTION

[0028] The purpose of recycling the nitration side reaction products in the production of 3-amino-1-adamantanol is achieved in the following way: in the process of producing 3-amino-1-adamantanol by using 1-adamantanamine as a starting raw material and adopting a technical process of nitration followed by hydrolysis, when neutralizing and alkalizing the acid solution that terminates the nitration reaction, the current process is not followed by one-step neutralization and alkalization, but staged neutralization and alkalization, and the nitration side reaction products are separated and taken out before continuing the subsequent production operation.

[0029] The method for recovering and utilizing the nitration side reaction products comprises the following steps:

[0030] 1. Recovery of nitration by-products:

[0031] In the neutralization-alkalization operation of the mixed acid solution of the nitration reaction in the production process of 3-amino-1-adamantanol, a staged adjustment operation mode is adopted. The material is first neutralized with a strong alkaline aqueous solution to adjust the pH to a range of 5 to 7, and then allowed to stand for more than 1 hour to allow the precipitated side reaction products to fully sink, and then the nitration side reaction solid precipitate is separated from the nitration mixed acid solution.

[0032] 2. Purification of nitration by-products:

[0033] The separated nitration side reaction precipitate is mechanically removed from the nitration acid by suction filtration or centrifugation, and the filter residue is washed with weakly acidic clean water at room temperature with a pH of 5 to 7 to fully remove the nitration acid and inorganic salts to obtain a relatively pure nitration side reaction product.

[0034] 3. Conversion reaction of nitration byproducts:

[0035] (1) Add the purified nitration by-reaction product into clean water of 4 to 5 times its weight, add 25% sodium hydroxide solution or 35% potassium hydroxide solution while stirring, and the nitration by-reaction product is dissolved after adding the alkali solution. The amount of the strong alkali solution added is 0.2 to 0.4 times the nitration by-reaction product, and the pH of the material liquid is > 14.

[0036] (2) Adding a reaction promoter, pyridine, the amount of pyridine added is 0.03 to 0.05 times the amount of the nitration side reaction product.

[0037] (3) The material liquid is then heated and pressurized to (0.05 MPa to 0.1 MPa; >100° C.) and reacted for about 0.5 to 1 hour at a high temperature until all the nitration byproducts are converted into 1,3-adamantanediol.

[0038] 4. Separation of the reaction product 1,3-adamantanediol:

[0039] The converted material liquid is cooled, and hydrochloric acid is added while stirring to neutralize and adjust the pH to 7-8. Then the neutralized material liquid is evaporated and concentrated under normal pressure or reduced pressure until a large amount of crystals are precipitated in the material liquid. The material is cooled to 5°C-10°C and allowed to stand for aging and crystallization for 2-3 hours.

[0040] The 1,3-adamantanediol is separated from the mother liquor by mechanical separation (suction filtration or centrifugation, etc.), and the filter residue is rinsed with an appropriate amount of cold water (5°C to 10°C) to remove impurities contained in the mother liquor.

[0041] The separated crystals are dried to remove moisture, thereby obtaining the target product 1,3-adamantanediol.

[0042] Example:

[0043] In the neutralization-alkalization operation of the mixed acid solution of the nitration reaction in the large-scale production process of 3-amino-1-adamantanol, the mixed acid solution after the nitration reaction is first neutralized and adjusted to a pH range of 5 to 7 with a sodium hydroxide aqueous solution, and then allowed to stand for 1 to 2 hours until the side reaction products precipitated in the acid solution are fully sunk, and then separated from the mixed acid solution. The collected nitration side reaction precipitates are centrifuged to remove the liquid, and then the filter residue is washed with normal temperature clean water with a pH of 5 to 7, and the water is removed for standby use.

[0044] Weigh 1000g of the nitration side reaction product filter residue, and measure the water content of the filter residue to be about 6.3%, and calculate the net weight of the nitration side reaction product filter residue to be 937g. Add the nitration side reaction product filter residue into an experimental pressure reactor pre-filled with 4000g of deionized water, start stirring, add 25% sodium hydroxide solution 290g, and then add pyridine 30g.

[0045] Install the reactor, heat it up until the pressure inside the reactor rises to 0.05MPa-0.1MPa, and keep the reaction for 40 minutes. Restore the reactor to normal pressure and cool it to room temperature.

[0046] The material after the reaction was transferred out and neutralized with hydrochloric acid to adjust the pH to 7-8. Then the material liquid was concentrated by reduced pressure evaporation with a rotary evaporator until more crystals were precipitated, and the concentrated material was transferred out and allowed to cool at 5℃-10℃ for more than 2 hours. While the material was still cold, it was transferred into an experimental centrifuge for centrifugal separation to remove the mother liquor, and the filter residue was rinsed with a small amount of cold water.

[0047] The collected filter residue was tested and analyzed, and it was determined to be 1,3-adamantanediol with a purity of 99.3%.

[0048] A total of 709 g of wet filter residue was obtained, and the moisture content of the filter residue was measured to be 4.1%. It was calculated that 675 g of pure 1,3-adamantanediol crystals were obtained.

Claims

1. A method for recycling side reaction products in the production of 3-amino-1-adamantanol, wherein the side reaction products are nitrated side reaction products produced in the production process of synthesizing the target product 3-amino-1-adamantanane by using 1-adamantanamine as the starting material and adopting the technical process of first nitration and then hydrolysis, and the nitrated side reaction products are not recycled in the current production. The method is characterized in that it comprises the following steps: (1) Recovery of nitration by-products: In the neutralization-alkalization operation of the nitration reaction mixed acid solution in the production process of 3-amino-1-adamantanol, a staged adjustment operation mode is adopted, the material is firstly neutralized with a strong alkali (sodium hydroxide or potassium hydroxide) aqueous solution to adjust the pH to a range of 3 to 8, preferably a pH range of 5 to 7, and then allowed to stand for more than 1 hour to allow the nitration side reaction products to be fully precipitated, and the nitration side reaction solid precipitate is separated from the nitration mixed acid solution; (2) Purification of nitration by-products: The separated nitration side reaction precipitate is filtered or centrifuged to remove the contained nitration acid solution, and the filter residue is washed with weakly acidic water at room temperature with a pH of 5 to 7 to fully remove the contained nitration acid solution to obtain a relatively pure nitration side reaction product; (3) Conversion reaction of nitration side products: The purified nitration side reaction product is dispersed with 4 to 5 times of its weight of clean water, and then a strong alkali solution is added to dissolve it, and then a reaction promoter pyridine is added; then the material liquid is heated and pressurized to react for about 0.5 to 1 hour, until the nitration side reaction product is completely converted into 1,3-adamantanediol; The reaction pressure here is 0.05MPa~0.1MPa, and the reaction temperature is>100℃; (4) Separation of the reaction product 1,3-adamantanediol: The converted material liquid is cooled, and adjusted to pH 7-8 by neutralization with hydrochloric acid solution; the neutralized material liquid is then evaporated and concentrated under normal pressure or reduced pressure, cooled for crystallization, separated for crystallization, and dried to obtain the reaction product 1,3-adamantanediol crystals.

2. A method for recycling side reaction products in the production of 3-amino-1-adamantanol according to claim 1, characterized in that: The strong alkali solution added in step (3) is an aqueous solution of inorganic alkali sodium hydroxide or potassium hydroxide, and the added amount converted into pure inorganic alkali is: the added amount of sodium hydroxide is 0.05 to 0.1 times the nitration side reaction product; the added amount of potassium hydroxide is 0.07 to 0.14 times the nitration side reaction product.

3. A method for recycling side reaction products in the production of 3-amino-1-adamantanol according to claim 1, characterized in that: The reaction accelerator added in step (3) is an organic base, preferably pyridine, and the amount of pyridine added is 0.03 to 0.05 times the amount of the nitration side reaction product.