Preparation method of high-purity tropic acid

Abstract

The present invention relates to a method for preparing high-purity tropic acid, which mainly utilizes the difference in pKa between tropic acid and organic acid impurities such as phenylacetic acid and atropic acid, and selects a suitable pH range to efficiently remove the main impurities in tropic acid, and the steps are: step 1. dissolving crude tropic acid in an alkaline aqueous solution; step 2. adjusting the pH value of the alkaline aqueous solution to 3.5-5.0 with an acid; step 3. adding an organic solvent to the solution for extraction to obtain an organic solution and an aqueous phase; step 4. taking the aqueous phase, adjusting the pH value to 1-2, cooling and crystallizing, filtering to obtain crystals, and drying the crystals to obtain high-purity tropic acid. The purity of the tropic acid prepared by the present invention can reach more than 99%, the organic solvent used for extraction and impurity removal can be reused, the preparation method has mild reaction conditions, simple operation, green environmental protection, and easy to achieve scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and drug preparation, and in particular relates to a method for preparing high-purity tropic acid. Background Art

[0002] Tropane alkaloid anticholinergic drugs have a long history of application and are widely used clinically as antispasmodics, mydriatics, secretion inhibitors, muscle relaxants, anesthetic adjuvants, antidotes for organophosphorus poisoning, etc. Many alkaloids are extracted from specific plants, but due to the influence of the environment, resource distribution, abundance of alkaloids in plants, and extraction and purification technology, the resources of natural alkaloids are limited. Chemically synthesized alkaloids have become an important source of this type of drugs, such as atropine, racemic anisodamine, hyoscyamine, butrotropium bromide, scopolamine, scopolamine butylbromide, oxitropium bromide, ipratropium bromide, etc. Tropical acid is an important intermediate in the chemical synthesis of the above alkaloids.

[0003] The production process of tropic acid usually uses methyl phenylacetate as raw material, reacts it with methyl formate and sodium methoxide to obtain methyl formylphenylacetate, and then reduces it with potassium borohydride to obtain methyl tropic acid, and then hydrolyzes and acidifies to obtain tropic acid. The reaction process is shown below.

[0004]

[0005] Tropical acid is a key intermediate for chemical synthesis of various alkaloids, and the quality of synthetic alkaloids is closely related to the purity of tropic acid. In conventional production processes, water, toluene and other solvents are usually used for recrystallization to reduce the impurity content in tropic acid, but because tropic acid contains more impurities close to the nature of tropic acid, such as phenylacetic acid and atropic acid, which are similar to tropic acid structures and belong to organic acids, these impurities are difficult to be effectively removed by recrystallization, and multiple recrystallizations are required to increase the purity of tropic acid to more than 97%, which seriously affects the yield, makes the production cost higher, and produces a large amount of three wastes. In addition, impurities such as phenylacetic acid and atropic acid have similar reactivity with tropic acid in the subsequent alkaloid preparation process, resulting in the synthetic alkaloids containing the same difficult to remove derivative impurities, making it difficult for product quality to stably meet the requirements of the high-end market.

[0006] In summary, conventional recrystallization methods are difficult to remove impurities with properties similar to tropic acid. Increasing the number of recrystallizations to improve product purity is not only not environmentally friendly, but also significantly increases production costs. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing high-purity tropic acid, so as to solve the problems of low purity, low yield, high cost and high generation of three wastes when purifying tropic acid by the existing recrystallization method.

[0008] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0009] The present invention relates to a method for preparing high-purity tropic acid, which comprises the following steps:

[0010] Step 1. Dissolve crude tropic acid in an alkaline aqueous solution;

[0011] Step 2. Adjust the pH value of the alkaline aqueous solution to 3.5-5.0 with an acid;

[0012] Step 3. adding an organic solvent to the solution for extraction to obtain an organic solution and an aqueous phase;

[0013] Step 4. Take the aqueous phase, adjust the pH value to 1-2, cool and crystallize, filter to obtain crystals, and dry the crystals to obtain high-purity tropic acid.

[0014] Preferably, in step 1, the alkaline aqueous solution used is one of sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate solution, potassium carbonate solution, and ammonia water.

[0015] Preferably, in step 1, the alkaline aqueous solution used is a sodium hydroxide solution or a potassium hydroxide solution.

[0016] Preferably, in step 2 and step 4, the acid used to adjust the pH value is hydrochloric acid or sulfuric acid.

[0017] Preferably, in step 2, the pH value of the alkaline aqueous solution is adjusted to 4.0-4.9.

[0018] Preferably, the organic solvent used for extraction in step 3 is one of dichloromethane, chloroform, toluene and ethyl acetate.

[0019] Preferably, the organic solvent used for extraction in step 3 is one of dichloromethane, chloroform and toluene.

[0020] Preferably, the extraction in step 3 is performed twice, and after the first extraction, the aqueous phase is taken, and an organic solvent is added to the aqueous phase for a second extraction.

[0021] Preferably, the crystallization temperature in step 4 is 0-20°C.

[0022] Preferably, the crystallization temperature in step 4 is 2-10°C.

[0023] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0024] 1. The method for preparing high-purity tropic acid of the present invention comprises adding acid to an alkaline aqueous solution of tropic acid, and adjusting the pH value to 3.5-5.0. At this pH value, phenylacetate, atropic acid salt, etc. are freed to generate organic acids such as phenylacetic acid and atropic acid, and tropic acid still exists in the form of tropic acid salt. The solubility of phenylacetic acid and atropic acid in organic solvents is much greater than that in water, while the solubility of tropic acid salt in organic solvents is very small. Then, organic acids such as phenylacetic acid and atropic acid are extracted, and tropic acid salt is still dissolved in the aqueous phase. The extracted aqueous phase is crystallized to obtain high-purity tropic acid. The main impurities are efficiently removed by utilizing the difference in pKa between tropic acid and main impurities such as phenylacetic acid and atropic acid, so that the purity and yield of the finished tropic acid product are higher.

[0025] 2. The preparation method of high-purity tropic acid of the present invention can extract high-purity tropic acid by only one crystallization. Compared with the traditional method, the number of crystallizations is reduced, the cost is effectively reduced, and the discharge of three wastes is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the HPLC spectrum of the crude product of tropic acid before refining in Example 1 of the present invention;

[0027] Figure 2 This is the HPLC spectrum of the refined product of tropic acid in Example 1 of the present invention;

[0028] Figure 3 It is the HPLC spectrum of the refined product of tropic acid in Example 4 of the present invention. DETAILED DESCRIPTION

[0029] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, but the protection scope of the present invention is not limited thereto.

[0030] Example 1

[0031] The specific steps of the preparation method of high-purity tropic acid involved in this embodiment include:

[0032] Step 1. Add 50 g of crude tropic acid into a reaction flask and Figure 1 The HPLC spectrum shown in the figure shows that the HPLC purity is 87.1%, containing 2.4% phenylacetic acid and 6.4% atropic acid; the specific components are shown in Table 1:

[0033] Table 1: Statistical table of the content of each component in crude tropic acid

[0034]

[0035] In the table, RT is retention time, area is peak area, %area is area percentage, and height is peak height.

[0036] Add 300g of sodium hydroxide aqueous solution with a concentration of about 4%, and stir at room temperature to dissolve;

[0037] Step 2. Adjust the pH to 4.1 with about 20% hydrochloric acid;

[0038] Step 3. Add 200 ml of dichloromethane to the solution and extract twice;

[0039] Step 4. The aqueous phase was adjusted to pH 1.8 with about 20% hydrochloric acid, cooled to 5°C, stirred for 1 hour, filtered, and dried to obtain 42.9 g of tropic acid.

[0040] Through Figure 2 It can be seen from the HPLC spectrum shown that after purification, the HPLC purity of the product is 99.84%, containing 0.03% phenylacetic acid and 0.01% atropic acid. The specific components are shown in Table 2.

[0041] Table 2: Statistical table of the content of each component in the prepared tropic acid

[0042] RT Area %Area Height 1 1.391 1818 0.02 382 2 1.566 10781388 99.84 1887769 3 2.131 1971 0.02 278 4 2.519 3152 0.03 516 5 3.477 937 0.01 140 6 3.806 764 0.01 112 7 4.600 3341 0.03 423 8 4.881 2502 0.02 311 9 5.517 705 0.01 62 10 5.799 1997 0.02 242

[0043] Example 2

[0044] The specific steps of the preparation method of high-purity tropic acid involved in this embodiment include:

[0045] Step 1. Add 20.7 g of crude tropic acid (HPLC purity: 87.1%, containing 2.4% phenylacetic acid and 6.4% atropic acid) into a reaction bottle, add 135 g of a 5% aqueous potassium hydroxide solution, and stir at room temperature to dissolve;

[0046] Step 2. Adjust the pH to 4.9 with about 25% sulfuric acid;

[0047] Step 3. Add 100 ml of toluene to the solution and extract twice;

[0048] Step 4. The aqueous phase was adjusted to pH 1.7 with about 25% sulfuric acid, cooled to 10°C, stirred for 1 hour, filtered, and dried to obtain 16.5 g of tropic acid.

[0049] After purification, the product had a HPLC purity of 99.22%, containing 0.09% phenylacetic acid and 0.42% atropic acid.

[0050] Example 3

[0051] The specific steps of the preparation method of high-purity tropic acid involved in this embodiment include:

[0052] Step 1. Add 20.4 g of crude tropic acid (HPLC purity: 90.7%, containing 1.9% phenylacetic acid and 4.7% atropic acid) into a reaction bottle, add 61 g of an aqueous sodium hydroxide solution with a concentration of about 8%, and stir at room temperature to dissolve;

[0053] Step 2. Adjust the pH to 4.3 with about 20% hydrochloric acid;

[0054] Step 3. Add 100 ml of chloroform to the solution and extract twice;

[0055] Step 4. The aqueous phase was adjusted to pH 1.5 with about 20% hydrochloric acid, cooled to 6°C, stirred for 1 hour, filtered, and dried to obtain 17.1 g of tropic acid.

[0056] After purification, the product had a HPLC purity of 99.51%, containing 0.28% phenylacetic acid and 0.08% atropic acid.

[0057] Example 4

[0058] The specific steps of the preparation method of high-purity tropic acid involved in this embodiment include:

[0059] Step 1. Add 10 kg of crude tropic acid (HPLC purity is 90.7%, containing 1.9% phenylacetic acid and 4.7% atropic acid) into a reactor, add 56 kg of sodium hydroxide aqueous solution with a concentration of about 5%, and stir to dissolve;

[0060] Step 2. Adjust the pH to 4.5 with about 18% hydrochloric acid;

[0061] Step 3. The solution was extracted twice with 30 kg and 25 kg of dichloromethane respectively;

[0062] Step 4. The aqueous phase was adjusted to pH 1.5 with about 18% hydrochloric acid, cooled to 3°C, stirred for 1 hour, filtered, and dried to obtain 8.7 kg of tropic acid.

[0063] After purification, the product HPLC purity is 99.64%, containing 0.04% phenylacetic acid and 0.02% atropic acid. Figure 3 The specific components of the prepared tropic acid are shown in Table 3.

[0064] Table 3: Statistical table of the content of each component in the prepared tropic acid

[0065] Peak Name RT Area %Area Height 1 1.391 1817 0.02 385 2 TPS 1.566 10389980 99.64 1823009 3 2.137 2046 0.02 295 4 BYS 2.522 3992 0.04 650 5 3.483 2372 0.02 338 6 3.848 13196 0.13 1090 7 4.607 4985 0.05 625 8 4.888 3248 0.03 409 9 6.278 5370 0.05 544

[0066] Example 5

[0067] The specific steps of the preparation method of high-purity tropic acid involved in this embodiment include:

[0068] Step 1. Add 3.2 kg of crude tropic acid (HPLC purity is 87.1%, containing 2.4% phenylacetic acid and 6.4% atropic acid) into a reactor, add 19 kg of sodium hydroxide aqueous solution with a concentration of about 5%, and stir to dissolve;

[0069] Step 2. Adjust the pH to 4.8 with about 18% hydrochloric acid;

[0070] Step 3. The solution was extracted twice with 10 kg and 7 kg of dichloromethane respectively;

[0071] Step 4. The aqueous phase was adjusted to pH 1 with about 18% hydrochloric acid, cooled to 5°C, stirred for 1 hour, filtered, and dried to obtain 2.7 kg of tropic acid.

[0072] After purification, the product had a HPLC purity of 99.25%, containing 0.09% phenylacetic acid and 0.38% atropic acid.

[0073] The preparation principle of high-purity tropic acid in Examples 1 to 5 is as follows: under a pH value of 3.5 to 5.0, phenylacetate, atropic acid salt, etc. are freed to generate organic acids such as phenylacetic acid and atropic acid, while tropic acid still exists in the form of tropic acid salt. The solubility of phenylacetic acid and atropic acid in organic solvents is much greater than that in water, while the solubility of tropic acid salt in organic solvents is very small, and then phenylacetic acid, atropic acid and other organic acids are extracted, and tropic acid salt is still dissolved in the aqueous phase. High-purity tropic acid can be obtained by crystallizing the aqueous phase after extraction, that is, the pKa difference between tropic acid and major impurities such as phenylacetic acid and atropic acid is utilized to efficiently remove the major impurities, so that the purity of the tropic acid product is higher and the yield is higher.

[0074] Comparative Example 1

[0075] In this comparative example, toluene was used to recrystallize the crude tropic acid, and the ratio was m product:m toluene=1:3.

[0076] Comparative Example 2

[0077] This comparative example adopts toluene / water m material: m toluene: m water = 1:0.5:5.

[0078] Comparative Example 3

[0079] In this comparative example, water was used to recrystallize the crude tropic acid, and the ratio was m product:m water=1:7.

[0080] Effect Example

[0081] This effect example has statistically analyzed the purity of tropic acid extracted in Examples 1 to 5 and Comparative Examples 1 to 3, and the statistical results are shown in Table 4:

[0082] Table 4: Purity statistics of tropic acid obtained in Examples and Comparative Examples

[0083] Serial number Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 purity 99.84％ 99.22％ 99.51％ 99.64％ 99.25％ 94.8％ 94.4％ 95.3％

[0084] According to the above statistics, the purity of tropic acid extracted in the examples is as high as 99% or even 99.84%, while the purity of tropic acid extracted by the prior art is about 95%. In addition, the organic solvent used for extraction and impurity removal in Examples 1 to 5 can be reused, and the preparation method has mild reaction conditions, simple operation, green and environmental protection, and is easy to achieve scale-up production.

[0085] The present invention is described in detail above in conjunction with the embodiments, but the contents described are only preferred embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. All equivalent changes and improvements made according to the scope of application of the present invention should still fall within the scope of the patent coverage of the present invention.

Claims

1. A method for preparing high-purity tropic acid, characterized in that, It includes the following steps: Step 1. dissolving crude tropic acid in an alkaline aqueous solution, wherein the crude tropic acid contains phenylacetic acid and atropic acid as impurities, and the alkaline aqueous solution is a sodium hydroxide solution or a potassium hydroxide solution; Step 2. Adjust the pH value of the alkaline aqueous solution to 4.0-4.9 with an acid; Step 3. adding an organic solvent to the solution for extraction, wherein the organic solvent is one of dichloromethane, chloroform, and toluene, and the extraction is performed twice, taking the aqueous phase after the first extraction, adding the organic solvent to the aqueous phase for secondary extraction, and finally obtaining an organic solution and an aqueous phase; Step 4. Take the aqueous phase, adjust the pH value to 1-2 with hydrochloric acid or sulfuric acid, cool and crystallize, filter to obtain crystals, and dry the crystals to obtain high-purity tropic acid.

2. The method for preparing high-purity tropic acid according to claim 1, wherein: The crystallization temperature in step 4 is 0-20°C.

3. The preparation method of high-purity tropic acid according to claim 1, characterized in that: The crystallization temperature in step 4 is 2-10°C.

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