A method for industrial preparation of high-purity 3,6-dichloro-4-isopropylpyridazine

Abstract

The application discloses an industrialized preparation method of high-purity 3,6-dichloro-4-isopropyl pyridazine, and belongs to the technical field of synthesis of pharmaceutical intermediates. The method utilizes the characteristics of Minisci reaction, reduces the reaction temperature, makes the industrialized production temperature interval better controlled, and then improves the reaction conversion rate and reduces the impurity generation. On the other hand, the method utilizes the low melting point characteristics of 3,6-dichloro-4-isopropyl pyridazine, adopts the low-temperature crystallization purification method in a suitable solvent to complete the purification of the product. The method overcomes the problem that high-temperature reaction will bring more impurities into the product in large-scale production of 3,6-dichloro-4-isopropyl pyridazine, and overcomes the difficulties of high production cost, high energy consumption and high equipment requirement in the existing purification method. The preparation method greatly improves the product quality and yield, meets the commercial production requirements, and the product purity can reach 99.5%, which can be directly used as a reaction raw material.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to an industrialized preparation method of high-purity 3,6-dichloro-4-isopropyl pyridazine. BACKGROUND

[0002] 3,6-dichloro-4-isopropyl pyridazine is a pharmaceutical intermediate, which is mainly used for synthesizing sersmetilu. The drug is an oral selective agonist of thyroid hormone receptor (THR)-beta, and is used for treating non-alcoholic steatohepatitis (NASH) with liver fibrosis. It is the first drug for treating non-alcoholic steatohepatitis in the world, has high selectivity, can play a core role in the liver by activating the beta receptor in liver cells, regulate lipid metabolism, reduce LDL-C, triglycerides and atherogenic lipoprotein, has no activity on the THR-alpha receptor, thereby not affecting the bone or heart parameters, and does not affect other hormones in the thyroid hormone pathway. The 3,6-dichloro-4-isopropyl pyridazine on the market is usually obtained by high-temperature reaction and high-temperature distillation, but some impurities are brought into the product, which are not easy to separate and remove, and are brought into the subsequent reaction system, resulting in difficulty in purifying the product, and the product is not suitable for being directly used as a reaction raw material. According to the physical and chemical properties of 3,6-dichloro-4-isopropyl pyridazine, high-purity 3,6-dichloro-4-isopropyl pyridazine is obtained by low-temperature crystallization.

[0003] At present, there are two common preparation methods of 3,6-dichloro-4-isopropyl pyridazine: column chromatography and rectification. It is disclosed in Chinese patent CN111909137B that 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid are dissolved in water, and stirring is carried out at 70 DEG C, and ammonium persulfate dissolved in water is slowly dropped into the bottle. After the reaction is completed, the reaction is quenched, extraction is carried out, and then the product is obtained by column chromatography. Although the product can be obtained by this method, the production cost is high, and the method does not meet the commercial production. It is disclosed in US patent US4628088A that 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid are dissolved in water, and stirring is carried out at 80 DEG C, and ammonium persulfate dissolved in water is slowly dropped into the bottle. After the reaction is completed, the reaction is quenched, extraction is carried out, and then the product is obtained by high-temperature distillation. Although the product can be obtained by this method, by-products are generated in the high-temperature process, and the by-products are not easy to remove, which affects the purity of the product. The distillation period is long in mass production, the production cost is high, and the method is not conducive to commercial production. SUMMARY

[0004] In view of the deficiencies in the prior art, the application provides an industrialized preparation method of high-purity 3,6-dichloro-4-isopropyl pyridazine. The method obtains high-purity 3,6-dichloro-4-isopropyl pyridazine by low-temperature crystallization, the product has high purity, the production cost and energy consumption are reduced, the whole process operation is simple, and the method is suitable for large-scale production.

[0005] To solve the above technical problems, the present application provides the following technical solutions:

[0006] An industrialized preparation method of high-purity 3,6-dichloro-4-isopropyl pyridazine, comprising the following steps:

[0007] S1: 3,6-dichloropyridazine, isobutyric acid, strong acid, catalyst and solvent are mixed and placed in a reaction kettle, stirred and heated to 40-50℃, ammonium persulfate solution is added dropwise, and the reaction continues until the reaction is completed;

[0008] S2: continue to add an alkane solvent to the reaction kettle; extract and wash the product to obtain an organic phase solution of 3,6-dichloro-4-isopropyl pyridazine;

[0009] S3: the organic phase solution of 3,6-dichloro-4-isopropyl pyridazine is added to the reaction kettle, and the temperature is lowered to-30 to-5℃ for crystallization, and then treated to obtain 3,6-dichloro-4-isopropyl pyridazine.

[0010] Further, the catalyst in S1 is silver nitrate or ferrous sulfate, preferably silver nitrate.

[0011] Further, the strong acid in S1 can be trifluoroacetic acid or concentrated sulfuric acid, preferably concentrated sulfuric acid.

[0012] Further, the solvent in S1 can be one or more of water, methanol, ethanol, acetonitrile, preferably water.

[0013] Further, the alkane solvent in S2 is selected from one or more of n-pentane, isopentane, n-hexane, cyclohexane, n-heptane, petroleum ether, etc., more preferably n-heptane. 3,6-dichloro-4-isopropyl pyridazine is a low-melting solid, which has good solubility in polar solvents, but if it is directly cooled and crystallized in this solvent system, the product will be clumped, and the effect of dispersion and purification cannot be achieved. By introducing an alkane solvent, extraction, crystallization dispersion and impurity removal can be achieved at low temperature; such solvents can be used as extraction solvents and crystallization solvents.

[0014] In some embodiments, the ammonium persulfate solution in S1 is added dropwise for 3-4h; after the ammonium persulfate solution is added dropwise, the reaction continues for 0.5-1h.

[0015] In some embodiments, the crystallization temperature in S3 is-20 to-15℃.

[0016] In some embodiments, the molar ratio of 3,6-dichloropyridazine to strong acid in S1 is 1:0.05-0.5, preferably 1:0.1.

[0017] In some embodiments, the molar ratio of 3,6-dichloropyridazine to catalyst in S1 is 1:0.02-0.1, preferably 1:0.04.

[0018] In some embodiments, the molar ratio of 3,6-dichloropyridazine to isobutyric acid in S1 is 1:0.9-2.0, preferably 1:1.05.

[0019] In some embodiments, the molar ratio of 3,6-dichloropyridazine to ammonium persulfate in S1 is 1:0.9-1.2, preferably 1:1.1.

[0020] Compared with the prior art, the present application has the following beneficial effects:

[0021] 1. In the prior art, when producing 3,6-dichloro-4-isopropylpyridazine on a large scale, high-temperature reaction is used, which releases oxygen and generates a large amount of heat, so that the product contains many impurities and is difficult to separate and remove, and the reaction is not easy to control. The present application uses the characteristics of Minisci reaction, controls the reaction temperature, and thus the temperature range of industrial production is better controlled, the reaction conversion rate is improved, the impurity generation is reduced, and the purity of the crude product in S2 can reach more than 96%.

[0022] 2. The present application uses the low melting point of 3,6-dichloro-4-isopropylpyridazine to purify the product by low-temperature crystallization in a suitable solvent. This method overcomes the difficulties of high production cost, high energy consumption and high equipment requirement in the prior art purification method, such as the use of a large amount of mixed solvent in column chromatography, the high cost of three waste treatment, the difficulty in controlling the reflux ratio due to the similar boiling points of impurities and products, and the instability of products under high temperature for a long time.

[0023] 3. The preparation method of the present application greatly improves the product quality and yield, meets the requirements of commercial production, and the product purity can reach 99.5%, which can be directly used as a reaction raw material. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The nuclear magnetic resonance spectrum of 3,6-dichloro-4-isopropylpyridazine obtained in Example 1 is shown in the figure.

[0025] Figure 2 The high performance liquid chromatogram of 3,6-dichloro-4-isopropylpyridazine obtained in Example 1 is shown in the figure. DETAILED DESCRIPTION

[0026] The present application will be further described below in conjunction with specific examples, but the content and scope of the present application are not limited by the following examples.

[0027] Unless otherwise specified, the reagents used in the examples of the present application are all commercially available.

[0028] Example 1

[0029] S1: In a 1000L reactor, 275kg of water, 110kg of 3,6-dichloropyridazine, 5kg of silver nitrate, 68.3kg of isobutyric acid, 7.4kg of concentrated sulfuric acid were added under stirring at room temperature, the temperature of the system was raised to 40-50°C, the temperature in the reactor was controlled at 40-50°C, when the temperature in the reactor reached 45°C, the prepared ammonium persulfate aqueous solution (185.3kg of ammonium persulfate + 330kg of water) was added dropwise, and the dropwise addition was completed in about 3-4h; after the dropwise addition was completed, the reaction was maintained for 0.5h, and HPLC control was started, the reaction was completed, 113.2kg of n-heptane was added for extraction, the organic phase was obtained after separation, the purity was 96.8%, and the yield was 99%.

[0030] S2: The organic phase from the previous step was added to a 500L reactor, and the temperature was lowered under stirring, when the temperature in the reactor was lowered to 0-5°C, solid was precipitated from the system, the temperature was further lowered to -20--15°C, and the system was maintained at -20--15°C for 1-2h for crystallization, then centrifugation was performed, the filter cake was rinsed with 56.4kg of n-heptane, and the solvent was removed to obtain 120.6kg of 3,6-dichloro-4-isopropylpyridazine, the HPLC purity was 99.8%, and the yield was 85.5%.

[0031] Figure 1 、 Figure 2 The nuclear magnetic resonance hydrogen spectrum and the high performance liquid chromatogram of 3,6-dichloro-4-isopropylpyridazine prepared in this example are shown in Figures 1 and 2 respectively, and the nuclear magnetic resonance hydrogen spectrum data are as follows:

[0032] 1HNMR (DMSO, 400MHz): δppm 1.24-1.26 (m, 6H), δppm 3.14-3.17 (m, 1H), δppm 7.98 (d, 1H).

[0033] Example 2

[0034] S1: at room temperature, under stirring, 275 kg of water, 110 kg of 3,6-dichloropyridazine, 5 kg of silver nitrate, 68.3 kg of isobutyric acid, 7.4 kg of concentrated sulfuric acid were added into a 1000 L reactor, the temperature of the system was increased to 40-50 °C, the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (202 kg of ammonium persulfate + 660 kg of water) was added dropwise, which was completed in about 3-4 h; after the dropwise addition was completed, the reaction was kept for 0.5 h, and then sampling was started for HPLC control, and after the reaction was completed, 113.2 kg of n-heptane was added for extraction, and the organic phase was obtained after separation and washing with a mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 kg, the purity was 96.1%, and the yield was 97%.

[0035] S2: the organic phase in the above step was added into a 500 L reactor, and the temperature was decreased, when the temperature in the reactor was decreased to 0-5 °C, the system would precipitate solids, and then the temperature was decreased to -20 to -15 °C, and the temperature was kept at -20 to -15 °C for 1-2 h for crystallization, then centrifugation was carried out, 56.4 kg of n-heptane was used for rinsing and the filter cake was dissolved to obtain 117.5 kg of 3,6-dichloro-4-isopropylpyridazine, the HPLC purity was 99.5%, and the yield was 83.3%.

[0036] Example 3

[0037] S1: at room temperature, under stirring, 275 kg of water, 110 kg of 3,6-dichloropyridazine, 5 kg of silver nitrate, 68.3 kg of isobutyric acid, 7.4 kg of concentrated sulfuric acid were added into a 1000 L reactor, the temperature of the system was increased to 40-50 °C, the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (202 kg of ammonium persulfate + 660 kg of water) was added dropwise, which was completed in about 3-4 h; after the dropwise addition was completed, the reaction was kept for 0.5 h, and then sampling was started for HPLC control, and after the reaction was completed, 113.2 kg of n-heptane was added for extraction, and the organic phase was obtained after separation and washing with a mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 kg, the purity was 96.1%, and the yield was 97%.

[0038] S2: the organic phase in the above step was added into a 500 L reactor, and the temperature was decreased, when the temperature in the reactor was decreased to 0-5 °C, the system would precipitate solids, and then the temperature was decreased to -20 to -15 °C, and the temperature was kept at -20 to -15 °C for 1-2 h for crystallization, then centrifugation was carried out, 56.4 kg of n-heptane was used for rinsing and the filter cake was dissolved to obtain 117.5 kg of 3,6-dichloro-4-isopropylpyridazine, the HPLC purity was 99.5%, and the yield was 83.3%.

[0039] Example 4

[0040] S1: at room temperature, under stirring, 275 kg of water, 110 kg of 3,6-dichloropyridazine, 5 kg of silver nitrate, 68.3 kg of isobutyric acid, 7.4 kg of concentrated sulfuric acid were added into a 1000 L reactor, the temperature of the system was increased to 40-50 °C, the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (185.3 kg of ammonium persulfate + 330 kg of water) was started to be added dropwise, the dropwise addition was completed in about 3-4 h; after the dropwise addition was completed, the reaction was kept for 0.5 h, sampling was started for HPLC control, the reaction was completed, 113.2 kg of n-heptane was added for extraction, the liquid was separated, and the mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 kg was used for washing, the liquid was separated, and the organic phase was obtained, the purity was 95.8%, and the yield was 95%.

[0041] S2: the organic phase obtained in the previous step was added into a 500 L reactor, the temperature was decreased, when the temperature in the reactor was decreased to 0-5 °C, the system would precipitate solids, the temperature was continuously decreased to -10--5 °C, and the system was kept at -10--5 °C for 1-2 h for crystallization, centrifugation was carried out, 56.4 kg of n-heptane was used for rinsing and the filter cake was dissolved, and 114.3 kg of 3,6-dichloro-4-isopropylpyridazine was obtained, the HPLC purity was 99.5%, and the yield was 81%.

[0042] Example 5

[0043] S1: at room temperature, under stirring, 275 kg of water, 110 kg of 3,6-dichloropyridazine, 5 kg of silver nitrate, 68.3 kg of isobutyric acid, 7.4 kg of concentrated sulfuric acid were added into a 1000 L reactor, the temperature of the system was increased to 40-50 °C, the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (185.3 kg of ammonium persulfate + 330 kg of water) was started to be added dropwise, the dropwise addition was completed in about 3-4 h; after the dropwise addition was completed, the reaction was kept for 0.5 h, sampling was started for HPLC control, the reaction was completed, 113.2 kg of n-hexane was added for extraction, the liquid was separated, and the mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 kg was used for washing, the liquid was separated, and the organic phase was obtained, the purity was 96.1%, and the yield was 96%.

[0044] S2: the organic phase obtained in the previous step was added into a 500 L reactor, the temperature was decreased, when the temperature in the reactor was decreased to 0-5 °C, the system would precipitate solids, the temperature was continuously decreased to -20--15 °C, and the system was kept at -20--15 °C for 1-2 h for crystallization, centrifugation was carried out, 56.4 kg of n-hexane was used for rinsing and the filter cake was dissolved, and 115.8 kg of 3,6-dichloro-4-isopropylpyridazine was obtained, the HPLC purity was 99.5%, and the yield was 82.1%.

[0045] Comparative Example 1 (non-alkane solvent was used as a low-temperature crystallization solvent)

[0046] S1: At room temperature, under stirring, 275 g of water, 110 g of 3,6-dichloropyridazine, 5 g of silver nitrate, 68.3 g of isobutyric acid, and then 7.4 g of concentrated sulfuric acid were added into a 1 L reactor, and the system was stirred well, and the temperature was raised to 40-50 °C, and the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (185.3 g of ammonium persulfate + 330 g of water) was added dropwise, and the dropping was completed in about 3-4 h; after dropping, the reaction was kept for 0.5 h, and then sampling was started for HPLC control, and after the reaction was completed, 113.2 g of methyl tert-butyl ether was added for extraction, and then the organic phase was obtained after separation and washing with a mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 g, and the purity was 96.7%, and the yield was 98%.

[0047] S2: The organic phase obtained in the previous step was added into a 500 mL reactor, and the temperature was lowered, and when the temperature in the reactor was lowered to 0-5 °C, the system would precipitate solids, and then the temperature was lowered to -20--15 °C, and the system was kept at -20--15 °C for 1-2 h for crystallization, and then centrifugation was performed, and the filter cake was rinsed with 56.4 g of methyl tert-butyl ether, and then the filter cake was dissolved, and 52.5 g of 3,6-dichloro-4-isopropylpyridazine was obtained, and the purity was 96.3% by HPLC, and the yield was 37.2%.

[0048] Comparative Example 2 (Minisci reaction at high temperature)

[0049] S1: At room temperature, under stirring, 275 g of water, 110 g of 3,6-dichloropyridazine, 5 g of silver nitrate, 68.3 g of isobutyric acid, and then 7.4 g of concentrated sulfuric acid were added into a 1 L reactor, and the system was stirred well, and the temperature was raised to 40-50 °C, and the temperature in the reactor was controlled at 40-50 °C, when the temperature in the reactor reached 45 °C, the prepared ammonium persulfate aqueous solution (185.3 g of ammonium persulfate + 330 g of water) was added dropwise, and the dropping was completed in about 3-4 h; after dropping, the reaction was kept for 0.5 h, and then sampling was started for HPLC control, and after the reaction was completed, 113.2 g of methyl tert-butyl ether was added for extraction, and then the organic phase was obtained after separation and washing with a mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 g, and the purity was 96.7%, and the yield was 98%.

[0050] S2: The organic phase obtained in the previous step was added into a 500 mL reactor, and the temperature was lowered, and when the temperature in the reactor was lowered to 0-5 °C, the system would precipitate solids, and then the temperature was lowered to -20--15 °C, and the system was kept at -20--15 °C for 1-2 h for crystallization, and then centrifugation was performed, and the filter cake was rinsed with 56.4 g of methyl tert-butyl ether, and then the filter cake was dissolved, and 52.5 g of 3,6-dichloro-4-isopropylpyridazine was obtained, and the purity was 96.3% by HPLC, and the yield was 37.2%.

[0051] Comparative Example 3 (crystallization temperature is too high)

[0052] S1: at room temperature, under stirring, 275 g of water, 110 g of 3,6-dichloropyridazine, 5 g of silver nitrate, 68.3 g of isobutyric acid, 7.4 g of concentrated sulfuric acid were added into a 1 L reactor, the system was fully stirred, the temperature of the system was increased to 40-50°C, the temperature in the reactor was controlled at 40-50°C, when the temperature in the reactor reached 45°C, the prepared ammonium persulfate aqueous solution (185.3 g of ammonium persulfate + 330 g of water) was started to be added dropwise, and the dropping was completed in about 3-4 h; after the dropping was completed, the reaction was kept for 0.5 h, and then sampling was started for HPLC control, and after the reaction was completed, 113.2 g of n-heptane was added for extraction, separation, and washing with a mixture of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate 110 g, separation, to obtain an organic phase with a purity of 95.8% and a yield of 98%.

[0053] S2: the organic phase obtained in the previous step was added into a 500 mL reactor, and stirring and cooling were performed, when the temperature in the reactor was decreased to 0-5°C, the system would precipitate solids, and the temperature was continuously decreased to 0-5°C, and the temperature was kept at 0-5°C for 1-2 h for crystallization, and then centrifugation was performed, 56.4 g of n-heptane was used for rinsing and filtering the cake to remove the solvent, to obtain 86.7 g of 3,6-dichloro-4-isopropylpyridazine with a purity of 96.5% by HPLC and a yield of 61.5%.

[0054] The product purity and yield of the crude products and the products after purification obtained in Examples 1-5 and Comparative Examples 1-3 were compared, and the experimental results were compared as shown in Table 1:

[0055] Table 1: Purity and yield of products prepared in each example and comparative example

[0056]

[0057] It was found through experimental data that the product purity obtained by using the material ratio, crystallization temperature, and crystallization solvent in the protection of the present application in Examples 1, 2, 3, 4, and 5 were all greater than 99.5%, and the yield fluctuation was within an acceptable range; the product would be caked in Comparative Example 1 using the ether solvent methyl tert-butyl ether, the crystallization dispersion effect was poor and could not be filtered; the reaction temperature of 80°C in Comparative Example 2 caused the ammonium persulfate to deteriorate, resulting in low conversion rate; the crystallization temperature of 0-5°C in Comparative Example 3 caused the product to melt, resulting in low yield; it was found through the comparative examples that high-purity and high-yield products could not be obtained. In summary, considering the product purification effect, production energy consumption, production safety, and cost control, Example 1 is the most preferred condition.

[0058] The above only describes the preferred embodiments of the present application, and it should be noted that for ordinary skilled persons in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. An industrial preparation method for high-purity 3,6-dichloro-4-isopropylpyridazine, characterized in that: The steps include: S1: 3,6-dichloropyridazine, isobutyric acid, strong acid, catalyst and solvent are mixed and placed in a reaction kettle, stirred and heated to 40-50°C, ammonium persulfate solution is added dropwise, and the reaction is continued until the reaction is completed; S2: Continue adding an alkane solvent to the reactor; extract and wash the product to obtain an organic phase solution of 3,6-dichloro-4-isopropylpyridazine; S3: adding the organic phase solution of 3,6-dichloro-4-isopropylpyridazine into a reaction kettle, cooling the temperature to between -30 and -5°C for crystallization, and then post-treating to obtain 3,6-dichloro-4-isopropylpyridazine; The catalyst in S1 is silver nitrate or ferrous sulfate; The strong acid in S1 is trifluoroacetic acid or concentrated sulfuric acid; The alkane solvent in S2 is selected from one or more of n-pentane, isopentane, n-hexane, cyclohexane, n-heptane, and petroleum ether.

2. The preparation method according to claim 1, characterized in that The alkane solvent in S2 is n-heptane.

3. The preparation method according to claim 1, characterized in that The catalyst in S1 is silver nitrate.

4. The preparation method according to claim 1, characterized in that The solvent in S1 is a mixture of one or more of water, methanol, ethanol, and acetonitrile.

5. The preparation method according to claim 1, characterized in that The ammonium persulfate solution in S1 is added dropwise for 3-4 hours.

6. The preparation method according to claim 1, characterized in that After the ammonium persulfate solution in S1 is added dropwise, the reaction is continued for 0.5-1 h.

7. The preparation method according to claim 1, characterized in that The crystallization temperature in S3 is -20 to -15°C.

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