Industrial preparation method of high-purity 3, 6-dichloro-4-isopropyl pyridazine

Abstract

The invention discloses an industrial preparation method of high-purity 3, 6-dichloro-4-isopropyl pyridazine, and belongs to the technical field of synthesis of drug intermediates. According to the method, the reaction temperature is reduced by utilizing the Minisci reaction characteristics, so that the industrial production temperature interval is better controlled, the reaction conversion rate is further improved, and the generation of impurities is reduced; on the other hand, the characteristic that the melting point of the 3, 6-dichloro-4-isopropyl pyridazine is low is utilized, and purification of the product is completed in a proper solvent in a low-temperature crystallization purification mode. According to the method, the problem that more impurities are brought into the product by adopting a high-temperature reaction during large-scale production of the 3, 6-dichloro-4-isopropyl pyridazine is solved, and meanwhile, the difficulties that a purification method in the prior art is high in production cost, high in energy consumption and high in equipment requirement are overcome. According to the preparation method, the product quality and yield are greatly improved, commercialized production requirements are met, the product purity can reach 99.5%, and the product can be directly used as a reaction raw material.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to an industrial preparation method of high-purity 3,6-dichloro-4-isopropylpyridazine. Background Art

[0002] 3,6-Dichloro-4-isopropylpyridazine is a pharmaceutical intermediate, mainly used to synthesize resmetirox. The drug is an oral selective agonist of thyroid hormone receptor (THR)-β, used to treat non-alcoholic steatohepatitis (NASH) with liver fibrosis. It is the world's first drug for the treatment of non-alcoholic steatohepatitis. It is highly selective and can play a core role in the liver by activating β receptors in hepatocytes, regulating lipid metabolism, reducing LDL-C, triglycerides and atherogenic lipoproteins. It is inactive to THR-α receptors, thus not affecting bone or heart parameters, and does not affect other hormones in the thyroid hormone pathway. 3,6-Dichloro-4-isopropylpyridazine on the market is usually obtained through high-temperature reaction and high-temperature distillation, but some impurities will be introduced into the product, which are not easy to separate and remove, and will be brought into the subsequent reaction system, making it difficult to purify the product, and it is not suitable to be directly used as a reaction raw material. According to the physical and chemical properties of 3,6-dichloro-4-isopropylpyridazine, high-purity 3,6-dichloro-4-isopropylpyridazine is obtained by low-temperature crystallization.

[0003] At present, there are two common methods for preparing 3,6-dichloro-4-isopropylpyridazine: column chromatography and distillation. Chinese patent CN111909137B discloses dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid in water, stirring at 70°C, and slowly dripping ammonium persulfate dissolved in water into a bottle. After the reaction is completed, the reaction is quenched, extracted, and then the product is obtained by column chromatography. Although this method can obtain the product, the production cost is high, but it is not suitable for commercial production. U.S. Patent US4628088A discloses dissolving 3,6-dichloropyridazine, isobutyric acid, silver nitrate and trifluoroacetic acid in water, stirring at 80°C, and slowly dripping ammonium persulfate dissolved in water into a bottle. After the reaction is completed, the reaction is quenched, extracted, and then the product is obtained by high-temperature distillation. Although this method can obtain the product, the high-temperature process will generate by-products, and the by-products are not easy to remove, which affects the purity of the product. The mass production distillation cycle is long, the production cost is high, and it is not conducive to commercial production. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention provides an industrial preparation method for high-purity 3,6-dichloro-4-isopropylpyridazine. The method obtains high-purity 3,6-dichloro-4-isopropylpyridazine by low-temperature crystallization. The product has high purity while reducing production costs and energy consumption. The entire process is simple to operate and is suitable for large-scale production.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0006] An industrial preparation method for high-purity 3,6-dichloro-4-isopropylpyridazine, the method 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°C, ammonium persulfate solution is added dropwise, and the reaction is continued 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-isopropylpyridazine;

[0009] 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.

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

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

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

[0013] Furthermore, the alkane solvent in S2 is selected from one or more of n-pentane, isopentane, n-hexane, cyclohexane, n-heptane, petroleum ether, etc., and n-heptane is more preferred. 3,6-Dichloro-4-isopropylpyridazine is a low melting point solid. Although it has good solubility in polar solvents, if it is directly cooled and crystallized, product agglomeration will occur in this solvent system, and the effect of dispersion and purification cannot be achieved. By introducing alkane solvents, extraction, crystallization and dispersion can be achieved at low temperatures and the purpose of impurity removal can be achieved; this type of solvent can be used as both an extraction solvent and a crystallization solvent.

[0014] In some embodiments, the ammonium persulfate solution in S1 is added dropwise for 3-4 hours; after the addition of the ammonium persulfate solution is completed, the reaction is continued for 0.5-1 hour.

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

[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 the 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 invention has the following beneficial effects:

[0021] 1. In the prior art, when 3,6-dichloro-4-isopropylpyridazine is produced on a large scale, a high temperature reaction is used, which will release heat violently and oxygen, so that more impurities are introduced into the product, which are not easy to separate and remove, and are not conducive to reaction control. The present invention utilizes the characteristics of the Minisci reaction, controls the reaction temperature, and makes the industrial production temperature range better controlled, thereby improving the reaction conversion rate, reducing the generation of impurities, and making the purity of the crude product in S2 reach more than 96%.

[0022] 2. The present invention utilizes the low melting point of 3,6-dichloro-4-isopropylpyridazine and uses a low-temperature crystallization purification method in a suitable solvent to purify the product. This method overcomes the difficulties of high production cost, high energy consumption, and high equipment requirements of the prior art purification methods. For example, the column chromatography method uses a large amount of mixed solvents that are difficult to recover and the three wastes are expensive to treat. The high-temperature distillation method has similar boiling points for impurities and products, making it difficult to control the reflux ratio, and the product is unstable at high temperatures for a long time.

[0023] 3. The preparation method of the present invention 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 THE DRAWINGS

[0024] Figure 1 is the H NMR spectrum of 3,6-dichloro-4-isopropylpyridazine obtained in Example 1;

[0025] Figure 2 This is the HPLC chromatogram of 3,6-dichloro-4-isopropylpyridazine obtained in Example 1. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with specific embodiments, but the content and scope of protection claimed in the present invention are not limited to the following embodiments.

[0027] Unless otherwise specified, the reagents used in the examples of the present invention are common commercially available products.

[0028] Embodiment 1:

[0029] S1: At room temperature, under stirring, add 275kg of water, 110kg of 3,6-dichloropyridazine, 5kg of silver nitrate, 68.3kg of isobutyric acid, and then add 7.4kg of concentrated sulfuric acid to a 1000L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3kg of ammonium persulfate + 330kg of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2kg of n-heptane for extraction and separation, and wash with 110kg of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 96.8% and a yield of 99%.

[0030] S2: Add the organic phase from the previous step into a 500L reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to between -20 and -15°C, and keep at -20 to -15°C for crystallization for 1 to 2 hours. Centrifuge, rinse with 56.4kg of n-heptane, and desolventize the filter cake to obtain 120.6kg of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 99.8% and a yield of 85.5%.

[0031] Figure 1 , Figure 2 They are respectively the H NMR spectrum and HPLC chromatogram of 3,6-dichloro-4-isopropylpyridazine prepared in this example. The H NMR spectrum data are as follows:

[0032] 1HNMR (DMSO, 400MHz): δppm1.24~1.26(m,6H), δppm 3.14~3.17(m,1H), δppm7.98(d,1H).

[0033] Example 2

[0034] S1: At room temperature, under stirring, add 275kg of water, 110kg of 3,6-dichloropyridazine, 5kg of silver nitrate, 68.3kg of isobutyric acid, and then add 7.4kg of concentrated sulfuric acid to a 1000L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (202kg of ammonium persulfate + 660kg of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2kg of n-heptane for extraction and separation, and wash with 110kg of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 96.1% and a yield of 97%.

[0035] S2: Add the organic phase from the previous step into a 500L reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to between -20 and -15°C, and keep at -20 to -15°C for crystallization for 1 to 2 hours. Centrifuge, rinse with 56.4kg of n-heptane, and desolventize the filter cake to obtain 117.5kg of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 99.5% and a yield of 83.3%.

[0036] Example 3

[0037] S1: At room temperature, under stirring, add 275kg of water, 110kg of 3,6-dichloropyridazine, 12.5kg of silver nitrate, 68.3kg of isobutyric acid, and then add 7.4kg of concentrated sulfuric acid to a 1000L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3kg of ammonium persulfate + 330kg of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2kg of n-heptane for extraction and separation, and wash with 110kg of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 96.7% and a yield of 97%.

[0038] S2: Add the organic phase from the previous step into a 500L reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to between -20 and -15°C, and keep at -20 to -15°C for crystallization for 1 to 2 hours. Centrifuge, rinse with 56.4kg of n-heptane, and desolventize the filter cake to obtain 117kg of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 99.6% and yield of 83%.

[0039] Example 4

[0040] S1: At room temperature, under stirring, add 275kg of water, 110kg of 3,6-dichloropyridazine, 5kg of silver nitrate, 68.3kg of isobutyric acid, and then add 7.4kg of concentrated sulfuric acid to a 1000L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3kg of ammonium persulfate + 330kg of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2kg of n-heptane for extraction and separation, and wash with 110kg of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 95.8% and a yield of 95%.

[0041] S2: Add the organic phase from the previous step into a 500L reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to -10--5°C and keep at -10--5°C for crystallization for 1-2h. Centrifuge, rinse with 56.4kg of n-heptane, and desolventize the filter cake to obtain 114.3kg of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 99.5% and yield of 81%.

[0042] Example 5

[0043] S1: At room temperature, under stirring, add 275kg of water, 110kg of 3,6-dichloropyridazine, 5kg of silver nitrate, 68.3kg of isobutyric acid, and then add 7.4kg of concentrated sulfuric acid to a 1000L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3kg of ammonium persulfate + 330kg of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2kg of n-hexane for extraction and separation, and wash with 110kg of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 96.1% and a yield of 96%.

[0044] S2: Add the organic phase from the previous step into a 500L reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to -20--15°C and keep at -20--15°C for crystallization for 1-2h. Centrifuge, rinse with 56.4kg of n-hexane, and desolventize the filter cake to obtain 115.8kg of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 99.5% and yield of 82.1%.

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

[0046] S1: At room temperature, under stirring, add 275g of water, 110g of 3,6-dichloropyridazine, 5g of silver nitrate, 68.3g of isobutyric acid, and then add 7.4g of concentrated sulfuric acid to a 1L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3g of ammonium persulfate + 330g of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2g of methyl tert-butyl ether for extraction and separation, and wash with 110g of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 96.7% and a yield of 98%.

[0047] S2: Add the organic phase from the previous step into a 500mL reaction kettle, stir and cool down. When the temperature in the kettle drops to 0-5°C, solid will precipitate from the system. Continue to cool to between -20 and -15°C, and keep at -20 to -15°C for crystallization for 1 to 2 hours. Centrifuge, rinse with 56.4g of methyl tert-butyl ether, and desolventize the filter cake to obtain 52.5g of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 96.3% and a yield of 37.2%.

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

[0049] S1: At room temperature, under stirring, add 275g of water, 110g of 3,6-dichloropyridazine, 5g of silver nitrate, 68.3g of isobutyric acid, and then add 7.4g of concentrated sulfuric acid to a 1L reactor, stir well, raise the temperature in the system to between 75 and 85°C, control the temperature in the reactor between 75 and 85°C, and when the temperature in the reactor reaches 75°C, start to drop the prepared ammonium persulfate aqueous solution (185.3g of ammonium persulfate + 330g of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2g of n-heptane for extraction and separation, and wash with 110g of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 95.1% and a yield of 94%.

[0050] S2: Add the organic phase from the previous step into a 500mL reaction kettle, stir and cool down. When the temperature in the kettle drops to 0-5°C, solid will precipitate from the system. Continue to cool to -20--15°C and keep at -20--15°C for crystallization for 1-2h. Centrifuge, rinse with 56.4g of n-heptane, and desolventize the filter cake to obtain 103.1g of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 96.1% and yield of 73.1%.

[0051] Comparative Example 3 (Crystallization Temperature Too High)

[0052] S1: At room temperature, under stirring, add 275g of water, 110g of 3,6-dichloropyridazine, 5g of silver nitrate, 68.3g of isobutyric acid, and then add 7.4g of concentrated sulfuric acid to a 1L reactor, stir well, raise the temperature in the system to between 40 and 50°C, control the temperature in the reactor between 40 and 50°C, and when the temperature in the reactor reaches 45°C, start to drop the prepared ammonium persulfate aqueous solution (185.3g of ammonium persulfate + 330g of water), and the dropwise addition is completed in about 3 to 4h; after the dropwise addition, keep the reaction warm for 0.5h, start sampling and HPLC control, the reaction is completed, add 113.2g of n-heptane for extraction and separation, and wash with 110g of a mixed solution of 5% sodium thiosulfate pentahydrate and 5% sodium bicarbonate, separate the liquids to obtain an organic phase with a purity of 95.8% and a yield of 98%.

[0053] S2: Add the organic phase from the previous step into a 500mL reactor, stir and cool down. When the temperature in the reactor drops to 0-5°C, solid will precipitate from the system. Continue to cool to between 0-5°C and keep at 0-5°C for crystallization for 1-2h. Centrifuge, rinse with 56.4g of n-heptane, and desolventize the filter cake to obtain 86.7g of 3,6-dichloro-4-isopropylpyridazine with HPLC purity of 96.5% and yield of 61.5%.

[0054] The product purity and yield of the crude product and the purified product obtained in Examples 1-5 and Comparative Examples 1-3 are compared. The experimental results are shown in Table 1:

[0055] Table 1 Purity and yield of products prepared in various embodiments and comparative examples

[0056]

[0057] Through experimental data, it is found that Examples 1, 2, 3, 4, and 5 use the material ratio, crystallization temperature, and crystallization solvent within the protection of the present invention, and the purity of the obtained products is greater than 99.5%, and the yield fluctuations are all within an acceptable range; Comparative Example 1 uses ether solvent methyl tert-butyl ether, and the product agglomeration phenomenon will occur, and the crystallization dispersion effect is poor and cannot be filtered; Comparative Example 2 uses a high temperature of 80°C for the reaction temperature, and the high temperature causes the ammonium persulfate to deteriorate and the reaction conversion rate is low; When the crystallization temperature of Comparative Example 3 is 0-5°C, the crystallization temperature is high and the product melting yield is low; It is found through the comparative examples that no high-purity and high-yield products can 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 is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An industrial preparation method of 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 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-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.

2. The preparation method according to claim 1, characterized in that: The alkane solvent in S2 is selected from one or more of n-pentane, isopentane, n-hexane, cyclohexane, n-heptane and petroleum ether.

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

4. The preparation method according to claim 1, characterized in that: The catalyst in S1 is silver nitrate or ferrous sulfate.

5. The preparation method according to claim 1 or 4, characterized in that: The catalyst in S1 is silver nitrate.

6. The preparation method according to claim 1, characterized in that: The strong acid in S1 is trifluoroacetic acid or concentrated sulfuric acid.

7. 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.

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

9. 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 0.5-1h.

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

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