A method of recrystallization of boronic esters

Abstract

The application discloses a recrystallization method of borate, and belongs to the technical field of purification. The recrystallization method of the borate adopts a mixed system of at least one of a recrystallization agent A of n-heptane, n-hexane and petroleum ether and at least one of a recrystallization agent B of isopropyl alcohol, dichloromethane and tetrahydrofuran as a recrystallization agent, so that a crystal of 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborinane with high purity is prepared at a high yield, is resistant to storage and is convenient to use.

Description

Technical Field

[0001] This invention belongs to the field of purification technology, specifically relating to a method for recrystallizing borate esters. Background Technology

[0002] Janus kinases (JAKs) belong to the tyrosine kinase family, consisting of JAK1, JAK2, JAK3, and TYK2. JAKs play a crucial role in cytokine signaling. Downstream substrates of JAK family kinases include transcriptional signaling and activation (STAT) proteins. JAK / STAT signaling has been involved in mediating many aberrant immune responses, such as allergies, asthma, autoimmune diseases like transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, as well as solid and hematologic malignancies such as leukemia and lymphoma.

[0003] Chinese patent CN106336413 A discloses a method for synthesizing JAK inhibitors using 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane. Therefore, the above compound is an important intermediate for JAK inhibitors.

[0004] In the prior art, the compound 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane is usually a liquid. For example, Chinese patent CN109574988 A discloses a purification method for the above-mentioned compound, in which the crude product obtained after concentration is separated and purified by column chromatography (PE / EA = 30 / 1 to 10 / 1) to obtain the target compound, which is a pale yellow oil.

[0005] The product obtained by column chromatography purification of the above compounds is usually an oily liquid. However, 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane, which is an oily liquid, is difficult to store for a long time and is difficult to weigh accurately in experiments. Summary of the Invention

[0006] The present invention was made to solve the above-mentioned problems, and its purpose is to provide a recrystallization method for preparing a high-purity and storage-resistant solid compound 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane.

[0007] One object of the present invention is to provide a method for recrystallizing borate esters for recrystallizing crude compound 1, wherein compound 1 is... Includes the following steps:

[0008] The crude compound 1 was dissolved in a recrystallization agent, and the temperature was controlled at -55℃ to -40℃. After holding at this temperature, the mixture was separated to obtain crystals of compound 1.

[0009] The recrystallizing agent is composed of recrystallizing agent A and recrystallizing agent B.

[0010] The recrystallizing agent A is selected from any one of n-heptane, n-hexane, and petroleum ether.

[0011] The recrystallizing agent B is selected from any one of isopropanol, dichloromethane, tetrahydrofuran, ethyl acetate, and methyl tert-butyl ether.

[0012] In one embodiment of the present invention, the recrystallization method specifically includes the following process:

[0013] The crude compound 1 is dissolved in recrystallizing agent A, then recrystallizing agent B is added, the temperature is controlled at -55℃ to -40℃, seed crystals are added, the temperature is controlled at -55℃ to -40℃, and the mixture is filtered to obtain compound 1 crystals.

[0014] The mass ratio of the seed crystal to the crude compound 1 is (0.001-0.01):1.

[0015] The purity of the seed crystal is greater than 90%, preferably greater than 95%, and more preferably greater than 98%.

[0016] The recrystallizing agent B is selected from any one of isopropanol, dichloromethane, and tetrahydrofuran.

[0017] The volume ratio of recrystallizing agent A to recrystallizing agent B is (8-10):1.

[0018] The recrystallizing agent is a mixture of n-heptane and tetrahydrofuran in a volume ratio of (8-10):1. Specifically, the volume ratio of n-heptane to tetrahydrofuran is 100:12.

[0019] The recrystallizing agent is a mixture of n-heptane and dichloromethane in a volume ratio of (8-10):1. Specifically, the volume ratio of n-heptane to tetrahydrofuran is 100:12.

[0020] The recrystallizing agent is a mixture of n-heptane and isopropanol in a volume ratio of (8-10):1. Specifically, the volume ratio of n-heptane to isopropanol is 10:1.

[0021] In one embodiment of the present invention, a method for recrystallizing a borate ester is provided for recrystallizing a crude product of compound 1, wherein compound 1 is... Specifically, the process includes the following steps:

[0022] The crude compound 1 was dissolved in a recrystallization agent, and the temperature was controlled at -30℃ to -15℃. After holding at this temperature, the mixture was separated to obtain crystals of compound 1.

[0023] The recrystallizing agent is selected from any one of n-heptane, n-hexane, and petroleum ether.

[0024] The temperature control range is -25℃ to -15℃. Specifically, -20℃ can be selected.

[0025] The crude compound 1 was prepared by the following method.

[0026] The reaction formula is as follows:

[0027]

[0028] Includes the following steps:

[0029] Compound 2, compound 3, palladium catalyst, and solvent were mixed and reacted completely to obtain compound 1.

[0030] The palladium catalyst is selected from Pd(dppf)Cl2.

[0031] The solvent is selected from either isopropyl acetate or 1,4-dioxane.

[0032] The role and effect of invention

[0033] According to the recrystallization method of borate esters involved in this application, since at least one of n-heptane, n-hexane, and petroleum ether is used as recrystallizing agent A and at least one of isopropanol, dichloromethane, and tetrahydrofuran as recrystallizing agent B, this application can obtain high-purity crystals of 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane in high yield. Attached Figure Description

[0034] Figure 1 This is the GC spectrum of compound 1 in Example 2 of the present invention;

[0035] Figure 2 This is the GC spectrum of compound 1 in Example 3 of the present invention. Detailed Implementation

[0036] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.

[0037] In the following examples, unless otherwise stated, all reactants are commercially available products.

[0038] In the following examples, the seed crystals of compound 1 were purchased from the Kemani Chemical Reagent Purchase Platform and had a purity greater than 98%.

[0039] In the following examples, KOAc is potassium acetate, CAS number: 127-08-2; Pd(dppf)Cl2 is dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, CAS number: 72287-26-4; IPAc is isopropyl acetate, CAS number: 108-21-4.

[0040] <Example 1>

[0041] Preparation of crude compound 1

[0042] This embodiment provides a method for preparing a solution containing compound 1, and the reaction formula is as follows:

[0043]

[0044] Includes the following steps:

[0045] 2.2 kg of compound 2, 1.96 kg of compound 3, 2.2 kg of KOAc, 66 g of Pd(dppf)Cl2 and 22 L of IPAc were added to a reaction vessel and reacted at 80 °C for 8 h under nitrogen protection to obtain a reaction solution.

[0046] The reaction solution was filtered through diatomaceous earth. 22 L of water was added to the filtrate. The organic phase was collected, concentrated, and 22 L of n-heptane and 220 g of activated carbon were added. The mixture was decolorized at 50 °C for 2 h and at 25 °C for 2 h. After filtration through diatomaceous earth, 2.1 kg of crude compound 1 with a purity of 85.4% was obtained as a yellow liquid.

[0047] <Example 2>

[0048] A recrystallization method for borate esters

[0049] This embodiment provides a method for recrystallizing crude compound 1, including the following steps:

[0050] Take 20g of crude compound 1 prepared using the method described in Example 1, add 100mL of n-heptane and then 12mL of tetrahydrofuran, and allow compound 1 to dissolve completely at room temperature. Cool down to -45°C, add 0.1g of seed crystals, maintain the temperature at -45°C, stir for 2 hours, filter, and vacuum dry the wet product at 40°C for 16 hours to obtain 13.5g of compound 1 crystals with a purity of 98.8%. The crystals are off-white granules.

[0051] The gas phase spectrum of the product is as follows Figure 1 As shown in the figure. Among them, the retention time of 13.682 min corresponds to compound 1.

[0052] <Example 3>

[0053] A recrystallization method for borate esters

[0054] This embodiment provides a method for recrystallizing crude compound 1, including the following steps:

[0055] Take 20g of crude compound 1 prepared using the method described in Example 1, add 100mL of n-heptane and then 10mL of isopropanol, and allow compound 1 to dissolve completely at room temperature. Cool down to -45°C, add 0.1g of seed crystals, maintain the temperature at -45°C, stir for 2 hours, filter, and vacuum dry the wet product at 40°C for 16 hours to obtain 12.8g of compound 1 crystals with a purity of 99.2%. The crystals are brown granules.

[0056] The gas phase spectrum of the product is as follows Figure 2 As shown in the figure. Among them, the retention time of 13.680 min corresponds to compound 1.

[0057] <Example 4>

[0058] Screening of recrystallization agents

[0059] In this embodiment, the recrystallizing agent and its dosage were screened using any one of the following methods:

[0060] Method 1: Take 20g of crude compound 1 prepared using the method described in Example 1, add 100mL of n-heptane to it, allow compound 1 to dissolve completely at room temperature, cool to -45℃, add 0.1g of seed crystals, control the temperature at -45℃, stir for 2h, filter, and vacuum dry the wet product at 40℃ for 16h to obtain compound 1.

[0061] Method 2: Take 20g of crude compound 1 prepared using the method described in Example 1, add recrystallizing agent A, then add recrystallizing agent B, and let compound 1 dissolve completely at room temperature. Cool down to -45°C, add 0.1g of seed crystals, control the temperature at -45°C, stir for 2 hours, filter, and vacuum dry the wet product at 40°C for 16 hours to obtain compound 1.

[0062] The screening results are shown in Table 1.

[0063] Table 1 Screening of recrystallization agents

[0064]

[0065]

[0066] a means cooling down to -20℃.

[0067] As shown in the table above, various recrystallizing agents can recrystallize compound 1 into crystals. In terms of purity, the recrystallization systems of n-heptane (-20℃) and n-heptane / isopropanol both yielded products with a purity of over 99%. Regarding the quality of the recovered crystals, the systems of n-heptane / isopropanol, n-heptane / dichloromethane, and n-heptane / tetrahydrofuran showed less loss during recrystallization. As for the properties of the recovered compound 1, the systems of n-heptane (-20℃), n-heptane / isopropanol, and n-heptane / tetrahydrofuran yielded white or off-white crystals.

[0068] However, it cannot crystallize smoothly in the n-heptane (-45℃) and n-heptane / tert-butyl methyl ether systems, and can only form a yellow sticky solid.

[0069] <Comparative Example>

[0070] Method for purifying crude compound 1

[0071] 20g of crude compound 1 was subjected to column chromatography with petroleum ether / ethyl acetate in a ratio of 20:1 (volume). The purified compound 1 was obtained as a pale yellow oily liquid, weighing 10.8g with a purity of 98.5%.

[0072] The role and effect of the embodiments

[0073] According to the recrystallization method of borate esters involved in the above embodiments, because a combination of recrystallizing agents such as n-heptane / tetrahydrofuran, n-heptane / isopropanol, and n-heptane / dichloromethane is used, compared with the column chromatography purification method in Comparative Example 1, the present application can obtain crystals of compound 1 with better yield and purity, thereby facilitating better storage and weighing for use.

[0074] For recrystallization of compound 1 in dual-solvent systems (such as n-heptane / tetrahydrofuran, n-heptane / isopropanol, etc.) at -55℃ to -45℃, compared with recrystallization at -20℃, the yield can be significantly improved, the loss of compound 1 can be reduced, and crystals with good properties can be obtained.

[0075] The embodiments provided above are preferred examples of the present invention and are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the present invention by those skilled in the art in conjunction with existing common knowledge also fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for recrystallizing a borate ester, used for recrystallizing a crude product of compound 1, wherein compound 1 is... Its characteristics are, Includes the following steps: The crude compound 1 is dissolved in recrystallizing agent A, then recrystallizing agent B is added, and the temperature is controlled at -45℃ to -40℃. Seed crystals are added, and the temperature is controlled at -45℃ to -40℃. After filtration, compound 1 crystals are obtained. The recrystallizing agent consists of recrystallizing agent A and recrystallizing agent B, and the volume ratio of recrystallizing agent A to recrystallizing agent B is (8-10):

1. The recrystallizing agent A is selected from n-heptane. The recrystallizing agent B is selected from any one of isopropanol, dichloromethane, tetrahydrofuran, and ethyl acetate.

2. The recrystallization method of borate ester according to claim 1, characterized in that: in, The mass ratio of the seed crystal to the crude compound 1 is (0.001-0.01):

1.

3. The recrystallization method of borate ester according to claim 1, characterized in that: in, The recrystallizing agent B is selected from any one of isopropanol, dichloromethane, and tetrahydrofuran.

4. The recrystallization method of borate ester according to claim 1, characterized in that: in, The recrystallizing agent is a mixture of n-heptane and tetrahydrofuran in a volume ratio of (8-10):1; Alternatively, the recrystallizing agent is a mixture of n-heptane and dichloromethane in a volume ratio of (8-10):

1.

5. The recrystallization method of borate ester according to claim 1, characterized in that: in, The crude compound 1 was prepared by the following method. The reaction formula is as follows: Includes the following steps: Compound 2, compound 3, palladium catalyst, and solvent were mixed and reacted completely to obtain compound 1.

6. The recrystallization method of borate ester according to claim 5, characterized in that: in, The palladium catalyst is selected from Pd(dppf)Cl2; the solvent is selected from either isopropyl acetate or 1,4-dioxane.

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