Refining method of baricitinib

Abstract

The invention discloses a baricitinib refining method, which comprises: mixing a baricitinib crude product, a mixed solvent of a solvent A and a solvent B, and water, and stirring at a temperature of 70-90 DEG C until the solution is clear; adding activated carbon, stirring, decolorizing and filtering to obtain filtrate; and cooling the filtrate, stirring for crystallization, filtering and drying to obtain a baricitinib finished product. According to the invention, the crude product with low purity can be subjected to one-step refining to obtain the high-purity finished product. The purity of the baricitinib finished product prepared by the method reaches 99.95% or above, the yield reaches 90% or above, and the method is suitable for industrial production. The baricitinib refining method disclosed by the invention is mild and simple in reaction condition, and convenient for reaction reproduction and amplified production.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis and relates to a method for refining baricitinib. Background Art

[0002] Baricitinib (trade name Olumiant), chemical name: 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile (English name: 1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitril e), CAS: 1187594-09-7, molecular formula: C 16 H 17 N7O2S. The drug molecule contains pyrrolopyrimidine, pyrazole, azetidine core structural fragments and has a quaternary carbon center. Its structural formula is as follows:

[0003]

[0004] Baricitinib is a Janus kinase inhibitor developed by Eli Lilly and Incyte Pharmaceuticals. It received EU approval on February 13, 2017, for the treatment of rheumatoid arthritis (RA) patients who have responded poorly to or are intolerant to disease-modifying antirheumatic drugs (DMARDs). Baricitinib has a strong inhibitory effect on JAK1 and JAK2, demonstrating good efficacy in RA with mild adverse reactions and good patient tolerance. In addition to RA, trials have shown that baricitinib can also treat conditions such as psoriasis.

[0005] Currently, there are many reported methods for the synthesis of baricitinib, but few involve purification methods.

[0006] The purity of baricitinib prepared in Examples 11, 12, and 13 of patent CN105294699A is 99.78%, 99.81%, and 99.79%, respectively, which is relatively low, and the patent does not involve a method for refining baricitinib.

[0007] The crude baricitinib obtained in Example 4 of patent CN115181103A has a purity of 98.83%. Its purification method involves recrystallization from a 50% tetrahydrofuran aqueous solution, yielding baricitinib with a purity of 99.90% and a single impurity content of ≤0.1%. However, this purification method is not supported by chromatographic evidence and produces a large amount of wastewater, making the 50% tetrahydrofuran aqueous solution unrecyclable.

[0008] Example 4 of patent CN112898306A uses methanol recrystallization to obtain a finished baricitinib product with a purity of ≥99.0%. Summary of the Invention

[0009] The object of the present invention is to provide a method for refining baricitinib, which can purify a crude baricitinib product with a purity of ≤99.2% to obtain a finished baricitinib product with a purity of ≥99.95%, and the yield is ≥90.0%.

[0010] The purpose of the present invention is achieved through the following technical solutions:

[0011] A method for refining baricitinib comprises the following steps:

[0012] Step (1), mixing the crude baricitinib, a mixed solvent of solvent A and solvent B, and water, stirring at a temperature of 70 to 90° C. until the mixture is dissolved; adding an appropriate amount of medicinal activated carbon, stirring to decolorize, and filtering to obtain a filtrate;

[0013] Step (2), cooling the filtrate, stirring and crystallizing, filtering, and drying to obtain the finished product of baricitinib.

[0014] The content of baricitinib in the crude baricitinib product is ≤99.2%, preferably 98.5% to 99.2%.

[0015] The crude baricitinib was prepared by the following synthetic route:

[0016]

[0017] The method comprises: firstly subjecting 4-chloro-pyrrolopyrimidine (compound 2) and chloromethyl pivalate (compound 3) to a condensation reaction under alkaline conditions to obtain compound 4; then subjecting compound 4 to a coupling reaction with 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (compound 5) under the action of a catalyst to obtain an intermediate product; then removing the protecting group of the intermediate product under acidic conditions to obtain compound 6; then subjecting compound 6 to a Michael addition reaction with compound 7 under the action of DBU to obtain compound 8; and finally removing the protecting group of compound 8 under alkaline conditions to obtain a crude product of baricitinib (compound 1).

[0018] Specifically, the crude baricitinib is prepared by the following method, comprising the following steps:

[0019] Step (a), using DMF or acetone as the reaction solvent, in the presence of a base, condensing 4-chloro-pyrrolopyrimidine (Compound 2) and chloromethyl pivalate (Compound 3). After the reaction is completed, water and methyl tert-butyl ether are added to the reaction solution, extracted, and the organic layer is taken and the solvent is evaporated to obtain Compound 4;

[0020] Step (b), using n-butanol as the reaction solvent and tetrakis(triphenylphosphine)palladium as the catalyst, under the protection of nitrogen or inert gas, compound 4 and 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (compound 5) undergo a coupling reaction under the action of the catalyst. After the reaction is completed, water is added to the reaction solution, the layers are separated, the n-butanol phase is collected, and the solvent is evaporated to obtain an intermediate product. The intermediate product is deprotected under acidic conditions, filtered, and the solid is dried to obtain compound 6;

[0021] Step (c), using methanol, ethanol, isopropanol or n-butanol as the reaction solvent, compound 6 and compound 7 undergo Michael addition reaction in the presence of DBU. After the reaction is completed, water is added to the reaction solution, crystallized, filtered, and the solid is dried to obtain compound 8;

[0022] Step (d), using one of methanol, ethanol, isopropanol or n-butanol as the reaction solvent, dissolving compound 8 in the solvent, removing the protecting group of compound 8 under alkaline conditions, and after the reaction is completed, adding water to the reaction solution, crystallizing, filtering, and drying to obtain a crude product of baricitinib (compound 1).

[0023] In step (a), the molar ratio of 4-chloro-pyrrolopyrimidine to chloromethyl pivalate is 1:2 to 1:3.

[0024] The molar ratio of the 4-chloro-pyrrolopyrimidine to the base is 1:2 to 1:3.

[0025] The base is one of organic bases such as triethylamine and N,N-diisopropylethylamine.

[0026] The temperature of the condensation reaction is -15 to 0°C.

[0027] In step (b), the molar ratio of compound 4 to compound 5 is 1:1.2 to 1:1.8.

[0028] The temperature of the coupling reaction is 60-80°C.

[0029] The hydrochloric acid is concentrated hydrochloric acid (mass fraction 30-36%).

[0030] The molar ratio of the compound 4 to hydrochloric acid (calculated as HCl) is 1:2 to 1:5.

[0031] At a temperature of 25 to 30°C, the intermediate product is deprotected under acidic conditions.

[0032] In step (c), the molar ratio of compound 6 to compound 7 is 1:1 to 1:1.5.

[0033] The molar ratio of compound 6 to DBU is 1:1.5 to 1:2.5.

[0034] The temperature of the Michael addition reaction is 10-30°C.

[0035] In step (d), the alkaline condition is provided by a base, and the base is one of lithium hydroxide monohydrate, sodium hydroxide or potassium hydroxide.

[0036] The molar ratio of the compound 8 to the base is 1:2 to 1:4.

[0037] The reaction temperature for removing the protecting group is 40-60°C.

[0038] Specifically, crude baricitinib (purity 98.92%) was prepared according to the following method:

[0039] Triethylamine (2.0 eq) was added to DMF, and the temperature was lowered to -10°C. 4-chloro-pyrrolopyrimidine (1.0 eq) was added and stirred until dissolved. The temperature was maintained at -10 to 0°C, and chloromethyl pivalate (2.5 eq) was added dropwise. After the addition was complete, the reaction was stirred for 3 hours. After the reaction was complete, drinking water (3 times the volume of DMF) was added to the reaction solution and stirred. Methyl tert-butyl ether (3 times the volume of DMF) was then added and the mixture was separated by stirring. The methyl tert-butyl ether phase was collected and the solvent was evaporated from the methyl tert-butyl ether to obtain compound 4.

[0040] Compound 4 (1.0 eq) was added to n-butanol, and under nitrogen protection, tetrakis(triphenylphosphine)palladium (0.01 eq) was added. The temperature was raised to 80°C, and 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (1.6 eq) was added while stirring. After the addition was completed, the reaction was carried out at 80°C for 3 hours. After the reaction was completed, drinking water with a volume 5 times that of n-butanol was added to the reaction solution, the temperature was lowered to 30°C, stirred and separated, the n-butanol phase was collected, and the n-butanol was evaporated at 70°C to obtain an intermediate product; the intermediate product and drinking water were mixed according to the amount ratio of the intermediate product to drinking water of 1:3 g / mL, concentrated hydrochloric acid (4.0 eq) was added to the system, and the reaction was stirred at 30°C for 2 hours to remove the protecting group. After the reaction was completed, the temperature was lowered to 5°C, and the wet product was filtered to obtain the wet product, which was dried to obtain compound 6;

[0041] Compound 6 (1.0 eq) was added to methanol at a ratio of 1:5 g / mL to methanol. DBU (2.0 eq) was added while stirring, followed by compound 7 (1.2 eq). Compounds 6 and 7 underwent Michael addition reaction at 25°C for 2 h. After the reaction was complete, drinking water (10 times the volume of methanol) was added to the reaction solution to precipitate a large amount of solid. The solution was cooled to 5°C and filtered to obtain a wet product, which was then dried to obtain compound 8.

[0042] According to the dosage ratio of compound 8 and methanol of 1:5g / mL, compound 8 (1.0eq) was added to methanol, and lithium hydroxide monohydrate (3.0eq) was added while stirring. The temperature was raised to 60°C and stirred for 2h. After the reaction was completed, the temperature was lowered to 15°C, and drinking water with a volume of 15 times that of methanol was added to the reaction solution. Crystallization was performed and the wet product was filtered to obtain a wet product. The wet product was dried to obtain a crude product of baricitinib. The HPLC chart of the crude product is shown in FIG. Figure 1 .

[0043] Baricitinib crude product (purity 99.13%) was prepared according to the following method:

[0044] Triethylamine (2.0 eq) was added to DMF, and the temperature was lowered to -10°C. 4-chloro-pyrrolopyrimidine (1.0 eq) was added and stirred until dissolved. The temperature was maintained at -10 to 0°C, and chloromethyl pivalate (2.5 eq) was added dropwise. After the addition was complete, the reaction was stirred for 3 hours. After the reaction was complete, drinking water (3 times the volume of DMF) was added to the reaction solution, and methyl tert-butyl ether (3 times the volume of DMF) was added after stirring. The mixture was stirred and separated, and the methyl tert-butyl ether phase was collected. The solvent was evaporated from the methyl tert-butyl ether phase to obtain compound 4;

[0045] Compound 4 (1.0 eq) was added to n-butanol, and under nitrogen protection, tetrakis(triphenylphosphine)palladium (0.01 eq) was added. The temperature was raised to 60°C, and 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (1.6 eq) was added while stirring. After the addition was completed, the reaction was carried out at 60°C for 3 h. After the reaction was completed, drinking water 5 times the volume of n-butanol was added to the system, the temperature was lowered to 30°C, and the liquid was separated by stirring. The n-butanol phase was collected and the n-butanol was evaporated at 70°C to obtain an intermediate product; the intermediate product was added to the drinking water according to the amount ratio of the intermediate product to drinking water of 1:3 g / mL, and concentrated hydrochloric acid (4.0 eq) was added to the system. The reaction was stirred at 30°C for 2 h to remove the protecting group. After the reaction was completed, the temperature was lowered to 5°C, and the wet product was filtered to obtain the wet product, which was dried to obtain compound 6;

[0046] Compound 6 (1.0 eq) was added to methanol at a ratio of 1:5 g / mL to methanol. DBU (2.0 eq) was added while stirring, followed by compound 7 (1.2 eq). Compounds 6 and 7 underwent Michael addition reaction at 15°C for 2 h. After the reaction was complete, drinking water (10 times the volume of methanol) was added to the reaction solution to precipitate a large amount of solid. The solution was cooled to 5°C and filtered to obtain a wet product, which was then dried to obtain compound 8.

[0047] According to the usage ratio of compound 8 and methanol of 1:5 g / mL, compound 8 (1.0 eq) was added to methanol, and lithium hydroxide monohydrate (2.0 eq) was added while stirring. The temperature was raised to 40°C and stirred for 2 hours. After the reaction was completed, the temperature was lowered to 20°C, and drinking water with a volume 10 times that of methanol was added to the reaction solution. Crystallization was carried out and the wet product was filtered to obtain the wet product, which was dried to obtain the crude product of baricitinib.

[0048] In step (1), the solvent A is one of acetonitrile and acetone, preferably acetonitrile; the solvent B is one of methanol, ethanol, isopropanol or n-butanol, preferably ethanol.

[0049] The mass ratio of the solvent A to the solvent B is 1:1 to 20:1, preferably 1:1 to 5:1, and most preferably 5:1.

[0050] The mass ratio of the crude baricitinib to the mixed solvent and water is 1:(1-10):(1-3), preferably 1:(5-10):(2-3), and more preferably 1:10:2.

[0051] The mass ratio of the crude baricitinib to pharmaceutical activated carbon is 1:0.01 to 1:0.06, preferably 1:0.02.

[0052] Preferably, an appropriate amount of medicinal activated carbon is added at a temperature of 70 to 90° C., the mixture is stirred for decolorization, and filtered while hot to obtain a filtrate.

[0053] In step (2), the crystallization temperature is 0-20° C., preferably 0-10° C., and the crystallization time is 1-5 h, preferably 2-3 h.

[0054] The drying temperature is 60°C.

[0055] Beneficial effects of the present invention:

[0056] 1. The refined solvent of the present invention has good selectivity, and a crude baricitinib product with low purity can be refined in one step to obtain a high-purity finished baricitinib product.

[0057] 2. The method of the present invention is used to prepare the finished product of baricitinib with a purity of over 99.95% and a yield of over 90%, which is suitable for industrial production. The method of the present invention has mild and simple reaction conditions, which facilitates the reproducible reaction and scale-up production.

[0058] 3. The solvent used in the refining method of the present invention can be effectively recovered because of its low moisture content and high recovery rate. Fresh solvent can be added in proportion and used for the next refining. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1This is the HPLC chart of crude baricitinib (purity 98.92%).

[0060] Figure 2 This is the HPLC chart of the finished product of baricitinib in Example 2.

[0061] Figure 3 This is the MS diagram of the finished product of baricitinib in Example 2. DETAILED DESCRIPTION

[0062] The technical solution of the present invention is further illustrated by the following examples, but these examples do not constitute any limitation to the present invention.

[0063] Example 1

[0064] 1. Systematic exploration of refined solvents

[0065] Take multiple portions of crude baricitinib (baricitinib purity 98.92%), 15 g each, and add them to a three-necked flask; add the solvent in Table 1 according to the mass ratio of crude baricitinib to solvent of 1:3, mix the crude baricitinib with the solvent, heat to 75 ° C, stir until dissolved, add 0.3 g of medicinal activated carbon at 75 ° C, decolorize for 30 minutes, filter while hot, cool the filtrate to 5 ° C, stir and crystallize for 3 hours to obtain baricitinib wet product; the wet baricitinib was dried at 60 ° C for 24 hours to obtain the finished baricitinib product, the purity and yield of which are shown in Table 1.

[0066] Table 1. Effect of refined solvents on the purity and yield of baricitinib finished product

[0067]

[0068] As shown in Table 1, when a single solvent, anhydrous acetonitrile, methanol, or ethanol, is used for purification, the purity of the obtained baricitinib finished product is relatively high, with a purity of ≥99.85%. The purity of the baricitinib finished product obtained by using other solvents for purification is relatively low; however, the yield of methanol is relatively low, indicating that the selectivity of methanol for the solubility of impurities is poorer than that of acetonitrile and ethanol. Therefore, acetonitrile, ethanol, or a mixed solvent of acetonitrile and ethanol is selected to purify the crude baricitinib.

[0069] 2. Effect of the Mass Ratio of Acetonitrile to Ethanol on the Purity and Yield of Baricitinib Finished Product

[0070] Referring to “I. Systematic exploration of refined solvents”, only the solvent was replaced with mixed solvents with mass ratios of acetonitrile and ethanol of 1:1, 3:1, 5:1, 10:1, and 20:1, respectively. The rest of the operations were the same. The results are shown in Table 2.

[0071] Table 2. Effect of the mass ratio of acetonitrile and ethanol on the purity and yield of baricitinib finished product

[0072]

[0073] As shown in Table 2, when a mixed solvent of acetonitrile and anhydrous ethanol is used, the purity of the finished baricitinib product reaches at least 99.85%. When the mass ratio of acetonitrile to anhydrous ethanol is 1:1 to 5:1, the purity of the finished baricitinib product reaches at least 99.85%, and the yield is greater than 90%. In particular, when the mass ratio of acetonitrile to anhydrous ethanol is 5:1, the purity of the finished baricitinib product is the highest and the yield is relatively high. Therefore, 5:1 is selected as the optimal mass ratio of acetonitrile to ethanol.

[0074] 3. Effect of Water Dosage on Purity and Yield of Baricitinib Finished Product

[0075] During the experiment, the inventors found that water would increase the solubility of crude baricitinib in a mixed system of ethanol and acetonitrile, resulting in a better purification effect, and would reduce the small amount of undissolved baricitinib in the system during hot filtration of activated carbon, thereby slightly increasing the yield of baricitinib.

[0076] Take multiple portions of crude baricitinib (baricitinib purity 99.13%), 15 g each, and add them to a three-necked flask; according to the mass ratio of crude baricitinib, mixed solvent (mass ratio of acetonitrile to anhydrous ethanol 5: 1) and purified water in Table 3, add the mixed solvent to the three-necked flask, add purified water under stirring, heat to 75 ° C, stir until dissolved, add 0.3 g of medicinal activated carbon at 75 ° C, decolorize for 30 minutes, filter while hot, cool the filtrate to 5 ° C, stir and crystallize for 3 hours to obtain baricitinib wet product; the baricitinib wet product is dried at 60 ° C for 24 hours to obtain baricitinib finished product, the purity and yield of which are shown in Table 3.

[0077] Table 3. Effect of water dosage on the purity and yield of baricitinib finished product

[0078]

[0079] As shown in Table 3, when the mass ratio of crude baricitinib to mixed solvent and water is 1:(1-10):(1-3), the purity of the finished baricitinib reaches at least 99.85%, and the yield is greater than 90%. When the mass ratio of crude baricitinib to mixed solvent and water is 1:(5-10):(2-3), the purity of the finished baricitinib reaches at least 99.95%, and the yield is greater than 91.5%. The optimal mass ratio of crude baricitinib to mixed solvent and water is 1:10:2, at which the purity of the finished baricitinib product is ≥99.95%, and the yield is ≥90.0%.

[0080] Example 2

[0081] Take 15 g of crude baricitinib (purity 99.13%), add it to a three-necked flask, add 150 g of mixed solvent (125 g of acetonitrile, 25 g of anhydrous ethanol), add 30 g of purified water while stirring, heat to 75 ° C, stir until dissolved, add 0.3 g of medicinal activated carbon at 75 ° C, decolorize for 30 minutes, filter while hot, cool the filtrate to 5 ° C, stir and crystallize for 3 hours to obtain baricitinib wet product; baricitinib wet product is dried at 60 ° C for 24 hours to obtain 16.5 g of baricitinib finished product with a purity of 99.98% and a yield of 91.7%.

[0082] LCMS (m / z): 372.12 [M+H] + .

Claims

1. A method for refining baricitinib, characterized in that: The following steps are involved: Step (1), mixing the crude baricitinib product, a mixed solvent of solvent A and solvent B, and water, stirring at a temperature of 70 to 90° C. until the mixture is clear; adding activated carbon, stirring to decolorize, and filtering to obtain a filtrate; wherein the solvent A is one of acetonitrile and acetone; the solvent B is one of methanol, ethanol, isopropanol or n-butanol; the mass ratio of the solvent A to the solvent B is 1:1 to 20:1; Step (2), cooling the filtrate, stirring and crystallizing, filtering, and drying to obtain the finished product of baricitinib.

2. The method for refining baricitinib according to claim 1, wherein: The content of baricitinib in the crude baricitinib product is ≤99.2%.

3. The method for refining baricitinib according to claim 2, wherein: The content of baricitinib in the crude baricitinib product is 98.5% to 99.2%.

4. The method for refining baricitinib according to any one of claims 1 to 3, characterized in that: The crude baricitinib was prepared by the following synthetic route: The method comprises: firstly subjecting 4-chloro-pyrrolopyrimidine and chloromethyl pivalate to a condensation reaction under alkaline conditions to obtain compound 4; then subjecting compound 4 to a coupling reaction with 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester under the action of a catalyst to obtain an intermediate product; then removing the protecting group of the intermediate product under acidic conditions to obtain compound 6; then subjecting compound 6 to a Michael addition reaction with compound 7 under the action of DBU to obtain compound 8; and then removing the protecting group of compound 8 under alkaline conditions to obtain a crude product of baricitinib.

5. The method for purifying baricitinib according to claim 1, wherein: In step (1), the solvent A is acetonitrile; the solvent B is ethanol.

6. The method for purifying baricitinib according to claim 1, wherein: In step (1), the mass ratio of solvent A to solvent B is 1:1 to 5:

1.

7. The method for purifying baricitinib according to claim 6, wherein: In step (1), the mass ratio of solvent A to solvent B is 5:

1.

8. The method for purifying baricitinib according to claim 1, wherein: In step (1), the mass ratio of the crude baricitinib to the mixed solvent and water is 1:(1-10):(1-3), preferably 1:(5-10):(2-3), and more preferably 1:10:

2.

9. The method for purifying baricitinib according to claim 1, wherein: In step (1), the mass ratio of the crude baricitinib to the pharmaceutical activated carbon is 1:0.01 to 1:0.06, preferably 1:0.

02.

10. The method for purifying baricitinib according to claim 1, wherein: In step (1) and step (2), the crystallization temperature is 0 to 20° C., preferably 0 to 10° C., and the crystallization time is 1 to 5 hours, preferably 2 to 3 hours.

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