Synthesis method of baricitinib key process impurity

Abstract

The invention discloses a synthesis method of a baricitinib key process impurity, which comprises the following steps: by taking a compound I as a raw material and acetonitrile as a solvent, adding DBU to adjust alkali, and carrying out Michael addition with a compound II in an alkaline environment; the reaction liquid is concentrated to be dry, and oily matter is obtained; and heating the oily substance, dissolving the oily substance in n-propyl alcohol, cooling, crystallizing, filtering and drying to obtain a target product. Compared with an existing method, the method has the advantages that DBU is used for alkali adjustment, and the molar equivalent is optimized; the post-treatment method is changed, and the yield and the purity of the target product are remarkably improved through improvement.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparation of raw materials and intermediate impurities, and in particular relates to a method for synthesizing a key process impurity of baricitinib. Background Art

[0002] In the process of API R&D, the research of impurities has attracted more and more attention at home and abroad. Impurity research and control is a systematic project. The CTD (Common Technical Document) application format reflects the concept of comprehensive and systematic drug quality control that combines process control and endpoint control, research and verification, and is more in line with the basic laws and logical thinking of impurity research and control. The International Council for Harmonization (ICH) and the State Food and Drug Administration have both issued corresponding guidelines. Drug impurities are related to the safety of drugs in clinical use. To ensure their safety, the impurities in the drugs must be fully analyzed and studied and controlled.

[0003] Baricitinib is a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, severe alopecia areata, etc. The molecular structure is as follows:

[0004]

[0005] During the quality study of baricitinib using the HPLC method, the inventors discovered an impurity with a relatively high content and a separation degree similar to that of baricitinib, which was identified to have a structure described by the following formula (III):

[0006]

[0007] In order to further confirm the structure of the impurity compound and accumulate a sufficient amount as a standard to determine the quality standard of baricitinib, the present invention provides a method for preparing a key process impurity of baricitinib (Compound III). The synthesis method is simple, has a high yield, and contains fewer impurities, which is of great significance for controlling the quality of drugs. Summary of the invention

[0008] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing key process impurities of baricitinib. Specifically, the present invention provides the following technical solutions:

[0009] A method for preparing a baricitinib impurity, wherein the baricitinib impurity is as shown in compound III:

[0010]

[0011] The preparation method comprises:

[0012] (1) Compound I is used as a raw material, mixed with an organic solvent, DBU is added to adjust the base, and Michael addition is performed with compound II in an alkaline environment;

[0013] (2) concentrating the reaction solution obtained in step (1) to dryness to obtain an oily substance;

[0014] (3) The oily substance obtained in step (2) is dissolved in n-propanol at a higher temperature, the temperature is lowered to crystallize, the crystals are separated and dried to obtain compound III.

[0015] The structural formula of the compound I is

[0016] The structural formula of the compound II is

[0017] The DBU is 1,8-diazabicycloundec-7-ene

[0018] Furthermore, the organic solvent in step (1) is selected from aprotic organic solvents;

[0019] Preferably, the aprotic organic solvent is selected from one or more of chloroform, dichloromethane, 1,2-dichloroethane, benzene, toluene, THF, dioxane, acetone, DMSO, DMF, nitromethane, nitrobenzene, and acetonitrile;

[0020] More preferably, the organic solvent is acetonitrile.

[0021] Furthermore, in step (1), the molar ratio of DBU to compound I is 0.5-1.0:1, and preferably, the molar ratio of DBU to compound I is 0.5-0.6:1.

[0022] Furthermore, in step (1), the molar ratio of compound II to compound I is 1.0-1.5:1, and preferably, the molar ratio of compound II to compound I is 1.1-1.2:1.

[0023] Furthermore, the Michael addition reaction temperature in step (1) is 10°C to 40°C, and the reaction time is 8 to 16 hours; preferably, the Michael addition reaction temperature in step (1) is 20 to 30°C, and the reaction time is 12 hours.

[0024] Furthermore, in step (1), the volume mass ratio of the organic solvent to compound I is 8.0-10.0:1. Preferably, the volume mass ratio of the organic solvent to compound I is 8.0:1.

[0025] Furthermore, in step (3), the volume mass ratio of n-propanol to compound I is 5.0-8.0:1. Preferably, the volume mass ratio of n-propanol to compound I is 6.0:1.

[0026] Furthermore, the heating in step (3) is to raise the temperature to 50°C to 80°C; preferably, the heating is to raise the temperature to 70°C to 80°C.

[0027] Furthermore, the cooling in step (3) is to lower the temperature to 0°C to 20°C; preferably, the cooling is to lower the temperature to 0°C to 10°C.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1) The reaction is an aprotic organic solvent-DBU system reaction, which reduces side reactions compared to the acetonitrile-water-NaOH system (Comparative Example 1) used as another exploratory solution during the development of the present invention. The present invention avoids cyano hydrolysis, reduces the difficulty of post-treatment, improves the reaction yield and purity, and is suitable for preparing impurity reference substances;

[0030] 2) The reaction is purified by using n-propanol, which improves the yield and obtains a solid material in a better state compared with the purification column;

[0031] 3) Through the improvements in the first two points, the yield and purity of the target product were significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the liquid phase spectrum of compound III prepared in Example 1;

[0033] Figure 2 This is the hydrogen spectrum of compound III prepared in Example 1;

[0034] Figure 3 This is the carbon spectrum of compound III prepared in Example 1. DETAILED DESCRIPTION

[0035] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0036] Example 1

[0037] Impurities in the key process of preparing baricitinib (III):

[0038]

[0039] 15.0 g of compound I (77.2 mmol) and 9.5 g of compound II (85.6 mmol) were put into a 250 ml three-necked flask, and 120 ml of acetonitrile and 7.1 g of DBU (46.2 mmol) were added. The temperature was raised to 30° C. and the reaction was kept at this temperature for 12 h.

[0040] (2) Concentrate the reaction solution to dryness.

[0041] (3) Add 90 ml of n-propanol, raise the temperature to 70° C., dissolve the system, cool to 0° C., filter, and vacuum dry at 50° C. for 12 h to obtain the key process impurity (III) of baricitinib.

[0042] Purity: 99.87%; Yield: 80%, the liquid phase spectrum of compound III is as follows Figure 1 The structure was confirmed as Figures 2-3 shown.

[0043] Comparative Example 1

[0044] Impurities in the key process of preparing baricitinib (III):

[0045] Put 15.0g of compound I and 9.5g of compound II into a 250ml three-necked flask, add 120ml of acetonitrile, 30ml of water, and 3.10g of NaOH, heat to 20-30°C, and keep the temperature for reaction for 12h.

[0046] (2) Extract with ethyl acetate, collect the organic phase, and concentrate the organic phase to dryness.

[0047] (3) Add 90 ml of n-propanol, raise the temperature to 70-80°C, the system becomes clear, cool to 0-10°C, filter, and dry in a vacuum at 45-50°C for 12 h. No target product is obtained, and it is speculated that the cyano group is hydrolyzed.

[0048] Comparative Example 2

[0049] Impurities in the key process of preparing baricitinib (III):

[0050] 15.0 g of compound I (77.2 mmol) and 9.5 g of compound II (85.6 mmol) were put into a 250 ml three-necked flask, and 120 ml of acetonitrile and 7.1 g of DBU (46.2 mmol) were added. The temperature was raised to 50° C. and the reaction was kept at this temperature for 12 h.

[0051] (2) Concentrate the reaction solution to dryness.

[0052] (3) Add 90 ml of n-propanol, raise the temperature to 70-80° C., dissolve the system, cool to 10° C., filter, and vacuum dry at 45° C. for 12 h to obtain the key process impurity (III) of baricitinib.

[0053] Purity: 77.30%; Yield: 78%.

[0054] 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. A method for preparing baricitinib impurities, characterized in that: The baricitinib impurity is shown in Compound III: The preparation method comprises: (1) Compound I is used as a raw material, mixed with an organic solvent, DBU is added to adjust the base, and Michael addition is performed with compound II under alkaline conditions. The structural formula of compound I is The structural formula of the compound II is (2) concentrating the reaction solution obtained in step (1) to dryness to obtain an oily substance; (3) The oily substance obtained in step (2) is dissolved in n-propanol at a higher temperature, the temperature is lowered to crystallize, the crystals are separated and dried to obtain compound III.

2. The method for preparing baricitinib impurities according to claim 1, characterized in that: The organic solvent in step (1) is selected from aprotic inert organic solvents; preferably, the aprotic inert organic solvent is selected from one or more of chloroform, dichloromethane, 1,2-dichloroethane, benzene, toluene, THF, dioxane, acetone, DMSO, DMF, nitromethane, nitrobenzene, and acetonitrile, and more preferably, the organic solvent is acetonitrile.

3. The method for preparing baricitinib impurities according to claim 1, characterized in that: In step (1), the molar ratio of DBU to compound I is 0.5-1.0:1, preferably, the molar ratio of DBU to compound I is 0.5-0.6:

1.

4. The method for preparing baricitinib impurities according to claim 1, characterized in that: In step (1), the molar ratio of compound II to compound I is 1.0-1.5:

1. Preferably, the molar ratio of compound II to compound I is 1.1-1.2:

1.

5. The method for preparing baricitinib impurities according to claim 1, characterized in that: The Michael addition reaction temperature in step (1) is 10°C to 40°C, and the reaction time is 8 to 16 hours; preferably, the Michael addition reaction temperature in step (1) is 20 to 30°C, and the reaction time is 12 hours.

6. The method for preparing baricitinib impurities according to claim 1, characterized in that: In step (1), the volume mass ratio of the organic solvent to compound I is 8.0-10.0:

1. Preferably, the volume mass ratio of the organic solvent to compound I is 8.0:

1.

7. The method for preparing baricitinib impurities according to claim 1, characterized in that: In step (3), the volume mass ratio of n-propanol to compound I is 5.0-8.0:

1. Preferably, the volume mass ratio of n-propanol to compound I is 6.0:

1.

8. The method for preparing baricitinib impurities according to claim 1, characterized in that: The heating in step (3) is to raise the temperature to 50°C to 80°C; preferably, the heating is to raise the temperature to 70°C to 80°C.

9. The method for preparing baricitinib impurities according to claim 1, characterized in that: The cooling in step (3) is to lower the temperature to 0°C to 20°C; preferably, the cooling is to lower the temperature to 0°C to 10°C.

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