Synthesis method of baricitinib-related substances

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to a method for synthesizing baricitinib-related substances. The baricitinib-related substances include at least one of related substances A and related substances B. The synthesis steps of related substance A are: (1) reacting a compound of formula III to obtain a compound of formula II, wherein the compound of formula III is 4,6-dichloro-5-pyrimidinecarboxylic acid, (2) reacting the compound of formula II with a compound of formula I to obtain related substance A; the synthesis steps of related substance B are: (1) reacting a compound of formula IV to obtain a compound of formula V, wherein the compound of formula IV is 4-hydroxypyrimidine, (2) reacting the compound of formula V to obtain a compound of formula VI, (3) reacting the compound of formula VI with a compound of formula I to obtain a compound of formula VII, and (4) reacting the compound of formula VII to obtain related substance B. The present invention can rapidly, simply and efficiently synthesize baricitinib-related substances A and B, and the reaction conditions are mild and controllable, the accuracy is good, and the product purity is high.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a method for synthesizing baricitinib-related substances. Background Art

[0002] Baricitinib, chemical name: 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile, chemical structure is as follows:

[0003]

[0004] Baricitinib tablets, traded under the name Olumiant, were jointly developed by Eli Lilly and Incyte. In February 2017, the European Union approved the product as a second-line treatment for moderate to severe active rheumatoid arthritis in adults, alone or in combination with methotrexate. In May 2022, the FDA approved baricitinib for the treatment of hospitalized adults with COVID-19 who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The FDA has authorized baricitinib for the treatment of severe alopecia areata.

[0005] Patent application with publication number CN106554363A discloses a method for synthesizing a compound of formula I:

[0006]

[0007] 4-Pyrazoleboronic acid pinacol ester undergoes Michael addition reaction with 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile under DBU catalysis to obtain the target compound of formula I.

[0008] Related substances A and B are degradation products of baricitinib. The chemical structures of related substances A and B are as follows:

[0009]

[0010] Related substances A and B as reference substances can improve the quality of baricitinib raw materials and preparations and reduce the risks of clinical drug use. However, there is currently no supply of related substances A and B reference substances at home and abroad, and there are no reports on the synthesis methods of related substances A and B in domestic and foreign literature and patents. Only the self-reference method can be used, which makes the qualitative and quantitative accuracy of related substances A and B poor, the preparation is time-consuming and inconvenient, the efficiency is low, the reaction conditions are not mild and controllable, and the product purity is low. Summary of the invention

[0011] The purpose of the present invention is to provide a method for synthesizing baricitinib-related substances, so as to achieve rapid, simple and efficient synthesis of baricitinib-related substances A and B, while the reaction conditions are mild and controllable, the accuracy is good, and the product purity is high.

[0012] A method for synthesizing baricitinib-related substances, wherein the baricitinib-related substances include at least one of related substance A and related substance B.

[0013] Preferably, the synthetic route of the related substance A is as follows:

[0014]

[0015] The synthesis of the related substance A comprises the following steps:

[0016] (1) The compound of formula III is reacted to obtain the compound of formula II,

[0017] (2) The compound of formula II reacts with the compound of formula I to obtain the related substance A.

[0018] Preferably, the synthetic route of the related substance B is as follows:

[0019]

[0020] The synthesis of the related substance B comprises the following steps:

[0021] (1) reacting the compound of formula IV to obtain the compound of formula V,

[0022] (2) reacting the compound of formula V to obtain the compound of formula VI,

[0023] (3) reacting the compound of formula VI with the compound of formula I to obtain the compound of formula VII,

[0024] (4) The compound of formula VII is reacted to obtain the related substance B.

[0025] By adopting the above technical scheme, the present invention can prepare baricitinib related substance A and related substance B. The related substances A and B as reference substances can improve the quality of baricitinib raw materials and preparations and reduce the risk of clinical drug use. However, there is currently no supply of related substance A and B reference substances at home and abroad, and there is no synthesis method of related substances A and B, and only the self-control method can be used. In comparison, the related substances A and B prepared by the present invention have better qualitative and quantitative accuracy, are fast, simple and efficient to prepare, have mild and controllable reaction conditions, and have higher product purity.

[0026] Preferably, the synthesis of the related substance A comprises the following steps:

[0027] (1) The compound of formula III is 4,6-dichloro-5-pyrimidinecarboxylic acid, and the compound of formula III is reacted with ammonia to obtain the compound of formula II, and the reaction temperature is -5 to 80°C;

[0028] The molar ratio of the compound of formula III to ammonia is 1:1-8, the ammonia is an ammonia solution, and the solvent of the ammonia solution includes at least one of an aqueous solution and a methanol solution;

[0029] (2) the compound of formula II and the compound of formula I are coupled to obtain the related substance A, the reaction temperature is 50-120° C., the reaction solvent is a mixed solvent of water and an organic solvent, the organic solvent includes at least one of DMF, 1,4-dioxane, acetonitrile, toluene, and ethanol;

[0030] The reaction is carried out under alkaline conditions, and the base includes at least one of K3PO4, K2CO3, Na2CO3, CsF, and Cs2CO3.

[0031] Preferably, in the synthesis step of the related substance A:

[0032] (1) the compound of formula III is reacted with ammonia and then treated to obtain the compound of formula II, the reaction temperature is 50-60°C;

[0033] The molar ratio of the compound of formula III to ammonia is 1:5, the ammonia is an ammonia solution, and the solvent of the ammonia solution is an aqueous solution;

[0034] (2) The compound of formula II and the compound of formula I are subjected to coupling reaction and then treated to obtain the related substance A, the reaction temperature is 80° C., the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is DMF and 1,4-dioxane;

[0035] The reaction is carried out under alkaline conditions, wherein the base is K2CO3.

[0036] Preferably, the synthesis of the related substance B comprises the following steps:

[0037] (1) The compound of formula IV is 4-hydroxypyrimidine, and the compound of formula IV reacts with bromine to obtain the compound of formula V;

[0038] The molar ratio of the compound of formula IV to bromine is 1:1 to 1:2;

[0039] (2) the compound of formula V is subjected to chlorination reaction with a chlorinating agent to obtain a compound of formula VI,

[0040] The chlorination agent is phosphorus oxychloride, and the molar ratio of the compound of formula V to the chlorination agent is 1:1 to 1:20;

[0041] (3) the compound of formula I and the compound of formula VI are reacted by catalytic coupling reaction to obtain the compound of formula VII, the reaction temperature being 50 to 110° C.;

[0042] The reaction solvent is a mixed solvent of water and an organic solvent, wherein the organic solvent comprises at least one of DMF, 1,4-dioxane, acetonitrile, toluene and ethanol;

[0043] The reaction is carried out under alkaline conditions, wherein the base includes at least one of K3PO4, K2CO3, Na2CO3, CsF, and Cs2CO3;

[0044] (4) the compound of formula VII reacts with cuprous cyanide to obtain the related substance B, the reaction temperature is 120-200°C;

[0045] The molar ratio of the compound of formula VII to cuprous cyanide is 1:1 to 1:3, and the reaction solvent includes at least one of DMF, N,N-dimethylacetamide and N-methylpyrrolidone.

[0046] Preferably, in the synthesis step of the related substance B:

[0047] (1) The compound of formula IV is reacted with bromine and then treated to obtain the compound of formula V,

[0048] The molar ratio of the compound of formula IV to bromine is 1:1.3;

[0049] (2) the compound of formula V is subjected to chlorination reaction with a chlorinating agent and then treated to obtain the compound of formula VI;

[0050] (3) The compound of formula I and the compound of formula VI are subjected to catalytic coupling reaction and then treated to obtain the compound of formula VII,

[0051] The reaction solvent is a mixed solvent of water and an organic solvent, wherein the organic solvent is 1,4-dioxane.

[0052] The reaction is carried out under alkaline conditions, wherein the base is K2CO3;

[0053] By adopting the above technical scheme, 1,4-dioxane has stable structural properties, is miscible with water, and can also act as a stabilizer in the reaction; K2CO3 is easily soluble in water, and the aqueous solution is alkaline. The advantage of K2CO3 compared with other alkaline solutions is that K2CO3 makes the extraction system more stable and balanced during extraction.

[0054] (4) The compound of formula VII reacts with cuprous cyanide to obtain the related substance B, and the reaction temperature is 150-180°C.

[0055] By adopting the above technical scheme, cuprous cyanide is easily soluble in ammonia water and concentrated hydrochloric acid.

[0056] The beneficial effects of the present invention are:

[0057] The present invention adopts directional synthesis to prepare baricitinib related substance A and related substance B. The related substances A and B are used as reference substances for the determination of baricitinib content and the detection of related substances, which can control and improve the quality of baricitinib raw materials and preparations. The present invention can prepare the related substance A through only two steps of reaction and prepare the related substance B through four steps;

[0058] This shows that the present invention can quickly, simply and efficiently synthesize baricitinib related substances A and B, and the reaction conditions are mild and controllable, the accuracy is good, the product purity is high, and the purity of the related substance A can reach 98.8%. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

[0060] In the attached picture:

[0061] Figure 1 is the baricitinib related substance A of the present invention 1 Schematic diagram of H NMR spectrum;

[0062] Figure 2 is the baricitinib related substance B of the present invention 1 Schematic diagram of H NMR spectrum. DETAILED DESCRIPTION

[0063] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0064] Unless otherwise specified, the reagents used in the examples can be easily obtained from commercial companies or prepared in-house.

[0065] Example 1

[0066] A method for synthesizing baricitinib-related substances, wherein the baricitinib-related substances include related substance A and related substance B.

[0067] The synthetic route of the substance A and the chemical structures of the compounds of formula I, formula II, formula III and the substance A are as follows:

[0068]

[0069] Table 1

[0070] name Amount of substance Mass percentage Addition amount Chemical name Compound of formula III 51.8mmol / 10.0g 4,6-Dichloro-5-pyrimidinecarboxylic acid Purified water / / 125ml / ammonia / 25％ 18ml / Ethanol / / 100ml /

[0071] Table 2

[0072] name Amount of substance Addition amount Compound of formula II 11.5mmol 2.0g Compounds of formula I 17.3mmol 6.57g 1,4-Dioxane / 30ml DMF / 30ml water / 30ml <![CDATA[K2CO3]]> 23.1mmol 3.2g

[0073] The synthesis of substance A comprises the following steps:

[0074] (1) Referring to Table 1 above, a compound of formula III, purified water and aqueous ammonia were added to a 250 ml single-mouth bottle and stirred at 55° C. for 4 h. Most of the water was evaporated at 60° C. to precipitate a light yellow solid. Ethanol was added and stirred. The mixture was cooled to 20-25° C. and filtered to obtain a filter cake. The filter cake was dried at 50° C. to obtain a compound of formula II. The compound of formula II was a light yellow solid in appearance. The specific parameters of the compound of formula II are shown in Table 7. The mass spectrum data of the compound of formula II is MS: [M+1] + =174.14, H NMR spectrum data is 1 H NMR (400MHz, DMSO-d6): δ7.38 (s, 2H), 8.02 (s, 1H).

[0075] (2) Referring to Table 2 above, a 250 ml three-necked flask was charged with the compound of formula II, the compound of formula I, 1,4-dioxane, DMF, water, and K2CO3, and the atmosphere was replaced with nitrogen. A catalyst Pd(dppf)Cl2 was added to react at 80°C for 3.5 h. After the reaction solution was cooled to room temperature, 80 ml of ethyl acetate was added for extraction. The ethyl acetate phase was discarded, and the obtained aqueous phase was extracted with 50 ml of n-butanol 3 times. The n-butanol phases were combined and evaporated to dryness under reduced pressure at 60°C. The evaporated residue was pulped with isopropanol at room temperature and then filtered. The filter cake obtained by filtration was dried under reduced pressure at 50°C to obtain the related substance A. The appearance of the related substance A was a gray solid. The specific parameters of the related substance A refer to Table 7;

[0076] Reference Figure 1 , the mass spectrum data of substance A is MS:[M+1] + =392.44, H NMR spectrum data is 1 HNMR (400MHz, DMSO-d6): δ8.55 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 6.71 (s, 2H), 4.43 (d, J=9 .2Hz, 2H), 4.19 (d, J=9.2Hz, 2H), 3.60 (s, 2H), 3.21 (q, J=7.3Hz, 2H), 1.24 (t, J=7.3Hz, 3H).

[0077] The synthetic route of the related substance B and the chemical structures of the compounds of formula I, formula IV, formula V, formula VI, formula VII and the related substance B are as follows:

[0078]

[0079] Table 3

[0080] name Amount of substance Addition amount Chemical name Acetic acid / 120ml / Compound of formula IV 11.4mmol 11g 4-Hydroxypyrimidine Anhydrous sodium acetate 17.2mmol 14.1g / Bromine 14.6mmol 7.5ml /

[0081] Table 4

[0082] name Amount of substance Addition amount Phosphorus oxychloride / 120ml Compounds of formula V 11.2mmol 19.6g DIPEA 11.2mmol 20ml Ethyl acetate / 250ml

[0083] Table 5

[0084] name Amount of substance Addition amount Compounds of formula VI 25.8mmol 5.0g Compounds of formula I 16.6mmol 6.3g <![CDATA[K2CO3]]> 33.3mmol 4.6g 1,4-Dioxane / 50ml water / 25ml

[0085] Table 6

[0086] name Amount of substance Addition amount Compound of formula VII 4.62mmol 1.9g DMF / 20.0ml Cuprous cyanide 11.2mmol 1.0g Ferric chloride hexahydrate / 3.0g Concentrated hydrochloric acid / 1.6ml Ethyl acetate / 80ml

[0087] The synthesis of substance B comprises the following steps:

[0088] (1) Referring to Table 3 above, the compound of formula IV and anhydrous sodium acetate were added to acetic acid, the temperature was controlled at 20-30° C., bromine was added dropwise with stirring, and the reaction was continued at 20-30° C. for 1.5 h after the addition was completed. Then, a filter cake was obtained by filtration. The filter cake was rinsed with acetic acid and ethyl acetate in sequence, and the filter cake was dried under reduced pressure to obtain a compound of formula V. The compound of formula V has an appearance of white solid. The specific parameters of the compound of formula V refer to Table 7;

[0089] (2) Referring to Table 4 above, a compound of formula V was added to phosphorus oxychloride, and the temperature was lowered to 10°C under nitrogen protection, and DIPEA was added dropwise. After the addition was completed, the temperature was raised to 40-45°C for reaction for 2 hours. The reaction solution obtained by the reaction was distilled under reduced pressure to obtain a concentrated residue. Ethyl acetate was added to the concentrated residue to dissolve it, and the concentrated residue was dropped into water for separation after dissolution. The organic phase obtained by separation was washed with saturated brine, and then concentrated and dried under reduced pressure to obtain a compound of formula VI. The appearance of the compound of formula VI is a brown oil. The specific parameters of the compound of formula VI are shown in Table 7;

[0090] (3) Referring to Table 5 above, the compound of formula VI, the compound of formula I, K2CO3, 1,4-dioxane and water were added to a reaction flask, stirred, replaced with nitrogen, and the catalyst Pd(dppf)Cl2 was added, replaced with nitrogen, and the temperature was raised to 80°C for 2 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added for extraction and separation. The organic phase was washed with saturated brine and then concentrated to dryness. The concentrated residue was separated by column chromatography. The eluent used for column chromatography was prepared as DCM:ethanol=70:1. After column chromatography, the compound of formula VII was obtained. The appearance of the compound of formula VII was a yellow solid. The specific parameters of the compound of formula VII are shown in Table 7;

[0091] (4) Referring to Table 6 above, the compound of formula VII was dissolved in DMF, and cuprous cyanide was added. The reaction was carried out at 150°C for 14 hours under nitrogen protection. The reaction solution was cooled to room temperature for standby use. Ferric chloride hexahydrate, concentrated hydrochloric acid and 12.5 ml of water were used to prepare a mixed solution. The mixed solution was added to the standby reaction solution and stirred for 10 minutes. Ethyl acetate and 80 ml of water were added. After stirring, the mixture was allowed to stand for separation. After separation, the ethyl acetate phase was washed with saturated brine and concentrated to dryness to obtain a related substance B. The appearance of the related substance B was a white solid. The specific parameters of the related substance B are shown in Table 7;

[0092] Reference Figure 2 , the mass spectrum data of substance B is MS:[M+1] + =358.34, H NMR spectrum data is 1 HNMR (400MHz, DMSO-d6): δ9.36 (s, 1H), 9.29 (s, 1H), 9.05 (d, J = 0.6Hz, 1H), 8.51 (d, J = 0.6Hz, 1H), 4. 53 (d, J=9.2Hz, 2H), 4.26 (d, J=9.2Hz, 2H), 3.70 (s, 2H), 3.23 (q, J=7.3Hz, 2H), 1.24 (t, J=7.3Hz, 3H).

[0093] The specific parameters of the compound of formula II, related substance A, the compound of formula IV, the compound of formula VI, the compound of formula VII, and related substance B are shown in the following Table 7:

[0094] Table 7

[0095]

[0096] Reference Figure 1 and Figure 2 As shown in Table 7 above, the present invention can quickly, simply and efficiently synthesize baricitinib related substances A and B, and the reaction conditions are mild and controllable, the accuracy is good, the product purity is high, and the purity of the related substance A can reach 98.8%.

[0097] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a substance related to baricitinib, characterized in that: The baricitinib-related substance includes at least one of related substance A and related substance B; The synthetic route of the related substance A is as follows: The synthesis of the related substance A comprises the following steps: (1) The compound of formula III is 4,6-dichloro-5-pyrimidinecarboxylic acid, and the compound of formula III is reacted with ammonia to obtain the compound of formula II, and the reaction temperature is 50-60°C; The molar ratio of the compound of formula III to ammonia is 1:1-8, the ammonia is an ammonia solution, and the solvent of the ammonia solution includes at least one of an aqueous solution and a methanol solution; (2) The compound of formula II and the compound of formula I are coupled to obtain the related substance A, the reaction temperature is 50-120°C; The reaction is carried out under alkaline conditions, wherein the base includes at least one of K3PO4, K2CO3, Na2CO3, CsF, and Cs2CO3; The synthetic route of the related substance B is as follows: The synthesis of the related substance B comprises the following steps: (1) The compound of formula IV is 4-hydroxypyrimidine, and the compound of formula IV reacts with bromine to obtain the compound of formula V; The molar ratio of the compound of formula IV to bromine is 1:1 to 1:2; (2) the compound of formula V is subjected to chlorination reaction with a chlorinating agent to obtain a compound of formula VI, The chlorination agent is phosphorus oxychloride, and the molar ratio of the compound of formula V to the chlorination agent is 1:1 to 1:20; (3) the compound of formula I and the compound of formula VI are reacted by catalytic coupling reaction to obtain the compound of formula VII, the reaction temperature being 50 to 110° C.; The reaction is carried out under alkaline conditions, wherein the base includes at least one of K3PO4, K2CO3, Na2CO3, CsF, and Cs2CO3; (4) The compound of formula VII reacts with cuprous cyanide to obtain the related substance B, the reaction temperature is 120-200° C.; the molar ratio of the compound of formula VII to cuprous cyanide is 1:1-1:

3.

2. The method for synthesizing the baricitinib-related substance according to claim 1, characterized in that: In the synthesis step of the related substance A, In step (2), the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent includes at least one of DMF, 1,4-dioxane, acetonitrile, toluene, and ethanol.

3. The method for synthesizing the baricitinib-related substance according to claim 2, characterized in that: In the synthesis step of the related substance A, (1) reacting the compound of formula III with ammonia and then treating to obtain the compound of formula II; The molar ratio of the compound of formula III to ammonia is 1:5, the ammonia is an ammonia solution, and the solvent of the ammonia solution is an aqueous solution; (2) The compound of formula II and the compound of formula I are subjected to coupling reaction and then treated to obtain the related substance A, the reaction temperature is 80° C., the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent is DMF and 1,4-dioxane; The reaction is carried out under alkaline conditions, wherein the base is K2CO3.

4. The method for synthesizing the baricitinib-related substance according to claim 1, characterized in that: In the synthesis step of the related substance B, In step (3), the reaction solvent is a mixed solvent of water and an organic solvent, and the organic solvent includes at least one of DMF, 1,4-dioxane, acetonitrile, toluene, and ethanol; In step (4), the reaction solvent includes at least one of DMF, N,N-dimethylacetamide, and N-methylpyrrolidone.

5. The method for synthesizing the baricitinib-related substance according to claim 4, characterized in that: In the synthesis step of the related substance B, (1) The compound of formula IV is reacted with bromine and then treated to obtain the compound of formula V, The molar ratio of the compound of formula IV to bromine is 1:1.3; (2) the compound of formula V is subjected to chlorination reaction with a chlorinating agent and then treated to obtain the compound of formula VI; (3) The compound of formula I and the compound of formula VI are subjected to a catalytic coupling reaction and then treated to obtain a compound of formula VII, the reaction solvent is a mixed solvent of water and an organic solvent, the organic solvent is 1,4-dioxane, and the reaction is carried out under alkaline conditions, the base is K2CO3; (4) The compound of formula VII reacts with cuprous cyanide to obtain the related substance B, and the reaction temperature is 150-180°C.

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