A process for the preparation of baricitinib
The synthesis route of baricitinib was simplified by using a three-step reaction method with nickel catalysts, Michael addition and Suzuki coupling reaction, which solved the problems of complex synthesis and high cost in the existing technology, and realized high-yield and environmentally friendly industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NORTHEAST FORESTRY UNIV
- Filing Date
- 2023-12-13
- Publication Date
- 2026-07-03
AI Technical Summary
Existing methods for synthesizing baricitinib suffer from problems such as complex synthesis processes, high costs, significant pollution, high toxicity, and unsuitability for industrial production.
A three-step reaction method using nickel as a catalyst was adopted to prepare baricitinib via Michael addition and Suzuki coupling reaction, avoiding the use of heavy metal palladium catalyst, simplifying the synthesis route and reducing catalytic costs.
It simplifies the synthesis route, increases the yield, reduces catalyst costs, reduces pollution, and is suitable for industrial production.
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Figure CN117720543B_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of drug synthesis technology, and in particular to a method for preparing baricitinib. Background Technology
[0002] Baricitinib is a novel oral JAK inhibitor that broadly inhibits inflammatory factors transmitted via JAK-STAT and is associated with the pathogenesis of several autoimmune diseases. It was approved in my country in June 2019 for the treatment of rheumatoid arthritis, and the US FDA has also approved it for the treatment of severe alopecia areata, moderate to severe atopic dermatitis, and severe COVID-19 in adults.
[0003] Currently, the main research methods for the synthesis of baricitinib include the following routes:
[0004] Synthetic route 1 as follows Figure 1 As shown, this route uses 4-chloropyrrolopyrimidine as the starting material. After introducing a protecting group R7 in one step, the pyrazole and 4-chloropyrrolopyrimidine are first coupled by a Suzuki-Miyaura coupling reaction under palladium catalysis with the protected 4-pyrazole borate. Then, the protecting group R10 on the pyrazole ring is removed to obtain intermediate 1. Intermediate 1 undergoes Michael addition with different types of Michael alkenes, and then the protecting group R7 on the pyrrolopyrimidine ring is removed to synthesize a series of different types of baricitinib derivatives.
[0005] This route uses readily available starting materials and is simple to operate. However, the synthesis of key intermediates involved in the reaction requires multiple protection and deprotection experiments, resulting in a lengthy experimental process and poor atom and step economy.
[0006] Synthesis route 2 as follows Figure 2 As shown, this method uses 4-pyrazoloboroate pinacol ester as the starting material, and reacts with 3-(cyanomethylene)azacyclobutane-1-carboxylic acid tert-butyl ester through Michael addition to prepare reaction intermediate 2, and then undergoes palladium-catalyzed coupling reaction to prepare intermediate 3. Intermediate 3 is desorbed by two molecules of Boc to obtain intermediate 4, which is then reacted with ethylsulfonyl chloride through sulfonation reaction to prepare baricitinib.
[0007] The Michael olefin prepared by this method is not sulfonated. The Michael olefin and 4-chloropyrrolopyrimidine are first protected with di-tert-butyl dicarbonate, then undergo a coupling reaction, followed by deprotection and the introduction of an ethanesulfonyl group. After deprotection, the product contains two NH groups. The sulfonation reaction has selectivity issues and is prone to generating impurities.
[0008] Synthetic route 3 as follows Figure 3As shown, the synthetic route first reacts aziridine-3-one hydrochloride with ethylsulfonyl chloride to generate intermediate 5, and then reacts intermediate 5 with cyanoacetic acid to prepare intermediate 6 ({1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]aziridine-3-yl}acetonitrile). Intermediate 6 then undergoes Michael addition with 3-halopyrazole, and then undergoes Suzuki-Miyaura coupling with 4-pyrrolopyrimidine boronic acid or boronic acid ester under palladium catalysis. When there is a protecting group, Boc needs to be removed to prepare baricitinib.
[0009] This scheme uses the heavy metal palladium as a catalyst, resulting in relatively high total cost, significant pollution, and high toxicity, making it unsuitable for industrial production.
[0010] Synthetic route 4 as follows Figure 4 As shown, this synthetic route uses 4-chloropyrrolopyrimidine as the starting material. First, amino protection is performed, followed by a one-pot substitution and cyclization reaction with hydrazine hydrate and acrolein to prepare intermediate 1. The starting material 3-dibromoacetone and ethylene glycol are condensed to give intermediate 2. Intermediate 2 is condensed with ethylsulfonamide to give intermediate 3. Intermediate 3 is reacted with diethyl cyanomethyl phosphate under alkaline conditions to prepare intermediate 4. Intermediates 1 and 4 undergo Michael addition under alkaline catalysis, followed by deprotection to give the target product baricitinib.
[0011] This route design does not require the use of a heavy metal palladium catalyst. First, a protecting group is introduced into 4-chloropyrrolopyrimidine, which is then reacted with acrolein and hydrazine hydrate to prepare the main reaction intermediate. Following Michael addition and deprotection, the target product is obtained. The construction of the pyrazole ring in this route requires the use of hydrazine hydrate, but hydrazine hydrate is highly carcinogenic and difficult to remove during post-processing, which is detrimental to subsequent purification. Summary of the Invention
[0012] This application provides a method for preparing baricitinib to solve the technical problems of complex synthesis process and high cost in existing preparation methods.
[0013] This application provides a method for preparing baricitinib, comprising the following steps:
[0014] Compound I and compound II Michael addition reaction yields intermediate I ;
[0015] Compound III Introducing a protecting group onto the amino group yields intermediate II. PG = H, Boc, POM, SEM, OTs, Fmoc, Cbz, Tfa, Trt, or PMB;
[0016] Intermediate I and Intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib. .
[0017] Optionally, compound I and compound II undergo a Michael addition reaction to obtain intermediate I, specifically comprising:
[0018] Compound I, compound II, and DBN were reacted in an organic solvent at 45°C to 60°C for 12 to 14 hours, and the reaction was quenched. The reaction product was washed, dried, and recrystallized to obtain intermediate I.
[0019] Optionally, the molar ratio of compound I, compound II and DBN is 1:1.01:0.2.
[0020] Optionally, the reaction can be quenched using a saturated ammonium chloride solution.
[0021] Optionally, the recrystallization step includes: adding a set amount of n-propanol to the system, stirring at room temperature, recrystallizing, and filtering to obtain a white solid powder as intermediate I; the set amount is twice the mass of the reaction product.
[0022] Optionally, a protecting group is introduced onto the amino group of compound III to obtain intermediate II, specifically comprising:
[0023] 4-Chloropyrrolopyrimidine, a protecting group reagent, and 4-dimethylaminopyridine were reacted together for 2 to 10 hours. After concentration under reduced pressure, the product was separated to obtain intermediate II.
[0024] Optionally, 4-chloropyrrolopyrimidine, a protecting group reagent, and 4-dimethylaminopyridine are dissolved in acetonitrile for the reaction at room temperature.
[0025] Optionally, the molar ratio of 4-chloropyrrolopyrimidine, the protecting group reagent, and 4-dimethylaminopyridine is 1:1.5:0.01.
[0026] Optionally, intermediate I and intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib, specifically including:
[0027] The catalyst and supporting ligand were dissolved in an ultra-dry solvent and stirred at 50℃~80℃ under a nitrogen atmosphere to obtain a complex solution. Intermediate I and Intermediate II were then added to the system. Neopentyl glycol was dissolved in water and added to the system. A base and a protecting group reagent were then added, and the reaction was carried out at 70℃~100℃ for 10h~48h to obtain baricitinib.
[0028] Optionally, the volume ratio of solvent water to ultra-dry solvent is 1:0 to 4.
[0029] Optionally, the volume ratio of solvent water to ultra-dry tetrahydrofuran is 1:0 to 4, more preferably 1:1.5.
[0030] Optionally, the molar ratio of intermediate I, intermediate II and base is 1.1–1.5:1:1.1–2.1.
[0031] Optionally, the amount of neopentyl glycol is 0 to 1.5 equivalents relative to the amount of compound II.
[0032] Optionally, the molar ratio of the catalyst to the dominant ligand is 1:1.1 to 1.2.
[0033] Optionally, the protecting group reagent includes di-tert-butyl dicarbonate (Boc)₂O, neopentyloxymethyl chloride POM-Cl, trimethylsilylethoxymethyl chloride SEM-Cl, p-toluenesulfonyl chloride OTs-Cl, fluorenylmethoxycarbonyl chloride Fmoc-Cl, benzyl carbonyl chloride Cbz-Cl, trifluoroacetyl chloride Tfa-Cl, trichlorotriphenylmethane Trt-Cl, p-methoxybenzyl bromide PMB-Br, or p-methoxybenzyl chloride PMB-Cl.
[0034] Optionally, the catalyst is NiX2 or L. n NiRX, where X is Cl or Br; R is o-methylphenyl or 2,4,6-trimethylphenyl or 2,6-dimethoxyphenyl or 2,4,6-triisopropylphenyl; L n It is a monodentate or bidentate nitrogen ligand or phosphine ligand: when n=2, L is PPh3, PCyPh2, PCy2Ph, PCy3, PCyp3, PBn3, PMePh2, PMe2Ph, PEt3, or P( n -Bu)3; when n=1, L is dppe, dppp, dppb, (S)-BINAP, dppf, dcpf, Xantphos or pyphos.
[0035] Optionally, the catalyst is (SP-4-3)-chloro(2-methylphenyl)bis(triphenylphosphine)nickel.
[0036] Optionally, the supporting ligand is a nitrogen ligand or a phosphine ligand;
[0037] and / or
[0038] The nitrogen ligand is 2,2'-bipyridine and its substituted forms, 1,10-phenanthroline and its derivatives and their substituted forms, pyridyl ligand or 1,2-diimino ligand, oxazoline ligand;
[0039] and / or
[0040] The phosphine ligands are PPh3, dppe, dppp, dppb, PCyPh2, PCy2Ph, PCy3, PCyp3, PBn3, PMePh2, PMe2Ph, PEt3, P( n -Bu)3, (S)-BINAP, dppf, dcpf or Xantphos.
[0041] Optional, when using L n When using NiRX type catalysts, the supporting ligands are dppb or dppf.
[0042] Optionally, the base may be at least one of potassium hydroxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium phosphate, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabispirocyclo[5.4.0]undecyl-7-ene, N,N-diisopropylethylamine, or triethylamine.
[0043] Optionally, the ultra-dry solvent includes at least one of ultra-dry tetrahydrofuran, ultra-dry 2-methyltetrahydrofuran, ultra-dry methanol, ultra-dry toluene, ultra-dry acetone, ultra-dry acetonitrile, ultra-dry dimethylformamide, ultra-dry dimethylacetamide, and ultra-dry methyl tert-butyl ether.
[0044] The technical solution provided by this invention has the following advantages compared with the prior art:
[0045] This invention provides a method for preparing baricitinib. The synthetic route is short and rationally designed, and the final product can be obtained in only three steps, which is highly economical. It can effectively avoid the formation of coupling byproducts, resulting in higher yield. The use of nickel as a catalyst not only reduces catalytic costs and makes the raw materials more readily available, but also reduces toxicity and pollution, which is conducive to environmental sustainability. Attached Figure Description
[0046] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application.
[0047] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0048] Figure 1 This is a schematic diagram of the synthetic route 1 for baricitinib in the prior art;
[0049] Figure 2 This is a schematic diagram of the synthetic route 2 for baricitinib in the prior art;
[0050] Figure 3 This is a schematic diagram of the synthetic route 3 for baricitinib in the prior art;
[0051] Figure 4 This is a schematic diagram of the existing synthetic route for baricitinib;
[0052] Figure 5 A schematic diagram of the synthetic route of baricitinib provided in the embodiments of this application. Detailed Implementation
[0053] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.
[0054] Various embodiments of this application may exist in the form of a range; it should be understood that the description in the form of a range is merely for convenience and brevity and should not be construed as a hard limitation on the scope of this application; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and single numbers within the range, such as 1, 2, 3, 4, 5, and 6, regardless of the range. Furthermore, whenever a numerical range is referred to herein, it means including any referenced number (fraction or integer) within the range referred to.
[0055] In this application, unless otherwise stated, terms including "comprising" and the like mean "including but not limited to". Relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. In this document, "and / or" describes the relationship between related objects, indicating that three relationships may exist; for example, A and / or B can represent: A alone, A and B simultaneously, or B alone. A and B can be singular or plural. In this document, "at least one" means one or more, and "more than one" means two or more. "At least one", "at least one of the following", or similar expressions refer to any combination of these items, including any combination of single or plural items. For example, "at least one of a, b, or c" or "at least one of a, b, and c" can both mean: a, b, c, ab (i.e., a and b), ac, bc, or abc, where a, b, and c can be a single or multiple.
[0056] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this application can be purchased from the market or prepared by existing methods.
[0057] This application provides a method for preparing baricitinib, the synthetic route as follows: Figure 5 As shown, it includes the following steps:
[0058] S1, Compound I and compound II Michael addition reaction yields intermediate I ;
[0059] S2, Compound III Introducing a protecting group onto the amino group yields intermediate II. PG = Boc, POM, SEM, OTs, Fmoc, Cbz, Tfa, Trt or PMB;
[0060] S3, intermediate I and intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib. .
[0061] In an optional embodiment, compound I and compound II in step S1 undergo a Michael addition reaction to obtain intermediate I, specifically including:
[0062] Compound I, compound II, and DBN were reacted in the organic solvent acetonitrile at 45°C–60°C for 12–14 h. The reaction was then quenched, and the reaction product was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid. After recrystallization from n-propanol, intermediate I was obtained.
[0063] In an optional embodiment, the recrystallization is performed by adding 2 times (by volume) of n-propanol to the system, stirring and recrystallizing at room temperature, and then filtering to obtain a white solid powder as intermediate I.
[0064] In an optional embodiment, the molar ratio of compound I, compound II, and DBN is 1:1.01:0.2.
[0065] In an optional embodiment, the quenching reaction is quenched using a saturated ammonium chloride solution.
[0066] In an optional embodiment, introducing a protecting group onto the amino group of compound III in step S2 yields intermediate II, specifically including:
[0067] 4-Chloropyrrolopyrimidine, a protecting group reagent, and 4-dimethylaminopyridine were reacted together for 2 to 10 hours. After concentration under reduced pressure, the product was separated by column chromatography to obtain intermediate II.
[0068] In an optional embodiment, 4-chloropyrrolopyrimidine, a protecting group reagent, and 4-dimethylaminopyridine are dissolved in acetonitrile for reaction at room temperature.
[0069] In an optional embodiment, the molar ratio of the 4-chloropyrrolopyrimidine, the protecting group reagent, and the 4-dimethylaminopyridine is 1:1.5:0.01.
[0070] In an optional embodiment, intermediate I and intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib, specifically including:
[0071] The catalyst and supporting ligand were dissolved in an ultra-dry solvent and stirred at 50℃~80℃ under a nitrogen atmosphere to obtain a complex solution. Intermediate I and Intermediate II were then added to the system. Neopentyl glycol was dissolved in water and added to the system. A base and protecting group reagent were then added, and the reaction was carried out at 70℃~100℃ for 10h~48h. The reaction product was then post-treated to obtain baricitinib.
[0072] In an optional embodiment, the post-processing specifically involves: after the reaction is complete, extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and then separating it by ethyl acetate column chromatography to obtain baricitinib.
[0073] In an optional embodiment, the volume ratio of solvent water to ultra-dry tetrahydrofuran is 1:0 to 4, such as 1:1, 1:1.5, 1:2, 1:3, 1:4, and more preferably 1:1.5.
[0074] In an optional embodiment, the molar ratio of intermediate I, intermediate II and base is 1.1–1.5:1:1.1–2.1.
[0075] In an optional embodiment, the amount of neopentyl glycol is 0 to 1.5 equivalents relative to the amount of compound II.
[0076] In an optional embodiment, the molar ratio of the catalyst to the dominant ligand is 1:1.1 to 1.2.
[0077] In optional embodiments, the protecting group reagent includes di-tert-butyl dicarbonate (Boc)₂O, neopentyloxymethyl chloride POM-Cl, trimethylsilylethoxymethyl chloride SEM-Cl, p-toluenesulfonyl chloride OTs-Cl, fluorenylmethoxycarbonyl chloride Fmoc-Cl, benzyl carbonyl chloride Cbz-Cl, trifluoroacetyl chloride Tfa-Cl, chlorotriphenylmethane Trt-Cl, p-methoxybenzyl bromide PMB-Br, or p-methoxybenzyl chloride PMB-Cl.
[0078] In an optional embodiment, the catalyst is NiX2 or L. n NiRX, where X is Cl or Br; R is o-methylphenyl or 2,4,6-trimethylphenyl or 2,6-dimethoxyphenyl or 2,4,6-triisopropylphenyl; L n It is a monodentate or bidentate nitrogen ligand or phosphine ligand: when n=2, L is PPh3, PCyPh2, PCy2Ph, PCy3, PCyp3, PBn3, PMePh2, PMe2Ph, PEt3, or P( n -Bu)3; when n=1, L is dppe, dppp, dppb, (S)-BINAP, dppf, dcpf, Xantphos or pyphos.
[0079] In an optional embodiment, the catalyst is (SP-4-3)-chloro(2-methylphenyl)bis(triphenylphosphine)nickel.
[0080] In an optional embodiment, the supporting ligand is a nitrogen ligand or a phosphine ligand;
[0081] and / or
[0082] The nitrogen ligand is 2,2'-bipyridine and its substituted forms, 1,10-phenanthroline and its derivatives and their substituted forms, pyridyl ligand or 1,2-diimino ligand, oxazoline ligand;
[0083] and / or
[0084] The phosphine ligands are PPh3, dppe, dppp, dppb, PCyPh2, PCy2Ph, PCy3, PCyp3, PBn3, PMePh2, PMe2Ph, PEt3, P( n -Bu)3, (S)-BINAP, dppf, dcpf or Xantphos.
[0085] In an optional implementation, L is selected. n When using NiRX type catalysts, the supporting ligands are dppb or dppf.
[0086] In an optional embodiment, the base includes at least one of potassium hydroxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium phosphate, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabispirocyclo[5.4.0]undecyl-7-ene, N,N-diisopropylethylamine, or triethylamine.
[0087] In an optional embodiment, the ultra-dry solvent includes at least one of ultra-dry tetrahydrofuran, ultra-dry 2-methyltetrahydrofuran, ultra-dry methanol, ultra-dry toluene, ultra-dry acetone, ultra-dry acetonitrile, ultra-dry dimethylformamide, ultra-dry dimethylacetamide, and ultra-dry methyl tert-butyl ether.
[0088] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to industry standards. If there is no corresponding industry standard, then common international standards, conventional conditions, or conditions recommended by the manufacturer are followed.
[0089] Example
[0090] This embodiment provides a method for preparing baricitinib, including the following steps:
[0091] S1, Compound I and compound II Michael addition reaction yields intermediate I ;
[0092] Specifically, the following steps are included:
[0093] 9.31 g (50 mmol) of 2-[1-(ethylsulfonyl)-3-azacyclobutanediyl]acetonitrile (compound I) was added to a 250 mL round-bottom flask, followed by 84 mL of acetonitrile. The mixture was stirred and dissolved at room temperature. Then, 9.81 g (50.5 mmol) of 4-pyrazoloboronic acid pinacol ester (compound II) and 1.24 g (10 mmol) of DBN were added. The mixture was heated in an oil bath at 60 °C overnight. The reaction was monitored by TLC until complete. The reaction was cooled to room temperature. The reaction solution was quenched with 150 mL of saturated ammonium chloride solution, and the organic phase was extracted with 300 mL of ethyl acetate. The organic phase was washed with 150 mL of saturated brine and dried over anhydrous sodium sulfate. The reaction product was concentrated under reduced pressure at 50 °C to give 19.7 g of a yellow solid. 39.4 mL of n-propanol was added to the 19.7 g of the yellow solid, and the mixture was stirred and recrystallized at room temperature. The residue was filtered to give a white solid powder, which was dried under vacuum to give 17.8 g of intermediate I (94% yield).
[0094] S2, Compound III Introducing a protecting group onto the amino group yields intermediate II. PG = Boc, POM, SEM, OTs, Fmoc, Cbz, Tfa, Trt or PMB;
[0095] Specifically, the following steps are included:
[0096] In a 100 mL round-bottom flask, 2.46 g (16.0 mmol) of 4-chloropyrrolopyrimidine (compound III), 24 mL of acetonitrile, 5.24 g (24.0 mmol) of di-tert-butyl dicarbonate, and 0.02 g (0.16 mmol) of 4-dimethylaminopyridine were added sequentially. The mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC until complete. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and purified by column chromatography (eluent: ethyl acetate). After concentration under reduced pressure, the product was dried under vacuum at 50 °C overnight to give 3.8 g of white solid intermediate II (yield 94%).
[0097] S3, intermediate I and intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib. ;
[0098] Specifically, the following steps are included:
[0099] In a 100 mL Schlenk tube, 0.36 g (0.5 mmol) of (SP-4-3)-chloro(2-methylphenyl)bis(triphenylphosphine)nickel (catalyst), 0.24 g (0.55 mmol) of 1,4-bis(diphenylphosphine)butane, and 15 mL of ultra-dry tetrahydrofuran were added sequentially. Nitrogen gas was purged three times, and the mixture was heated in an oil bath at 50 °C for 0.5 h. The system changed from bright yellow to deep yellow. Then, 2.85 g (7.5 mmol) of 1-(ethylsulfonyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl]-3-azacyclobutaneacetonitrile (intermediate I) and 1.27 g (5 mmol) of 4-chloropyrrolo[2,3-D]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate II) were added to the Schlenk tube. 0.78 g (7.5 mmol) of neopentyl glycol was dissolved in 10 mL of water. This solution was added to the system, followed by the addition of 0.59 g (10.5 mmol) of potassium hydroxide and 1.42 g of di-tert-butyl dicarbonate. The system was purged with nitrogen three times, and the mixture was heated to 100 °C and stirred for 48 h. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain a pale yellow oil. The organic phase was extracted with dichloromethane, and column chromatography yielded 1.7 g (91%) of baricitinib as a white solid.
[0100] As can be seen from the above embodiments, the synthetic route of baricitinib provided in this invention is short, and the yield of each intermediate and the final product is higher than 90%, which is a high yield. Using nickel as a catalyst not only reduces the catalytic cost and makes the raw materials more readily available, but also reduces toxicity and pollution, which is conducive to the sustainable development of the environment.
[0101] The above description is merely a specific embodiment of this application, enabling those skilled in the art to understand or implement this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.
Claims
1. A method for preparing baricitinib, characterized in that, Includes the following steps: Compound I and compound II Michael addition reaction yields intermediate I ; Compound III Introducing a protecting group onto the amino group yields intermediate II. PG = Boc, POM, SEM, OTs, Fmoc, Cbz, Tfa, Trt or PMB; Intermediate I and Intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib. ; The reaction of compound I and compound II by Michael addition yields intermediate I, which specifically includes: Compound I, compound II, and DBN were reacted in an organic solvent at 45°C to 60°C for 12 to 14 hours, and the reaction was quenched. The reaction product was washed, dried, and recrystallized to obtain intermediate I. Introducing a protecting group onto the amino group of compound III yields intermediate II, which specifically includes: Compound III, 4-chloropyrrolopyrimidine, a protecting group reagent, and 4-dimethylaminopyridine were reacted together for 2 to 10 hours. After concentration under reduced pressure, intermediate II was obtained by column chromatography. The intermediate I and the intermediate II undergo a Suzuki coupling process under the action of a catalyst to obtain baricitinib, specifically comprising: The catalyst and supporting ligand were dissolved in an ultra-dry solvent and stirred at 50℃~80℃ under a nitrogen atmosphere to obtain a complex solution. Intermediate I and Intermediate II were added to the system, neopentyl glycol was dissolved in water and added to the system, and base and protecting group reagent were added. The reaction was carried out at 70℃~100℃ for 10h~48h to obtain baricitinib. The catalyst is (SP-4-3)-chloro(2-methylphenyl)bis(triphenylphosphine)nickel, and the supporting ligand is 1,4-bis(diphenylphosphine)butane.
2. The method for preparing baricitinib according to claim 1, characterized in that, The reaction was quenched using a saturated ammonium chloride solution; and / or The recrystallization method specifically includes: adding a set amount of n-propanol to the system for recrystallization, and then filtering the crystals.
3. The method for preparing baricitinib according to claim 1, characterized in that, The protecting group reagents include di-tert-butyl dicarbonate (Boc)₂O, neopentyloxymethyl chloride POM-Cl, trimethylsilylethoxymethyl chloride SEM-Cl, p-toluenesulfonyl chloride OTs-Cl, fluorenemethoxycarbonyl chloride Fmoc-Cl, benzylcarbonyl chloride Cbz-Cl, trifluoroacetyl chloride Tfa-Cl, chlorotriphenylmethane Trt-Cl, p-methoxybenzyl bromide PMB-Br, or p-methoxybenzyl chloride PMB-Cl.
4. The method for preparing baricitinib according to claim 1, characterized in that, The base includes at least one of potassium hydroxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium phosphate, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabispirocyclo[5.4.0]undecyl-7-ene, N,N-diisopropylethylamine, and triethylamine.
5. The method for preparing baricitinib according to claim 1, characterized in that, The ultra-dry solvent includes at least one of ultra-dry tetrahydrofuran, ultra-dry 2-methyltetrahydrofuran, ultra-dry methanol, ultra-dry toluene, ultra-dry acetone, ultra-dry acetonitrile, ultra-dry dimethylformamide, ultra-dry dimethylacetamide, and ultra-dry methyl tert-butyl ether.