Preparation method of baricitinib key intermediate
By using strong bases such as sodium hydroxide and reducing expensive catalysts in the synthesis of key intermediates of baricitinib, and replacing column chromatography purification with petroleum ether extraction, the problems of harsh reaction conditions and high costs in existing technologies have been solved, enabling efficient and safe industrial production.
Patent Information
- Application Number
- CN202510988069.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-17
- Publication Date
- 2025-10-31
AI Technical Summary
Existing methods for synthesizing key intermediates of baricitinib suffer from problems such as harsh reaction conditions, poor safety, high cost, and difficulty in large-scale production.
Using N,N-dimethylformamide as a solvent and strong bases such as sodium hydroxide as deprotonating agents, intermediate a was prepared by substitution reaction. The amount of tetra(triphenylphosphine)palladium was reduced in the Suzuki coupling reaction, and petroleum ether extraction was used instead of column chromatography for purification. Finally, the protecting group was removed under acidic conditions, simplifying the operation process.
It improves production safety, reduces costs, simplifies operating procedures, increases total yield and product purity, is suitable for industrial production, and solves the bottleneck of large-scale production.
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Figure CN120865272A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of drug synthesis technology, and in particular to a method for preparing a key intermediate of baricitinib. Background Technology
[0002] Baricitinib (trade name) Baricitinib is a selective tyrosine kinase (JAK) inhibitor co-developed by Eli Lilly and Incyte in December 2009. This inhibitor preferentially targets JAK1 and JAK2, exhibiting significantly higher selectivity than conventional JAK inhibitors such as TYK2, thus fundamentally blocking the formation of inflammatory mediators. Baricitinib received EU approval in February 2017 and is primarily used clinically for the treatment of rheumatoid arthritis and other inflammatory diseases, demonstrating good safety and tolerability. Furthermore, the US Food and Drug Administration has approved baricitinib for the treatment of severe alopecia areata and moderate to severe atopic dermatitis, indicating a promising market prospect.
[0003] Currently reported synthetic methods for baricitinib mainly involve a Michael addition reaction between a key intermediate and compound A to obtain compound B. The resulting intermediate B then undergoes deprotection of the protecting group on the nitrogen atom of the pyrrole ring, ultimately yielding the baricitinib product (reaction route shown below). This synthetic route is technically mature and has reached the production scale. The synthesis of the key intermediate is crucial. Therefore, exploring the synthetic process of the key intermediate is of practical significance for the large-scale production of baricitinib active pharmaceutical ingredient.
[0004]
[0005] The main synthetic routes for key intermediates of baricitinib reported so far are as follows:
[0006] Route 1:
[0007]
[0008] The original research company first protected the amino group on the pyrrolopyrimidine (I) with 2-(trimethylsilyl)ethoxymethyl chloride (1) in the presence of sodium hydride (NaH). The resulting product (II) underwent a Suzuki coupling reaction with 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester (2) to prepare 4-[1-(1-ethoxyethyl)-1H-pyrazole-4-yl]-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (III). Compound (III) was then deprotected with hydrochloric acid to obtain the key intermediate 4-(1H-pyrazole-4-yl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (IV). This method has a high overall yield and product purity. However, the use of flammable and explosive NaH reagents, expensive palladium catalysts in Suzuki coupling, and column chromatography purification techniques have limited the large-scale industrial production of this route.
[0009] Route 2:
[0010]
[0011] Synthetic route 2 also involves first reacting (Ⅰ) with (1) to obtain an amino-protected intermediate (Ⅱ), and then Suzuki coupling (Ⅱ) with 4-pyrazoleboronic acid pinacol ester to obtain the key intermediate (Ⅳ). Compared with other synthetic routes reported in the literature, this method is shorter, but the overall yield is not high, making it difficult to achieve industrial production.
[0012] Route 3:
[0013]
[0014] Synthetic route 3 involves Suzuki coupling of pinacol diboronate with compound (II) to yield compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (V). Compound (V) then undergoes a Grignard reaction with 4-bromopyrazole to obtain the key intermediate (IV). This method yields a high amount, but requires a large amount of the key catalyst Ni(PCy3)2Cl2, resulting in high production costs. Furthermore, the Grignard reaction has stringent production conditions, hindering large-scale industrial application. Summary of the Invention
[0015] To address the problems of harsh reaction conditions, poor process safety, high preparation costs, and unfavorable conditions for large-scale production in existing methods for preparing key intermediates of baricitinib, this invention provides a method for preparing key intermediates of baricitinib.
[0016] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:
[0017] A method for preparing a key intermediate of baricitinib includes the following steps:
[0018] Step a: Using N,N-dimethylformamide as solvent and a strong base as deprotonating agent, 4-chloropyrrolopyrimidine and 2-(chloromethoxy)ethyltrimethylsilane undergo a substitution reaction. After the reaction is complete, petroleum ether is added to the reaction solution for extraction. The resulting extract is washed and dried to obtain intermediate a as shown in formula (II); wherein the strong base is at least one of sodium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide.
[0019]
[0020] In step b, under alcoholic solution and alkaline conditions, intermediate a and 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester are subjected to a Suzuki coupling reaction using tetra(triphenylphosphine)palladium as a catalyst to obtain intermediate b as shown in formula (III); wherein the molar ratio of tetra(triphenylphosphine)palladium to 4-chloropyrrolopyrimidine is 0.0015:1 to 0.003:1;
[0021]
[0022] Step c, intermediate b undergoes a deprotection reaction under acidic conditions to obtain the key intermediate of baricitinib shown in formula (Ⅳ);
[0023]
[0024] The method for preparing the key intermediate of baricitinib provided by this invention has the following advantages compared with the original synthetic route:
[0025] (1) The safety of raw materials is greatly improved and the production cost is reduced: The use of inexpensive strong alkali instead of flammable and explosive sodium hydride as the deprotonating agent for the substitution reaction improves the safety of the production process and reduces the production cost, making it more suitable for safety management and cost control in industrial production.
[0026] (2) The purification process is simpler: The original synthetic route relies on column chromatography purification technology, which is complex, time-consuming and not suitable for large-scale production; while in step a, the intermediate a is separated and purified by petroleum ether extraction, and the product is obtained by washing and drying the extracted phase. This avoids the cumbersome operation of column chromatography separation technology, simplifies the operation process, reduces production costs, and the crude yield of intermediate a after the improvement reaches 98.6%, and the HPLC purity is ≥95.5%.
[0027] (3) Catalyst cost is significantly reduced: When preparing intermediate b by the Suzuki coupling reaction, the amount of expensive catalyst tetra(triphenylphosphine)palladium is reduced by about 50%, which greatly reduces production costs and reduces environmental pollution, making it more conducive to industrial application.
[0028] As a specific embodiment of the present invention, the method for preparing the key intermediate of baricitinib specifically includes the following steps:
[0029] Step a: Dissolve 4-chloropyrrolopyrimidine and a strong base in N,N-dimethylformamide, add 2-(chloromethoxy)ethyltrimethylsilane dropwise, and after the addition is complete, react at 10℃~50℃ for 4h~6h, quench with water, add petroleum ether to the reaction solution for extraction, wash the obtained extract phase, dry and concentrate to obtain intermediate a.
[0030] Step b: Dissolve intermediate a in an alcohol solution, then add alkali metal carbonate, 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and tetra(triphenylphosphine)palladium, react at 70℃~120℃ for 5h~10h under an inert atmosphere, cool, separate solid and liquid, add ethyl acetate to the obtained liquid phase for extraction, wash, dry, concentrate, and obtain intermediate b;
[0031] Step c: Dissolve intermediate b in an organic solution, add hydrochloric acid solution, react at 10℃~50℃ for 4h~6h, separate the solid and liquid, add the obtained solid to acetonitrile and slurry to obtain the key intermediate of baricitinib.
[0032] The synthesis process for key intermediates of baricitinib provided by this invention simplifies the operation process and improves production efficiency. While ensuring high overall yield and product purity, it solves the bottleneck problem that the original route is difficult to scale up for industrial production. It comprehensively improves the economy, safety and operability of the process, and has greater potential for industrial application. It provides a new route for the large-scale production of key intermediates of baricitinib and has high practical value.
[0033] Further, in step a, the molar ratio of 4-chloropyrrolopyrimidine to the strong base is 1:(1.2 to 1.4).
[0034] Adding too little strong base results in incomplete reaction of the reactants and a low yield; adding more strong base increases the yield, but when the ratio exceeds 1:1.4, the amount of impurities produced increases, and the yield decreases. Therefore, a molar ratio of 4-chloropyrrolopyrimidine to strong base of 1:(1.2–1.4) is chosen.
[0035] Further, in step a, the molar ratio of 4-chloropyrrolopyrimidine to 2-(chloromethoxy)ethyltrimethylsilane is 1:(1 to 1.2).
[0036] Further, in step a, the molar volume ratio of 4-chloropyrrolopyrimidine to N,N-dimethylformamide is 1 mmol:(1-3) mL.
[0037] Using N,N-dimethylformamide as a reaction solvent can promote the substitution reaction in step a, increase the reaction yield, and in the post-processing, N,N-dimethylformamide as a reaction solvent is easier to separate from petroleum ether compared with other solvents. The target product and impurities can be initially separated through efficient phase separation, thereby simplifying the post-processing and improving the purity of intermediate a.
[0038] Further, in step a, the strong base is sodium hydroxide or potassium hydroxide.
[0039] Preferably, in step a, the strong base is sodium hydroxide.
[0040] Using sodium hydroxide as a deprotonating agent can achieve a yield comparable to that of sodium hydride, while sodium hydroxide is cheaper, safer, and more conducive to industrial production applications.
[0041] Specifically, in step a, the strong base is added to the reaction system in batches.
[0042] Further, in step b, the molar ratio of 4-chloropyrrolopyrimidine, 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and alkali metal carbonate is 1:(1-1.2):(2-3).
[0043] Further, in step b, the mass-to-volume ratio of the 4-chloropyrrolopyrimidine to the alcohol solution is 1 g:(15-20) mL.
[0044] Further, in step b, the volume ratio of alcohol to water in the alcohol solution is (2-3):1.
[0045] Further, in step b, the alkali metal carbonate includes at least one of potassium carbonate, sodium carbonate, or cesium carbonate.
[0046] Further, in step b, the alcohol solution is at least one of methanol solution, ethanol solution, n-propanol solution or isopropanol solution.
[0047] Further, in step c, the organic solution is an aqueous solution of tetrahydrofuran, wherein the volume ratio of tetrahydrofuran to water is 1:(4-6).
[0048] Further, in step c, the mass-to-volume ratio of intermediate b to organic solution is 1 g:(4-6) mL.
[0049] Further, in step c, the mass concentration of the hydrochloric acid solution is 10% to 30%.
[0050] Further, in step c, the molar ratio of intermediate b to HCl in the hydrochloric acid solution is 1:(2-5).
[0051] Furthermore, in step c, the pulping temperature is 20℃~40℃, and the pulping time is 1h~3h.
[0052] The crude product of the key intermediate of baricitinib was purified by acetonitrile pulping. Compared with the original recrystallization purification method, the production cycle was shortened and the product yield was increased by nearly 10%, making it more suitable for industrial production applications.
[0053] The method for preparing the key intermediate of baricitinib provided by this invention, by adjusting the existing production process of the key intermediate of baricitinib, increases the overall yield of the route from the original 73% to more than 84%, and the purity of the prepared key intermediate of baricitinib is greater than 99.5%. Moreover, the entire production process does not use column chromatography purification, significantly reduces the amount of expensive catalysts, significantly reduces production costs and production cycle, is simple to operate, has mild production conditions, high safety, and is environmentally friendly. It is conducive to realizing the industrial production of the key intermediate of baricitinib and has high practical value. Attached Figure Description
[0054] Figure 1 This is a high-performance liquid chromatography (HPLC) chromatogram of the key intermediate of baricitinib synthesized in Example 1 of the present invention;
[0055] Figure 2 The 1H NMR spectrum of the key intermediate of baricitinib synthesized in Example 1 of this invention (…) 1 H-NMR spectrum;
[0056] Figure 3 yes Figure 1 This is a high-resolution mass spectrometry (HRMS) image of the key intermediate of baricitinib synthesized in Example 1 of this invention. Detailed Implementation
[0057] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0058] The high-performance liquid chromatography (HPLC) conditions for detecting the key intermediate of the synthesized baricitinib in the following examples are as follows:
[0059] Detector: Thermo UltiMate 3000 UV detector;
[0060] Column: Thermo Acclaim 120C18;
[0061] Flow rate: 1.0 mL / min;
[0062] Detection wavelength: 251nm;
[0063] Column temperature: 30℃;
[0064] Mobile phase A: Acetonitrile;
[0065] Mobile phase B: 0.05% aqueous phosphoric acid solution;
[0066] Isocratic elution, mobile phase A: mobile phase B = 50:50;
[0067] Washing time: 40 min.
[0068] To better illustrate the present invention, further examples are provided below.
[0069] Example 1
[0070] This invention provides a method for synthesizing a key intermediate of baricitinib, specifically including the following steps:
[0071] Step a, Synthesis of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(II)
[0072] 5.00 g (32.6 mmol) of 4-chloropyrrolopyrimidine and 40 mL of N,N-dimethylformamide were added sequentially to a 100 mL reaction flask. The mixture was stirred at room temperature for 30 min. 1.56 g (39.1 mmol) of solid sodium hydroxide flakes was added in portions, and the mixture was stirred for another 30 min. 5.97 g (35.8 mmol) of 2-(chloromethoxy)ethyltrimethylsilane was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 5 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). Water (20 mL) was added to quench the reaction, and petroleum ether (40 mL × 2) was added to extract the aqueous phase. The organic phases were combined and washed sequentially with water (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.11 g of crude (II) crude product (pale yellow oil), with a yield of 98.6% and an HPLC purity of 95.5%. The crude product was directly added to the next reaction without further purification.
[0073]
[0074] 1HNMR (500MHz, DMSO-d6) δ8.67(s,1H),7.86(d,J=3.7Hz,1H),6.70(d,J=3.6Hz,1H),5.64(s,2H),3.53-3.49(m,2H),0.83-0.79(m,2H),0.12(s,9H).
[0075] Step b, Synthesis of 4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine(III)
[0076] Ethanol (75 mL) and water (25 mL) were added to intermediate (II) above. After stirring at room temperature for 30 min, potassium carbonate 10.13 g (73.3 mmol), 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester 9.10 g (34.2 mmol) and tetrakis(triphenylphosphine)palladium 0.056 g (0.049 mmol) were added sequentially. Nitrogen gas was purged three times, and the mixture was heated to reflux for 8 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). The mixture was cooled to room temperature, filtered, and ethyl acetate (50 mL × 2) was added to the filtrate to extract the aqueous phase. The organic phases were combined and washed sequentially with water (80 mL × 2) and saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude oil product (III) of 12.30 g, with a yield of 97.5%. The crude product was directly added to the next reaction without purification.
[0077]
[0078] Step c, Synthesis of 4-(4-pyrazolyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (IV)
[0079] Add 11 mL of tetrahydrofuran and 55 mL of water to the above intermediate (III), stir at room temperature for 10 min, add 40.88 g (112 mmol) of 10% hydrochloric acid, and continue stirring for 5 h (the reaction process was monitored by TLC, petroleum ether: ethyl acetate = 1:5, v / v), filter, add 30 mL of acetonitrile to the obtained wet filter cake, slurry at room temperature for 2 h, filter, and dry the filter cake under vacuum at 45 °C for 3 h to obtain 8.68 g of off-white solid (IV). The yield was calculated based on 1 equivalent of 4-chloropyrrolopyrimidine, the overall yield of the three steps was 84.5%, the HPLC purity was 99.5%, and the melting point was (185–187) °C.
[0080] 1H NMR data for compound (Ⅳ): 1H-NMR (500MHz, DMSO-d6) δ13.40(s,1H),8.74(d,J=3.6Hz,1H),8.67(s,1H),8.34(s,1H),7.73(d,J=3.6Hz,1 H),7.10(d,J=3.7Hz,1H),5.62(d,J=3.5Hz,2H),3.55-3.49(m,2H),0.86-0.80(m,2H),0.11(d,J=3.2Hz,9H).
[0081] High-resolution mass spectrometry data of compound (Ⅳ): HRMS, m / z: C 15 H 21 N5OSi: Calculated value 316.1588; Measured value [M+H] + :316.1583.
[0082] Example 2
[0083] This invention provides a method for synthesizing a key intermediate of baricitinib, specifically including the following steps:
[0084] Step a, Synthesis of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(II)
[0085] 5.00 g (32.6 mmol) of 4-chloropyrrolopyrimidine and 70 mL of N,N-dimethylformamide were added sequentially to a 100 mL reaction flask. The mixture was stirred at room temperature for 30 min. 1.83 g (45.8 mmol) of solid sodium hydroxide flakes were added in portions, and the mixture was stirred for another 30 min. 5.56 g (33.3 mmol) of 2-(chloromethoxy)ethyltrimethylsilane was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). Water (20 mL) was added to quench the reaction, and petroleum ether (40 mL × 2) was added to extract the aqueous phase. The organic phases were combined and washed sequentially with water (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.01 g of crude (II) crude product (pale yellow oil), with a yield of 97.5% and an HPLC purity of 95.4%. The crude product was directly added to the next reaction without further purification.
[0086]
[0087] Step b, Synthesis of 4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine(III)
[0088] Ethanol (50 mL) and water (25 mL) were added to intermediate (II) above. After stirring at room temperature for 30 min, potassium carbonate 10.13 g (73.3 mmol), 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester 9.60 g (36.1 mmol) and tetrakis(triphenylphosphine)palladium 0.112 g (0.098 mmol) were added sequentially. Nitrogen gas was purged three times, and the mixture was heated to reflux for 10 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). The mixture was cooled to room temperature, filtered, and ethyl acetate (50 mL × 2) was added to the filtrate to extract the aqueous phase. The organic phases were combined and washed sequentially with water (80 mL × 2) and saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude oil product (III) of 12.25 g, with a yield of 97.0%. The crude product was directly added to the next reaction without purification.
[0089]
[0090] Step c, Synthesis of 4-(4-pyrazolyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (IV)
[0091] Add 10 mL of tetrahydrofuran and 60 mL of water to the above intermediate (III), stir at room temperature for 10 min, add 20.44 g (112 mmol) of 20% hydrochloric acid, and continue stirring for 6 h (the reaction process was monitored by TLC, petroleum ether: ethyl acetate = 1:5, v / v), filter, add 30 mL of acetonitrile to the obtained wet filter cake, slurry at room temperature for 2 h, filter, and dry the filter cake under vacuum at 45 °C for 3 h to obtain 8.84 g of off-white solid (IV). The yield was calculated based on 1 equivalent of 4-chloropyrrolopyrimidine, the overall yield of the three steps was 86.0%, the HPLC purity was 99.6%, and the melting point was (185–187) °C.
[0092] Example 3
[0093] This invention provides a method for synthesizing a key intermediate of baricitinib, specifically including the following steps:
[0094] Step a, Synthesis of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine(II)
[0095] 5.00 g (32.6 mmol) of 4-chloropyrrolopyrimidine and 90 mL of N,N-dimethylformamide were added sequentially to a 100 mL reaction flask. The mixture was stirred at room temperature for 30 min. 1.70 g (42.5 mmol) of flake sodium hydroxide solid was added in portions, and the mixture was stirred for another 30 min. 6.48 g (38.9 mmol) of 2-(chloromethoxy)ethyltrimethylsilane was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 6 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). Water (20 mL) was added to quench the reaction, and petroleum ether (40 mL × 2) was added to extract the aqueous phase. The organic phases were combined and washed sequentially with water (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 9.06 g of crude (II) crude product (pale yellow oil), with a yield of 98.0% and an HPLC purity of 95.3%. The crude product was directly added to the next reaction without further purification.
[0096]
[0097] Step b, Synthesis of 4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine(III)
[0098] Ethanol (75 mL) and water (25 mL) were added to intermediate (II) above. After stirring at room temperature for 30 min, potassium carbonate 10.13 g (73.3 mmol), 10.40 g (39.1 mmol) of 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and tetrakis(triphenylphosphine)palladium 0.073 g (0.064 mmol) were added sequentially. Nitrogen gas was purged three times, and the mixture was heated to reflux for 6 h (the reaction was monitored by TLC, petroleum ether:ethyl acetate = 2:1, v / v). The mixture was cooled to room temperature, filtered, and ethyl acetate (50 mL × 2) was added to the filtrate to extract the aqueous phase. The organic phases were combined and washed sequentially with water (80 mL × 2) and saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude oil product (III) of 12.28 g, with a yield of 97.2%. The crude product was directly added to the next reaction without purification.
[0099]
[0100] Step c, Synthesis of 4-(4-pyrazolyl)-7-[[2-(trimethylsilyl)ethoxy]methyl]-7H-pyrrolo[2,3-d]pyrimidine (IV)
[0101] Add 11 mL of tetrahydrofuran and 44 mL of water to the above intermediate (III), stir at room temperature for 10 min, add 13.62 g (112 mmol) of 30% hydrochloric acid, and continue stirring for 4 h (the reaction process was monitored by TLC, petroleum ether: ethyl acetate = 1:5, v / v), filter, add 30 mL of acetonitrile to the obtained wet filter cake, slurry at room temperature for 3 h, filter, and dry the filter cake under vacuum at 45 °C for 3 h to obtain 8.76 g of off-white solid (IV). The yield was calculated based on 1 equivalent of 4-chloropyrrolopyrimidine, the overall yield of the three steps was 85.5%, the HPLC purity was 99.5%, and the melting point was (185–187) °C.
[0102] Example 4
[0103] This embodiment provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that sodium hydroxide in step a of Example 1 is replaced with potassium hydroxide. The rest is exactly the same. The yield of the crude pale yellow oily product (II) prepared in step a is 97.8%, and the HPLC purity is 95.0%.
[0104] Example 5
[0105] This embodiment provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that sodium hydroxide in step a of Example 1 is replaced with sodium methoxide. The rest is exactly the same. The yield of the crude pale yellow oily product (II) prepared in step a is 95.8%, and the HPLC purity is 94.8%.
[0106] Example 6
[0107] This embodiment provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that sodium hydroxide in step a of Example 1 is replaced with sodium ethoxide. The rest is exactly the same. The yield of the crude pale yellow oily product (II) prepared in step a is 94.6%, and the HPLC purity is 94.7%.
[0108] Example 7
[0109] This embodiment provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that the molar ratio of sodium hydroxide to 4-chloropyrrolopyrimidine in step a of Example 1 is 1.6:1. The rest is exactly the same. The yield of the crude pale yellow oily product (II) prepared in step a is 93.7%, and the HPLC purity is 92.1%.
[0110] Comparative Example 1
[0111] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that sodium hydroxide in step a of Example 1 is replaced with potassium carbonate, while the rest is exactly the same.
[0112] The yield of the crude pale yellow oily substance (II) prepared in step a was 85.6%, and the HPLC purity was 90.3%.
[0113] Comparative Example 2
[0114] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that sodium hydroxide in step a of Example 1 is replaced with triethylamine. As a result, no pale yellow oily crude product (II) was detected, proving that the reaction did not occur when triethylamine was added.
[0115] Comparative Example 3
[0116] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that the reaction solvent N,N-dimethylformamide in step a of Example 1 is replaced with an equal amount of ethylene glycol dimethyl ether. The yield of the crude pale yellow oily product (II) prepared in step a is 70.5%, and the HPLC purity is 91.2%.
[0117] Comparative Example 4
[0118] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that the reaction solvent N,N-dimethylformamide in step a of Example 1 is replaced with an equal amount of isopropanol. The yield of the crude pale yellow oily product (II) prepared in step a is 50.2%, and the HPLC purity is 89.0%.
[0119] Comparative Example 5
[0120] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that the reaction solvent N,N-dimethylformamide in step a of Example 1 is replaced with an equal amount of tetrahydrofuran. The yield of the crude pale yellow oily product (II) prepared in step a is 93.2%, and the HPLC purity is 90.3%.
[0121] Comparative Example 6
[0122] This comparative example provides a method for synthesizing a key intermediate of baricitinib. The only difference from Example 1 is that the reaction solvent N,N-dimethylformamide in step a of Example 1 is replaced with an equal amount of acetonitrile. The yield of the crude pale yellow oily product (II) prepared in step a is 95.4%, and the HPLC purity is 91.5%.
[0123] In summary, the embodiments of this invention, by using a more stable and inexpensive strong alkali such as sodium hydroxide to replace flammable and explosive NaH, reducing the amount of expensive tetra(triphenylphosphine)palladium catalyst, replacing column chromatography purification with operations such as petroleum ether extraction, and selecting N,N-dimethylformamide as the reaction solvent, not only improve the overall yield and product purity of baricitinib's key intermediates, but also reduce production costs, simplify the operation process, shorten the production cycle, improve production safety, and are more environmentally friendly. This overcomes the limitations of large-scale industrial production of the original research route and has high practical value and industrial application potential.
[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing a key intermediate of baricitinib, characterized in that, Includes the following steps: Step a: Using N,N-dimethylformamide as solvent and a strong base as deprotonating agent, 4-chloropyrrolopyrimidine and 2-(chloromethoxy)ethyltrimethylsilane undergo a substitution reaction. After the reaction is complete, petroleum ether is added to the reaction solution for extraction. The resulting extract is washed and dried to obtain intermediate a as shown in formula (II); wherein the strong base is at least one of sodium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide. In step b, under alcoholic solution and alkaline conditions, intermediate a and 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester are subjected to a Suzuki coupling reaction using tetra(triphenylphosphine)palladium as a catalyst to obtain intermediate b as shown in formula (III); wherein the molar ratio of tetra(triphenylphosphine)palladium to 4-chloropyrrolopyrimidine is 0.0015:1 to 0.003:1; Step c, intermediate b undergoes a deprotection reaction under acidic conditions to obtain the key intermediate of baricitinib shown in formula (Ⅳ); 2. The method for preparing the key intermediate of baricitinib as described in claim 1, characterized in that, Specifically, the steps include the following: Step a: Dissolve 4-chloropyrrolopyrimidine and a strong base in N,N-dimethylformamide, add 2-(chloromethoxy)ethyltrimethylsilane dropwise, and after the addition is complete, react at 10℃~50℃ for 4h~6h, quench with water, add petroleum ether to the reaction solution for extraction, wash the obtained extract phase, dry and concentrate to obtain intermediate a. Step b: Dissolve intermediate a in an alcohol solution, then add alkali metal carbonate, 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and tetra(triphenylphosphine)palladium, react at 70℃~120℃ for 5h~10h under an inert atmosphere, cool, separate solid and liquid, add ethyl acetate to the obtained liquid phase for extraction, wash, dry, concentrate, and obtain intermediate b; Step c: Dissolve intermediate b in an organic solution, add hydrochloric acid solution, react at 10℃~50℃ for 4h~6h, separate the solid and liquid, add the obtained solid to acetonitrile and slurry to obtain the key intermediate of baricitinib.
3. The method for preparing the key intermediate of baricitinib as described in claim 1 or 2, characterized in that, In step a, the molar ratio of 4-chloropyrrolopyrimidine to the strong base is 1:(1.2–1.4); and / or In step a, the molar ratio of 4-chloropyrrolopyrimidine to 2-(chloromethoxy)ethyltrimethylsilane is 1:(1 to 1.2).
4. The method for preparing the key intermediate of baricitinib as described in claim 1 or 2, characterized in that, In step a, the molar volume ratio of 4-chloropyrrolopyrimidine to N,N-dimethylformamide is 1 mmol:(1-3) mL.
5. The method for preparing the key intermediate of baricitinib as described in claim 1 or 2, characterized in that, In step a, the strong base is sodium hydroxide or potassium hydroxide.
6. The method for preparing the key intermediate of baricitinib as described in claim 2, characterized in that, In step b, the molar ratio of 4-chloropyrrolopyrimidine, 1-(1-ethoxyethyl)-4-pyrazoleboronic acid pinacol ester and alkali metal carbonate is 1:(1-1.2):(2-3).
7. The method for preparing the key intermediate of baricitinib as described in claim 2, characterized in that, In step b, the mass-to-volume ratio of the 4-chloropyrrolopyrimidine to the alcohol solution is 1 g:(15-20) mL; and / or In step b, the volume ratio of alcohol to water in the alcohol solution is (2-3):
1.
8. The method for preparing the key intermediate of baricitinib as described in claim 2, characterized in that, In step b, the alkali metal carbonate includes at least one of potassium carbonate, sodium carbonate, or cesium carbonate; and / or In step b, the alcohol solution is at least one of methanol solution, ethanol solution, n-propanol solution or isopropanol solution.
9. The method for preparing the key intermediate of baricitinib as described in claim 2, characterized in that, In step c, the organic solution is an aqueous solution of tetrahydrofuran, wherein the volume ratio of tetrahydrofuran to water is 1:(4-6); and / or In step c, the mass-to-volume ratio of intermediate b to organic solution is 1 g:(4-6) mL.
10. The method for preparing the key intermediate of baricitinib as described in claim 2, characterized in that, In step c, the mass concentration of the hydrochloric acid solution is 10% to 30%; and / or In step c, the pulping temperature is 20℃~40℃, and the pulping time is 1h~3h.