A method for preparing an abrocitinib intermediate
Through the new preparation method, the reaction of Compound 1 with p-toluenesulfonyl chloride, p-nitrobenzenesulfonylmethylamide and sodium thioglycolate avoids the isomers and urea impurities generated by the rearrangement reaction, and improves abuxitinib The preparation efficiency and purity of the intermediates solve the problems of low yield and limited production in the prior art, and achieve a safer and more efficient production process.
Patent Information
- Application Number
- CN202411272923.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-12
- Publication Date
- 2024-12-10
- Estimated Expiration
- 2044-09-12
AI Technical Summary
The existing abuxitinib preparation methods have problems such as low yield, difficulty in removing by-products and impurities and limited production, especially the rearrangement reaction to produce isomers and urea impurities, resulting in low reaction yield and difficulty in refining.
A new preparation method is adopted, including the substitution reaction of Compound 1 with p-toluenesulfonyl chloride, followed by reaction with p-nitrobenzenesulfonylmethylamine and base, followed by reaction with sodium thioglycolate, and finally removal of the Boc protecting group, through these Steps to avoid rearrangement reactions to produce isomers and urea impurities, improving chemical selectivity and refinement.
The efficient preparation of compounds is achieved, the use of flammable and hazardous reagents is avoided, the reaction conditions are safer, the reaction time of each step is controlled within 12 hours, the total yield and total cost are obvious advantages compared to the existing methods, and are suitable for commercial amplification of production. .
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Figure CN118772161B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an abrocitinib intermediate. Background Art
[0002] Atopic dermatitis is a chronic, relapsing, inflammatory skin disease. Patients often suffer from severe itching symptoms, which seriously affects their quality of life. The pathogenesis of atopic dermatitis is complex and may involve multiple inflammatory and immune pathways. The JAK-STAT signaling pathway can exert its effects by participating in multiple immune pathways and affecting multiple downstream inflammatory factors. Therefore, JAK inhibitors play an important role in the treatment of atopic dermatitis. Among them, JAK1 selective inhibitors can avoid inhibiting JAK2 kinase (JAK2 can regulate the signaling of erythropoietin and thrombopoietin), which is a reasonable treatment method.
[0003] Abrocitinib is an oral JAK1 selective inhibitor developed by Pfizer, which is suitable for adult patients with moderate to severe atopic dermatitis who are refractory to other systemic treatments such as hormones or biologics. Development of a Nitrene-Type Rearrangement for the Commercial Route of the JAK1 Inhibitor Abrocitinib (Christina G. Connor et. Al., Org. Process Res. Dev. 2021, 25, 3, 608–61) disclosed abrocitinib, and its chemical reaction formula is as follows:
[0004] .
[0005] The first step, Curtius rearrangement reaction, generates an azide intermediate, which is highly dangerous and limits scale-up production. The second step uses lithium borohydride, which is a flammable and explosive reagent and is relatively dangerous to use. The total yield is low at 15.4-24.3%, the synthesis efficiency is low, and the overall cost is high. The preparation of compound 10 from compound 9 also produces compound 14 as a by-product and isomeric impurities, which are difficult to purify.
[0006] In addition, the document also discloses another method for preparing Abrocitinib, the reaction formula is as follows
[0007] .
[0008] Among them, compound 22 has no Ts electron-withdrawing substituent, resulting in low electrophilic reactivity of compound 22. The reaction time of compound 19 and compound 22 is as long as 48 hours, and the reaction conversion is slow. Amplification may require a longer reaction time.
[0009] Compound 17 has poor solubility in organic solvents. When reacting with compound 21 for sulfonylation, the NH of pyrrole will compete with it, and the by-products will affect the yield. Impurities with similar structures are also difficult to remove. Although the selectivity of compound abrocitinib (1) was improved by low temperature control, the scale-up production was limited. The total yield of the synthetic route was 45.6%, and the yields of the individual steps were not high.
[0010] It has been reported that the preparation method of abrocitinib generally uses a racemic compound as the starting material, and constructs a cis-tetracyclic chiral intermediate through rearrangement, enzymatic chiral reduction, etc. However, the rearrangement process cannot avoid the generation of isomeric impurities and urea by-products, resulting in low reaction yield, difficult purification and obvious scale-up effect, which limits the application of these technologies in production scale-up. Summary of the invention
[0011] In view of the problems of low yield of abrocitinib in the prior art, difficulty in removing by-products and impurities, and limited scale-up production, the present invention provides a method for preparing an abrocitinib intermediate, which avoids the use of rearrangement reactions to generate isomers and urea impurities, has better chemical selectivity, is easier to purify, has a higher yield, and has safer reaction conditions.
[0012] The present invention is achieved through the following technical solutions:
[0013] A method for preparing an abrocitinib intermediate comprises the following steps:
[0014] (1) Compound 1, a base and a catalyst are dissolved, p-toluenesulfonyl chloride is added, a substitution reaction is carried out, and compound 2 is separated from the reaction solution:
[0015] (2) dissolving p-nitrobenzenesulfonylmethylamide and a base, adding compound 2 to react, and separating compound 3 from the reaction solution;
[0016] (3) Compound 3, a base and sodium thioglycolate are dissolved and reacted to obtain compound 4 from the reaction solution;
[0017] (4) dissolving compound 4, compound 5 and a base, reacting them, and separating compound 6 from the reaction solution;
[0018] (5) Compound 6 was dissolved, and the Boc protecting group was removed by adding acid, followed by separation and purification to obtain compound 7;
[0019] .
[0020] Furthermore, in step (1), the molar ratio of compound 1 to p-toluenesulfonyl chloride is 1:1-1.5; and in step (2), the molar ratio of p-nitrobenzenesulfonylmethylamide to compound 2 is 1:0.9-1.2.
[0021] Furthermore, in step (3), the molar ratio of compound 3 to sodium thioglycolate is 1:1-2; and in step (4), the molar ratio of compound 4 to compound 5 is 1:0.8-1.2.
[0022] Furthermore, in step (1), the molar ratio of compound 1 to the base and the catalyst is 1:2:0.2; in step (2), the molar ratio of p-nitrobenzenesulfonylmethylamide to the base is 1:1-2; in step (3), the molar ratio of compound 3 to the base is 1:1-2; and in step (4), the molar ratio of compound 4 to the base is 1.1:2-3.
[0023] Furthermore, the base described in steps (1) to (4) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-amylate, potassium carbonate, and sodium carbonate; and the acid in step (5) is hydrochloric acid.
[0024] Furthermore, the concentration of HCl in the solvent in step (5) is 4M.
[0025] Furthermore, the solvent used for dissolving in step (1) is one or more of dichloromethane, tetrahydrofuran and acetonitrile; the solvent used for dissolving in step (2) is one or more of 1,4-dioxane, tetrahydrofuran and N,N-dimethylformamide; the solvent used for dissolving in step (3) is methanol and / or tetrahydrofuran; the solvent used for dissolving in step (4) is isopropanol or acetonitrile; and the solvent used for dissolving in step (5) is ethyl acetate.
[0026] Furthermore, in step (1), the catalyst is 4-dimethylaminopyridine.
[0027] Furthermore, the substitution reaction temperature in step (1) is 20-40°C, and the reaction time is 4-10 h; the reaction temperature in step (2) is 45-55°C, and the reaction time is 10-20 h; the reaction temperature in step (3) is 20-50°C, and the reaction time is 6-12 h; the reaction temperature in step (4) is 50-80°C, and the reaction time is 8-16 h; the reaction temperature in step (5) is 20-50°C, and the reaction time is 1-5 h.
[0028] Furthermore, TLC was used to monitor the reaction progress.
[0029] Beneficial effects achieved by the present invention:
[0030] In the present invention, OTs is selected as the leaving group in step (1), and the OTs connected to the secondary carbon does not easily leave spontaneously to generate S N1 reaction, so that compound 2 has sufficient stability and reactivity in the subsequent reaction, avoiding the production of racemic products or other degradation by-products. Step (2) Selecting p-nitrobenzenesulfonylmethylamide (compound 2a) can not only efficiently introduce methylamine groups into the product structure, but also 2a still has sufficient nucleophilicity after strong base hydrogen extraction and reacts with compound 2 to complete S N 2 configuration flipping solves the difficulty of constructing the chiral center of the reported patents and avoids the technical difficulties of using (Curitus, Lossen) rearrangement reactions to generate isomers and ureas that are difficult to remove byproducts. Step (3) uses the mild conditions of sodium thioglycolate to directly remove the p-nitrobenzenesulfonyl group. The reaction is clean with few byproducts, easy to purify and high yield; avoid introducing protective groups that require strong acid and base conditions for deprotection, which leads to other side reactions: for example, the debenzylation of benzylmethylamine requires palladium carbon hydrogenation to increase costs, the deprotection of p-toluenesulfonylmethylamine with toluenesulfonylmethylamine cannot be completely removed even with strong base and high temperature, and the deprotection of benzylmethylamine with strong base and high temperature for a long time will cause partial degradation of the product; in addition, if an acidic deprotection group is used, a de-Boc byproduct will be produced. Therefore, it is crucial to select p-nitrobenzenesulfonylmethylamine as the nucleophilic reagent in step (2).
[0031] In summary, the present invention avoids the generation of difficult-to-remove isomers and urea impurities by rearrangement reaction, the overall stereoselectivity and chemical selectivity of the route are good, the product is easier to purify, and the yield of each step is high; at the same time, the use of flammable and dangerous reagents (such as lithium borohydride) is avoided, and the reaction conditions are safer; the reaction of each step is efficient and can be completed within 12 hours, and the production period is controllable; the total yield and total cost of the present invention have obvious advantages over the reported methods, and are suitable for commercial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Figure 1 is the H NMR spectrum of compound 2;
[0033] Figure 2 is the H NMR spectrum of compound 3;
[0034] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound 6;
[0035] Figure 4 This is the hydrogen NMR spectrum of compound 7. DETAILED DESCRIPTION
[0036] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.
[0037] Example 1
[0038] (1) Preparation of compound 2 (trans-(1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate):
[0039] At room temperature, 500 mL of dichloromethane, 100 g (0.53 mol, 1.0 eq) of compound 1 (tert-butyl trans-((1r,3r)-3-hydroxycyclobutyl)carbamate), 107 g (1.06 mol, 2.0 eq) of triethylamine and 13 g (0.11 mmol, 0.2 eq) of DMAP were added to a 1 L round-bottom flask in sequence. 112 g (0.58 mol, 1.1 eq) of p-toluenesulfonyl chloride was added under stirring, and the reaction was carried out at 20-30 °C for 6 h.
[0040] The conversion of compound 1 was complete as monitored by TLC. The reaction solution was concentrated, and 500 mL of ethyl acetate and 500 mL of water were added for extraction and separation. The aqueous phase was extracted twice with 200 mL of ethyl acetate. The organic phases were combined and washed once with 800 mL of saturated sodium chloride solution. The organic phase was separated, 20 g of anhydrous sodium sulfate was added for drying, filtration, and concentration to an oily substance. 600 ml of n-heptane: methyl tert-butyl ether (5V:1V) was added, and the mixture was stirred at 0-10 °C for crystallization for 2 h. The mixture was filtered and dried to obtain 171.7 g of compound 2 as a white solid with a yield of 94.88%.
[0041] The sample is subjected to nuclear magnetic resonance hydrogen spectrum to detect the structure of the substance. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 1 As shown, the hydrogen spectrum is consistent with that of compound 2; 1 H- NMR (400 MHz, DMSO- d 6 ): δ 7.80 – 7.72 (m, 2H), 7.48 (d, J =7.9 Hz, 2H), 7.20 (d, J = 6.1 Hz, 1H), 4.95 – 4.88 (m, 1H), 3.95 (s, 1H), 2.42(s, 3H), 2.29 (ddd, J = 13.3, 8.4, 4.9 Hz, 2H), 2.21 – 2.08 (m, 2H), 1.34 (s, 9H).
[0042] (2) Preparation of compound 3 (cis-tert-butyl 3-((N-methyl-4-nitrophenyl)sulfonamido)cyclobutyl)carbamate):
[0043] At 20-30 °C, dissolve 86.5 g (0.4 mol, 1.0 eq) of p-nitrobenzenesulfonylmethylamine and 49.4 g (0.44 mol, 1.1 eq) of potassium tert-butoxide in 430 mL of N,N-dimethylformamide and stir for 30 min. Add 136.6 g (0.4 mol, 1.0 eq) of compound 2 to the reaction solution, then heat to 45-55 °C and react for 10 h.
[0044] The reaction of compound 2 was complete by TLC detection. The reaction was cooled to room temperature, and then 500 mL of water was added slowly and then quickly to quench the reaction. Then 500 mL of ethyl acetate was added to extract the reaction solution, and then 300 ml of ethyl acetate was used to extract twice. The organic phases were combined, washed twice with 1 L of saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain a crude compound 3. Then 800 ml of n-heptane: isopropyl acetate (90V:10V) solution was added, and the mixture was slurried, filtered, and dried to obtain compound 3125.2 g as a light yellow solid with a yield of 81.2%;
[0045] The sample is subjected to nuclear magnetic resonance hydrogen spectrum to detect the structure of the substance. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 2 As shown, the hydrogen spectrum is consistent with that of compound 3; 1 H- NMR (400 MHz, DMSO- d 6 ): δ 8.46 – 8.37 (m, 2H), 8.09 – 7.98 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 3.77 (p, J = 8.6 Hz, 1H), 3.58 (q, J = 8.1 Hz,1H), 2.66 (s, 3H), 2.22 (d, J = 9.0 Hz, 2H), 1.93 (q, J = 9.3, 8.3 Hz, 2H), 1.34(s, 9H).
[0046] (3) Preparation of compound 4 (cis-(3-(methylamino)cyclobutyl)carbamic acid tert-butyl ester):
[0047] At 20-30 °C, 116 g (0.3 mol, 1.0 eq) of compound 3, 50 g (0.36 mol, 1.2 eq) of potassium carbonate and 42 g (0.36 mol, 1.2 eq) of sodium thioglycolate were dissolved in 900 mL of solvent (methanol:tetrahydrofuran = 5 V:1 V) and stirred for 8 h. The reaction of compound 3 was complete by TLC. The reaction solution was concentrated to obtain an oily substance. 500 mL of water was added and then the reaction solution was extracted with 300 mL of ethyl acetate for 3 times. The organic phases were combined and concentrated, washed once with 500 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried to obtain 55.7 g of yellow solid compound 4 with a yield of 92.7%. The solid was not further purified and was directly used in the next step.
[0048] (4) Preparation of compound 6 (tert-butyl cis-(3-(methyl(7-p-methylbenzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate):
[0049] 50 g crude product of compound 4 (0.25 mol, 1.1 eq), 70 g (0.23 mol, 1.0 eq) of compound 5 (4-chloro-7-p-toluenesulfonyl-7H-pyrrolo[2,3d]pyrimidine), and 73.4 g (0.57 mol, 2.5 eq) of N,N-diisopropylethylamine were dissolved in 500 ml of isopropanol and the temperature was raised to 75-80 °C for reaction for 10 h. The reaction of compound 4 was completed by TLC monitoring. After the reaction was completed, the temperature was lowered to 10-20 °C for crystallization, and the filter cake was washed with 100 ml of isopropanol. The solid was dried to obtain 103 g of white solid compound 6 with a yield of 94.9%.
[0050] The sample is subjected to nuclear magnetic resonance hydrogen spectrum to detect the structure of the substance. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 3 As shown, the hydrogen spectrum is consistent with that of compound 6; 1 H -NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.96 (d, J =8.4 Hz, 2H), 7.61 (d, J = 4.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.5Hz, 1H), 6.97 (d, J = 4.1 Hz, 1H), 4.82 (s, 1H), 3.75 (q, J = 8.1 Hz, 1H), 3.20(s, 3H), 2.43 (d, J= 7.4 Hz, 2H), 2.35 (s, 3H), 2.15 (dd, J = 14.5, 6.2 Hz, 2H), 1.37 (s, 9H).
[0051] (5) Preparation of Compound 7 (cis-N-methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diamine dihydrogen hydrochloride)
[0052] Compound 6 94.3g (0.2mol, 1.0eq) was dissolved in 500ml of 4M hydrogen chloride ethyl acetate solution, stirred at 20-30℃ for 4h, TLC detected that compound 6 was completely reacted, cooled to 0-10℃ for crystallization for 1h, filtered to obtain compound 7 hydrochloride, then added with 500ml of ethyl acetate solution, stirred at 0-10℃ for slurrying, and filtered to obtain compound 7 85.4g, with a yield of 96.0%;
[0053] The sample is subjected to nuclear magnetic resonance hydrogen spectrum to detect the structure of the substance. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 4 As shown, the hydrogen spectrum is consistent with that of compound 7, indicating that the obtained sample is compound 7 (abroxitinib intermediate); 1 H -NMR (400 MHz, DMSO-d6) δ 8.52 (s, 3H), 8.26 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 4.0Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 4.0 Hz, 1H), 5.00 (s, 1H), 3.47(s, 1H), 3.30 (s, 3H), 2.47 (s, 4H), 2.35 (s, 3H).
[0054] The reaction formula is as follows:
[0055] .
[0056] Example 2
[0057] (1) Preparation of compound 2 (trans-(1r,3r)-3-((tert-butyloxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate):
[0058] At room temperature, tetrahydrofuran 50 mL, compound 1 (tert-butyl trans-((1r,3r)-3-hydroxycyclobutyl)carbamate) 10 g (53 mmol, 1.0 eq), triethylamine 11 g (109 mmol, 2.0 eq) were added to a 1 L round-bottom flask in sequence, and p-toluenesulfonyl chloride 15 g (80 mmol, 1.5 eq) was added under stirring. The reaction was carried out at 20-30 °C for 10 h.
[0059] The conversion of compound 1 was complete as monitored by TLC. The reaction solution was concentrated, and 100 mL of ethyl acetate and 100 mL of water were added for extraction and separation. The aqueous phase was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed once with 100 mL of saturated sodium chloride solution. The organic phase was separated, 2 g of anhydrous sodium sulfate was added for drying, filtration, and concentration to an oil. 90 ml of n-heptane: methyl tert-butyl ether (5V:1V) was added, and the mixture was stirred at 0-10 °C for crystallization for 2 h. The mixture was filtered and dried to obtain 16.1 g of compound 2 as a white solid with a yield of 88.9%.
[0060] (2) Preparation of compound 3 (cis-tert-butyl 3-((N-methyl-4-nitrophenyl)sulfonamido)cyclobutyl)carbamate):
[0061] At 20-30 °C, add 40 ml of dry tetrahydrofuran solution to 8.6 g (40 mmol, 1.0 eq) of p-nitrobenzenesulfonylmethylamine, replace the nitrogen three times with stirring, control the temperature of the reaction solution at 10-20 °C, slowly add 40 ml of lithium bis(trimethylsilyl)amide (1M THF solution) with a syringe, stir and react for 30 min. Dissolve 15.4 g (40 mmol, 1.0 eq) of compound 2 in 20 ml of tetrahydrofuran and add to the reaction solution, then heat to 45-55 °C and react for 10 h;
[0062] TLC detected that the reaction of compound 2 was complete. The reaction solution was concentrated to one-third of the volume and cooled to room temperature. Then 100 mL of water was added slowly and then quickly to quench the reaction. Then 100 mL of ethyl acetate was added to extract the reaction solution. The aqueous phase was extracted twice with 100 ml of ethyl acetate. The organic phases were combined and washed once with 500 ml of saturated sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain a crude compound 3. Then 100 ml of n-heptane: isopropyl acetate (90V:10V) solution was added, and the mixture was slurried, filtered, and dried to obtain 12.2 g of compound 3 as a light yellow solid with a yield of 78.9%.
[0063] (3) Preparation of compound 4 (cis-(3-(methylamino)cyclobutyl)carbamic acid tert-butyl ester):
[0064] At 20-30 °C, 11.6 g (30 mmol, 1.0 eq) of compound 3, 50 g (0.36 mol, 1.2 eq) of potassium carbonate and 6.3 g (0.36 mol, 1.8 eq) of sodium thioglycolate were dissolved in 90 mL of methanol and stirred for 8 h. The reaction of compound 3 was complete by TLC. The reaction solution was concentrated to obtain an oily substance. 50 mL of water was added and then the reaction solution was extracted twice with 50 mL of ethyl acetate. The organic phases were combined and concentrated, washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried to obtain 5.3 g of a yellow solid of compound 4 with a yield of 88.7%. The solid was not further purified and was directly used in the next step.
[0065] (4) Preparation of compound 6 (tert-butyl cis-(3-(methyl(7-p-methylbenzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate):
[0066] 5 g crude product of compound 4 (25 mmol, 1.0 eq), 7.7 g (25 mmol, 1.0 eq) of compound 5 (4-chloro-7-toluenesulfonyl-7H-pyrrolo[2,3d]pyrimidine), and 7.6 g (75 mmol, 3 eq) of triethylamine were dissolved in 50 ml of acetonitrile and heated to 80 °C for reaction for 14 h. The reaction of compound 4 was completed under TLC monitoring. After the reaction was completed, the temperature was lowered to 10-20 °C for crystallization, and the filter cake was rinsed with 20 ml of isopropanol and the solid was dried to obtain 10.9 g of white solid compound 6 with a yield of 92.5%.
[0067] (5) Preparation of Compound 7 (cis-N-methyl-N-{7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diamine dihydrogen hydrochloride)
[0068] Compound 6 9.4 g (20 mmol, 1.0 eq) was dissolved in 47 ml of 4M hydrogen chloride ethyl acetate solution, stirred at 20-30 °C for 2 h, TLC detected that compound 6 was completely reacted, cooled to 0-10 °C for crystallization for 1 h, filtered to obtain compound 7 hydrochloride, then added with 30 ml of ethyl acetate solution, stirred and slurried at 0-10 °C, and filtered to obtain compound 7 8.3 g, with a yield of 93.8%.
Claims
1. A method for preparing an abrocitinib intermediate, characterized in that: The following steps are involved: (1) Compound 1, a base and a catalyst are dissolved, p-toluenesulfonyl chloride is added, a substitution reaction is carried out, and compound 2 is separated from the reaction solution: (2) dissolving p-nitrobenzenesulfonylmethylamide and a base, adding compound 2 to react, and separating compound 3 from the reaction solution; (3) Compound 3, a base and sodium thioglycolate are dissolved and reacted to obtain compound 4 from the reaction solution; (4) dissolving compound 4, compound 5 and a base, reacting them, and separating compound 6 from the reaction solution; (5) Compound 6 was dissolved, and the Boc protecting group was removed by adding acid, followed by separation and purification to obtain compound 7; The base described in step (1) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-amylate, potassium carbonate, and sodium carbonate; the base described in step (2) is one or more of potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-amylate; the base described in step (3) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium tert-amylate, potassium carbonate, and sodium carbonate; the base described in step (4) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, potassium carbonate, and sodium carbonate; The substitution reaction temperature in step (1) is 20-40°C and the reaction time is 4-10 h; the reaction temperature in step (2) is 45-55°C and the reaction time is 10-20 h; the reaction temperature in step (3) is 20-50°C and the reaction time is 6-12 h; the reaction temperature in step (4) is 50-80°C and the reaction time is 8-16 h; the reaction temperature in step (5) is 20-50°C and the reaction time is 1-5 h; 。 2. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to p-toluenesulfonyl chloride is 1:1-1.5; in step (2), the molar ratio of p-nitrobenzenesulfonylmethylamide to compound 2 is 1:0.9-1.
2.
3. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: In step (3), the molar ratio of compound 3 to sodium thioglycolate is 1:1-2; in step (4), the molar ratio of compound 4 to compound 5 is 1:0.8-1.
2.
4. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to base and catalyst is 1:2:0.2; in step (2), the molar ratio of p-nitrobenzenesulfonylmethylamide to base is 1:1-2; in step (3), the molar ratio of compound 3 to base is 1:1-2; in step (4), the molar ratio of compound 4 to base is 1.1:2-3.
5. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: The acid in step (5) is hydrochloric acid.
6. The method for preparing an abrocitinib intermediate according to claim 5, characterized in that: The concentration of HCl in the solvent of step (5) is 4 M.
7. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: The solvent used for dissolving in step (1) is one or more of dichloromethane, tetrahydrofuran and acetonitrile; the solvent used for dissolving in step (2) is one or more of 1,4-dioxane, tetrahydrofuran and N,N-dimethylformamide; the solvent used for dissolving in step (3) is methanol and / or tetrahydrofuran; the solvent used for dissolving in step (4) is isopropanol or acetonitrile; the solvent used for dissolving in step (5) is ethyl acetate.
8. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: The catalyst in step (1) is 4-dimethylaminopyridine.
9. The method for preparing an abrocitinib intermediate according to claim 1, characterized in that: The progress of the reaction was monitored by TLC.