Synthesis method of JAK inhibitor drug compound and application thereof

Abstract

The application discloses a kind of synthesis method of JAK inhibitor drug compound and application thereof.The compound A with structure as shown in formula (II) is removed tertiary-butyloxycarbonyl under the action of trifluoroacetic acid in the application, and compound B with structure as shown in formula (III) is obtained;the double bond of compound B is reduced by catalytic hydrogenation with palladium-carbon, and trifluoroacetic acid intermediate (IV) is obtained;2,2-difluorocyclopropane carboxylic acid is first reacted with N,N'-carbonyldiimidazole in the first step, and then trifluoroacetic acid intermediate (IV) is added to carry out the second step reaction, and JAK inhibitor drug compound is obtained.The method provided in the application has the advantages of green economy and simple operation, and is more suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology of pharmaceuticals, specifically relating to a method for synthesizing JAK inhibitor drug compounds and their applications. Background Technology

[0002] The chemical name of compound (I) shown below is N-(5-(2-(2,2-difluorocyclopropanecarbonyl)-2-azaspiro[3.5]non-7-yl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)cyclopropanecarboxamide. It contains triazolopyridine and azaspirocyclic structures and can selectively inhibit JAK kinase. It has applications in treating various diseases such as rheumatoid arthritis, atopic dermatitis, and alopecia areata.

[0003]

[0004] WO2020 / 038457 discloses a synthetic method for compound (I) consisting of three steps: deamination of the protecting group, hydrogenation reduction of the double bond, and acid-amine condensation. The process route is as follows:

[0005]

[0006] The above process route has the following problems: (1) After removing the tert-butyloxycarbonyl group with hydrochloric acid, the intermediate is a hydrochloride salt with poor solubility. The first step of deprotection and the second step of hydrogenation cannot remove impurities by purification. The subsequent steps require column chromatography purification; (2) The first step of deprotection with hydrochloric acid has large impurities, which increases the purification pressure of the subsequent steps; (3) The acid-amine condensation step has low conversion rate and many impurities, which requires column chromatography purification.

[0007] Therefore, it is both necessary and beneficial to develop a new synthetic route for compound (I) that features fewer impurities, higher yield, no need for column chromatography purification, simpler operation, and is more suitable for large-scale industrial production. Summary of the Invention

[0008] In view of the above-mentioned current state of the technology, the primary objective of this invention is to provide a method for synthesizing JAK inhibitor drug compounds.

[0009] Another object of the present invention is to provide an application of the method for synthesizing the above-mentioned JAK inhibitor drug compounds.

[0010] The objective of this invention is achieved through the following technical solution:

[0011] A method for synthesizing a JAK inhibitor drug compound, the process route is as follows:

[0012]

[0013] Specifically, the steps include the following:

[0014] (1) Deprotection: Compound A, with the structure shown in formula (II), is deprotected by trifluoroacetic acid to obtain compound B, with the structure shown in formula (III);

[0015] (2) Compound B with the structure shown in formula (III) was hydrogenated and reduced with palladium on carbon to obtain trifluoroacetic acid intermediate (IV);

[0016] (3) 2,2-Difluorocyclopropylcarboxylic acid first reacts with N,N'-carbonyldiimidazole in the first step, and then trifluoroacetic acid intermediate (IV) is added to carry out the second step reaction to obtain compound (I), which is a JAK inhibitor drug compound.

[0017] Compound A can be custom-made by a compound synthesis company or synthesized using existing methods, preferably prepared by the following method:

[0018] (I) 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide were reacted with an organolithium reagent to prepare compound C';

[0019] (II) Compound C' was dehydrated to obtain a compound with the structure shown in formula (II).

[0020] The molar ratio of the 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and the N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide is calculated to be 0.8 to 1.2:1; a more preferred molar ratio is 0.9 to 1.1:1; and the most preferred molar ratio is 1:1.

[0021] The organolithium reagent mentioned in step (I) can be at least one of common organolithium reagents, such as n-butyllithium, tert-butyllithium, isopropyllithium, ethyllithium, methyllithium and phenyllithium; preferably at least one of n-butyllithium, tert-butyllithium and isopropyllithium.

[0022] The amount of the organolithium reagent used in step (I) is preferably calculated based on a molar ratio of 1.5 to 2.3:1 between the organolithium reagent and the N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide; a more preferred molar ratio is 1.8 to 2.1; and the most preferred molar ratio is 1.9 to 2.0.

[0023] The reaction temperature in step (I) is preferably -65℃ to -80℃; more preferably -65℃ to -70℃, -70℃ to -75℃, -75℃ to -78℃ or -78℃ to -80℃.

[0024] The organolithium reagent described in step (I) is first reacted with N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide for 0.5 to 3 h, preferably 0.5 to 2 h, more preferably 1.5 h; then 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester is added and reacted for 1 to 6 h, preferably 1.5 to 6 h.

[0025] The dehydrating agent used in step (II) is selected from at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfoxide and Burgess reagent; preferably at least one of hydrochloric acid, p-toluenesulfonic acid and Burgess reagent.

[0026] The dehydration temperature is preferably 65℃~115℃; more preferably 65℃~75℃ or 105℃~115℃.

[0027] The dehydration time is preferably 10-20 hours; more preferably 12-18 hours.

[0028] The specific operation of deprotection described in step (1) is as follows: In organic solvent A, compound A reacts with trifluoroacetic acid to obtain compound B; the more preferred specific steps are as follows: In order to dissolve compound A in organic solvent A, the temperature of the obtained solution A is controlled below 20°C, trifluoroacetic acid is added, and the reaction is carried out; the organic phase of the obtained reactant is concentrated, a crystallization solvent is added to the concentrated product and stirred, a white solid precipitates, is filtered, dried, and compound B is obtained.

[0029] The organic solvent A is preferably dichloromethane.

[0030] The organic solvent A is used as a reaction medium and does not participate in the reaction; its amount is preferably calculated according to a ratio of 8-12 L to 1 kg of compound A; more preferably, it is calculated according to a ratio of 10 L to 1 kg of compound A.

[0031] The amount of trifluoroacetic acid used is preferably 2 to 6 times the mass of compound A.

[0032] The temperature of solution A is preferably 0–20°C.

[0033] The preferred reaction conditions are 0–45°C for 0.5–4 h; more preferably, 15–40°C for 1–1.5 h.

[0034] The preferred method of concentration is vacuum concentration. The purpose of concentration is to remove organic solvent A.

[0035] The preferred crystallization solvent is ethyl acetate.

[0036] The amount of the crystallization solvent is preferably calculated at a ratio of 24-26 L to 1 kg of compound A.

[0037] The stirring time is preferably 1 to 2 hours; more preferably 1.5 hours.

[0038] The preferred steps of step (2) are as follows: In organic solvent B, under hydrogen replacement conditions, compound B undergoes a hydrogenation reduction reaction of the double bond catalyzed by palladium on carbon to obtain trifluoroacetic acid intermediate (IV); more preferably, in organic solvent B, under hydrogen replacement conditions, compound B undergoes a hydrogenation reduction reaction of the double bond catalyzed by palladium on carbon to obtain a reaction solution, which is then filtered, the filter cake is washed, purified, filtered under vacuum, and dried to obtain trifluoroacetic acid intermediate (IV).

[0039] The organic solvent B is preferably methanol.

[0040] The organic solvent B is used as a reaction medium and does not participate in the reaction; its amount is preferably calculated according to a ratio of 10-50 L to 1 kg of compound B; more preferably, it is calculated according to a ratio of 15-45 L to 1 kg of compound B.

[0041] The preferred reaction conditions are as follows: stirring at 20±5℃ and hydrogen pressure of 1.0~3.0MPa; more preferably, stirring at 20±5℃ and hydrogen pressure of 1.1~2.0MPa.

[0042] The stirring reaction time is preferably 6 to 30 hours; more preferably 8 to 24 hours; most preferably 12 to 22 hours; and even more preferably 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, or 22 hours.

[0043] The preferred solvent for the purification process is a mixture of ethyl acetate and methanol.

[0044] The drying process is preferably vacuum drying.

[0045] The amount of N,N'-carbonyldiimidazole used in step (3) is preferably calculated based on a molar ratio of 1.0 to 1.3:1 between N,N'-carbonyldiimidazole and 2,2-difluorocyclopropanecarboxylic acid; the molar ratio is preferably 1.1 to 1.25:1, and more preferably 1.15 to 1.22:1.

[0046] The amount of 2,2-difluorocyclopropylcarboxylic acid used in step (3) is preferably calculated based on a molar ratio of 1.0 to 1.25 between it and the trifluoroacetic acid intermediate (IV); the molar ratio is preferably 1.1 to 1.2.

[0047] The reaction time in step (3) is 0.5 to 6 hours; preferably 1 to 4 hours, more preferably 2 to 4 hours.

[0048] The reaction time in step (3) is 6 to 24 hours; preferably 10 to 22 hours; more preferably 12 to 20 hours, and even more preferably 12 hours, 13 hours, 15 hours, or 20 hours.

[0049] Step (3) also includes the following steps: after the second step reaction is complete, water is added to quench the reaction, extract, the obtained organic phase is washed, dried, filtered, and the obtained filtrate is concentrated to obtain the target compound (I).

[0050] The preferred solvent for extraction is ethyl acetate.

[0051] The preferred solvent for washing is saturated brine.

[0052] The dehydration is preferably carried out using sodium sulfate drying.

[0053] The above-mentioned synthetic methods for JAK inhibitor drugs are applied in the preparation of JAK inhibitor drugs.

[0054] An intermediate of a JAK inhibitor drug compound, prepared by the above method, has the structure shown in formula (III) or formula (IV):

[0055]

[0056] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0057] The method used in this invention uses trifluoroacetic acid instead of hydrochloric acid to remove the tert-butyloxycarbonyl group, and the resulting intermediates (III) and (IV) are trifluoroacetic acid salts. The polarity of trifluoroacetic acid salts is lower than that of hydrochloride salts, and the intermediates can be purified by crystallization. Using N,N'-carbonyldiimidazole instead of the three reagents (carbodiimide hydrochloride, 1-hydroxybenzotriazole and diisopropylethylamine) results in higher atom economy and is more environmentally friendly. It also has fewer impurities, does not require column chromatography purification, and is more suitable for large-scale industrial production. Attached Figure Description

[0058] Figure 1 It is compound (I) 1 HNMR spectrum.

[0059] Figure 2 It is compound (I) 13 CNMR spectrum. Detailed Implementation

[0060] The present invention will be further described in detail below with reference to the embodiments and accompanying drawings, but the implementation of the present invention is not limited thereto.

[0061] The intermediate with the structure shown in formula (II) used in the examples was prepared by the following steps:

[0062] (1) Add 16.9 kg of tetrahydrofuran (THF) and 0.96 kg of N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide (molecular weight 281.1) to the reaction vessel to obtain reaction solution A. Start stirring and cool reaction solution A to -70°C. Then, add n-butyllithium solution (2.19 L, 2.5 M, hexane solvent) dropwise using a peristaltic pump. Stir at -70°C for 0.5 h to obtain reaction solution B. At -70°C, add 8.5 kg of THF solution containing 813 g of 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (molecular weight 239.3) dropwise to reaction solution B. After the addition is complete, stir the reaction at -70°C for 1.5 h to obtain reaction solution C. After the reaction was complete, 24 kg of saturated ammonium chloride solution was added to reaction solution C to quench the reaction, and then 20 kg of water was added to dilute the reaction system. The system was then extracted with ethyl acetate (27 kg) to obtain the organic phase. The organic phase was washed with water (30 kg), then with saturated brine (40 kg), dried with Na₂SO₄ (4.8 kg), filtered, and concentrated to obtain 1.23 kg of a white solid, which was 7-(2-(cyclopropanecarboxamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (molecular weight 441.5), with a yield of 81% and a purity of 97.9%.

[0063] The obtained compound was analyzed, and the NMR and mass spectrometry data are as follows:

[0064] 1 HNMR (400MHz, DMSO-d6): 10.99 (s, 1H), 7.66 ~ 7.56 (m, 2H), 7.26 ~ 7.24 (d, 1H), 5.60 (s, 1H), 3.74 (m, 2H), 3.49 (m, 2H ), 2.79~2.77(m, 2H), 2.10(m,1H), 1.94~1.91(m, 2H), 1.71~1.68(m, 2H), 1.49~1.38(m,11H), 0.85~0.83(m, 4H); ESI m / s 442.3[M+H] + .

[0065] (2) Add 32 kg of THF and 2.4 kg of 7-(2-(cyclopropanecarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-7-hydroxy-2-azaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester to the reaction vessel, stir until homogeneous, and obtain reaction solution D. Add 3.24 kg of Burgess reagent to reaction solution D, heat to 70 °C, the solution becomes clear, and then stir at 70 °C for 12 hours to obtain reaction solution E. Cool reaction solution E to room temperature, add 12 kg of water to dilute reaction solution E, and then extract with ethyl acetate (27 kg) to obtain the organic phase. Wash the organic phase with water (24 kg), then wash with 10.6 kg of saturated brine, dry with anhydrous sodium sulfate (1.3 kg), filter, and concentrate to obtain crude product. The crude product was added to ethyl acetate (4.5 kg) and purified by slurry mixing. After filtration and vacuum drying, 1.97 kg of white solid was obtained, which was 7-(2-(cyclopropanecarbamoyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylic acid tert-butyl ester (i.e., intermediate (II)), with a yield of 82%.

[0066] The obtained compound was analyzed, and the NMR and mass spectrometry data are as follows:

[0067] 1 HNMR (400MHz, DMSO-d6): 10.99 (s, 1H), 7.60 ~ 7.57 (m, 2H), 7.04 ~ 7.02 (m, 1H), 6.8 (s, 1H), 3.69 ~ 3.61 (m, 4H), 2.68(m, 2H), 2.51(m, 2H), 2.06~1.99(m, 1H), 1.92~1.89(m, 2H), 1.39(s, 9H), 0.85~0.82(m, 4H); ESI m / s 424.3[M+H] + .

[0068] Example 1:

[0069] first step:

[0070] 16 L of dichloromethane (DCM) and 1.60 kg of intermediate (II) were sequentially added to a reactor. The reactor temperature was adjusted to 15 °C. 7.4 kg of trifluoroacetic acid was slowly added to the reactor, and the mixture was stirred at 15 °C for 1 hour. The reaction was stopped, and the organic phase was concentrated under reduced pressure to a yellow viscous oily liquid. 40 L of ethyl acetate was added to the resulting residue (i.e., the yellow viscous oily liquid), and the mixture was stirred for 1.5 hours. A white solid precipitated, which was filtered and dried under vacuum to obtain 1.50 kg of white solid intermediate (III), with a yield of 91%.

[0071] The obtained compound was analyzed, and the NMR and mass spectrometry data are as follows:

[0072] 1 HNMR (500MHz, DMSO-d6): 11.04 (s, 1H), 8.99 (s, 2H), 7.64~7.59 (m, 2H), 7.06~-7.04 (m, 1H), 6.8 3(s, 1H), 3.85~3.76(m, 4H), 2.69(s, 2H), 2.61(s, 2H), 2.04~1.99(m, 3H), 0.85~0.83(m, 4H); ESI m / s 324.20[M+H] + 322.05 [MH] - .

[0073] Step Two:

[0074] 1.50 kg of intermediate (III), 22.5 L of methanol, and 0.3 kg of palladium on carbon (10% palladium content) were sequentially added to a high-pressure reactor. Hydrogen was used to purge the reaction mixture, and the reaction system was stirred at 20 ± 5 °C and 2 MPa for 12 hours. The reaction was stopped, the reaction solution was filtered, and the filter cake was washed with 100 L of methanol. The filtrate was concentrated to dryness under reduced pressure, purified by adding a mixture of ethyl acetate and methanol (ethyl acetate / methanol = 20:1 v / v), filtered, and the solid was collected and dried under vacuum to obtain 1.39 kg of off-white solid intermediate (IV), with a yield of 92%.

[0075] The obtained compound was analyzed, and the NMR and mass spectrometry data are as follows:

[0076] 1 HNMR (500MHz, DMSO-d6): 11.03 (s, 1H), 8.99 (s, 2H), 7.62 ~ 7.59 (m, 1H), 7.56 ~ 7.54 (m, 1H), 6.98 ~ 96 (m, 1H), 3.81 (s, 2H), 3.68(s, 2H), 3.31~3.25(m, 1H), 2.16~2.14(m, 2H), 2.05~1.99(m, 3H), 1.65~1.52(m, 4H), 0.84~0.82(m, 4H); ESI m / s 326.20[M+H] + 324.15 [MH] - .

[0077] Step 3:

[0078] 0.38 kg of 2,2-difluorocyclopropylcarboxylic acid (also known as difluorocyclopropylcarboxylic acid, CAS No. 107873-03-0) and 19.5 L of tetrahydrofuran were added to a reaction vessel. Then, 0.52 kg of N,N'-carbonyldiimidazole was added to the reaction vessel, and the mixture was stirred at 25 °C for 2 hours. Next, 1.30 kg of intermediate (IV) (molecular weight 439.44) was added to the reaction vessel, and the mixture was stirred at 25 °C for 12 hours.

[0079] The reaction was stopped, and 20 L of water was added to the reactor, followed by 40 L of ethyl acetate for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 1.2 kg of a white solid, which was compound (I) (molecular weight 429.47), with a yield of 97%. The NMR spectrum is attached. Figure 1 and 2 ESI m / s 431.25 [M+H] + 428.20 [MH] - .

[0080] Example 2

[0081] first step

[0082] 60 L of dichloromethane and 6.0 kg of intermediate (II) were sequentially added to a reactor. The reactor temperature was controlled at 15 °C. 28.0 kg of trifluoroacetic acid was slowly added to the reactor, and the mixture was stirred at 40 °C for 1 hour. The reaction was stopped, and the organic phase was concentrated under reduced pressure to a yellow, viscous, oily liquid. 150 L of ethyl acetate was added to the resulting residue, and the mixture was stirred for 1.5 hours. A white solid precipitated, which was filtered and dried under vacuum to obtain 5.8 kg of white solid intermediate (III), with a yield of 94%.

[0083] Step Two:

[0084] 2.8 kg of intermediate (III), 126 L of methanol, and 0.56 kg of palladium on carbon (10% palladium content) were sequentially added to a high-pressure reactor. Hydrogen was used to purge the reaction mixture, and the system was stirred at 20 ± 5 °C and 1.1 MPa for 22 hours. The reaction was stopped, the reaction solution was filtered, the filter cake was washed with methanol (42 L), the organic phase was concentrated to dryness under reduced pressure, purified with a mixture of ethyl acetate and methanol (20:1 v / v), filtered, and dried under vacuum to obtain 2.6 kg of off-white solid intermediate (IV), with a yield of 92%.

[0085] Step 3:

[0086] 1.6 kg of 2,2-difluorocyclopropionic acid and 75 L of tetrahydrofuran were added to the reactor, followed by 2.2 kg of N,N'-carbonyldiimidazole. The mixture was stirred at 25°C for 4 hours. Then, 5.0 kg of intermediate (IV) was added to the reactor, and the mixture was stirred at 25°C for 20 hours.

[0087] The reaction was stopped, and 77 L of water was added to the reactor. Then, 154 L of ethyl acetate was added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 4.83 kg of compound (I) as a white solid, with a yield of 99%.

[0088] Example 3

[0089] first step:

[0090] 40 L of dichloromethane and 4.0 kg of intermediate (II) were sequentially added to a reactor. The reactor temperature was controlled at 20 °C. 8.0 kg of trifluoroacetic acid was slowly added to the reactor, and the mixture was stirred at 30 °C for 1.5 hours. The reaction was stopped, and the organic phase was concentrated under reduced pressure to a yellow, viscous, oily liquid. 100 L of ethyl acetate was added to the resulting residue, and the mixture was stirred for 1.5 hours. A white solid precipitated, which was filtered and dried under vacuum to obtain 3.76 kg of white solid intermediate (III), with a yield of 91%.

[0091] Step Two:

[0092] 3.5 kg of intermediate (III), 70 L of methanol, and 0.7 kg of palladium on carbon (10% palladium content) were sequentially added to a high-pressure reactor. Hydrogen was used to purge the reaction mixture, and the system was stirred at 20 ± 5 °C and 1.5 MPa for 18 hours. The reaction was stopped, the reaction solution was filtered, the filter cake was washed with methanol (53 L), the organic phase was concentrated to dryness under reduced pressure, purified by adding a mixture of ethyl acetate and methanol (volume ratio 20:1), filtered, and dried under vacuum to obtain 3.3 kg of off-white solid intermediate (IV), with a yield of 94%.

[0093] Step 3:

[0094] 0.83 kg of 2,2-difluorocyclopropanecarboxylic acid and 45 L of tetrahydrofuran were added to the reactor, followed by 1.22 kg of N,N'-carbonyldiimidazole. The mixture was stirred at 25°C for 3 hours. Then, 3.0 kg of intermediate (IV) was added to the reactor, and the mixture was stirred at 25°C for 15 hours.

[0095] The reaction was stopped, and 46 L of water was added to the reactor, followed by 90 L of ethyl acetate for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 2.81 kg of compound (I) as a white solid, with a yield of 96%.

[0096] Example 4

[0097] first step

[0098] 25 L of dichloromethane and 2.5 kg of intermediate (II) were sequentially added to a reactor. The reactor temperature was controlled at 0–5 °C. 15.0 kg of trifluoroacetic acid was slowly added to the reactor, and the mixture was stirred at 30 °C for 1.5 hours. The reaction was stopped, and the organic phase was concentrated under reduced pressure to a yellow, viscous, oily liquid. 63 L of ethyl acetate was added to the residue, and the mixture was stirred for 1.5 hours. A white solid precipitated, which was filtered and dried under vacuum to obtain 2.38 kg of white solid intermediate (III), with a yield of 92%.

[0099] Step Two:

[0100] 2.2 kg of intermediate (III), 66 L of methanol, and 0.44 kg of palladium on carbon (10% palladium content) were sequentially added to a high-pressure reactor. Hydrogen was used to purge the reaction mixture, and the system was stirred at 20 ± 5 °C and 1.8 MPa for 16 hours. The reaction was stopped, the reaction solution was filtered, the filter cake was washed with methanol (66 L), the organic phase was concentrated to dryness under reduced pressure, purified by adding a mixture of ethyl acetate and methanol (20:1 v / v), filtered, and dried under vacuum to obtain 2.05 kg of off-white solid intermediate (IV), with a yield of 93%.

[0101] Step 3:

[0102] 0.61 kg of 2,2-difluorocyclopropionic acid and 45 L of tetrahydrofuran were added to the reactor, followed by 0.92 kg of N,N'-carbonyldiimidazole. The mixture was stirred at 25°C for 2 hours. Then, 2.0 kg of intermediate (IV) was added to the reactor, and the mixture was stirred at 25°C for 13 hours.

[0103] The reaction was stopped, and 30 L of water was added to the reactor, followed by 60 L of ethyl acetate for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 1.90 kg of compound (I) as a white solid, with a yield of 97%.

[0104] Example 5: Optimized Example of Acid and Condensing Agent

[0105] Referring to the process method of Example 1, a comparative experiment was conducted on the types of acid and condensing agent in the first and third steps, and the effects were observed. The specific results are shown in Tables 1 and 2.

[0106] Table 1. Comparison of the effects of different acid types used for the detert-butoxycarbonylation of intermediate (II)

[0107]

[0108] Note: The only difference from Example 1 is the type of acid used in the first step.

[0109] Table 2 Comparison of the effects of condensing agents used for intermediate (IV) and 2,2-difluorocyclopropylcarboxylic acid

[0110]

[0111] Note: *Two reaction times: 2,2-difluorocyclopropylcarboxylic acid first reacts with N,N'-carbonyldiimidazole for 2 hours, and then reacts for another 12 hours after adding intermediate (IV).

[0112] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a JAK inhibitor drug compound, characterized in that... The process route is as follows: ； Specifically, the steps include the following: (1) Deprotection: Compound A, with the structure shown in formula (II), is deprotected by trifluoroacetic acid to obtain compound B, with the structure shown in formula (III); (2) The double bond of compound B, which has the structure shown in formula (III), was reduced by palladium on carbon catalysis to obtain trifluoroacetic acid intermediate (IV). (3) 2,2-Difluorocyclopropylcarboxylic acid first reacts with N,N'-carbonyldiimidazole in the first step, and then trifluoroacetic acid intermediate (IV) is added to carry out the second step reaction to obtain compound (I), which is a JAK inhibitor drug compound.

2. The method for synthesizing JAK inhibitor drug compounds according to claim 1, characterized in that: Compound A was prepared by the following method: (I) 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide were reacted with an organolithium reagent to prepare compound C'; (II) Compound C' was dehydrated to obtain a compound with the structure shown in formula (II); The compound C' is 7-(2-(cyclopropaneformamido)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-7-hydroxy-2-azaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester, with the following structure: 。 3. The method for synthesizing JAK inhibitor drug compounds according to claim 2, characterized in that: The molar ratio of the 7-oxo-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and the N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide is 0.8 to 1.2:1; The organolithium reagent mentioned in step (I) is at least one of n-butyllithium, tert-butyllithium, isopropyllithium, ethyllithium, methyllithium, and phenyllithium; The molar ratio of the organolithium reagent described in step (I) to the N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide is 1.5 to 2.3:1; The reaction temperature described in step (I) is -65℃ to -80℃; The organolithium reagent described in step (I) is first reacted with N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropaneformamide for 0.5–3 h; then 7-oxo-2-azaspiro[3,5]nonane-2-carboxylic acid tert-butyl ester is added and reacted for 1–6 h. The dehydrating agent used in step (II) is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfoxide and Burgess reagent; The dehydration temperature is 65℃~115℃; The dehydration time is 10-20 hours.

4. The method for synthesizing JAK inhibitor drug compounds according to claim 1, characterized in that: The specific deprotection operation described in step (1) is as follows: In organic solvent A, compound A reacts with trifluoroacetic acid to obtain compound B; The specific steps of step (2) are as follows: In organic solvent B, under hydrogen replacement conditions, compound B undergoes hydrogenation reduction of double bonds catalyzed by palladium on carbon to obtain trifluoroacetic acid intermediate (IV).

5. The method for synthesizing JAK inhibitor drug compounds according to claim 4, characterized in that: The specific deprotection operation described in step (1) is as follows: Dissolve compound A in organic solvent A, control the temperature of the resulting solution A at 0-20℃, add trifluoroacetic acid, and react; concentrate the organic phase of the obtained reactants, add crystallization solvent to the concentrated product and stir, a white solid precipitates, filter, dry, and obtain compound B; The specific steps of step (2) are as follows: In organic solvent B, under hydrogen replacement conditions, compound B undergoes palladium-carbon catalytic hydrogenation reduction of the double bond to obtain the reaction solution. The reaction solution is filtered, the filter cake is washed, purified, filtered under vacuum, and dried to obtain trifluoroacetic acid intermediate (IV). The organic solvent A is dichloromethane; The crystallization solvent is ethyl acetate; The organic solvent B is methanol; The purified solvent is a mixture of ethyl acetate and methanol.

6. The method for synthesizing JAK inhibitor drug compounds according to claim 5, characterized in that: The amount of trifluoroacetic acid used is 2 to 6 times the mass of compound A; The ratio of the crystallization solvent to compound A is 24-26 L: 1 kg; The molar ratio of the N,N'-carbonyldiimidazole to the 2,2-difluorocyclopropionic acid is 1.0 to 1.3:1; The molar ratio of the 2,2-difluorocyclopropylcarboxylic acid to the trifluoroacetic acid intermediate (IV) is 1.0 to 1.25:

1.

7. The method for synthesizing JAK inhibitor drug compounds according to claim 5, characterized in that: In step (1): The reaction conditions are as follows: reaction at 0–45°C for 0.5–4 hours; The concentration method described is vacuum concentration; The stirring time is 1 to 2 hours; In step (2) The reaction conditions are as follows: stirring at 20±5℃ and hydrogen pressure of 1.0~3.0MPa; The stirring reaction time is 6–30 hours; In step (3): The reaction time for the first step is 0.5 to 6 hours. The reaction time for the second step is 6 to 24 hours.

8. The method for synthesizing JAK inhibitor drug compounds according to any one of claims 1 to 7, characterized in that: Step (3) also includes the following steps: after the second step reaction is complete, water is added to quench the reaction, extract, the obtained organic phase is washed, dried, filtered, and the obtained filtrate is concentrated to obtain compound (I).

9. The method for synthesizing JAK inhibitor drug compounds according to claim 8, characterized in that: The solvent used for extraction in step (3) is ethyl acetate; The washing solvent mentioned in step (3) is saturated saline solution; The drying process described in step (3) is performed using sodium sulfate.

10. The application of the method for synthesizing JAK inhibitor drug compounds according to any one of claims 1 to 9 in the preparation of JAK inhibitor drug compounds, characterized in that: The JAK inhibitor drug compound is a compound (I) with the following structure; 。

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