Preparation method of pyrrolopyrimidine compound or pharmaceutically acceptable salt thereof

Abstract

The invention relates to a preparation method of a pyrrolopyrimidine compound or a pharmaceutically acceptable salt thereof. The method comprises the following steps: carrying out protection and substitution reaction on a compound 1 to obtain a compound 2, carrying out ring closing reaction to obtain a compound 3, carrying out amino protection and Michael addition to obtain a compound 5, and carrying out amino deprotection and other reactions on the compound 5 to obtain the pyrrolopyrimidine compound as shown in the formula I. The preparation method is simple and convenient to operate, mild in reaction condition, simple and convenient in post-treatment and suitable for industrial production; and the product yield of each step is high and can basically reach 80% or above.

Description

Preparation method of pyrrolopyrimidine compound or pharmaceutically acceptable salt thereof Technical Field

[0001] The present application belongs to the field of drug synthesis. Specifically, the present application relates to a method for preparing a pyrrolopyrimidine compound and related intermediates thereof. Background Art

[0002] Janus kinases (JAKs) are a class of non-receptor tyrosine kinases (PTKs). Members of this family possess seven homology domains (JH1-7), of which JH1 is the kinase domain and JH2 is the pseudokinase domain. Unlike other PTKs, JAKs lack the Src homology 2 (SH2) domain. This allows them to not only catalyze the tyrosine phosphorylation of their associated cytokine receptors but also phosphorylate and activate various signaling molecules containing specific SH2 domains. The Janus kinase family consists of four members: JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are widely expressed in various tissue cells, while JAK3 is restricted to the bone marrow and lymphatic system. The JAK-STAT signaling pathway, a recently discovered cellular signaling pathway closely associated with inflammatory cytokines and tumors, is widely involved in important biological processes in human health and disease, including cell proliferation, differentiation, metastasis, apoptosis, regulation of immune responses, and cellular homeostasis. Cytokine-stimulated signals are transmitted through the JAK-STAT pathway. The JAK-STAT pathway transmits extracellular chemical signals through the cell membrane to gene promoters located on DNA in the cell nucleus, ultimately affecting changes in DNA transcription and activity levels in the cell. The JAK-STAT pathway consists of three main components: 1) receptors; 2) Janus kinases (JAKs); and 3) signal transducers and activators of transcription (STATs). The receptors can be activated by interferons, interleukins, growth factors, or other chemical messengers, which leads to JAK autophosphorylation; STAT proteins then bind to the phosphorylated receptors, causing STATs to be phosphorylated by JAKs; the phosphorylated STAT proteins then dissociate from the receptors, dimerize, and translocate to the cell nucleus to bind to specific DNA sites and alter transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6):1153-9).

[0003] The Janus kinase family plays a role in cytokine-dependent regulation of cell proliferation and functional immune responses. They are primarily used to screen for therapeutics for rheumatoid arthritis, hematologic diseases, tumors, and other skin immune disorders. Numerous inhibitors of Janus kinase or related kinases have been reported, with Tofacitinib and Ruxolitinib already approved by the FDA.

[0004] JAK1 plays an important role in a variety of cytokine and growth factor signaling pathways, and its disorder is associated with a variety of diseases. For example, the increase in IL-6 levels in rheumatoid arthritis is closely related to the disease (Fonesca, JE et al., Autoirnity Reviews, 8:538-42, 2009), and IL-6 is partially signaled through JAK1. By inhibiting JAK1 directly or indirectly antagonizing IL-6, the symptoms of rheumatoid arthritis can be alleviated (Smolen, JS et al. Lancet 371:987, 2008). Moreover, mutations in JAK1 in some cancers lead to abnormal growth and survival of tumor cells (Mullighan CG, Proc Natl Acad Sci US A.106:9414-8, 2009; Flex E. et al. J Exp Med.205:751-8, 2008). In other autoimmune diseases and cancers, the increase in systemic levels of inflammatory cytokines activated by the JAK1 pathway can contribute to the occurrence of these diseases and related diseases. Therefore, inhibiting JAK1 could benefit patients with these diseases. Selective JAK1 inhibitors are expected to maintain therapeutic efficacy for these diseases while avoiding potential side effects such as immunosuppression, anemia, and thrombocytopenia associated with inhibiting other JAK kinases (JAK2 and / or JAK3).

[0005] Small molecule drugs with pyrrolopyrimidine structures have been a key focus of JAK inhibitor development in recent years. Tofacitnib, Itacitinib, Ruxolitinib, and Baricitinib all possess pyrrolopyrimidine molecular structures, and several other JAK small molecules containing this structure have been reported. Patent CN201711248947.4 discloses a variety of JAK inhibitors, including the 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile compound shown in Part 1 below.

[0006] The preparation method of Compound I disclosed in patent CN201711248947.4 is as follows:

[0007] The yields of the last three steps of this route are low, reaching only around 50-60%, and even after further optimization, there has been no significant improvement. Furthermore, this method also suffers from the problem of high impurities and difficulty in separating them. Consequently, this route is costly and unsuitable for commercial production.

[0008] SUMMARY OF THE INVENTION

[0009] The present application provides a new method for preparing compound I, which has the characteristics of simple operation, environmental friendliness, high synthesis yield and excellent product quality.

[0010] The preparation method of the pyrrolopyrimidine compound represented by formula I comprises:

[0011] Compound 2 is obtained by protecting and substituting compound 1.

[0012] Compound 3 is obtained by cyclization of compound 2 with a hydrazine compound.

[0013] Compound 5 is obtained by protecting compound 3 and performing Michael addition.

[0014] Compound 5 is subjected to deprotection and condensation reactions to obtain a pyrrolopyrimidine compound of formula I:

[0015] Wherein, R1 and R3 are selected from hydrogen or an amino protecting group, and R2 is selected from hydrogen.

[0016] In some embodiments, compound 1 is protected and substituted to obtain compound 2; the R1 protecting group includes but is not limited to 2-(trimethylsilyl)ethoxymethyl (SEM), tert-butyloxycarbonyl (Boc), and hydroxymethyl.

[0017] In some embodiments, obtaining compound 3 from compound 2 comprises reacting compound 2 with a hydrazine compound and an optional acetal compound to prepare compound 3.

[0018] In some embodiments, the hydrazine compound includes but is not limited to hydrazine, hydrazine salts, such as hydrazine hydrate, hydrazine aqueous solution; the molar ratio of the compound 2 to the hydrazine compound is 1:1.0 to 50.0.

[0019] In some embodiments, the acetal compound includes but is not limited to N,N-di(C1-C4 alkyl)formamide di(C1-C4 alkyl)acetal, such as N,N-dimethylformamide dimethyl acetal.

[0020] In some embodiments, obtaining compound 5 from compound 3 comprises:

[0021] The 3-amino group of the pyrazole ring of compound 3 was amino-protected to obtain compound 4;

[0022] Compound 4 undergoes Michael addition reaction with compound M1 in the presence of a base to obtain compound 5;

[0023] Compound 3 is subjected to Michael addition reaction with compound M1 to obtain compound 5A; the 3-amino group of compound 5A is amino-protected to obtain compound 5;

[0024] Wherein, R1, R3, and R4 are as defined above.

[0025] In some embodiments, the R3 protecting group is a cyclic imide protecting group, such as succinimide or phthalimide. The protecting group can be formed using a corresponding acid anhydride, such as succinic anhydride or phthalic anhydride. The molar ratio of the acid anhydride to compound 3 or 5A can be 0.8 to 1.3:1.

[0026] In some embodiments, in the Michael addition reaction, the base includes, but is not limited to, 1,8-diazabicycloundec-7-ene (DBU). The molar ratio of the base to the reaction compound is 0.05 to 5.0:1.0. The reaction solvent includes, but is not limited to, N,N-dimethylformamide.

[0027] The preparation method of formula I further includes the steps of deprotecting and reducing compound 5 to obtain compound 8, for example:

[0028] Compound 5 is subjected to removal of the R1 and R3 protecting groups to obtain compound 7;

[0029] Compound 7 is reduced to give compound 8;

[0030] wherein R3 is as defined above; R1 is as defined above, including but not limited to 2-(trimethylsilyl)ethoxymethyl (SEM); and R4 is an amino protecting group other than 3-fluoro-2-(trifluoromethyl)isonicotinoyl.

[0031] In the process of removing the protecting group to obtain compound 7, the elimination reagent includes but is not limited to trifluoroacetic acid, trifluoromethanesulfonic acid, boron trifluoride, lithium tetrafluoroborate, sodium tetrafluoroborate, potassium tetrafluoroborate; ammonia gas, ammonia water, ethylenediamine, propylenediamine, ethanolamine, propanolamine, hydrazine, hydrazine hydrate, hydrazine salt, organic solution of hydrazine, or a combination thereof. The molar ratio of the elimination reagent to compound 5 is 1.0-20.0:1.0.

[0032] The preparation method of formula I also includes the step of preparing the pyrrolopyrimidine compound of formula I from compound 8 and 3-fluoro-2-(trifluoromethyl)isonicotinic acid or its acyl chloride:

[0033] In the above condensation reaction:

[0034] The molar ratio of the base to compound 8 used is 0.05-10.0:1.0;

[0035] The molar ratio of the condensing agent to the reaction compound 8 is: 0.8-10.0:1.0;

[0036] The reaction temperature can be selected from -20 to 80°C, for example, 20 to 40°C, 50 to 70°C.

[0037] In some embodiments, R1 can be hydrogen or an amino protecting group, including but not limited to hydroxymethyl, 2-(trimethylsilyl)ethoxymethyl (SEM).

[0038] R2 may be hydrogen;

[0039] R3 may be a cyclic imide protecting group such as succinimide, methylsuccinimide, 2,2-dimethylsuccinimide and phthalimide;

[0040] R4 may be hydrogen or an amino protecting group including, but not limited to, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), benzyl (Bn).

[0041] In some embodiments, the compound of formula I can be further reacted with an acid to obtain a pharmaceutically acceptable salt thereof, including but not limited to fumaric acid and succinic acid.

[0042] On the other hand, the present application relates to an intermediate compound 5 having the formula

[0043] Wherein, R1 may be 2-(trimethylsilyl)ethoxymethyl (SEM), R3 may be a cyclic imide protecting group, and R4 may be a hydrogen or amino protecting group.

[0044] Specifically, these compounds can be selected from the following compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m, 5n, 5o:

[0045] wherein SEM refers to 2-(trimethylsilyl)ethoxymethyl; Boc refers to tert-butyloxycarbonyl; Cbz refers to benzyloxycarbonyl; and Bn refers to benzyl. DETAILED DESCRIPTION

[0046] 1. Obtaining Compound 3

[0047] In some embodiments, obtaining compound 3 from compound 2 comprises reacting compound 2 with a hydrazine compound and an optional acetal compound to prepare compound 3.

[0048] In some embodiments, the hydrazine compound is selected from an aqueous solution of hydrazine, an organic solution of hydrazine, or a salt of hydrazine. The reaction ratio of the hydrazine compound (molar ratio, based on 1.0 eq of compound 2) ranges from 1.0 eq to 50.0 eq, for example, from 2.0 eq to 20.0 eq, or from 3.0 eq to 10.0 eq.

[0049] In some embodiments, the reaction of compound 2 with a hydrazine compound is carried out in the presence of an optional acetal compound. "Optional acetal compound" means that the acetal compound may or may not be present during the reaction. The inventors have found that when there is no acetal compound, the reaction of compound 2 with a hydrazine compound can also produce the desired compound 3, but there will be about 10-20% of undesirable by-products. However, when an acetal compound is used in the reaction process, the undesirable by-product can be effectively converted into the desired compound 3, which can greatly improve the yield of the target compound 3. In some embodiments, the acetal compound includes but is not limited to N, N-di(C1-C4 alkyl) formamide di(C1-C4 alkyl) acetal, such as N, N-dimethylformamide dimethyl acetal.

[0050] In one embodiment, the reaction ratio range of the acetal compound (molar ratio, based on 1.0 eq of compound 2) is 0.1 to 0.3 eq, 0.3 to 0.5 eq, 0.5 to 1.0 eq, or 1.0 eq to 5.0 eq.

[0051] 2. Obtaining Compound 5

[0052] Compound 5 can be obtained from compound 3 by following the steps below:

[0053] 1. Compound 3 was protected by amino group and reacted with M1 by Michael addition reaction to obtain compound 5

[0054] The process includes the following steps:

[0055] The 3-amino group of the pyrazole ring of compound 3 was amino-protected to obtain compound 4;

[0056] Compound 4 is subjected to Michael addition reaction with compound M1 in the presence of a base to obtain compound 5;

[0057] Wherein, R1, R3, and R4 are as defined above.

[0058] In one embodiment, the unprotected 3-amino group of compound 3 is protected using a cyclic imide protecting agent. The reaction ratio (molar ratio, based on 1.0 eq of compound 3) of the cyclic imide protecting agent, such as an acid anhydride, is 0.8 to 1.3 eq, for example, 1.0 to 1.2 eq, 1.0 eq to 1.1 eq, with a molar ratio of 0.8 to 1.3:1. The reaction can be carried out in a reaction solvent, which can be toluene, xylene, or a mixture thereof.

[0059] In the Michael addition reaction, the reaction ratio of the base (molar ratio, based on 1.0 eq of compound 4) can range from 0.05 eq to 5.0 eq, for example, from 0.1 eq to 3.0 eq, and preferably ranges from 0.1 to 1.0 eq.

[0060] 2. Michael addition of compound 3 to compound M1 (non-3-fluoro-2-(trifluoromethyl)isonicotinoyl protecting group) to afford compound 5A;

[0061] The 3-amino group of compound 5A was amino-protected to obtain compound 5;

[0062] Wherein, R1, R3, and R4 are as defined above.

[0063] In summary, compound 3 can be protected first and then subjected to Michael addition to give compound 5, or first subjected to Michael addition with M1 to give 5A, and then protected to give compound 5. The above two processes can be described as follows:

[0064] The Michael addition reaction in the above reaction process can also be referred to the above description of the Michael addition reaction process, which will not be repeated here.

[0065] Similarly, the process of amino protection of the 3-amino group of the pyrazole ring of compound 3 or 5A can also refer to the above amino protection reaction process, which will not be repeated here.

[0066] 3. Obtaining the pyrrolopyrimidine compound of formula I

[0067] 1. Compound 8 can be obtained from compound 5 (R4 is a protecting group other than 3-fluoro-2-(trifluoromethyl)isonicotinoyl) by the following steps:

[0068] Compound 5 is deprotected to obtain compound 7;

[0069] Compound 7 is reduced and R4 is removed to obtain compound 8;

[0070] Wherein, R1, R3, and R4 are as defined above.

[0071] Compound 5 is subjected to removal of R1 and R3 to obtain compound 7, wherein the elimination reagent is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, boron trifluoride, ammonia gas, ammonia water, ethylenediamine, hydrazine, hydrazine hydrate, an organic solution of hydrazine, or a combination thereof; in one embodiment, the molar ratio of the elimination reagent to compound 5 is 1.0 to 50.0:1, for example, the reaction ratio ranges from 1.0 eq to 25.0 eq, or 1.5 eq to 6.0 eq. The reaction solvent is selected from acetonitrile, ethanol, and isopropanol.

[0072] Furthermore, compound 7 is reduced to remove R4 to obtain compound 8, where R4 can be selected from benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), etc. The corresponding protecting group removal method can be achieved by conventional methods in the art, for example, but not limited to, referring to "Greene's Protective Groups in Organic Synthesis, 5th Edition" published by Wiley Publishing House and "Protective Group Chemistry" published by Chemical Industry Press.

[0073] A method for preparing a pyrrolopyrimidine compound of formula I from compound 8 and 3-fluoro-2-(trifluoromethyl)isonicotinic acid or its acid chloride, anhydride, or ester compound:

[0074] In some embodiments, in the above condensation reaction, the molar ratio of the base to the reaction compound 8 is 0.05eq~50eq:1eq, for example, 2.0eq~5.0eq; the molar ratio of the condensing agent to the reaction compound 8 is 0.8eq~10.0eq:1eq, for example, 1.0eq~2.0eq; the reaction temperature can be selected from -20~80℃, for example, 20~40℃.

[0075] It should be noted that those skilled in the art can change the order of the reactions according to actual conditions, or combine two or more reactions to occur simultaneously, all within the scope of protection of this application. For example, in the following process: compound 1 is protected and substituted to obtain compound 2, which is then reacted with a hydrazine compound to prepare compound 3 by ring closure, and is protected by amino to prepare compound 4, compound 4 is reacted with compound M1 to prepare compound 5, compound 5 is prepared by conversion of R1 and R3 functional groups and reduction and removal of R4 to obtain compound 8, and compound 8 is condensed with a 3-fluoro-2-(trifluoromethyl)isonicotinic acid derivative to obtain compound 1; "a process of obtaining compound 2 from compound 1, obtaining compound 3 from compound 2, and then preparing compound 4 by amino protection" can be a process of preparing compound 4 by amino protection after obtaining compound 3 from compound 2 without purifying compound 3. Other steps or processes can also be carried out similarly.

[0076] In order to better illustrate the implementation of this application, relevant information and terms are explained and defined in the description and some implementation plans of this application.

[0077] In this application, compound numbering follows the following principles

[0078] (1) Arabic numerals refer to a class of compounds with specific structurally defined substituents, such as:

[0079] (2) The combination of Arabic numerals and lowercase letters refers to a specific compound with a specific structure, such as:

[0080] As used herein, "SEM-" refers to 2-(trimethylsilyl)ethoxymethyl.

[0081] As used herein, "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0082] In this application, "DMF-DMA" refers to N,N-dimethylformamide dimethyl acetal.

[0083] In the present application, "hydrazine compounds" include aqueous solutions and organic solutions of hydrazine, and salt compounds of hydrazine.

[0084] In this application, the functional group and position referred to by "3-amino group" are as shown in the figure below. The box shows:

[0085] In this application, The chemical bond indicated does not limit the direction of the chemical bond and the connected olefinic group. For example, compound 3 may contain the following two configurations.

[0086] In the present application, the amino protecting group or cyclic imide protecting group and the method for connecting or removing the same can be achieved by conventional methods in the art, and the method can be completed by one or more steps.

[0087] In the present application, the reaction can be optionally carried out in a solvent. All solvents used in the present application are commercially available solvents and can be used without purification.

[0088] The preparation method of the present application has the advantages of simple operation, mild reaction conditions, quick post-processing, easy to obtain intermediates, reduced costs by adjusting the order of group introduction, high product yield in each step, which can basically reach more than 80%, and is suitable for industrial production.

[0089] DETAILED DESCRIPTION

[0090] The following examples provide further non-limiting details of the technical solutions of the present invention, which should not be considered as limiting the scope of the present invention, but are merely exemplary descriptions and typical representatives of the present invention.

[0091] Example 1

[0092] Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I).

[0093] Step A: 4-chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine

[0094] To a 100L reactor, add 38.0kg of N,N-dimethylformamide, 5.0kg (32.56mol, 1.0eq) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (SM1), and 21.2kg (65.07mol, 2.0eq) of cesium carbonate to a 100L reactor with stirring at room temperature. After the addition is complete, stir. Then, add 6.5kg (37.04mol, 1.14eq) of 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) dropwise. After the addition is complete, raise the temperature and allow the reaction to proceed at 80-90°C. After the reaction is complete, cool the temperature and dissolve 2.6kg (39.36mol, 1.2eq) of malononitrile in 10.0kg of N,N-dimethylformamide. Add the solution dropwise to the reactor and allow the reaction to proceed at 90-100°C. After the reaction was complete, about 100 kg of water was added, and 6N hydrochloric acid was added to adjust the pH to 6-7. A large amount of solid was precipitated, centrifuged and filtered, and dried to obtain 8.7 kg of product with a yield of 86.1%.

[0095] 1 H-NMR(DMSO-d6,500MHz,): δ12.95(s,1H),8.20(s,1H),7.59(dd,1H),7.01(dd,1H),5.5 5(s,2H),3.53-3.49(m,2H),0.84-0.81(m,3H),-0.05--0.07(m,9H); m / z=312.1304[M+H] + .

[0096] Step B: 3-amino-2-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylonitrile

[0097] A 200L hydrogenation reactor was charged with 50.0kg of ethanol, 7.0kg (22.33mol, 1.0eq) of 4-chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine, and 2.1kg of palladium on carbon. The atmosphere was replaced with nitrogen three times, then with hydrogen three times. The reaction was stirred, heated to 45-55°C, and pressurized with hydrogen at 0.3-0.4MPa. After the reaction was complete, the palladium on carbon was filtered off, and the product was concentrated to obtain 6.3kg of product with a yield of 90.1%.

[0098] 1 H-NMR(DMSO-d6,500MHz): δ8.56-8.51(m,2H),8.24(s,1H),8.08(d,1H),7.10(d,1H),6.97(s,1H),6 .57(s,2H,),5.60(s,2H,),3.52-3.49(m,2H),0.84-0.81(m,2H),-0.09(m,9H); m / z=316.1593[M+H] + .

[0099] Step C: 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine

[0100] To a 10-L reaction flask, add 5.0 L of N,N-dimethylformamide and 805 g (2.55 mol, 1.0 eq) of 3-amino-2-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylonitrile (3-amino-2-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylonitrile (3-amino-2-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)acrylonitrile) under stirring at room temperature. Stir to dissolve. Add 800 g (12.78 mol, 5.0 eq) of hydrazine hydrate, and heat to 90-100°C for 6 h. Stop the reaction and cool to room temperature. Transfer the reaction mixture to a 20-L transfer drum, add 10.0 L of water, and stir. Solids precipitate, centrifuge, and dry the filter cake at 55°C. The weight is 660 g, for a yield of 78.3%.

[0101] 1 H-NMR (400MHz, DMSO-d6): δ12.01 (s, 1H), 8.65 (s, 1H), 8.24 (s, 1H), 7.62 (d, 1H, J = 3.2Hz), 7.02 (d, 1H, J = 3.5Hz), 6. 57(s,2H),5.60(s,2H),3.54-3.51(m,2H,J=8.0Hz),0.85-0.81(m,2H,J=8.0Hz),-0.09(s,9H); m / z=331.1661[M+H] + .

[0102] Step D: 1-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-yl)pyrrolidinyl-2,5-dione

[0103] To a 3L reaction flask, 1.5L of toluene, 165g (0.50mol, 1.0eq) of 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine, and 55.0g (0.55mol, 1.1eq) of succinic anhydride were added with stirring at room temperature. A water separator was installed and the reaction was heated to reflux for 8 hours, followed by removal of water. The reaction was then stopped and cooled. 600mL of isopropyl ether was added to the reaction system, stirred to crystallize, and filtered. The resulting solid was dried at 55°C to constant weight. The product weighed 176g, for a yield of 85.3%.

[0104] 1 H-NMR (400MHz, CDCl3): δ12.03 (s, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 7.25 (d, 2H, J = 4.0Hz), 6.55 (s, 2H, J = 4.0Hz) ,5.58(s,2H),3.50(m,2H,J=8.0Hz),2.97(m,4H),0.92-0.88(m,2H,J=8.0Hz),-0.06(s,9H); m / z=413.53[M+H] + .

[0105] Step E: Benzyl 3-(cyanomethyl)-3-(3-(2,5-dioxopyrrolidin-1-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-yl)piperidine-1-carboxylate

[0106] In a 2 L reaction flask, 124 g (0.30 mol, 1.0 eq) of 1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-yl]pyrrolidine-2,5-dione, 54.91 g (0.36 mol, 1.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene, 480 mL of DMF, and 102.8 g (0.33 mol, 1.1 eq) of 3-(cyanomethylene)azetidin-1-ylpiperidine-carboxylic acid benzyl ester were added. The temperature was raised to 30-40° C. and the reaction was stirred for 1 h. The reaction was stopped, and ethyl acetate, ethanol, and water were added to extract the solution. The ethyl acetate was concentrated and evaporated to dryness. 600 mL of isopropanol and isopropyl ether (1 / 3) were added, and the mixture was stirred for crystallization. The mixture was filtered and the resulting solid was dried at 55° C. to obtain a brown solid. Weighing 99.02g, yield 45.61%, HPLC: 88.12%.

[0107] 1 H-NMR (400MHz, DMSO-d6): δ9.01 (s, 1H), 8.72 (s, 1H), 7.83 (d, 1H, J = 3.6Hz), 7.28~7. 43(m,5H),7.18(s,1H),5.63(s,2H),5.06(s,2H),3.79(d,4H,J=8.1Hz),3.58(s,4H) ,3.51(t,2H,J=7.9Hz),3.03(s,2H),2.91(s,4H),2.45(s,1H),1.67(d,2H,J=11.2Hz ),1.14(d,2H,J=8.5Hz),0.79~0.83(t,2H,J=7.9Hz),-0.11(s,9H); m / z=724.91[M+H] + .

[0108] Step F: 3-(Cyanomethyl)-3-(3-(2,5-dioxopyrrolidin-1-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-yl)piperidine

[0109] Under stirring conditions at room temperature, 90 g (0.12 mol, 1.0 eq) of benzyl 3-(cyanomethyl)-3-(3-(2,5-dioxopyrrolidin-1-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-yl)piperidine-1-carboxylate and 1.0 L of tetrahydrofuran were added to a 2 L reaction flask and stirred to dissolve. 9 g of Pd / C (10%) was added and hydrogen was replaced three times. The temperature was controlled at 40-50 ° C. The reaction was stirred overnight, filtered, and the filter cake was dried. The weight was 66.04 g, with a yield of 90.0%, and HPLC: 92.02%.

[0110] 1 H-NMR (400MHz, DMSO-d6): δ9.48 (s, 1H), 8.12 (s, 1H), 7.27 (d, 1H, J = 3.7Hz), 6.09 (d, 1H, J = 4. 2Hz), 5.62 (s, 2H), 3.87 (d, 2H, J = 8.1Hz), 3.65 (d, 2H, J = 13.2Hz), 3.33 (t, 2H, J = 8.0Hz), 2.92 (s,4H),2.79(d,2H,J=9.0Hz),2.69-2.75(m,4H),2.65(m,1H),2.00(s,1H),1.67(d,2H,J=10 .3Hz), 1.43 (d, 2H, J = 8.9Hz), 0.81 (dd, 2H, J = 15.0, 7.0Hz), -0.10 (s, 9H,); m / z = 590.78 [M+H] + .

[0111] Step G: 2-{3-[3-(2,5-dioxopyrrolidin-1-yl)-4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}azetidin-3-yl)acetonitrile

[0112] Under stirring at room temperature, 24.75 g (0.12 mol, 1.1 eq) of 3-fluoro-2-(trifluoromethyl)isonicotinic acid, 24.75 g (0.13 mol, 1.2 eq) of EDCI, and HOSu were added to a 2 L reaction flask. 14.5g (0.13mol, 1.2eq) and DMF 200ml, stir and dissolve to react for 2h, control the temperature at 20-30℃, then slowly add dropwise to a DMF (100ml) solution of 65.0g (0.11mol, 1.0eq) of 3-(cyanomethyl)-3-(3-(2,5-dioxopyrrolidin-1-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-yl)piperidine, control the temperature at 20-30℃, and continue to control the temperature and stir for 3h to stop the reaction. The reaction mixture was quenched with 3 L of water and 1 L of ethyl acetate was added, stirred, and allowed to stand for separation. The ethyl acetate was concentrated under reduced pressure, and the resulting residue was added to 480 mL of methyl tert-butyl ether for slurry crystallization. The residue was filtered to obtain an off-white solid, which was air-dried at 55°C to constant weight. The product weighed 69.5 g, with a yield of 84.7%. HPLC analysis showed a yield of 95.16%.

[0113] 1 H-NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.67(d,1H,J=4.6Hz),8.27(s,1H),7.93(t,1H,J=4.5Hz),7.85(d,1H,J =3.7Hz),7.20(d,1H,J=3.7Hz),5.61(s,2H),4.10(q,2H,J=5.2Hz),3.88(d,2H,J=7.8Hz),3.64(d,2H,J=5.2Hz) ,3.52(t,2H,J=8.0Hz),3.29(s,1H),3.21(s,2H),3.13(t,1H,J=10.3Hz),2.91(s,4H),2.63(s,1H),1.82(d,1H, J=9.3Hz),1.70(d,1H,J=12.4Hz),1.28(d,2H,J=31.8Hz),0.80(t,2H,J=8.0Hz),-0.09(s,9H); m / z=781.86[M+H] + .

[0114] Step H: 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile

[0115] Under stirring at room temperature, 65.0 g (0.09 mol, 1.0 eq) of 2-{3-[3-(2,5-dioxopyrrolidin-1-yl)-4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinyl]piperidin-4-yl}azetidin-3-yl)acetonitrile and 300 mL of acetonitrile were added to a 1 L reaction bottle. 24.5 g (0.17 mol, 5.0 eq) of boron trifluoride ether solution was slowly added dropwise using a constant pressure funnel. After the addition was completed, the temperature was raised to 40-50°C and the reaction was stirred for 5 h. The reaction was stopped and the acetonitrile was recovered by distillation under reduced pressure. The residue was added with 300 mL of ethanol and 32.0 g (0.50 mol, 6.0 eq) of hydrazine hydrate. The mixture was refluxed for 8 h. After cooling, 2.4 L of water was added and stirred for 1 h to crystallize. The mixture was filtered to obtain a pale yellow solid. The solid was air-dried at 60°C to constant weight. The weight was 25.33 g, with a yield of 52.39%. HPLC analysis showed a yield of 90.11%.

[0116] 1 H NMR (400MHz, DMSO-d6): δ12.08(s,1H),8.69(q,2H,J=4.8Hz),8.54(s,1H),7.94(t,1H, J=4.7Hz),7.52-7.65(m,1H),7.09(dd,1H,J=3.4,1.5Hz),6.35(s,2H),3.72(d,2H,J=7. 6Hz),3.42-3.58(m,6H),3.26-3.33(m,1H),3.12(t,1H,J=10.0Hz),2.58(s,1H),1.81(d ,1H,J=10.2Hz),1.68(d,1H,J=10.4Hz),1.29(dd,2H,J=31.2,8.9Hz); m / z=569.54[M+H] + .

[0117] Example 2

[0118] Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I)

[0119] Step A: Benzyl 4-(3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-yl)piperidine-1-carboxylate

[0120] To a 1 L reaction flask, 300 mL of N,N-dimethylformamide, 60.0 g (0.18 mol, 1.0 eq) of 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine, 4.60 g (0.04 mol, 0.2 eq) of tetramethylguanidine, and 68.5 g (0.22 mol, 1.2 eq) of benzyl 3-(cyanomethylene)azetidin-1-carboxylate were added with stirring at room temperature. The reaction was allowed to proceed at 45°C for 24 h, after which the reaction was terminated. The reaction solution was quenched with water and extracted with 300 mL of ethyl acetate twice. The organic phase was washed with 200 mL of water twice, dried, and evaporated to dryness. The resulting residue was stirred with 300 mL of isopropanol to crystallize. The solid was filtered and dried at 55°C to a constant weight. Weighing 99.2g, yield 85.2%, HPLC: 92.33%.

[0121] 1 H NMR (400MHz, DMSO-d6): δ8.75(s,1H),8.56(s,1H),7.75(d,1H,J=3.6Hz),7.33(m,5H),7 .20(d,1H,J=3.6Hz),6.37(s,1H),5.64(s,2H),5.02(s,2H),3.71(dd,4H,J=20.0,10.6H z),3.44-3.59(m,4H),2.91(s,3H),2.37(dd,2H,J=12.4,5.8Hz),1.65(d,2H,J=10.4Hz) ,1.44(s,1H),1.01-1.08(m,2H),0.85(t,2H,J=7.9Hz),-0.08(s,9H); m / z=642.85[M+H] + .

[0122] Step C: 2-(3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azetidin-3-yl)acetonitrile

[0123] Under stirring at room temperature, 96.3 g (0.15 mol, 1.0 eq) of benzyl 4-(3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-yl)piperidine-1-carboxylate, 600 mL of methanol, and 19.3 g of palladium on carbon were added to a 2 L reaction flask. The hydrogen atmosphere was replaced three times, and the temperature was raised to 40-50°C and the pressure was ≤0.4 MPa. After completion of the reaction, the mixture was filtered through a pad of diatomaceous earth and concentrated to obtain the product, weighing 60.9 g, with a yield of 80.0%, and HPLC: 93.45%.

[0124] 1 H-NMR (400MHz, DMSO-d6): 8.53 (s, 1H), 7.57 (d, 1H, J = 3.5Hz), 7.09 (d, 1H, J = 3.6Hz), 6, 34(d,2H,J=11.2Hz),3.66(d,2H,J=8.1Hz),3.41-3.53(m,6H),3.35(s,2H),2.94(d,2H, J=11.9Hz), 2.44(t,2H,J=11.1Hz), 2.24(t,1H,J=9.6Hz), 1.65(d,2H,J=10.1Hz), 1.06-1.22(m,2H),0.82(dd,2H,J=15.0,7.0Hz),-0.09(s,9H,); m / z=508.72[M+H] + .

[0125] Step D: Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azacyclyl-3-yl)acetonitrile

[0126] To a 5 L reaction flask, add 60.0 g (0.12 mol, 1.0 eq) of 2-(3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azetidin-3-yl)acetonitrile and 240 mL of acetonitrile. Stir at room temperature. Add 85.2 g (0.60 mol, 5.0 eq) of boron trifluoride in ether dropwise. After addition, raise the temperature to 40-50°C and stir for 1 h. Stop the reaction, concentrate the reaction solution, adjust the pH of the residue to 9-10 with saturated sodium carbonate solution, extract with 500 mL of ethyl acetate, and concentrate to obtain an oily product.

[0127] Dissolve the oily product in 500 ml of ethanol, add 100 g (0.72 mol, 6.0 eq) of aqueous ammonia (25% content), and stir at room temperature (20-30°C) for 5 hours. Stop the reaction, concentrate, and obtain a foamy product. Add 150 ml of ethanol and stir to crystallize to obtain a light yellow solid. Weigh 23.5 g, yield 52.0%, HPLC: 85.55%.

[0128] 1 H-NMR (400MHz, DMSO-d6): δ8.69 (s, 1H), 8.53 (s, 1H), 7.57 (d, 1H, J = 3.5Hz), 7.09 (d, 1H, J = 3.6Hz), 6, 34 (d, 2H, J = 11.2Hz), 3.66 (d, 2H, J = 8.1Hz), 3. 41-3.53(m,6H),2.94(d,2H,J=11.9Hz),2.44(t,2H,J=11.1Hz),2.24(t,1 H, J=9.6Hz), 1.65 (d, 2H, J=10.1Hz), 0.74-1.15 (m, 2H); m / z=378.46[M+H] + .

[0129] Step E: Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I)

[0130] In a 2L reaction flask, 20.0 g (0.05 mol, 1.0 eq) of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azacyclyl)acetonitrile, 250 ml of N,N-dimethylformamide / 250 ml of acetonitrile, 15.4 g (0.08 mol, 1.5 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 9.2 g of N-hydroxysuccinimide were added. A mixture of 39.5 g (0.39 mol, 3.0 eq) of triethylamine and 11.7 g (0.05 mol, 1.1 eq) of 3-fluoro-2-trifluoromethyl-isonicotinic acid was stirred and dissolved. The mixture was heated to 30-40°C for 4 h. The reaction was stopped, and 2.5 L of water and 1.5 L of ethyl acetate were added for extraction and concentration. The mixture was stirred and crystallized with 200 mL of ethanol. The filter cake was filtered and dried at 55-60°C to obtain a light yellow solid. The weight was 23.1 g, with a yield of 81.33%. The HPLC result was 90.21%.

[0131] Example 3

[0132] Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I).

[0133] Step A: tert-Butyl 3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-carboxylate

[0134] To a 1 L reaction flask, 300 mL of N,N-dimethylformamide, 60.0 g (0.18 mol, 1.0 eq) of 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine, 9.20 g (0.08 mol, 0.4 eq) of tetramethylguanidine, and 42.0 g (0.22 mol, 1.2 eq) of tert-butyl 3-(cyanomethylene)azetidin-1-carboxylate were added with stirring at room temperature. The reaction was allowed to proceed at 45°C for 24 h, after which the reaction was terminated. The reaction solution was quenched with water and extracted with 300 mL of ethyl acetate twice. The organic phase was washed with 200 mL of water twice, dried, and evaporated to dryness. The resulting residue was stirred with 300 mL of isopropanol to crystallize. The solid was filtered and dried at 55°C to a constant weight. Weighing 75.16 g, yield 78.9%, HPLC: 92.11%.

[0135] 1 H NMR (400MHz, DMSO-d6): δ8.75(s,1H),8.56(s,1H),7.75(d,1H,J=3.6Hz),7.20(d,1H ,J=3.6Hz),6.37(s,1H),5.64(s,2H),3.71(dd,4H,J=20.0,10.6Hz),3.44-3.59(m,4 H),2.91(s,3H),2.37(dd,2H,J=12.4,5.8Hz),1.65(d,2H,J=10.4Hz),1.44(s,1H),1 .40(s,9H),1.01-1.08(m,2H),0.85(t,2H,J=7.9Hz),-0.08(s,9H); m / z=608.84[M+H] + .

[0136] Step B: tert-Butyl 3-(cyanomethyl)-3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-carboxylate

[0137] To a 2 L reaction flask, tert-butyl 3-(3-amino-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-carboxylate (78.6 g (0.15 mol, 1.0 eq), toluene (600 mL), and phthalic anhydride (24.5 g (0.16 mol, 1.1 eq)) were added under stirring at room temperature. A water separator was installed and the reaction was heated to reflux for 6 h, followed by removal of water. Heating was stopped and the temperature was allowed to cool. 600 mL of n-hexane was added to the reaction system, stirred to induce crystallization, and filtered. The filter cake was washed with isopropyl ether (300 mL) and stirred, then filtered. The resulting solid was dried at 55-60°C to a constant weight. The product weighed 84.3 g, with a yield of 86.0%. HPLC analysis indicated a product weight of 90.12%.

[0138] 1 H-NMR (400MHz, DMSO-d6): δ9.07(s,1H),8.26(s,1H),7.94-8.09(m,4H),7.86(d,1H,J=3.7Hz ),7.20(d,1H,J=3.7Hz),5.62(s,2H),3.87(d,2H,J=8.1Hz),3.77(d,2H,J=13.2Hz),3.59-3.7 0(m,4H),3.51(t,2H,J=8.0Hz),2.92(d,2H,J=9.0Hz),2.47(s,1H),1.69(d,2H,J=10.3Hz),1 .41(s,9H),1.06-1.22(m,2H),0.82(dd,2H,J=15.0,7.0Hz),-0.09(s,9H,); m / z=738.94[M+H] + .

[0139] Step C: 2-(3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile

[0140] Under stirring at room temperature, 78.5 g (0.12 mol, 1.0 eq) of tert-butyl 3-(cyanomethyl)-3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-1-carboxylate and 600 mL of ethyl acetate were added to a 2 L reaction flask. The mixture was stirred to dissolve. 90 mL of 4 N HCl in ethyl acetate was added and the temperature was controlled at 10-20°C. The reaction was stirred and reacted. After completion of the reaction, the mixture was filtered, dried, and weighed 69.9 g, with a yield of 86.4%. HPLC analysis showed 85.61%.

[0141] 1 H-NMR (400MHz, DMSO-d6): δ9.07(s,1H),8.26(s,1H),7.94-8.09(m,4H),7.86(d,1H,J=3.7Hz),7.20(d,1H,J=3.7Hz),5.62(s,2H),3.87(d,2 H,J=8.1Hz),3.77(d,2H,J=13.2Hz),3.60-3.75(m,4H),3.33(t,2H,J=8.0Hz),2.77(d,2H,J=9.0Hz),2.69-2.75(m,4H),2.63(m,1H),2.00(s, 1H),1.69(d,2H,J=10.3Hz),1.41(d,2H,J=8.9Hz),0.82(dd,2H,J=15.0,7.0Hz),-0.09(s,9H,); m / z=638.82[M+H] + .

[0142] Step D: 2-(3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile

[0143] Under stirring at room temperature, 23.0 g (0.11 mol, 1.1 eq) of 3-fluoro-2-(trifluoromethyl)isonicotinic acid, 23.0 g (0.12 mol, 1.2 eq) of EDCI, and HOSu were added to a 1 L reaction flask. 13.8g (0.12mol, 1.2eq) and DMF300ml, stir and dissolve to react for 2h, control the temperature at 20-30℃, then slowly add dropwise to a DMF (200ml) solution of 63.8g (0.10mol, 1.0eq) of 2-(3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile and 30.4g (0.30mol, 3.0eq) of triethylamine, control the temperature at 20-30℃, and after the addition is completed, continue to control the temperature and stir for 3h to stop the reaction. The reaction mixture was quenched with 3 L of water and 1 L of ethyl acetate was added, stirred, and allowed to stand for separation. The ethyl acetate was concentrated under reduced pressure, and the resulting residue was added to 480 mL of methyl tert-butyl ether for slurry crystallization. The residue was filtered to obtain an off-white solid, which was air-dried at 55°C to constant weight. The product weighed 68.2 g, with a yield of 82.3%. HPLC analysis showed a product weight of 90.26%.

[0144] 1 H-NMR (400MHz, DMSO-d6): δ9.07(s,1H),8.69(d,1H,J=4.6Hz),8.26(s,1H),8.01(ddd,4H,J=12.5,7.4,3.6Hz),7.94( t,1H,J=4.5Hz),7.86(d,1H,J=3.7Hz),7.19(d,1H,J=3.7Hz),5.62(s,2H),4.11(q,2H,J=5.2Hz),3.89(d,2H,J=7.8Hz ),3.65(d,2H,J=5.2Hz),3.51(t,2H,J=8.0Hz),3.28(s,1H),3.20(s,2H),3.12(t,1H,J=10.3Hz),2.64(s,1H),1.83(d ,1H,J=9.3Hz),1.69(d,1H,J=12.4Hz),1.29(d,2H,J=31.8Hz),0.81(t,2H,J=8.0Hz),-0.10(s,9H); m / z=829.90[M+H] + .

[0145] Step E: 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile

[0146] Under stirring at room temperature, 66.3 g (0.08 mol, 1.0 eq) of 2-(3-(3-(1,3-dioxoisoindolin-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile and 500 mL of acetonitrile were added to a 2 L reaction bottle, and 34.0 g (0.24 mol, 3.0 eq) of boron trifluoride etherate was slowly added dropwise. After the addition was completed, the temperature was raised to 40-50°C and the reaction was stirred for 8 h. The reaction was stopped, and 40.0 g (0.64 mol, 8.0 eq) of hydrazine hydrate was slowly added to the reaction system. The temperature was raised to reflux for 8 h, and the reaction was stopped. The reaction solution was concentrated, and the residue was slurried in 500 mL of water. The residue was filtered, and the resulting solid was air-dried at 60°C to constant weight. The product weighed 28.3 g, with a yield of 88.1%. HPLC analysis showed a product weight of 90.17%.

[0147] Example 4

[0148] Preparation of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile (I)

[0149] Step A 2-{4-[7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-3-yl}isoindole-1,3-dione

[0150] To a 3 L reaction flask, 1.5 L of toluene, 165 g (0.50 mol, 1.0 eq) of 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine, and 81.5 g (0.55 mol, 1.1 eq) of phthalic anhydride were added with stirring at room temperature. A water separator was installed and the reaction was heated to reflux for 8 h. The reaction was then stopped, cooled, and filtered. The resulting solid was dried at 55-60°C to a constant weight. The product weighed 191 g, with a yield of 83.1%. HPLC analysis indicated a yield of 92.32%.

[0151] 1H-NMR (400MHz, DMSO-d6): δ13.85(s,1H),8.97(d,1H,J=1.6Hz),8.25(s,1H),8.14–7.91(m,4H),7.80(d,1H,J=3.7H z),7.12(d,1H,J=3.7Hz),5.61(s,2H),3.52(t,2H,J=8.0Hz),0.82(t,2H,J=8.0Hz),-0.09(s,9H); m / z=461.57[M+H] + .

[0152] Step B: Benzyl 4-{3-(cyanomethyl)-3-[3-(1,3-phthaloyl-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate

[0153] In a 2L reaction flask, 138 g (0.30 mol, 1.0 eq) of 2-{4-[7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-3-yl}isoindole-1,3-dione, 9.13 g (0.06 mol, 0.2 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and N,N-dimethylformamide were added. 450 mL of amide and 102.7 g (0.33 mol, 1.1 eq) of benzyl 4-(3-(cyanomethyl)azetidin-1-yl)piperidine-1-carboxylate were heated to 30-40°C and stirred for 3 h. The reaction was stopped and 5 L of water and 1.5 L of ethyl acetate were added to the reaction solution for extraction. After ethyl acetate was concentrated, 600 mL of isopropanol was added, stirred for crystallization, and filtered. The resulting solid was dried at 55-60°C to obtain an off-white solid. Weighing 200.8 g, the yield was 86.9%, and the HPLC: 95.43%.

[0154] 1H-NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.28(s,1H),8.08–7.97(m,4H),7.87(d,1H,J =3.7Hz),7.47–7.31(m,5H),7.20(d,1H,J=3.7Hz),5.63(s,2H),5.10(s,2H),3.87(t,4 H,J=13.2Hz),3.65(d,4H,J=8.0Hz),3.52(t,2H,J=8.0Hz),3.35(s,3H),3.07(s,2H),1 .73(d,2H,J=10.3Hz,),1.21(dd,2H),-0.09(s,9H,J=24.3,14.7Hz); m / z=772.95[M+H] + .

[0155] Step C: Benzyl 4-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-yl)piperidine-1-carboxylate

[0156] To a 2 L reaction flask, add 154 g (0.20 mol, 1.0 eq) of benzyl 4-{3-(cyanomethyl)-3-[3-(1,3-phthaloyl-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate and 700 mL of acetonitrile. Stir at room temperature, then dropwise add 85.2 g (0.60 mol, 3.0 eq) of boron trifluoride in ether. After addition, raise the temperature to 40-50°C and stir for 5 h. Stop the reaction, concentrate the reaction solution, adjust the pH to 9-10 with saturated sodium carbonate solution, extract with 1 L of ethyl acetate, and concentrate to obtain an oily product.

[0157] Dissolve the oily product in 500 mL of ethanol, add 100 g (1.2 mol, 6.0 eq) of hydrazine hydrate (60% content), and heat to 70-80°C with stirring for 5 hours. Stop the reaction, add 2 L of water, cool, stir, and crystallize. Filter, wash the filter cake with 300 mL of water, and dry at 55-60°C to obtain a light yellow solid. Weigh 92.1 g, yield 90.0%, HPLC: 95.55%.

[0158] 1H-NMR (400MHz, DMSO-d6): δ12.08(s,1H),8.69(s,1H),8.53(s,1H),7.57(d,1H,J=3 .5Hz),7.30-7.46(m,5H),7.09(d,1H,J=3.6Hz),6.34(d,2H,J=11.4Hz),5.10(s,2H ),3.76-3.90(m,2H),3.70(d,2H,J=8.0Hz),3.44-3.56(m,4H),3.06(s,2H),2.44(d d,1H,J=10.3,6.9Hz),1.69(d,2H,J=10.2Hz),1.12-1.24(m,2H); m / z=512.59[M+H] + .

[0159] Step D: Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azacyclyl-3-yl)acetonitrile

[0160] To a 5 L reaction flask, add 76.7 g (0.15 mol, 1.0 eq) of benzyl 4-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidin-1-yl)piperidine-1-carboxylate and 760 mL of methanol / tetrahydrofuran. Heat to 50-60°C and stir to dissolve. Add 7.6 g of Pd / C (0.015 mol, 0.1 eq) and allow to reduce for 8 h. The reaction is then stopped, cooled, filtered, and concentrated. Add 500 mL of isopropyl ether, stir to crystallize, filter, and dry the filter cake at 55-60°C to obtain a light yellow solid. The product weighs 52.1 g, with a yield of 92.0%. HPLC analysis indicates 96.41%.

[0161] 1 H-NMR (400MHz, DMSO-d6): δ8.69 (s, 1H), 8.53 (s, 1H), 7.57 (d, 1H, J = 3.5Hz), 7.09 (d, 1H, J = 3.6Hz), 6.34 (d, 2H, J = 11.2Hz), 3.66 (d, 2H, J = 8.1Hz), 3. 41-3.53(m,6H),2.94(d,2H,J=11.9Hz),2.44(t,2H,J=11.1Hz),2.24(t,1 H, J=9.6Hz), 1.65 (d, 2H, J=10.1Hz), 0.74-1.15 (m, 2H); m / z=378.46[M+H] + .

[0162] Step E: Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I)

[0163] In a 2L reaction flask, 50.0 g (0.13 mol, 1.0 eq) of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(piperidin-4-yl)azacyclyl)acetonitrile, 250 ml of N,N-dimethylformamide / 250 ml of acetonitrile, 30.7 g (0.16 mol, 1.2 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 18.4 g of N-hydroxysuccinimide were added. A mixture of 39.5 g (0.39 mol, 3.0 eq) of triethylamine (0.16 mol, 1.2 eq), and 29.3 g (0.14 mol, 1.1 eq) of 3-fluoro-2-trifluoromethyl-isonicotinic acid was stirred and dissolved. The mixture was heated to 30-40°C and reacted for 4 h. The reaction was stopped, and 2.5 L of water and 1.5 L of ethyl acetate were added for extraction and concentration. 200 mL of ethanol was added for stirring and crystallization. The mixture was filtered and the filter cake was dried at 55-60°C to obtain a light yellow solid. The weight was 65.7 g, with a yield of 87.25%. HPLC analysis showed a yield of 98.71%.

[0164] 1 H NMR (400MHz, DMSO-d6): δ12.08(s,1H),8.69(q,2H,J=4.8Hz),8.54(s,1H),7.94(t,1H, J=4.7Hz),7.52-7.65(m,1H),7.09(dd,1H,J=3.4,1.5Hz),6.35(s,2H),3.72(d,2H,J=7. 6Hz),3.42-3.58(m,6H),3.26-3.33(m,1H),3.12(t,1H,J=10.0Hz),2.58(s,1H),1.81(d ,1H,J=10.2Hz),1.68(d,1H,J=10.4Hz),1.29(dd,2H,J=31.2,8.9Hz); m / z=569.54[M+H] + .

[0165] Example 5

[0166] Preparation of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile (I)

[0167] Step A 2-{4-[7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-3-yl}isoindole-1,3-dione

[0168] To a 3 L reaction flask, 1.5 L of toluene, 165 g (0.50 mol, 1.0 eq) of 4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-3-amine, and 81.5 g (0.55 mol, 1.1 eq) of phthalic anhydride were added with stirring at room temperature. A water separator was installed and the reaction was heated to reflux for 8 h. The reaction was then stopped, cooled, and filtered. The resulting solid was dried at 55-60°C to a constant weight. The product weighed 191 g, with a yield of 83.1%. HPLC analysis indicated a yield of 92.32%.

[0169] Step B: 2-(1-(piperidin-4-yl)azetidin-3-ylidene)acetonitrile hydrochloride

[0170] To a 1L reaction flask, add 50.0g (0.38mol, 1.0eq) of 2-(3-azetidinylidene)acetonitrile hydrochloride and 75.7g (0.38mol, 1.0eq) of N-tert-butyloxycarbonylpiperidone. Using 500ml of dichloromethane as the solvent, cool the mixture to 0-10°C. Then, add 161.1g (0.76mol, 2.0eq) of sodium acetate borohydride in portions and allow the reaction to proceed at controlled temperature. After the reaction is complete, slowly add the hydrolysis agent, maintaining the temperature at 0-10°C. Stir and allow the mixture to stand for separation. Wash the mixture twice with 500ml of water, dry, and concentrate to obtain a pale yellow product. The resulting yellow product is dissolved in 200ml of ethyl acetate, and 120ml of 6N hydrochloric acid solution is slowly added. Stir and maintain the temperature at 10-20°C for 5 hours. A large amount of white solid precipitates, which is filtered and dried to obtain 69.0g of an off-white product with an 85.01% yield (HPLC: 91.23%).

[0171] Step C: 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile

[0172] To a 500 mL reaction flask, add 70 g (0.33 mol, 1.1 eq) of 3-fluoro-2-(trifluoromethyl)isonicotinic acid, 41.9 g (0.33 mol, 1.1 eq) of oxalyl chloride, 2 ml of N,N-dimethylformamide, and 250 ml of dichloromethane. Stir and react at room temperature (10-20°C) for 3 h, then stop the reaction. Add 65.0 g (0.30 mol, 1.0 eq) of 3-fluoro-2-(trifluoromethyl)isonicotinic acid and 60.7 g (0.60 mol, 2.0 eq) of triethylamine in 200 ml of dichloromethane and allow to react at 10-20°C. After the reaction is complete, add 1 L of water, stir, and allow the mixture to stand for separation. Wash twice with 500 ml of water, dry, and concentrate to obtain an oily product. Add 100 ml of ethyl acetate and 300 ml of methyl tert-butyl ether, stir, and crystallize. Filter and dry to obtain 66.5 g of an off-white solid with a yield of 60.2%. HPLC: 92.54%.

[0173] Step D: 2-(3-(3-(1,3-dioxoisoindole-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile

[0174] To a 1 L reaction flask, 59.9 g (0.13 mol, 1.0 eq) of 2-{4-[7-{[2-(trimethylsilyl)ethoxy]methyl}-7Hpyrrolo[2,3-d]pyrimidin-4-yl]-1H-pyrazol-3-yl}isoindole-1,3-dione, 60.0 g (0.16 mol, 1.2 eq) of 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile, 39.6 g (0.26 mol, 2.0 eq) of DBU, and 240 ml of N,N-dimethylformamide were added, and the mixture was stirred at room temperature for 5 h. After the reaction is complete, the reaction solution is added to 1.2 L of water and 1 L of ethyl acetate, stirred, and allowed to stand for separation. The ethyl acetate is concentrated, and 500 ml of isopropanol is added for slurry crystallization. The product is filtered and dried to obtain 46.0 g of the product with a yield of 42.7%, HPLC: 89.03%.

[0175] Step E: Preparation of 2-(3-(3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (I).

[0176] To a 1 L reaction flask, add 40.0 g (0.05 mol, 1.0 eq) of 2-(3-(3-(1,3-dioxoindole-2-yl)-4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidin-4-yl)azetidin-3-yl)acetonitrile and 200 ml of acetonitrile. Stir at room temperature. Then, add dropwise 35.5 g (0.25 mol, 5.0 eq) of boron trifluoride in ether. After addition, stir at room temperature for 5 h. Stop the reaction, concentrate the reaction solution, adjust the pH of the residue to 9-10 with saturated sodium carbonate solution, extract with 500 ml of ethyl acetate, and concentrate to obtain an oily product. The oily product was dissolved in 200 ml of methanol, and 14.0 g (0.1 mol, 2.0 eq) of aqueous ammonia was added and stirred for 6 h. After the reaction was complete, the mixture was concentrated and then 100 ml of ethanol was added to crystallize to obtain 19.6 g of the product with a yield of 69.1% and an HPLC value of 94.36%.

[0177] 1 H NMR (400MHz, DMSO-d6): δ12.08(s,1H),8.69(q,2H,J=4.8Hz),8.54(s,1H),7.94(t,1H, J=4.7Hz),7.52-7.65(m,1H),7.09(dd,1H,J=3.4,1.5Hz),6.35(s,2H),3.72(d,2H,J=7. 6Hz),3.42-3.58(m,6H),3.26-3.33(m,1H),3.12(t,1H,J=10.0Hz),2.58(s,1H),1.81(d ,1H,J=10.2Hz),1.68(d,1H,J=10.4Hz),1.29(dd,2H,J=31.2,8.9Hz); m / z=569.54[M+H] + .

[0178] Example 6

[0179] Preparation of 2-{3-[3-amino-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(isopropylsulfonyl)azetidin-3-yl}acetonitrile (I) fumarate

[0180] Take 2.0 g of the compound obtained in Example 5 and 0.41 g of fumaric acid, add 18 ml of tetrahydrofuran and 3 ml of ethanol, stir evenly, heat to 60-70 ° C, stir to dissolve and clarify, add 18 ml of n-heptane after 0.5 h, slowly cool and crystallize for 12 hours, filter, and dry under reduced pressure at 50 ° C to obtain the product.

Claims

1. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that: The method comprises the following steps: Wherein, R1, R3, and R4 are independently selected from hydrogen or an amino protecting group, and R2 is selected from hydrogen.

2. The preparation method according to claim 1, characterized in that The method of preparing compound 3 from compound 2 comprises reacting compound 2 with a hydrazine compound and an optional acetal compound to obtain compound 3.

3. The preparation method according to claim 2, characterized in that: The hydrazine compound is selected from hydrazine or a salt of hydrazine.

4. The preparation method according to claim 2 or 3, characterized in that: The acetal compound is selected from N,N-di(C1-C4 alkyl)formamide di(C1-C4 alkyl)acetal.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The process of obtaining compound 5 from compound 3 comprises the following steps: The 3-amino group of the pyrazole ring of compound 3 is protected by amino group to obtain compound 4; Compound 4 undergoes Michael addition reaction with compound M1 in the presence of a base to obtain compound 5; The process of obtaining compound 5 from compound 3 comprises the following steps: Compound 3 and compound M1 undergo Michael addition reaction to obtain compound 5A; the 3-amino group of compound 5A is amino protected to obtain compound 5; Wherein, R1, R3, and R4 are as defined in claim 1.

6. The preparation method according to claim 5, characterized in that: The R3 protecting group is a cyclic imide type protecting group.

7. The preparation method according to any one of claims 1 to 6, characterized in that The method comprises the following steps: Compound 5 is deprotected from R1 and R3 to obtain compound 7; Compound 7 is reduced to obtain compound 8; Wherein, R3 is defined as in claim 1.

8. The preparation method according to claim 7, wherein R1 is selected from 2-(trimethylsilyl)ethoxymethyl (SEM), and R4 is selected from amino protecting groups other than 3-fluoro-2-(trifluoromethyl)isonicotinyl.

9. The preparation method according to any one of claims 1 to 8, wherein: R1 is selected from hydrogen, tert-butyloxycarbonyl (Boc) and 2-(trimethylsilyl)ethoxymethyl (SEM); R2 is selected from hydrogen; R3 is selected from hydrogen, succinimidyl, methylsuccinimidyl, 2,2-dimethylsuccinimidyl and phthalimidyl; R4 is selected from hydrogen, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn) and 3-fluoro-2-(trifluoromethyl)isonicotinoyl.

10. The preparation method according to claim 9, wherein: R1 is selected from 2-(trimethylsilyl)ethoxymethyl (SEM); R2 is selected from hydrogen; R3 is selected from succinimidyl or phthalimide; R4 is selected from tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).

11. The method according to any one of claims 1 to 10, further comprising the step of obtaining a compound of formula I from compound 8:

12. The method according to claim 11, further comprising the step of preparing a pharmaceutically acceptable salt thereof from the compound of formula I.

13. The method according to claim 12, wherein: The pharmaceutically acceptable salt is selected from fumarate or succinate.

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