Preparation method for JAK inhibitor compound, and crystal form and intermediate of JAK inhibitor compound

Abstract

The present invention provides a preparation method for a JAK inhibitor compound, and a crystal form and an intermediate of the JAK inhibitor compound. Specifically, the present invention provides a preparation method for a compound of formula (I), and a crystal form of the compound of formula (I). The preparation method for the crystal form of the compound of formula I provided by the present invention is simple, achieves a high product yield and low costs, has a robust process, and achieves a high product purity.

Description

A method for preparing a JAK inhibitor compound, its crystal form, and its intermediates.

[0001] This application claims priority to Chinese patent application 2025100572511, filed on January 14, 2025, and Chinese patent application 2025120582380, filed on December 31, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of drug synthesis. Specifically, this invention relates to a method for preparing a JAK inhibitor compound represented by Formula I, its crystal form, and its intermediates. Background Technology

[0003] The JAK-STAT signaling pathway is a cytokine-stimulated signal transduction pathway discovered in recent years. JAKs play an important role in cytokine signal transduction, and downstream substrates of the JAK kinase family include signal transducers and activators of transcription proteins (STATs). JAK proteins are important members of this pathway, and abnormally increased JAK activity often leads to disease. Many diseases are related to abnormal cellular responses in the JAK-STAT signaling pathway, including autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergic reactions and asthma, and Alzheimer's disease.

[0004] Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by joint swelling, pain, stiffness, deformity, and severe functional impairment, with a prevalence of 0.5%-1.0%. Because the pathogenesis of RA is not fully understood, its pathological process is difficult to control, resulting in a high rate of disability and severely impacting patients' physical and mental health, thus reducing their quality of life. Currently, the main drugs used to treat RA include nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), and antibody drugs. For a long time, DMARDs have been the first-line treatment for RA. In 1988, the first DMARD, methotrexate (MTX), was approved by the FDA for the treatment of RA, marking a significant milestone in RA treatment history. This drug is widely used due to its efficacy, tolerability, and safety, but it also has adverse reactions including nausea, vomiting, stomach upset, and hepatotoxicity. In contrast, newly developed antibody drugs have shown better efficacy and safety profiles for moderate to severe RA. However, because they target specific cytokines, the population that can benefit from them is significantly limited. At the same time, the cost of treatment and the method of administration by injection also limit the promotion of these drugs.

[0005] Over the past 20 years, RA treatment has made significant progress, and patients' conditions can now be effectively controlled with existing treatments. Nevertheless, RA patients still suffer from disease relapse, unsatisfactory treatment effectiveness, poor long-term tolerability, and various adverse reactions. More importantly, the quality of life of RA patients, including the function of organs such as joints, has not been truly improved with current treatments. Therefore, there remains a significant unmet clinical need in this area to restore patients' normal function.

[0006] Studies have shown that the core therapeutic role in rheumatoid arthritis (RA) is played by monocytes / macrophages and lymphocytes infiltrating the synovial tissue and cells of RA, which produce a large number of cytokines through autocrine mechanisms. These cytokines interact and activate the JAK / STAT signaling pathway (Janus kinase / signal transducer and activators of transcription signaling pathway) through different pathways. By specifically inhibiting the JAK / STAT signaling pathway, the cascade amplification effect of the above-mentioned cytokines can be blocked, thereby improving the symptoms of the damaged joints in RA patients. Therefore, the JAK / STAT signaling pathway has become a potential target for the treatment of RA.

[0007] Because JAK kinases participate in various important physiological processes in the body, broad inhibition of different subtypes may produce adverse reactions. Tofacitinib, used in patients with moderate to severe RA who have an inadequate response to or are intolerant to methotrexate (MTX), has been observed to have certain adverse reactions in clinical trials, including infection, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. Tofacitinib has significant inhibitory activity against JAK1, JAK2, and JAK3 subtypes. Since JAK2 activity is related to erythrocyte differentiation and lipid metabolism, some of the aforementioned adverse reactions are believed to be related to the non-selective inhibitory characteristics of this drug. Therefore, the search for selective JAK1 and / or JAK3 inhibitors will become a new direction in RA drug research. Currently, JAK inhibitors have been proven to be used for the treatment of hematologic disorders, tumors, rheumatoid arthritis, and psoriasis. However, the number of JAK inhibitor compositions available for topical administration remains very limited.

[0008] In summary, there is a lack in the art of suitable JAK inhibitor compositions for topical administration, as well as their corresponding preparation processes and crystal forms. Summary of the Invention

[0009] One object of the present invention is to provide a method for preparing methyl 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) ester, a JAK inhibitor compound of Formula I.

[0010] Another object of the present invention is to provide the crystal form of the JAK inhibitor compound shown in Formula I above and a method for preparing the same.

[0011] Another object of the present invention is to provide an intermediate for preparing the JAK inhibitor compound shown in Formula I.

[0012] Another object of the present invention is to provide the crystal form of the D-(+)-di-p-methylbenzoyl tartrate (i.e., Formula I·D-DTTA) of the JAK inhibitor compound shown above.

[0013] In a first aspect of the invention, a crystal form of a compound of formula I is provided:

[0014] The crystal form has the following X-ray powder diffraction characteristic peaks: 6.876°±0.3°, 20.599°±0.3°, 24.878°±0.3°, 13.947°±0.3°, 11.129°±0.3°, 12.507°±0.3°, and 19.465°±0.3°.

[0015] In another preferred embodiment, the crystal form of the compound of formula I has the following X-ray powder diffraction characteristic peaks: 6.876°±0.3°, 20.599°±0.2°, 24.878°±0.2°, 13.947°±0.2°, 11.129°±0.2°, 12.507°±0.2°, and 19.465°±0.2°.

[0016] In another preferred embodiment, the crystal form of the compound of formula I has the following X-ray powder diffraction characteristic peaks: 6.876°±0.2°, 20.599°±0.2°, 24.878°±0.2°, 13.947°±0.2°, 11.129°±0.2°, 12.507°±0.2°, and 19.465°±0.2°.

[0017] In another preferred embodiment, the crystal form of the compound of formula I further has one or more (e.g., 2, 3, 5, 8 or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 17.068°±0.2°, 25.150°±0.2°, 27.560°±0.2°, 14.755°±0.2°, 17.545°±0.2°, 20.026°±0.2°, 22.523°±0.2°, 24.461°±0.2°, 24.038°±0.2°, 7.651°±0.2°, 21.432°±0.2°, 18.772°±0.2°, and 23.560°±0.2°.

[0018] In another preferred embodiment, the crystal form of the compound of formula I further has one or more (e.g., 2, 3, 5, 8, or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 18.292°±0.2°, 19.066°±0.2°, 16.365°±0.2°, 31.347°±0.2°, 28.212°±0.2°, 15.438°±0.2°, 23.147°±0.2°, 31.993°±0.2°, 13.510°±0.2°, 31.638°±0.2°, 26.203°±0.2°, 3 0.270°±0.2°, 34.962°±0.2°, 30.522°±0.2°, 38.671°±0.2°, 33.027°±0.2°, 22.076°±0.2°, 10.218°±0.2°, 15.846°±0.2°, 29.727°±0.2°, 32.561°±0.2°, 9.272°±0.2°, 35.781°±0.2°, 36.749°±0.2°, 39.559°±0.2°, 29.384°±0.2°, 37.708°±0.2°.

[0019] In another preferred embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of the compound of formula I include: 18.292°±0.2°, 19.066°±0.2°, 16.365°±0.2°, 31.347°±0.2°, 28.212°±0.2°, 15.438°±0.2°, 23.147°±0.2°, 31.993°±0.2°, 13.510°±0.2°, 31.638°±0.2°, 26.203°±0.2°, 30.270°±0.2°, 34 0.962°±0.2°, 30.522°±0.2°, 38.671°±0.2°, 33.027°±0.2°, 22.076°±0.2°, 10.218°±0.2°, 15.846°±0.2°, 29.727°±0.2°, 32.561°±0.2°, 9.272°±0.2°, 35.781°±0.2°, 36.749°±0.2°, 39.559°±0.2°, 29.384°±0.2°, 37.708°±0.2°.

[0020] In another preferred embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of the compound of formula I include 6.876°±0.2°, 20.599°±0.2°, 24.878°±0.2°, 13.947°±0.2°, 11.129°±0.2°, 12.507°±0.2°, 19.465°±0.2°, 17.068°±0.2°, 25.150°±0.2°, and 27.560°±0.2°. °, 14.755°±0.2°, 17.545°±0.2°, 20.026°±0.2°, 22.523°±0.2°, 24.461°±0.2°, 24.038°±0.2°, 7.651°±0.2°, 21.432°±0.2°, 18.772°±0.2°, 23.560°±0.2°, 18.292°±0.2°, 19.066°±0.2°, 16. 365°±0.2°, 31.347°±0.2°, 28.212°±0.2°, 15.438°±0.2°, 23.147°±0.2°, 31.993°±0.2°, 13.510°±0.2°, 31.638°±0.2°, 26.203°±0.2°, 30.270°±0.2°, 34.962°±0.2°, 30.522°±0.2°, 38.671° ±0.2°, 33.027°±0.2°, 22.076°±0.2°, 10.218°±0.2°, 15.846°±0.2°, 29.727°±0.2°, 32.561°±0.2°, 9.272°±0.2°, 35.781°±0.2°, 36.749°±0.2°, 39.559°±0.2°, 29.384°±0.2°, 37.708°±0.2°.

[0021] In another preferred embodiment, the X-ray powder diffraction characteristic peaks and relative intensities of the crystal form of the compound of formula I are as follows:

[0022] In another preferred embodiment, the crystal form of the compound of formula I has an XRPD spectrum substantially as shown in Figure 1.

[0023] In another preferred embodiment, the crystal form of the compound of formula I, when heated to 120±3°C, for example 120°C, exhibits a weight loss of 0%-0.06%, for example, 0.03%, during thermogravimetric analysis (TGA).

[0024] In another preferred embodiment, the crystal form of the compound of formula I has a TGA diagram that is essentially as shown in Figure 2.

[0025] In another preferred embodiment, the crystal form of the compound of formula I, when heated to 86°C ± 3°C by differential scanning calorimetry (DSC), exhibits an endothermic signal, for example, 86°C.

[0026] In another preferred embodiment, the crystal form of the compound of formula I has a DSC diagram that is essentially as shown in FIG3.

[0027] In another preferred embodiment, the compound of formula I has the structure shown in formula D or formula E:

[0028] In another preferred embodiment, the compound of formula I is a mixture of the compound of formula D and the compound of formula E.

[0029] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is x:1; where x is any positive number that is not zero.

[0030] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is (0.6 to 1.5):1.

[0031] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is 1:1.

[0032] In a second aspect of the invention, a crystal form of formula I·D-DTTA is provided.

[0033] In another preferred embodiment, the crystal form of Formula I·D-DTTA has the following X-ray powder diffraction characteristic peaks: 21.831°±0.2°, 15.903°±0.2°, 14.651°±0.2°, 13.848°±0.2°, 15.015°±0.2°, 17.248°±0.2°, and 24.551°±0.2°.

[0034] In another preferred embodiment, the crystal form of Formula I·D-DTTA further has one or more (e.g., 2, 3, 5, 8 or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.793°±0.2°, 9.130°±0.2°, 18.310°±0.2°, 20.986°±0.2°, 24.270°±0.2°, 18.974°±0.2°, 24.977°±0.2°, 26.223°±0.2°, 26.613°±0.2°, 16.431°±0.2°, 19.755°±0.2°, 11.400°±0.2°, 25.737°±0.2°, and 5.246°±0.2°.

[0035] In another preferred embodiment, the crystal form of Formula I·D-DTTA further has one or more (e.g., 2, 3, 5, 8, or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 20.324°±0.2°, 10.469°±0.2°, 22.509°±0.2°, 29.183°±0.2°, 11.881°±0.2°, 27.941°±0.2°, and 23.512°±0.2°. 27.082°±0.2°, 32.152°±0.2°, 30.418°±0.2°, 38.995°±0.2°, 6.866°±0.2°, 35.087°±0.2°, 33.918°±0.2°, 38.042°±0.2°, 37.128°±0.2°, 39.408°±0.2°, 36.788°±0.2°, 36.124°±0.2°.

[0036] In another preferred embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of Formula I·D-DTTA include: 20.324°±0.2°, 10.469°±0.2°, 22.509°±0.2°, 29.183°±0.2°, 11.881°±0.2°, 27.941°±0.2°, 23.512°±0.2°, 27.082°±0.2°, 32.152°±0.2°, 30.418°±0.2°, 38.995°±0.2°, 6.866°±0.2°, 35.087°±0.2°, 33.918°±0.2°, 38.042°±0.2°, 37.128°±0.2°, 39.408°±0.2°, 36.788°±0.2°, 36.124°±0.2°.

[0037] In another preferred embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of Formula I·D-DTTA include: 21.831°±0.2°, 15.903°±0.2°, 14.651°±0.2°, 13.848°±0.2°, 15.015°±0.2°, 17.248°±0.2°, 24.551°±0.2°, and 12.793°±0.2°. 0.2°, 9.130°±0.2°, 18.310°±0.2°, 20.986°±0.2°, 24.270°±0.2°, 18.974°±0.2°, 24.977°±0.2°, 26.223°±0.2°, 26.613°±0.2°, 16.431°±0.2°, 19.755°±0.2°, 11.400 °±0.2°, 25.737°±0.2°, 5.246°±0.2°, 20.324°±0.2°, 10.469°±0.2°, 22.509°±0.2°, 29.183°±0.2°, 11.881°±0.2°, 27.941°±0.2°, 23.512°±0.2°, 27.082°±0.2°, 32. 152°±0.2°, 30.418°±0.2°, 38.995°±0.2°, 6.866°±0.2°, 35.087°±0.2°, 33.918°±0.2°, 38.042°±0.2°, 37.128°±0.2°, 39.408°±0.2°, 36.788°±0.2°, 36.124°±0.2°.

[0038] In another preferred embodiment, the X-ray powder diffraction characteristic peaks and relative intensities of the crystal form of Formula I·D-DTTA are as follows:

[0039] In another preferred embodiment, the crystal form of the formula I·D-DTTA has a basic XRPD spectrum as shown in Figure 4.

[0040] In another preferred embodiment, the crystal form of the formula I·D-DTTA, when heated to 127°C ± 3°C by differential scanning calorimetry (DSC), exhibits an endothermic signal, for example, 127.5°C.

[0041] In another preferred embodiment, the crystal form of the formula I·D-DTTA has a DSC diagram as shown in FIG11.

[0042] In another preferred embodiment, the crystal form of Formula I·D-DTTA, when heated to 120±3°C, for example 120°C, exhibits a weight loss of 0%-0.06%, for example, 0.0407%, during thermogravimetric analysis (TGA).

[0043] In another preferred embodiment, the crystal form of the formula I·D-DTTA has a TGA diagram as shown in FIG12.

[0044] In another preferred embodiment, the compound of formula I·D-DTTA has the structure shown in formula D·D-DTTA or formula E·D-DTTA:

[0045] In another preferred embodiment, the compound of formula I·D-DTTA is a mixture of the compound of formula D·D-DTTA and the compound of formula E·D-DTTA.

[0046] In another preferred embodiment, the molar ratio of the compound of formula D·D-DTTA to the compound of formula E·D-DTTA in the mixture is x:1; where x is any positive number that is not zero.

[0047] In another preferred embodiment, the molar ratio of the compound of formula D·D-DTTA to the compound of formula E·D-DTTA in the mixture is (0.6 to 1.5):1.

[0048] In another preferred embodiment, the molar ratio of the D·D-DTTA compound to the E·D-DTTA compound in the mixture is 1:1.

[0049] In a third aspect of the present invention, a method for preparing a compound of formula I is provided, comprising the following steps:

[0050] Step (1) involves reacting compound g to obtain compound j or its salt;

[0051] In step (2), compound j or its salt undergoes a condensation reaction with cyanoacetic acid to obtain compound I;

[0052] X is selected from hydrogen and halogens.

[0053] In another preferred embodiment, the compound of formula I has the structure shown in formula D or formula E:

[0054] In another preferred embodiment, the compound of formula I is a mixture of the compound of formula D and the compound of formula E.

[0055] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is x:1; where x is any positive number that is not zero.

[0056] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is (0.6 to 1.5):1.

[0057] In another preferred embodiment, the molar ratio of compound D to compound E in the mixture is 1:1.

[0058] In another preferred embodiment, the compound of formula g has the structure shown in formula gA or formula gB:

[0059] In another preferred embodiment, the compound of formula g is a mixture of compound of formula gA and compound of formula gB.

[0060] In another preferred embodiment, the molar ratio of compound gA to compound gB in the mixture is x:1; where x is any positive number that is not zero.

[0061] In another preferred embodiment, the molar ratio of compound gA to compound gB in the mixture is (0.6 to 1.5):1.

[0062] In another preferred embodiment, the molar ratio of compound gA to compound gB in the mixture is 1:1.

[0063] In another preferred embodiment, when X is Cl, the compound of formula g is a compound of formula g-1;

[0064] In another preferred embodiment, the compound of formula g-1 is a mixture of compound of formula g-1-A and compound of formula g-1-B;

[0065] In another preferred embodiment, the molar ratio of compound g-1-A to compound g-1-B in the mixture is x:1; where x is any positive number that is not zero.

[0066] In another preferred embodiment, the molar ratio of compound g-1-A to compound g-1-B in the mixture is (0.6 to 1.5):1.

[0067] In another preferred embodiment, the molar ratio of compound g-1-A to compound g-1-B in the mixture is 1:1.

[0068] In another preferred embodiment, the compound of formula g has the structure shown in formula g-1-A or formula g-1-B:

[0069] In another preferred embodiment, the compound of formula j has the structure shown in formula jA or formula jB:

[0070] In another preferred embodiment, the compound of formula j is a mixture of compound jA and compound jB.

[0071] In another preferred embodiment, the molar ratio of compound jA to compound jB in the mixture is x:1; where x is any positive number that is not zero.

[0072] In another preferred embodiment, the molar ratio of compound jA to compound jB in the mixture is (0.6 to 1.5):1.

[0073] In another preferred embodiment, the molar ratio of compound jA to compound jB in the mixture is 1:1.

[0074] In another preferred embodiment, X is hydrogen, chlorine, bromine, or iodine; more preferably, X is hydrogen or chlorine.

[0075] In another preferred embodiment, step (1) is carried out under a hydrogenation catalyst; preferably, the hydrogenation catalyst is palladium on carbon.

[0076] In another preferred embodiment, in step (1), the palladium on carbon is 10% palladium on carbon.

[0077] In another preferred embodiment, step (1) is performed in the presence of a hydrogen source; preferably, the hydrogen source is hydrogen gas.

[0078] In another preferred embodiment, step (1) includes the following steps: reacting compound g to obtain compound j or its hydrohalate.

[0079] In another preferred embodiment, in step (1), when X is a halogen, the product obtained is a hydrohalate of compound j or a hexafluorophosphate of hydrohalate of compound j; preferably, a hexafluorophosphate of hydrohalate of compound j.

[0080] In another preferred embodiment, in step (1), when X is chlorine, the product obtained is the hydrochloride salt of compound j or the hexafluorophosphate hydrochloride of compound j; preferably the hexafluorophosphate hydrochloride of compound j.

[0081] In another preferred embodiment, in step (1), when X is hydrogen, the product obtained is a compound of formula j, a hydrohalate of compound j, or a hexafluorophosphate of hydrohalic acid; preferably, a hexafluorophosphate of hydrochloride of compound j; preferably, a hydrochloride of compound j.

[0082] In another preferred embodiment, when X is a halogen, the debenzylation and dehalogenation in step (1) can be performed separately or simultaneously.

[0083] In another preferred embodiment, when X is a halogen, step (1) proceeds through the intermediate / intermediate state shown in the following formula:

[0084] In another preferred embodiment, the compound of formula j-2 has the structure shown in formula j-2-A or formula j-2-B:

[0085] In another preferred embodiment, the compound of formula j-2 is a mixture of compound j-2-A and compound j-2-B.

[0086] In another preferred embodiment, the molar ratio of compound j-2-A to compound j-2-B in the mixture is x:1; where x is any positive number that is not zero.

[0087] In another preferred embodiment, the molar ratio of compound j-2-A to compound j-2-B in the mixture is (0.6 to 1.5):1.

[0088] In another preferred embodiment, the molar ratio of compound j-2-A to compound j-2-B in the mixture is 1:1.

[0089] In another preferred embodiment, when X is a halogen, step (1) proceeds through an intermediate / intermediate state as shown in the following formula:

[0090] In another preferred embodiment, the compound of formula g-2 has the structure shown in formula g-2-A or formula g-2-B:

[0091] In another preferred embodiment, the compound of formula g-2 is a mixture of compound of formula g-2-A and compound of formula g-2-B.

[0092] In another preferred embodiment, the molar ratio of compound g-2-A to compound g-2-B in the mixture is x:1; where x is any positive number that is not zero.

[0093] In another preferred embodiment, the molar ratio of compound g-2-A to compound g-2-B in the mixture is (0.6 to 1.5):1.

[0094] In another preferred embodiment, the molar ratio of compound g-2-A to compound g-2-B in the mixture is 1:1.

[0095] In another preferred embodiment, step (1) further includes a salting purification step of compound j: compound j reacts with an acid to form a salt of compound j, which serves as the starting material for step (2).

[0096] In another preferred embodiment, step (1) further includes a salting purification step of the hydrohalate of compound j: the hydrohalate of compound j reacts with an acid to form a salt of compound j, which serves as the starting material for step (2).

[0097] In another preferred embodiment, in step (1), the acid used for salt purification is hydrochloric acid, hexafluorophosphate, formic acid, sulfuric acid, methanesulfonic acid, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogens on the phenyl group being substituted by a group selected from the group consisting of C1-C3 alkyl, hydroxyl, and halogen; preferably, the acid is hydrochloric acid, hexafluorophosphate, substituted or unsubstituted dibenzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogens on the phenyl group being substituted by a group selected from the group consisting of C1-C3 alkyl, hydroxyl, and halogen; more preferably, the acid is hydrochloric acid, hexafluorophosphate, or combinations thereof.

[0098] In another preferred embodiment, in step (1), the reaction time is 1 to 48 hours, more preferably 5 to 10 hours.

[0099] In another preferred embodiment, in step (1), the reaction temperature is 25–40 °C.

[0100] In another preferred embodiment, step (1) further includes a post-processing step: filtering the reaction solution, washing the filter cake with tetrahydrofuran, concentrating the filtrate, and obtaining a compound of formula j or its salt.

[0101] In another preferred embodiment, in step (2), the molar ratio of compound j or its salt to cyanoacetic acid is 1:(0.7-3); more preferably 1:(1-2);

[0102] In another preferred embodiment, in step (2), the condensation reaction is carried out in a C1-C6 haloalkane solvent, preferably dichloromethane;

[0103] In another preferred embodiment, in step (2), the mass ratio of the cyanoacetic acid to the C1-C6 haloalkane solvent is 1:(10-50); more preferably, it is 1:(20-30).

[0104] In another preferred embodiment, in step (2), the condensation reaction is carried out under alkaline conditions.

[0105] In another preferred embodiment, in step (2), the condensation reaction is carried out under the condition of a condensing agent.

[0106] In another preferred embodiment, in step (2), the molar ratio of cyanoacetic acid to condensing agent is 1:(0.7-2); more preferably, it is 1:(1.5-2).

[0107] In another preferred embodiment, in step (2), the molar ratio of cyanoacetic acid to base is 1:(0.7-3); more preferably, it is 1:(2-3).

[0108] In another preferred embodiment, in step (2), the condensing agent is a commonly used condensing agent in the art, including HATU, EDCI, DCC, HOBt, HBTU, TATU, TBTU, PyBOP, BOP, BOP-Cl, PyBroP, CDI, DIAD, DIC and T3P, preferably HATU and EDCI.

[0109] In this invention,

[0110] In another preferred embodiment, in step (2), the base is diisopropylethylamine, triethylamine, pyridine, sodium bicarbonate, preferably diisopropylethylamine.

[0111] In another preferred embodiment, in step (2), the reaction time is 0.5 to 20 h; more preferably 1 to 10 h.

[0112] In another preferred embodiment, in step (2), the reaction temperature is -20 to 40°C; more preferably 20 to 30°C.

[0113] In another preferred embodiment, step (2) includes the following step: in the presence of a condensing agent and a base, the compound of formula j or its salt undergoes a condensation reaction with cyanoacetic acid.

[0114] In another preferred embodiment, step (2) includes the following steps: providing a solution of cyanoacetic acid, HATU and diisopropylethylamine in a C1-C6 haloalkane solvent at -20 to 0 °C, adding a solution of compound j or its salt in a C1-C6 haloalkane solvent, and reacting at 20 to 30 °C for 1 to 10 hours.

[0115] In another preferred embodiment, step (2) further includes post-processing, including the steps of separation, washing the organic phase with NaHCO3 aqueous solution, water, citric acid aqueous solution, NaHCO3 aqueous solution and water.

[0116] In another preferred embodiment, the compound of formula g is prepared by comprising the following steps:

[0117] In step (Y1), in the presence of a base, compound c and compound f react to give compound g.

[0118] Wherein, X is selected from hydrogen and halogens;

[0119] Alternatively, the compound of formula g can be prepared by the following steps:

[0120] In step (X1), under the action of a base, compound d and compound c react to obtain compound k.

[0121] In step (X2), under the action of a base, compound k reacts with compound e to give compound g.

[0122] X is selected from hydrogen and halogens.

[0123] In another preferred embodiment, the compound of formula c has the structure shown in formula cA or formula cB:

[0124] In another preferred embodiment, the compound of formula c is a mixture of compound of formula cA and compound of formula cB.

[0125] In another preferred embodiment, the molar ratio of compound cA to compound cB in the mixture is x:1; where x is any positive number that is not zero.

[0126] In another preferred embodiment, the molar ratio of compound cA to compound cB in the mixture is (0.6 to 1.5):1.

[0127] In another preferred embodiment, the molar ratio of compound cA to compound cB in the mixture is 1:1.

[0128] In another preferred embodiment, the compound of formula k has the structure shown in formula kA or formula kB:

[0129] In another preferred embodiment, the compound of formula k is a mixture of compound of formula kA and compound of formula kB.

[0130] In another preferred embodiment, the molar ratio of compound kA to compound kB in the mixture is x:1; where x is any positive number that is not zero.

[0131] In another preferred embodiment, the molar ratio of compound kA to compound kB in the mixture is (0.6 to 1.5):1.

[0132] In another preferred embodiment, the molar ratio of compound kA to compound kB in the mixture is 1:1.

[0133] In another preferred embodiment, X is hydrogen, chlorine, bromine, or iodine; more preferably, X is hydrogen or chlorine.

[0134] In another preferred embodiment, step (Y1) includes one or more of the following features:

[0135] (a) The molar ratio of compound c to compound f is (0.7–3):1; preferably (1–1.5):1;

[0136] (b) The molar ratio of the base to the compound of formula f is (0.7–3):1; preferably (1–1.5):1; and

[0137] (c) The base mentioned is an inorganic base or an organic base.

[0138] In another preferred embodiment, in step (Y1), the base is an inorganic base, preferably sodium hydride, cesium carbonate, potassium carbonate, sodium carbonate, or a combination thereof.

[0139] In another preferred embodiment, in step (Y1), the base is an organic base, preferably diisopropylethylamine, triethylamine, pyridine, or a combination thereof.

[0140] In another preferred embodiment, in step (Y1), the reaction temperature is -10 to 10°C, more preferably 0 to 5°C.

[0141] In another preferred embodiment, step (Y1) is carried out in a solvent selected from the group consisting of C2-C8 ether solvents, water, or combinations thereof; preferably tetrahydrofuran.

[0142] In another preferred embodiment, step (Y1) includes the following specific operations: cooling a tetrahydrofuran solution of compound f under an inert gas atmosphere, adding a base; and adding compound c to react.

[0143] In another preferred embodiment, in step (Y1), the reaction time is 0-3 hours, more preferably 0.5-1 hour.

[0144] In another preferred embodiment, in step (Y1), compound c is slowly added over 0.5 to 2 hours.

[0145] In another preferred embodiment, in step (Y1), the alkali is added in batches.

[0146] In another preferred embodiment, the post-processing in step (Y1) includes: filtration and rinsing the filter cake with water.

[0147] In another preferred embodiment, the post-treatment in step (Y1) includes rinsing followed by drying.

[0148] In another preferred embodiment, in step (X1), the base is an inorganic base, preferably sodium hydride, cesium carbonate, potassium carbonate, sodium carbonate, or a combination thereof.

[0149] In another preferred embodiment, in step (X1), the base is an organic base, preferably diisopropylethylamine, triethylamine, pyridine, or a combination thereof.

[0150] In another preferred embodiment, in step (X2), the base is an inorganic base, preferably sodium hydride, cesium carbonate, potassium carbonate, sodium carbonate, or a combination thereof.

[0151] In another preferred embodiment, in step (X2), the base is an organic base, preferably diisopropylethylamine, triethylamine, pyridine, or a combination thereof.

[0152] In another preferred embodiment, the method further includes the following steps:

[0153] Step (XY1) involves the compound of formula g forming a salt with an acid to obtain a salt of compound of formula g.

[0154] Step (XY2) involves the release of the salt of compound g to obtain compound g;

[0155] In another preferred embodiment, in step (XY1), the molar ratio of the compound of formula g to the acid is (0.7-3):1; more preferably (1-2):1.

[0156] In another preferred embodiment, the acid is hydrochloric acid, formic acid, sulfuric acid, methanesulfonic acid, hexafluorophosphate, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogen atoms on the phenyl group being substituted by a group selected from the group consisting of: deuterium, C1-C3 alkyl, C1-C3 alkoxy, cyano, hydroxyl, and halogen; preferably, the acid is hydrochloric acid, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogen atoms on the phenyl group being substituted by a group selected from the group consisting of: C1-C3 alkyl, hydroxyl, and halogen; more preferably, the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), L-(-)-di-p-methylbenzoyl tartaric acid (L-DTTA), or combinations thereof.

[0157] In another preferred embodiment, the acid is or its isomers, or combinations thereof; wherein R1 is selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, cyano, hydroxyl, or halogen.

[0158] In another preferred embodiment, the acid is When R1 is used in combination with or is an isomer of R1 ... alkyl group, R1 is preferably a C1-C3 alkyl group.

[0159] In another preferred embodiment, the acid is (i.e., D-DTTA) (i.e., L-DTTA) or (i.e., DTTA).

[0160] In another preferred embodiment, when the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), the salt of the compound of formula g is:

[0161] In another preferred embodiment, when the acid is L-(-)-di-p-methylbenzoyl tartaric acid (L-DTTA), the salt of the compound of formula g is:

[0162] In another preferred embodiment, when the acid is di-p-methylbenzoyl tartaric acid (DTTA), the salt of the compound of formula g is:

[0163] In another preferred embodiment, in step (XY1), the salt formation step is carried out in a solvent selected from the group consisting of C2-C8 ether solvents, water, or combinations thereof; preferably tetrahydrofuran.

[0164] In another preferred embodiment, in step (XY1), the acid is added in batches.

[0165] In another preferred embodiment, in step (XY1), the acid is dissolved in a C2-C8 ether solvent and added dropwise to the system.

[0166] In another preferred embodiment, step (XY1) includes the following specific operation: the acid is prepared into a solution and added dropwise to the reaction system.

[0167] In another preferred embodiment, in step (XY2), the salt of compound g is freed in an alkaline solution.

[0168] In another preferred embodiment, in step (XY2), the salt of compound g is released in an alkaline solution to obtain a tetrahydrofuran solution of compound g.

[0169] In another preferred embodiment, step (XY2) includes the following steps: washing a tetrahydrofuran solution of the salt of compound g with an alkaline aqueous solution to obtain a tetrahydrofuran solution of compound g.

[0170] In another preferred embodiment, step (XY2) further includes: adding silica gel to the obtained tetrahydrofuran solution of compound g, stirring, filtering, and obtaining a tetrahydrofuran solution of compound g.

[0171] In another preferred embodiment, in step (XY2), the alkaline aqueous solution is an aqueous solution of sodium bicarbonate and sodium chloride.

[0172] In another preferred embodiment, in step (XY2), the alkaline aqueous solution is an aqueous solution of sodium bicarbonate.

[0173] In another preferred embodiment, step (1) includes the following steps:

[0174] Add hexafluorophosphate (HPF6) to the compound of formula j obtained by reacting with the compound of formula g, or the hydrohalate thereof, to form a salt, thereby obtaining hexafluorophosphate of compound j or hydrohalic acid hexafluorophosphate of compound j.

[0175] In another preferred embodiment, when X is a halogen, the steps further include the following operation: in an aromatic solvent, an alkane solvent, or a mixture thereof, a salt is formed with hexafluorophosphate using compound j·hydrohalate, thereby obtaining compound j·hydrohalate hexafluorophosphate (j·HX·HPF6).

[0176] In another preferred embodiment, when X is hydrogen, the steps further include the following operation: salting the compound of formula j with hexafluorophosphate in an aromatic solvent, an alkane solvent, or a mixture thereof, thereby obtaining hexafluorophosphate of compound j.

[0177] In another preferred embodiment, the hydrohalic acid and hexafluorophosphate in the compound of formula j (j·HX·HPF6) are in any ratio, preferably 1:1.

[0178] In another preferred embodiment, the hydrohalic acid in the compound of formula j (j·HX·HPF6) is in any proportion, and the ratio of compound j to hydrohalic acid is 1:(0.5-2.0), preferably 1:1.

[0179] In another preferred embodiment, the hexafluorophosphate in the compound of formula j (j·HX·HPF6) is in any proportion, and the ratio of compound j to hexafluorophosphate is 1:(0.1-2.0), preferably 1:0.5.

[0180] In another preferred embodiment, the aromatic solvent is toluene;

[0181] In another preferred embodiment, the alkane solvent is n-heptane.

[0182] In another preferred embodiment, the steps further include the following operation: a solution of compound j or its hydrohalate with hexafluorophosphate is evaporated or the solvent is replaced with an aromatic solvent.

[0183] In another preferred embodiment, the salt formation temperature is 20–30°C.

[0184] In another preferred embodiment, the salt formation time is 1 to 48 hours; more preferably 2 to 24 hours.

[0185] In another preferred embodiment, the steps further include the following post-processing operations: filtration, washing the filter cake with n-heptane, drying, to obtain compound j, hydrohalic acid hexafluorophosphate (j·HX·HPF6).

[0186] In another preferred embodiment, the compound of formula c is prepared by the following method:

[0187] Compound a reacts with compound b to give compound c.

[0188] In another preferred embodiment, the compound of formula a has the structure shown in formula aA or formula aB:

[0189] In another preferred embodiment, the compound of formula a is a mixture of compound of formula aA and compound of formula aB.

[0190] In another preferred embodiment, the molar ratio of compound aA to compound aB in the mixture is x:1; where x is any positive number that is not zero.

[0191] In another preferred embodiment, the molar ratio of compound aA to compound aB in the mixture is (0.6 to 1.5):1.

[0192] In another preferred embodiment, the molar ratio of compound aA to compound aB in the mixture is 1:1.

[0193] In another preferred embodiment, compound c is prepared by reacting compound a and compound b in the presence of sodium bicarbonate and tetrabutylammonium bisulfate to obtain compound c.

[0194] In another preferred embodiment, the reaction temperature is room temperature, more preferably 5–25°C, and even more preferably 10–15°C.

[0195] In another preferred embodiment, the reaction time is 1 to 10 hours, more preferably 2 to 5 hours.

[0196] In another preferred embodiment, the preparation of the compound of formula c is carried out in a first solvent selected from the group consisting of C1-C6 haloalkane solvents, water, or combinations thereof.

[0197] In another preferred embodiment, compound c is prepared by the following method: in a first solvent, in the presence of sodium bicarbonate and tetrabutylammonium bisulfate, compounds a and b are reacted at 0–15°C for 1–10 hours to obtain compound c.

[0198] In another preferred embodiment, compound c is prepared by the following method: a mixture of sodium bicarbonate, tetrabutylammonium bisulfate, a first solvent and compound a is cooled to 0–5°C, compound b is slowly added dropwise, and the mixture is heated to 10–15°C and stirred for 3–5 hours to obtain compound c.

[0199] In another preferred embodiment, the method includes post-processing.

[0200] In another preferred embodiment, the post-treatment includes: allowing the reaction solution to stand and separating the phases; extracting the aqueous phase with dichloromethane; combining the organic phases and washing them sequentially with dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution and water; drying with anhydrous sodium sulfate; filtering; and vacuum concentrating to obtain an oily compound of formula c.

[0201] In another preferred embodiment, the molar ratio of compound a to compound b is 1:(1-2).

[0202] In another preferred embodiment, the method further includes the following steps:

[0203] Step (3) The compound of formula I reacts with an acid to form a salt, thus obtaining a salt of the compound of formula I;

[0204] Step (4) releases the salt of compound I to obtain compound I.

[0205] In another preferred embodiment, the acid is hydrochloric acid, formic acid, sulfuric acid, methanesulfonic acid, hexafluorophosphate, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogen atoms on the phenyl group being substituted by a group selected from the group consisting of: deuterium, C1-C3 alkyl, C1-C3 alkoxy, cyano, hydroxyl, and halogen; preferably, the acid is hydrochloric acid, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogen atoms on the phenyl group being substituted by a group selected from the group consisting of: C1-C3 alkyl, hydroxyl, and halogen; more preferably, the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), L-(-)-di-p-methylbenzoyl tartaric acid (L-DTTA), or combinations thereof.

[0206] In another preferred embodiment, the acid is or its isomers, or combinations thereof; wherein R1 is selected from hydrogen, deuterium, C1-C3 alkyl, C1-C3 alkoxy, cyano, hydroxyl, or halogen.

[0207] In another preferred embodiment, the acid is When R1 is used in combination with or is an isomer of R1 ... alkyl group, R1 is preferably a C1-C3 alkyl group.

[0208] In another preferred embodiment, the acid is (i.e., D-DTTA) (i.e., L-DTTA) or (i.e., DTTA).

[0209] In another preferred embodiment, in step (3), when the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), the salt of the compound of formula (I) is:

[0210] In another preferred embodiment, in step (3), when the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), the resulting compound of formula I, 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl ester, is in the crystal form of D-(+)-di-p-methylbenzoyl tartaric acid, i.e., the crystal form of formula I·D-DTTA as described above:

[0211] In another preferred embodiment, in step (3), when the acid is L-(-)-di-p-methylbenzoyl tartaric acid (L-DTTA), the salt of the compound of formula (I) is:

[0212] In another preferred embodiment, in step (3), when the acid is di-p-methylbenzoyl tartaric acid (DTTA), the salt of the compound of formula (I) is:

[0213] In another preferred embodiment, in step (3), the molar ratio of the compound of formula I to the acid is 1:(0.1 to 10); more preferably it is 1:(0.3 to 2).

[0214] In another preferred embodiment, in step (3), when the acid is D-(+)-di-p-methylbenzoyl tartaric acid, the weight ratio of the compound of formula I to D-(+)-di-p-methylbenzoyl tartaric acid is 1:(0.1-10); more preferably it is 1:(0.3-2).

[0215] In another preferred embodiment, in step (3), when the acid is D-(+)-di-p-methylbenzoyl tartaric acid, the weight ratio of the compound of formula j or its salt to D-(+)-di-p-methylbenzoyl tartaric acid is 1:(0.1-10); more preferably it is 1:(0.3-2).

[0216] In another preferred embodiment, step (3) includes the following steps: dissolving the compound of formula I obtained in step (2) in an ether solvent and adding acid to form a salt.

[0217] In another preferred embodiment, when the acid is D-(+)-di-p-methylbenzoyl tartaric acid, step (3) includes the following steps: dissolving the compound of formula I obtained in step (2) in an ether solvent and adding D-(+)-di-p-methylbenzoyl tartaric acid to form a salt.

[0218] In another preferred embodiment, when the acid is D-(+)-di-p-methylbenzoyl tartaric acid, step (3) includes the following steps: at 30-45°C, the compound of formula I obtained in step (2) is dissolved in an ether solvent, and D-(+)-di-p-methylbenzoyl tartaric acid is added to form a salt.

[0219] In another preferred embodiment, in step (3), the ether solvent used to dissolve compound I is methyl tert-butyl ether.

[0220] In another preferred embodiment, step (3) further includes purifying the salt of compound I by pulping or crystallization in a solvent; preferably, the solvent is water, an alcohol solvent, an ether solvent, an alkane solvent, or a combination thereof; more preferably, the solvent is a combination of water and ethanol or a combination of methyl tert-butyl ether and n-heptane.

[0221] In another preferred embodiment, when water and ethanol are used in step (3) crystallization or pulping crystallization, the weight ratio of water to ethanol is (0.5-10):1; more preferably (1-5):1.

[0222] In another preferred embodiment, when ether solvents and alkane solvents are used in step (3) crystallization or pulping crystallization, the weight ratio of ether solvents to alkane solvents is (0.1-10):1; more preferably (0.2-2):1.

[0223] In another preferred embodiment, seed crystals need to be added in step (3).

[0224] In another preferred embodiment, when the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), step (3) requires the addition of I-D-DTTA seed crystals;

[0225] In another preferred embodiment, step (3) includes the following operations: filtering, washing, and drying.

[0226] In another preferred embodiment, the product obtained in step (4) is methyl 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) ester, which is the crystal form of the JAK inhibitor compound shown in Formula I as described above.

[0227] In another preferred embodiment, step (4) includes a detachment operation.

[0228] In another preferred embodiment, the detachment operation in step (4) includes: dissolving a salt of the compound of formula I in a solvent, detaching or washing it with an alkali or an aqueous alkali solution, or a solution of the compound of formula I.

[0229] In another preferred embodiment, the ionization operation in step (4) is carried out in an ether solvent, a haloalkane solvent, or a combination thereof; preferably, the solvent is dichloromethane.

[0230] In another preferred embodiment, step (4) includes a crystallization operation.

[0231] In another preferred embodiment, step (4) includes the following crystallization operation: dissolving the compound of formula I obtained in the free operation in step (4) in an ether solvent to obtain an ether solvent solution of compound I.

[0232] In another preferred embodiment, the ether solvent solution of the compound of formula I obtained in the crystallization operation of step (4) is a methyl tert-butyl ether solution of the compound of formula I.

[0233] In another preferred embodiment, step (4) includes the following crystallization operation: adding an alkane solvent to the ether solvent solution of the obtained compound of formula I, crystallizing to obtain compound of formula I.

[0234] In another preferred embodiment, the alkane solvent added to the ether solvent solution of the obtained compound of formula I in step (4) crystallization is a C1-C8 alkane solvent; preferably, the alkane solvent is n-heptane; preferably, the alkane solvent is n-hexane.

[0235] In another preferred embodiment, the weight ratio of ether solvent to alkane solvent used in the crystallization operation of step (4) is (0.1-10):1; more preferably (1-5):1.

[0236] In another preferred embodiment, seed crystals need to be added in step (4);

[0237] In another preferred embodiment, step (4) requires the addition of a seed crystal of compound I;

[0238] In another preferred embodiment, step (4) includes the following operations: filtering, washing, and drying.

[0239] In a fourth aspect of the present invention, a method for preparing a JAK inhibitor compound of Formula I is provided, comprising the following steps:

[0240] Step (4) releases formula I·D-DTTA to obtain compound I.

[0241] In a fifth aspect of the present invention, a method for preparing formula I·D-DTTA is provided, comprising the following steps:

[0242] Step (1) involves reacting compound g to obtain compound j or its salt;

[0243] In step (2), compound j or its salt undergoes a condensation reaction with cyanoacetic acid to obtain the compound shown in formula I;

[0244] In step (3), compound I reacts with D-(+)-di-p-methylbenzoyl tartaric acid to form a salt, yielding compound I·D-DTTA;

[0245] X is selected from hydrogen and halogens.

[0246] In a sixth aspect of the invention, an intermediate compound is provided, said compound having a structure selected from the group consisting of:

[0247] In another preferred embodiment, the compound of formula g DTTA refers to a mixture of compound of formula g·D-DTTA and compound of formula g·L-DTTA; preferably, in the mixture, the molar ratio of compound of formula g·D-DTT to compound of formula g·L-DTTA is (0.6 to 1.5):1.

[0248] In another preferred embodiment, the formula I·DTTA refers to a mixture of formula I·D-DTTA and formula I L-DTTA; preferably, the molar ratio of formula I·D-DTTA to formula I L-DTTA in the mixture is (0.6~1.5):1.

[0249] The crystal forms of JAK inhibitor compounds and their salts shown in Formula I

[0250] This invention provides the crystal form of methyl 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) ester, a JAK inhibitor compound of Formula I;

[0251] Specifically, the compound of Formula I has the following X-ray powder diffraction characteristic peaks: 6.876°±0.3°, 20.599°±0.3°, 24.878°±0.3°, 13.947°±0.3°, 11.129°±0.3°, 12.507°±0.3°, and 19.465°±0.3°.

[0252] In another preferred embodiment, the crystal form of the compound of formula I has the following X-ray powder diffraction characteristic peaks: 6.876°±0.3°, 20.599°±0.2°, 24.878°±0.2°, 13.947°±0.2°, 11.129°±0.2°, 12.507°±0.2°, and 19.465°±0.2°.

[0253] In another preferred embodiment, the crystal form of the compound of formula I has the following X-ray powder diffraction characteristic peaks: 6.876°±0.2°, 20.599°±0.2°, 24.878°±0.2°, 13.947°±0.2°, 11.129°±0.2°, 12.507°±0.2°, and 19.465°±0.2°.

[0254] In another preferred embodiment, the crystal form of the compound of formula I further has one or more (e.g., 2, 3, 5, 8 or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 17.068°±0.2°, 25.150°±0.2°, 27.560°±0.2°, 14.755°±0.2°, 17.545°±0.2°, 20.026°±0.2°, 22.523°±0.2°, 24.461°±0.2°, 24.038°±0.2°, 7.651°±0.2°, 21.432°±0.2°, 18.772°±0.2°, and 23.560°±0.2°.

[0255] In another preferred embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of the compound of formula I include: 18.292°±0.2°, 19.066°±0.2°, 16.365°±0.2°, 31.347°±0.2°, 28.212°±0.2°, 15.438°±0.2°, 23.147°±0.2°, 31.993°±0.2°, 13.510°±0.2°, 31.638°±0.2°, 26.203°±0.2°, 30.270°±0.2°, 34 0.962°±0.2°, 30.522°±0.2°, 38.671°±0.2°, 33.027°±0.2°, 22.076°±0.2°, 10.218°±0.2°, 15.846°±0.2°, 29.727°±0.2°, 32.561°±0.2°, 9.272°±0.2°, 35.781°±0.2°, 36.749°±0.2°, 39.559°±0.2°, 29.384°±0.2°, 37.708°±0.2°.

[0256] In one embodiment, the crystal form of the compound of formula I has an XRPD pattern substantially as shown in FIG1.

[0257] In one embodiment, the crystal form of the compound of formula I has a TGA diagram that is essentially as shown in Figure 2.

[0258] In one embodiment, the crystal form of the compound of formula I has a DSC diagram that is essentially as shown in FIG3.

[0259] As shown in Figures 5-6, the crystal form of the Formula I compound provided by this invention has excellent stability. After being placed under accelerated conditions (40±2℃ / 75±5%RH) for 6 months, the crystal form did not change; after being placed under long-term conditions (5±3℃) for 12 months, the crystal form did not change.

[0260] The present invention also provides a crystal form of the salt formed by the JAK inhibitor compound 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl ester and D-(+)-di-p-methylbenzoyl tartrate, namely the crystal form of Formula I·D-DTTA, which has the following structure:

[0261] Since the compound of formula I obtained directly from the reaction is difficult to purify directly by crystallization or other methods, this invention develops a method to obtain compound of formula I·D-DTTA by salting compound of formula I with D-(+)-di-p-methylbenzoyl tartaric acid, and then purifying it by pulping, crystallization, etc. to obtain compound of formula I with higher purity. At this time, compound of formula I is more conducive to purification by crystallization.

[0262] In one embodiment, the crystal form of Formula I·D-DTTA has the XRPD diagram shown in FIG4.

[0263] In another embodiment, the crystal form of Formula I·D-DTTA has the following X-ray powder diffraction characteristic peaks: 21.831°±0.2°, 15.903°±0.2°, 14.651°±0.2°, 13.848°±0.2°, 15.015°±0.2°, 17.248°±0.2°, and 24.551°±0.2°;

[0264] In another embodiment, the crystal form of Formula I·D-DTTA also has one or more (e.g., 2, 3, 5, 8 or 10) X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.793°±0.2°, 9.130°±0.2°, 18.310°±0.2°, 20.986°±0.2°, 24.270°±0.2°, 18.974°±0.2°, 24.977°±0.2°, 26.223°±0.2°, 26.613°±0.2°, 16.431°±0.2°, 19.755°±0.2°, 11.400°±0.2°, 25.737°±0.2°, and 5.246°±0.2°.

[0265] In another embodiment, the X-ray powder diffraction characteristic peaks of the crystal form of Formula I·D-DTTA include: 20.324 0±0.2°, 10.469°±0.2°, 22.509°±0.2°, 29.183°±0.2°, 11.881°±0.2°, 27.941°±0.2°, 23.512°±0.2°, 27.082°±0.2°, 32.152°±0.2°, 30.418°±0.2°, 38.995°±0.2°, 6.866°±0.2°, 35.087°±0.2°, 33.918°±0.2°, 38.042°±0.2°, 37.128°±0.2°, 39.408°±0.2°, 36.788°±0.2°, 36.124°±0.2°.

[0266] In a seventh aspect of the present invention, a method for preparing a compound of formula g is provided, comprising the steps of reacting a compound of formula c and a compound of formula f in a solvent in the presence of a base to prepare a compound of formula g.

[0267] Where X is hydrogen or halogen.

[0268] In one embodiment of the present invention, the halogen is fluorine, chlorine, bromine or iodine; preferably chlorine.

[0269] In one embodiment of the present invention, X is hydrogen or chlorine.

[0270] In one embodiment of the present invention, the compound of formula c is Or a molar ratio of 1:1

[0271] In one embodiment of the present invention, the compound of formula f is

[0272] In one embodiment of the present invention, the compound of formula g is The molar ratio is 1:1 Or a molar ratio of 1:1

[0273] In the preparation method of the compound of formula g, the solvent is a conventional solvent for this type of reaction in the art; for example, an organic solvent, and also for example, an ether solvent and / or an amide solvent; the ether solvent may be tetrahydrofuran or methyl tert-butyl ether; for example, anhydrous tetrahydrofuran or aqueous tetrahydrofuran; the amide solvent may be N,N-dimethylformamide.

[0274] In the preparation method of the compound of formula g, the base is a conventional base for this type of reaction in the art; for example, an inorganic base; or, for example, an alkali metal carbonate or an alkali metal hydride; the alkali metal carbonate may be potassium carbonate; the alkali metal hydride may be sodium hydride; for example, 60% sodium hydride.

[0275] In one aspect of the present invention, when X is a halogen, the base is an alkali metal hydride as described above; the solvent may be an ether solvent as described above.

[0276] In one embodiment of the present invention, when X is H, the base is an alkali metal carbonate as described above; the solvent may be an amide solvent as described above.

[0277] In the preparation method of compound g, the molar ratio of compound f to compound c is a conventional molar ratio for this type of reaction in the art; for example, 1:(1.0-4.0); or for example, 1:1.3 or 1:3.

[0278] In the preparation method of the compound of formula g, the molar ratio of the compound of formula f to the base of formula f is a conventional molar ratio for this type of reaction in the art; for example, 1:(1.0-4.0); or for example, 1:1.3 or 1:3.

[0279] In the preparation method of the compound of formula g, the molar mass ratio of the compound of formula f to the solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.1-0.5 mmol / g; or for example, 0.31 mmol / g or 0.1 mmol / g.

[0280] In the preparation method of the compound of formula g, the reaction temperature is the temperature of a conventional reaction of this type in the art; for example, -5℃ to 60℃; or for example, -5℃ to 5℃ or 40 to 60℃; further for example, 0 to 5℃ or 50℃.

[0281] In one aspect of the present invention, when the base is an alkali metal hydride, the reaction temperature is -5°C to 5°C; for example, 0°C to 5°C.

[0282] In one aspect of the present invention, when the alkali is an alkali metal carbonate, the reaction temperature is 40-60°C, for example, 50°C.

[0283] In one aspect of the present invention, in the method for preparing compound g, the reaction time is 0.5-28 h; for example, 0.5-1 h or 24 h.

[0284] In one aspect of the present invention, the preparation method of the compound of formula g further includes the following post-processing steps: extraction (e.g., first adding water and then extracting with an ester solvent (e.g., ethyl acetate), washing (e.g., saturated sodium chloride aqueous solution), drying (e.g., anhydrous sodium sulfate), filtration, concentration (e.g., vacuum concentration) and separation by silica gel column chromatography (e.g., ethyl acetate: petroleum ether = 0-100%).

[0285] Alternatively, quench (e.g., acetic acid), separate (e.g., NaHCO3 solution; or, for example, 4% NaHCO3 solution), concentrate, separate (e.g., n-heptane, 4% NaHCO3 solution), add silica gel and stir to obtain filtrate.

[0286] In one aspect of the present invention, the preparation method of compound g further includes the following steps: in a solvent, in the presence of an alkali metal bicarbonate and a phase transfer catalyst, compound a and compound b react to prepare compound c.

[0287] In one embodiment of the present invention, the compound of formula a is Or a molar ratio of 1:1

[0288] In the preparation method of compound c, the solvent is a conventional solvent for this type of reaction in the art; for example, an organic solvent and / or water; the organic solvent may be an alkane solvent; for example, dichloromethane.

[0289] In one embodiment of the present invention, in the preparation method of the compound of formula c, the alkali metal bicarbonate is sodium bicarbonate.

[0290] In one aspect of the present invention, in the preparation method of the compound of formula c, the phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst; for example, Bu4NHSO4.

[0291] In the preparation method of compound c, the molar ratio of compound a to compound b is a conventional molar ratio for this type of reaction in the art; for example, 1:(1-3); or for example, 1:1.2.

[0292] In the preparation method of the compound of formula c, the molar ratio of the compound of formula a to the alkali metal bicarbonate is a conventional molar ratio for this type of reaction in the art; for example, 1:(1-5); or for example, 1:3.3.

[0293] In the preparation method of the compound of formula c, the molar ratio of the compound of formula a to the phase transfer catalyst is a conventional molar ratio for this type of reaction in the art; for example, 1:(0.04-0.10); or for example, 1:0.08.

[0294] In the preparation method of the compound of formula c, the molar mass ratio of the compound of formula a to the solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.1-0.4 mmol / g; or for example, 0.25 mmol / g.

[0295] In one aspect of the present invention, in the preparation method of compound c, the mass ratio of water to organic solvent is 1:(1-2); for example, 1:1.33.

[0296] In one aspect of the present invention, in the preparation method of compound c, the reaction temperature is 0-30°C; for example, 10-15°C.

[0297] In one aspect of the present invention, in the method for preparing compound c, the reaction time is 1-8 hours; for example, 3-5 hours.

[0298] In one aspect of the present invention, the preparation method of the compound of formula g further includes the following steps: in a solvent and in the presence of a base, the compound of formula d reacts with the compound of formula e to prepare the compound of formula f;

[0299] In one embodiment of the present invention, the compound of formula d is

[0300] In the preparation method of the compound of formula f, the base is a conventional base for this type of reaction in the art; for example, an alkali metal carbonate; or, for example, potassium carbonate.

[0301] In the preparation method of compound f, the solvent is a conventional solvent for this type of reaction in the art; for example, water.

[0302] In the preparation method of compound f, the molar ratio of compound d to compound e is a conventional molar ratio for this type of reaction in the art; for example, 1:(1-3); or for example, 1:1.1.

[0303] In the preparation method of compound f, the molar ratio of compound d to the base is a conventional molar ratio for this type of reaction in the art; for example, 1:(2-4); or for example, 1:3.

[0304] In the preparation method of compound f, the molar mass ratio of compound d to solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.2-0.6 mmol / g; or for example, 0.41 mmol / g.

[0305] In one aspect of the present invention, in the method for preparing compound f, the reaction is carried out under reflux conditions.

[0306] In one aspect of the present invention, in the method for preparing compound f, the reaction time is 24-72 h; for example, 48 h.

[0307] In an eighth aspect of the present invention, a method for preparing a compound of formula g·DTTA is provided, comprising the following steps: reacting a compound of formula g and a compound of formula DTTA in a solvent as described above to prepare a compound of formula g·DTTA.

[0308] Wherein, X is defined as described in any embodiment of the present invention.

[0309] In one embodiment of the present invention, the DTTA compound is: Or a molar ratio of 1:1

[0310] In one embodiment of the present invention, the compound of formula g·DTTA is The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 Or a molar ratio of 1:1

[0311] In the preparation method of the compound of formula g·DTTA, the solvent is a conventional solvent for this type of reaction in the art; for example, an organic solvent and / or water; the organic solvent is an ether solvent and / or an amide solvent; the ether solvent and amide solvent are as described in any embodiment of the present invention; preferably, the solvent is an organic solvent and water.

[0312] In one embodiment of the present invention, the mass ratio of the organic solvent to water is 1:(0.2-0.8); for example, 1:0.5.

[0313] In the preparation method of the compound of formula g·DTTA, the molar ratio of the compound of formula g to the compound of formula DTTA is a conventional molar ratio for this type of reaction in the art; for example, 1:(1.0-2.0); or for example, 1:1.3.

[0314] In the preparation method of the compound of formula g·DTTA, the molar mass ratio of the compound of formula g to the solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.05-0.3 mmol / g; or for example, 0.1 mmol / g.

[0315] In the preparation method of the compound of formula g·DTTA, the reaction temperature is the temperature of a conventional reaction of this type in the art; for example, 15-35℃; or for example, 20-25℃.

[0316] In one embodiment of the present invention, the preparation method of the compound of formula g·DTTA further includes a preparation method of compound g; the preparation method of the compound of formula g is as described in any embodiment of the present invention.

[0317] In one aspect of the present invention, the preparation method of the compound of formula g·DTTA includes the following steps:

[0318] Step 1: In a solvent and in the presence of a base, compound c and compound f react to obtain a reaction solution;

[0319] Step 2: Mix the reaction solution from Step 1, the DTTA compound of formula g, and the solvent; react to obtain the DTTA compound of formula g.

[0320] The operation and conditions of the reaction in step 1 are independently as described in the preparation method of compound g in any of the present invention;

[0321] In step 2, the DTTA compound and the g·DTTA compound are independently as described in any embodiment of the present invention.

[0322] In step 2, the solvent is a conventional solvent for this type of reaction in the art; for example, water.

[0323] The molar ratio of compound f in step 1 to compound DTTA in step 2 is a conventional molar ratio for this type of reaction in the art; for example, 1:(1.0-2.0); or for example, 1:1.3 or 1:1.

[0324] The molar ratio of compound f in step 1 to solvent in step 2 is a conventional molar ratio for this type of reaction in the art; for example, 0.1-0.3 mmol / g; or for example, 0.15 mmol / g.

[0325] The reaction temperature in step 2 is the conventional reaction temperature for this type of reaction in the art; for example, 15-35℃; or for example, 20-25℃.

[0326] In one aspect of the present invention, the preparation method of the compound of formula g·DTTA includes the following post-processing steps: filtration, washing the filter cake (e.g., washing with water or an alkane solvent (e.g., n-heptane)), and drying.

[0327] In a ninth aspect of the present invention, a method for preparing a compound of formula j HCl HPF6 is provided, comprising the following steps: reacting the compound of formula j HCl with hexafluorophosphoric acid in a solvent to prepare the compound of formula j HCl HPF6;

[0328] In one embodiment of the present invention, the HCl compound of formula j is Or a molar ratio of 1:1

[0329] In one embodiment of the present invention, the compound of formula j HCl HPF6 is... Or a molar ratio of 1:1

[0330] In one embodiment of the present invention, in the method for preparing the compound of formula j HCl HPF6, the solvent is an organic solvent; for example, selected from one or more of alkane solvents, benzene solvents, and ether solvents; for example, "alkane solvents and benzene solvents" or "benzene solvents and ether solvents"; the alkane solvent may be dichloromethane and / or n-heptane; the benzene solvent may be toluene; the ether solvent is as described in any embodiment of the present invention.

[0331] In one aspect of the present invention, the hexafluorophosphate is present in the form of an aqueous solution; for example, a 60% aqueous solution of hexafluorophosphate.

[0332] In the preparation method of the compound of formula j HCl HPF6, the molar ratio of the compound of formula j HCl to hexafluorophosphoric acid is a conventional molar ratio for this type of reaction in the art; for example, 1:(0.1-2.0); or for example, 1:0.4, 1:0.9 or 1:1.0.

[0333] In the preparation method of the compound of formula j HCl HPF6, the molar mass ratio of the compound of formula j HCl to the solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.1-0.8 mmol / g; or for example, 0.2 mmol / g.

[0334] In one embodiment of the present invention, the mass ratio of the alkane solvent to the benzene solvent is 1:(1.5-4); for example, 1:2.5.

[0335] In one embodiment of the present invention, the mass ratio of dichloromethane to n-heptane is 1:(1.2-2); for example, 1:1.52.

[0336] In one aspect of the present invention, in the method for preparing the compound of formula j HCl HPF6, the reaction temperature is 10-40℃; for example, 20-30℃.

[0337] In one aspect of the present invention, the preparation method of the compound of formula j HCl HPF6 includes the following steps; the steps are any of the following schemes:

[0338] Option 1: Hexafluorophosphate is dissolved in an alkane solvent of formula j HCl and concentrated to obtain a concentrate; the concentrate is further concentrated in a benzene solvent and then reacted in a benzene solvent and an alkane solvent; the alkane solvent is preferably added dropwise; preferably, hexafluorophosphate is dissolved in dichloromethane solvent of j HCl and concentrated to obtain a concentrate; the concentrate is further concentrated in toluene and then reacted in toluene and n-heptane to prepare compound j HCl HPF6.

[0339] Scheme 2: The alkane solvent of compound j HCl is dried by an inert gas; then it is reacted with hexafluorophosphoric acid in an ether solvent to prepare compound j HCl HPF6; the inert gas can be nitrogen; the ether solvent is as described in any scheme of the present invention.

[0340] In one aspect of the present invention, the preparation method of the compound of formula j HCl HPF6 further includes the following post-processing steps:

[0341] Filtration, washing of the filter cake (e.g., rinsing with alkane solvents as described above), and drying;

[0342] Alternatively, it can be dried with an inert gas (e.g., nitrogen), pulped (e.g., with an alkane solvent as described above), and filtered.

[0343] In one aspect of the present invention, the preparation method of the compound of formula j HCl HPF6 further includes the following steps: in a solvent, in the presence of a reducing agent and a catalyst, the compound of formula g-1 is reacted to prepare the compound of formula j HCl.

[0344] In one embodiment of the present invention, the compound of formula g-1 is... Or a molar ratio of 1:1

[0345] In the preparation method of the HCl compound of formula j, the solvent is a conventional solvent for this type of reaction in the art; for example, an organic solvent and / or water; the organic solvent may be an ether solvent; or, for example, tetrahydrofuran.

[0346] The reducing agent is a conventional reducing agent for this type of reaction in the art; for example, hydrogen.

[0347] The catalyst is a conventional catalyst for this type of reaction in the art; for example, a palladium-on-carbon catalyst; or, for example, 10% palladium-on-carbon.

[0348] In the preparation method of the HCl compound of formula j, the molar mass ratio of the compound of formula g-1 to the solvent is a conventional molar mass ratio for this type of reaction in the art.

[0349] In the preparation method of the HCl compound of formula j, the molar ratio of the compound of formula g-1 to the reducing agent is the conventional amount used in this type of reaction in the art.

[0350] In the preparation method of the HCl compound of formula j, the molar ratio of the compound of formula g-1 to the catalyst is a conventional molar ratio for this type of reaction in the art; for example, 1:(0.01-1); or for example, 1:0.1 or 1:0.2.

[0351] In one aspect of the present invention, in the preparation method of the HCl compound of formula j, the reaction temperature is 30-60°C; for example, 30-38°C, 30-40°C, or 40-50°C.

[0352] In one aspect of the present invention, in the method for preparing the HCl compound of formula j, the reaction time is 1 hour, 55 hours, or 8-10 hours.

[0353] In one aspect of the present invention, the preparation method of the compound of formula j HCl further includes the following steps: in a solvent, in the presence of a base, the compound of formula g-1·D-DTTA is used to prepare the compound of formula g-1;

[0354] In one embodiment of the present invention, the compound of formula g-1·D-DTTA is The molar ratio is 1:1 Or a molar ratio of 1:1

[0355] In one aspect of the present invention, in the method for preparing the compound of formula g-1, the solvent is an organic solvent; for example, an ether solvent as described above.

[0356] In one embodiment of the present invention, the alkali is an alkali metal carbonate or an alkali metal bicarbonate; for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate; and also, for example, sodium bicarbonate.

[0357] In one aspect of the present invention, in the preparation method of the compound of formula g-1, the sodium bicarbonate exists in the form of an aqueous solution of sodium bicarbonate.

[0358] In one aspect of the present invention, in the method for preparing the compound of formula g-1, the mass-to-volume ratio of the compound of formula g-1 to the solvent is 0.05-0.5 g / mL; for example, 0.089 g / mL, 0.136 g / mL or 0.228 g / mL.

[0359] In one aspect of the present invention, in the method for preparing the compound of formula g-1, the mass ratio of the compound of formula g-1 to the base is 2-10; for example, 4.73, 5.45 or 7.12.

[0360] In one aspect of the present invention, the preparation method of the compound of formula g-1 further includes the addition of sodium chloride; the sodium chloride may be in the form of an aqueous solution of sodium chloride; for example, a semi-saturated aqueous solution of sodium chloride or a saturated aqueous solution of sodium chloride.

[0361] In one aspect of the present invention, the preparation method of the compound of formula g-1 further includes the addition of silica gel.

[0362] In one aspect of the present invention, in the preparation method of the compound of formula g-1, the reaction temperature is -5℃ to 5℃; or, for example, 0℃ to 5℃.

[0363] In one aspect of the present invention, the method for preparing the compound of formula j HCl HPF6 includes the following steps:

[0364] Step 1: In a solvent, in the presence of sodium bicarbonate and sodium chloride, the compound of formula g-1·D-DTTA reacts to obtain a reaction solution;

[0365] Step 2: Mix the reaction solution from Step 1, the reducing agent as described above, the catalyst as described above, and the compound of formula g-1 as described above, and allow the reaction to occur; to obtain the reaction solution;

[0366] Step 3: Mix the reaction solution and solvent from Step 2, the compound of formula j HCl, with hexafluorophosphoric acid, and react to obtain the compound of formula j HCl HPF6;

[0367] The operation and conditions of step 1 are independently as described in the preparation method of compound g-1.

[0368] In one embodiment of the present invention, in the preparation method of the compound of formula j HCl HPF6, the solvent in step 2 further includes water.

[0369] In one aspect of the present invention, in the preparation method of the compound of formula j HCl HPF6, in step 3, the solvent is an organic solvent, such as benzene solvents and / or alkane solvents as described above.

[0370] In the preparation method of the compound of formula j HCl HPF6, the molar ratio of the compound of formula g-1·D-DTTA in step 1 to the catalyst in step 2 is a conventional molar ratio for this type of reaction in the art; for example, 1:(0.01-1); or for example, 1:0.1 or 1:0.2.

[0371] In the preparation method of the compound of formula j HCl HPF6, the molar ratio of the compound of formula g-1·D-DTTA in step 1 to the reducing agent in step 2 is a conventional molar ratio for this type of reaction in the art; for example, 1:(2-5); or for example, 1:2 or 1:2.5.

[0372] In the preparation method of the compound of formula j HCl HPF6, the molar ratio of the compound of formula g-1·D-DTTA in step 1 to the hexafluorophosphate in step 3 is a conventional molar ratio for this type of reaction in the art; for example, 1:(0.1-2.0); or for example, 1:0.4, 1:0.9 or 1:1.0.

[0373] When a solvent is present in step 2; in the preparation method of the compound of formula j HCl HPF6, the molar mass ratio of the compound of formula g-1·D-DTTA in step 1 to the solvent in step 2 is a conventional molar mass ratio for this type of reaction in the art; for example, 3-10 mmol / g; or for example, 7.1 mmol / g.

[0374] In the preparation method of the compound of formula j HCl HPF6, the molar mass ratio of the compound of formula g-1·D-DTTA in step 1 to the solvent in step 3 is a conventional molar mass ratio for this type of reaction in the art; for example, 0.1-1 mmol / g; or for example, 0.25 mmol / g.

[0375] In one aspect of the present invention, in the preparation method of the compound of formula j HCl HPF6, in step 2, the reaction temperature is 30-60℃; for example, 30-38℃, 30-40℃ or 40-50℃.

[0376] In one embodiment of the present invention, in the preparation method of the compound of formula j HCl HPF6, in step 3, the reaction temperature is 10-40℃; for example, 20-30℃.

[0377] In one aspect of the present invention, step 2 of the method for preparing the compound of formula j HCl or the method for preparing the compound of formula j HCl HPF6 further includes a post-processing step of any of the following: Scheme 1: filtration, washing (e.g., rinsing with an ether solvent as described above), and concentration (e.g., vacuum distillation); Scheme 2: filtration, washing (e.g., rinsing with an ether solvent as described above), concentration (e.g., vacuum concentration), and then dissolving in an alkane solvent as described above; Scheme 3: filtration, concentration (e.g., vacuum distillation), and then dissolving in an alkane solvent as described above, and washing (e.g., washing with a saturated sodium chloride aqueous solution).

[0378] In a tenth aspect of the present invention, a method for preparing the crystal form of the formula ID-DTTA as described above is provided, comprising the following steps: reacting a compound of formula I with a compound of formula D-DTTA in a solvent to prepare the crystal form of formula ID-DTTA.

[0379] In one embodiment of the present invention, the compound of formula I is Or a molar ratio of 1:1

[0380] In one embodiment of the present invention, the formula I D-DTTA is: Or a molar ratio of 1:1

[0381] In the method for preparing the crystal form of the aforementioned ID-DTTA, the solvent is a conventional solvent for this type of reaction in the art; for example, an organic solvent; or, for example, an ether solvent; the ether solvent may be tetrahydrofuran or methyl tert-butyl ether; for example, methyl tert-butyl ether.

[0382] In the method for preparing the crystal form of the aforementioned formula ID-DTTA, the molar mass ratio of the compound of formula I to the solvent is a conventional molar mass ratio for this type of reaction in the art; for example, 0.05-0.3 mmol / g; or for example, 0.1 mmol / g or 0.25 mmol / g.

[0383] In the method for preparing the crystal form of the ID-DTTA, the molar ratio of the compound of formula I to the compound of formula DTTA is a conventional molar ratio for this type of reaction in the art; for example, 1:(1.0-2.0); or for example, 1:1.3 or 1:1.

[0384] In the method for preparing the crystal form of the aforementioned ID-DTTA, the reaction temperature is 15-60℃; for example, 30-35℃, 35-40℃, 20-25℃, or 28℃.

[0385] In one aspect of the present invention, in the method for preparing the crystal form of formula I·D-DTTA, the reaction time is 6-24 h; for example, 12 h or 16 h.

[0386] In one aspect of the present invention, the method for preparing the crystal form of formula I·D-DTTA further includes adding the crystal form of formula ID-DTTA as a seed crystal; the crystal form of the compound of formula I·DTTA is prepared by the preparation method described above.

[0387] In one aspect of the present invention, the method for preparing the crystal form of the compound of formula I·DTTA includes the following post-processing steps: filtration and washing of the filter cake (e.g., washing with an alcohol solvent and water or washing with an ether solvent and an alkane solvent); the alcohol solvent may be ethanol; the ether solvent may be methyl tert-butyl ether; the alkane solvent may be n-heptane; the washing may be, for example, rinsing; the number of washing cycles may be, for example, 2.

[0388] In an eleventh aspect of the present invention, a method for preparing the crystal form of the compound of formula I as described above is provided, comprising the following steps: mixing a mixture of the positive solvent and the antisolvent of the compound of formula I and then crystallizing to obtain the crystal form of the compound of formula I.

[0389] In one embodiment of the present invention, in the method for preparing the crystal form of the compound of formula I, the normal solvent is an ether solvent; the ether solvent is as described in any embodiment of the present invention.

[0390] In one embodiment of the present invention, in the method for preparing the crystal form of the compound of formula I, the antisolvent is an alkane solvent; the alkane solvent is as described in any embodiment of the present invention.

[0391] In one embodiment of the present invention, the mass ratio of the compound of formula I to the positive solvent is 1:(2-5); for example, 1:3.7.

[0392] In one embodiment of the present invention, the mass ratio of the compound of formula I to the antisolvent is 1:(0.8-2); for example, 1:1.37.

[0393] In one aspect of the present invention, the crystallization temperature is 15-50°C; for example, 25-35°C.

[0394] In one aspect of the present invention, the crystallization time is 14-40 hours; for example, 20-32 hours.

[0395] In one aspect of the present invention, the method for preparing the crystal form of the compound of formula I includes the following steps: dissolving the compound of formula I in a positive solvent, and then adding an antisolvent (e.g., slowly); first cooling to 30-45°C (e.g., 30-35°C), and adding the compound of formula I as a seed crystal; then stirring at 30-45°C (e.g., 30-35°C) for 12-30 hours (e.g., 16-24 hours); then cooling a second time to 15-30°C (e.g., 25-30°C), and stirring for 2-10 hours (e.g., 4-8 hours).

[0396] In one aspect of the present invention, the method for preparing the crystal form of the compound of formula I further includes a purification step; replacing the compound of formula I with the crystal form of the compound of formula I; repeating the method for preparing the crystal form of the compound of formula I as described above; the repetition may be repeated once.

[0397] In one aspect of the present invention, the method for preparing the crystal form of the compound of formula I further includes the following post-processing steps: filtration, washing the filter cake (e.g., washing with ether solvents and alkane solvents), and drying (e.g., drying at 45°C or with an inert gas; for example, nitrogen).

[0398] In a twelfth aspect, the present invention provides a compound as shown below: For example, The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1. The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 Or a molar ratio of 1:1

[0399] In one aspect of the present invention, the compound When heated to 140±3℃, for example 120℃, the weight loss during thermogravimetric analysis (TGA) is 25%-30%, for example, 28.23%.

[0400] In one aspect of the present invention, the compound It has a basic TGA diagram as shown in Figure 8.

[0401] In one aspect of the present invention, the compound During differential scanning calorimetry (DSC), there is an endothermic signal when heated to 74℃±3℃, for example, 74℃; and / or an endothermic signal when heated to 142℃±3℃, for example, 142℃.

[0402] In one aspect of the present invention, the compound It has a basic DSC diagram as shown in Figure 7.

[0403] In one aspect of the present invention, the compound When heated to 120±3℃, for example 120℃, the weight loss during thermogravimetric analysis (TGA) is 0.1%-0.9%, for example 0.59%.

[0404] In one aspect of the present invention, the compound It has a basic TGA diagram as shown in Figure 10.

[0405] In another preferred embodiment, the compound During differential scanning calorimetry (DSC), there is an endothermic signal when heated to 64℃±3℃, for example, 64℃; an endothermic signal when heated to 116℃±3℃, for example, 116℃; and / or an endothermic signal when heated to 234℃±3℃, for example, 234℃.

[0406] In another preferred embodiment, the compound It has a basic DSC diagram as shown in Figure 9.

[0407] Preparation method

[0408] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0409] Typically, the preparation process of the compounds of the present invention is as shown in the embodiments of the present invention, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0410] The compound of formula I of the present invention can be obtained by a variety of preparation routes, for example,

[0411] Route 1

[0412] Route 2:

[0413] The general steps for both Route 1 and Route 2:

[0414] (1) In the presence of a base, compound c reacts with compound f-1 to give compound g-1;

[0415] (2) Compound g-1 forms a salt with D-(+)-di-p-methylbenzoyl tartaric acid to give compound g-1·D-DTTA;

[0416] (3) Compound g-1·D-DTTA is released to obtain g-1; under a hydrogen atmosphere, palladium on carbon is added to react and compound j·hydrochloride is obtained; in route 2, hexafluorophosphate is added after salt formation to obtain compound j·hydrochloride hexafluorophosphate; since compound j·hydrochloride hexafluorophosphate is solid at room temperature, the separation of compound j·hydrohalide can be simplified by adding hexafluorophosphate to form a salt.

[0417] (4) Compound j·hydrochloride or compound j·hydrochloride hexafluorophosphate undergoes a condensation reaction with cyanoacetic acid to obtain the compound shown in Formula I;

[0418] (5) The compound shown in Formula I is salted with D-(+)-di-p-methylbenzoyl tartaric acid to obtain the salt form of the compound shown in Formula I as described in the second aspect of the present invention, to obtain Formula I·D-DTTA;

[0419] (6) The salt of the compound of formula I·D-DTTA is released to obtain the compound of formula I.

[0420] In the method of the present invention, the temperature and time of each reaction can be conventionally selected according to the reaction type and specific reaction conditions, or carried out according to the reaction time and temperature provided in the present invention.

[0421] In this invention, the amount of each reactant and solvent can be selected according to the type of conventional experiment, or based on the standard that the reaction can proceed normally.

[0422] Furthermore, the present invention also provides other preparation routes: for example,

[0423] Route 3:

[0424] In Route 3, unlike Route 1 and Route 2 which use chlorine-containing substrates (such as f-1 and g-1), Route 3 uses non-chlorine-containing substrates (such as f-2 and g-2).

[0425] Route 4:

[0426] (a) The compound of formula m (tofacitinib) is reacted with 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) to give the silanized compound of formula n;

[0427] (b) The compound of formula n reacts with trifluoroacetic acid (TFA) to give the hydroxymethylated compound of formula p or its salt;

[0428] (c) Compound p of formula condenses with compound a of formula to give the compound shown in formula I;

[0429] (d) The compound shown in Formula I reacts with an acid to form a salt, yielding a salt of the compound of Formula I;

[0430] (e) The salt of the compound of formula I is released to obtain the compound of formula I;

[0431] The acid is preferably hydrochloric acid, hexafluorophosphate, or di-p-methylbenzoyl tartaric acid and its isomers, or mixtures thereof;

[0432] In addition to the salt purification method described in step de, the compound represented by formula I can also be purified by other methods, such as column chromatography, reverse preparation, etc.

[0433] Route 5:

[0434] (1) Compound a reacts with compound b to give compound c;

[0435] (2) In the presence of a base, compound c reacts with compound d to give compound k;

[0436] (3) In the presence of a base, compound k reacts with compound e to give compound g;

[0437] (4) Compound g forms a salt with D-(+)-di-p-methylbenzoyl tartaric acid to give compound g·D-DTTA;

[0438] (5) Compound g·D-DTTA free D-DTTA; under a hydrogen atmosphere, palladium on carbon is added to react and give compound j·hydrohalate;

[0439] (6) The compound shown in Formula I undergoes a condensation reaction with cyanoacetic acid to obtain the compound shown in Formula I;

[0440] (7) The compound shown in Formula I forms a salt with D-(+)-di-p-methylbenzoyl tartrate to obtain the crystal form of the compound shown in Formula I as described in the second aspect of the present invention, namely the crystal form of Formula I·D-DTTA.

[0441] (8) The D-(+)-di-p-methylbenzoyl tartrate of the compound of formula I is released to obtain the compound of formula I.

[0442] Intermediate compound used in the synthesis of 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester

[0443] The present invention also provides an intermediate compound for preparing methyl 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) ester.

[0444] In one specific embodiment, the present invention provides an intermediate compound of formula c as shown, which is methyl 4-ethyloctanoate.

[0445] In one specific embodiment, the present invention provides the intermediate 4-ethyloctanoic acid (4-(((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)(methyl)amino)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl ester and its salts as shown below:

[0446] Wherein, the compound g-1·DTTA (mixture) refers to a mixture of compound g-1·D-DTTA and compound g-1·L-DTTA; preferably, the molar ratio of compound g-1·D-DTTA and compound g-1·L-DTTA in the mixture is any ratio, preferably (0.6~1.5):1.

[0447] In one specific embodiment, the present invention provides the intermediate 4-ethyloctanoic acid (4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl ester and its salts as shown below:

[0448] In one specific embodiment, the present invention provides the intermediate 4-ethyloctanoic acid (2-chloro-4-(methyl((3R,4R)-4-methylpiperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester as shown below.

[0449] In one specific embodiment, the present invention provides the D-(+)-di-p-methylbenzoyl tartrate of the intermediate 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester as shown below.

[0450] In one specific embodiment, the present invention provides the L-(-)-di-p-methylbenzoyl tartrate of the intermediate 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester as shown below.

[0451] In one specific embodiment, the present invention provides the di-p-methylbenzoyl tartrate of the intermediate 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester as follows:

[0452] Wherein, the compound formula I·DTTA (mixture) refers to a mixture of formula I·D-DTTA and compound formula I·L-DTTA; preferably, the molar ratio of compound formula I·D-DTTA and compound formula I·L-DTTA in the mixture is any ratio, preferably (0.6~1.5):1.

[0453] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0454] the term

[0455] In this document, unless otherwise specified, all abbreviations have their conventional meanings as understood by those skilled in the art.

[0456] The term "hydroxyl group" refers to the -OH group.

[0457] The term "cyano" refers to -CN.

[0458] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0459] In this document, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group comprising 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups. The terms "C1-C4 alkyl" and "C1-C3 alkyl" have similar meanings.

[0460] In this document, "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. C1-C3 alkoxy groups are preferred.

[0461] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0462] In this invention, the term 1-6 refers to 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings.

[0463] The term "isomer" refers to the structural formula described in this invention and is intended to include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers with double bonds, etc. Therefore, any single stereochemical isomer of the compound of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0464] As used herein, the term "tautomer" refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton shifts) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via some bonding electron recombination.

[0465] The term "alkane solvent" refers to saturated hydrocarbon organic solvents composed of carbon and hydrogen, including alkanes and cycloalkanes; preferably "C1-C8 alkane solvents", such as pentane, n-heptane, cyclohexane, n-hexane, etc.

[0466] The term "ether solvents" refers to a class of organic compounds containing ether bonds (COC), which typically have low boiling points and good solubility. Common ether solvents include diethyl ether, propylene oxide, and tetrahydrofuran.

[0467] The solvents used herein are commercially available. The abbreviations used in this application are as follows: D-DTTA represents D-(+)-di-p-methylbenzoyl tartaric acid; L-DTTA represents L-(-)-di-p-methylbenzoyl tartaric acid; DTTA represents di-p-methylbenzoyl tartaric acid; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; EDCI represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; DCC represents N,N'-bicyclohexafluorophosphate. Hexylcarbodiimide; HOBt represents 1-hydroxybenzotriazole; HBTU represents benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; TATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea tetrafluoroborate; TBTU represents 2-(1H-benzotriazolyl-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate; PyBOP represents 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate; BOP represents benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; BOP-Cl represents bis(2-oxo-3-oxazolyl)phosphine chloride; PyBrOP represents tripyrrolidinylphosphonium hexafluorophosphate; DIC represents N,N'-diisopropylcarbodiimide; T3P represents 1-n-propylphosphonic anhydride; CDI represents carbonyl diimidazole; HPF6 represents hexafluorophosphate; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; THF represents... Table 1: Tetrahydrofuran; H2O represents water; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; TEA represents triethylamine; K2CO3 represents potassium carbonate; NaHCO3 represents sodium bicarbonate; NaH represents sodium hydride; Bu4NHSO4 represents tetrabutylammonium bisulfate; Pd / C represents palladium on carbon; SEMCl represents 2-(trimethylsilyl)ethoxymethyl chloride; XRPD represents X-ray powder diffraction; TGA represents thermogravimetric analysis; DSC represents differential scanning calorimetry.

[0468] As used in this article, unless otherwise specified, solvents or solutions are added by pouring directly or adding at a constant rate.

[0469] As used in this article, the "slow addition" method includes, but is not limited to: adding drop by drop, adding slowly along the container wall, etc.

[0470] As used herein, “Formula I crystal form” or “Formula I compound crystal form” refers to the crystal form of methyl 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) ester, a JAK inhibitor compound shown in Formula I herein.

[0471] As used herein, “Formula I·D-DTTA crystal form” or “Formula I·D-DTTA compound crystal form” refers to the crystal form of D-(+)-di-p-methylbenzoyl tartrate of the JAK inhibitor compound 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) methyl ester as shown in Formula I in this article.

[0472] As used in this article, the term "room temperature" generally refers to 5–30°C, and more preferably 20–35°C.

[0473] As used herein, “D-(+)-di-p-methylbenzoyl tartrate of 4-ethyloctanoic acid (4-(((3R,4R)-1-(2-cyanoacetyl)-4-methylpiperidin-3-yl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl ester,” “ID-(+)-di-p-methylbenzoyl tartrate,” “D-(+)-di-p-methylbenzoyl tartrate of Formula I,” “I·D-DTTA,” or “ID-DTTA” refers to the salt formed by the compound of Formula I with D-DTTA, wherein the ratio of the compound of Formula I to the equilibrium ion (D-DTTA) can be any non-zero value, such as 0.1, 0.5, 1, 1.5, 2, 3, 5, or 10. Other similar names have the same meaning, for example, I·L-DTTA, g·D-DTTA, g·L-DTTA, g·DTTA.

[0474] As used in this article, the terms "hexafluorophosphate" and HPF6 are used interchangeably.

[0475] As used herein, "compound j·hydrohalic acid hexafluorophosphate", "j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", "compound j·hydrohalic acid hexafluorophosphate", or "j·HCl·HPF6", "j·HClHPF6", "jHCl·HPF6", "compound j·hydrohalic acid hexafluorophosphate", or "compound j·HCl·HPF6", ... "compound j·HCl·HPF6", "compound j·HClHPF6", "compound jHCl·HPF6", "compound j·HCl·HPF6", "compound j·HClHPF6", "compound j·HClHPF6" indicate that compound j forms a salt with hydrohalic acid and hexafluorophosphate. The ratio of compound j to the equilibrium ion (hydrohalic acid and / or hexafluorophosphate) can be any non-zero value, such as 0.1, 0.5, 1, 1.5, 2, 3, 5 or 10. The ratio of compound j to hydrohalic acid and the ratio of compound j to hexafluorophosphate are mutually exclusive and do not affect each other.

[0476] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0477] The reagents and raw materials used in this invention are all commercially available.

[0478] The main advantages of this invention include:

[0479] (1) In this invention, the compound shown in Formula I is reacted with D-(+)-di-p-methylbenzoyl tartaric acid to form a salt, and a salt-type solid is precipitated. The purity is improved by operations such as pulping, which is beneficial for the subsequent crystallization and purification of the compound of Formula I.

[0480] (2) The synthesis method shown in Formula I of this invention has readily available raw materials, high yield, and low cost.

[0481] (3) The preparation method of the compound and crystal form of the present invention is simple to operate, with high yield and high purity. Attached Figure Description

[0482] Figure 1 shows the XRPD spectrum of the crystal form of compound I of this invention.

[0483] Figure 2 is a TGA diagram of the crystal form of compound I of this invention.

[0484] Figure 3 is a DSC diagram of the crystal form of compound I of this invention.

[0485] Figure 4 is an XRPD diagram of the I·D-DTTA crystal form of this invention.

[0486] Figure 5 shows the XRPD image of the crystal form of Compound I of this invention after being placed under accelerated conditions for 6 months.

[0487] Figure 6 shows the XRPD image of the crystal form of compound I of this invention after being stored for 12 months.

[0488] Figure 7 is the DSC diagram of the formula g-1·D-DTTA of this invention.

[0489] Figure 8 is a TGA diagram of the present invention, g-1·D-DTTA.

[0490] Figure 9 shows the DSC diagram of compound j, hexafluorophosphate hydrochloride.

[0491] Figure 10 shows the TGA chromatogram of compound j, hexafluorophosphate hydrochloride.

[0492] Figure 11 shows the DSC diagram of the crystal form of Formula I·D-DTTA.

[0493] Figure 12 shows the TGA diagram of the crystal form of Formula I·D-DTTA. Detailed Implementation

[0494] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0495] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0496] The parameters of the differential scanning calorimetry (DSC) method described in this invention are as follows:

[0497] Instruments: Differential Scanning Calorimeter (DSC), analytical balance, aluminum crucible

[0498] Heating rate: 10℃ / min, temperature range: 30℃-300℃

[0499] Gas: Nitrogen

[0500] Gas flow rate: 50 mL / min

[0501] Measurement procedure: Weigh approximately 5-10 mg of sample, set the instrument according to the above instrument parameters, and start collecting sample data after stabilization.

[0502] The parameters of the thermogravimetric analysis (TGA) method described in this invention are as follows:

[0503] Instruments: TGA thermal analyzer or similar instrument, analytical balance, aluminum crucible

[0504] Heating rate: 10℃ / min

[0505] Temperature range: 30℃-300℃

[0506] Gas: Nitrogen

[0507] Gas flow rate: 50 mL / min

[0508] Determination steps: Accurately weigh an appropriate amount of the test sample, prepare the sample crucible, place it in the furnace of the thermal analyzer, enter the sample name, batch number and sample quantity, select the starting temperature of 30℃ and the ending temperature of 300℃, set the heating program to 10℃ / min, and click "START" to start the program.

[0509] Data processing: Select a suitable temperature range from the obtained TGA spectrum to obtain the weight loss at that temperature range.

[0510] The method parameters for the crystal form (XPRD) described in this invention are as follows:

[0511] Instruments: X-ray powder diffractometer, single-crystal silicon sample disk with glass slide

[0512] Instrument parameters: Light source: CuKa (1.54184 Å)

[0513] Pipe pressure: 30kV

[0514] Pipe current: 10mA

[0515] Launch slit: 1.0mm

[0516] Acceptable slit: 3mm

[0517] 2θ scan range: 3°-40°

[0518] Scan rate per step: 0.5 s / step

[0519] Step size: 0.02

[0520] Measurement Procedure: Place the ground sample onto the single-crystal silicon sample disk, and use a glass slide to ensure the sample is level with the surface of the sample disk. Place the prepared sample disk on the instrument's sample stage for data acquisition and processing.

[0521] The compound represented by Formula I can be obtained via the following routes 1 and 2:

[0522] Route 1

[0523] Route 2:

[0524] Example 1: Preparation of compound c (routes 1 & 2)

[0525] Add water (500g), sodium bicarbonate (97.5g), Bu4NHSO4 (10g), dichloromethane (665g), and compound a (50g) to the flask in sequence. Cool to 0-5℃, slowly add compound b (57.5g), heat to 10-15℃ and stir for 3-5 hours.

[0526] After standing, the aqueous phase was separated and extracted with dichloromethane (332 g * 1). The organic phases were combined and washed successively with dilute hydrochloric acid (500 g * 1, 5% hydrochloric acid aqueous solution), saturated sodium bicarbonate aqueous solution (500 g * 1), and water (500 g * 1). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain oily compound c (67.8 g, yield: 106%, purity: 94.04%).

[0527] 1 ¹H NMR (400MHz, CDCl₃) δ 5.71 (s, 2H), 2.36 (t, J = 7.8Hz, 2H), 1.59–1.65 (m, 2H), 1.25–1.31 (m, 9H), 0.84–0.91 (m, 6H). GCMS (+EI): m / z: Calculated: 191.1 [C 11 H 21 ClO2-C2H5] .+ Measured value: 191.1 (100%, [M-C2H5]) .+ )

[0528] Example 2: Preparation of compound f-1 (routes 1 & 2)

[0529] Compound d-1 (30 g), compound e (51 g), potassium carbonate (66.3 g), and water (390 g) were added sequentially to a flask, heated to reflux, and stirred for 2 days. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with water (75 g x 2). Methyl tert-butyl ether (50.1 g) and n-heptane (19.9 g) were added to the filter cake, and the mixture was heated to 60°C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with a mixed solvent of methyl tert-butyl ether and n-heptane. The resulting wet cake was dried under vacuum at 60°C to obtain solid compound f-1 (56.8 g, yield: 96.2%, purity: 99.52%).

[0530] 1H NMR (400MHz, DMSO-d6) δ7.32(br,2H),7.33(br,2H),7.23-7.27(m,1H),7.13(d,J=2.7Hz,1H),6.61(br,1H),4.93(br,1H),3 .43-3.54(m,5H),2.62(br,1H),2.77(m,1H),2.30(br,2H),2.12(br,1H),1.61(br,1H),1.70(br,1H),0.88(d,J=6.3Hz,3H).

[0531] (MS+ESI): m / z: calculated value: 370.2, 372.2 for [C 20 H 24 ClN5+H] + Measured values: 370.1, 372.1 (100%, [M+H]) + )

[0532] Example 3: Preparation of compound g-1·D-DTTA (Route 1 & 2)

[0533] Compound f-1 (27.4 g) was added to anhydrous THF (241.4 g) under a nitrogen atmosphere and cooled to 0-5 °C. 60% sodium hydride (3.84 g) was added in portions, and the mixture was stirred at 0-5 °C for 1 hour. Compound c (21.26 g) was then slowly added dropwise, and the mixture was stirred at 0-5 °C for another 0.5-1 hour.

[0534] Maintaining the system temperature at 5–10 °C, D-(+)-di-p-methylbenzoyl tartaric acid (37.21 g) was added in portions to the reaction solution, followed by slow dropwise addition of water (480 g). The mixture was heated to room temperature (20–25 °C) and stirred for 1 hour. After filtration, the filter cake was washed with water (250 g) to obtain a white powdery solid compound g-1·D-DTTA (76.47 g, yield: 110%, purity: 97.76%); melting point: 128.0–130.0 °C.

[0535] 1H NMR (400MHz, DMSO-d6) δ13.70(br,2H),7.89(d,J=8.1Hz,4H),7.28-7.38(m,10H),6.69(br,1H),6.06(dd,J=10.8H z,J=11.0Hz,2H),5.79(s,2H),5.03(br,1H),3.75(br,2H),3.45(br,3H),3.08(br,2H),2.78(br,2H),2.39(s,6H) ,2.27(t,J=7.5Hz,2H),2.17(br,1H),1.78(br,1H),1.61(br,1H),1.44(dd,(J=12.8Hz,J=7.2Hz,2H),1.09-1.16(m,9H),0.92(d,J=6.7Hz,3H),0.79(t,J=7.5Hz,3H),0.72((t,J=7.2Hz,3H).(MS+ESI):m / z:Calculated values:554.3,556.3for[C 51 H 62 ClN5O 10 -C 20 H 18 O8+H] + Measured values: 554.4, 556.3 (100%), [MC] 20 H 18 O8+H] + ).

[0536] When differential scanning calorimetry (DSC) was performed, g-1·D-DTTA exhibited an endothermic peak when heated to approximately 74°C, and another endothermic peak appeared upon further heating to 142°C. Its DSC is shown in Figure 7. When thermogravimetric analysis (TGA) was performed, g-1·D-DTTA showed a mass loss gradient of approximately 28.23% when heated from 30°C to 120°C. Its TGA is shown in Figure 8. This invention relates to g-1·D-DTTA.

[0537] Based on the 1:1 ratio of the characteristic hydrogen of g-1 (6.06 dd, J = 10.8 Hz, J = 11.0 Hz, 2H) to the characteristic hydrogen of D-DTTA (5.79 s, 2H), it can be determined that g-1·D-DTTA is a single-molecule salt.

[0538] Example 3-1: Compound f-2 (100 mg, 0.3 mmol), compound c (200 mg, 0.9 mmol), and K2CO3 (125 mg, 0.90 mmol) were added sequentially to DMF (3 mL) and reacted at 50 °C for 24 hours. Water (25 mL) was added to the reaction solution, and the aqueous phase was extracted three times with ethyl acetate (25 mL). The organic phases were combined and washed with water (25 mL) and saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain g-2 (140 mg, yield: 90%).

[0539] Example 3-2: Similar to the operation in Example 3, compound f-1 (20g) was added and separated by silica gel column chromatography to obtain g-1 (30g, yield 100%).

[0540] Example 4: Preparation of compound j·hydrochloride (Route 1)

[0541] Compound g-1·D-DTTA (76.47 g) was added to tetrahydrofuran (764.7 g) and stirred until dissolved. A mixed aqueous solution of sodium bicarbonate and sodium chloride was added (sodium bicarbonate (16.18 g) was dissolved in water (200 g), and then a saturated aqueous solution of sodium chloride (200 g) was added to prepare the mixed solution). The mixture was allowed to stand, and the layers were separated to obtain a tetrahydrofuran organic layer solution. This process was repeated three times, and the results were combined to obtain a 479.12 g solution of the pale yellow compound g-1 tetrahydrofuran.

[0542] Take 202.39 g of compound g-1 tetrahydrofuran solution, add 5.7 g of 10% palladium on carbon, replace with hydrogen gas three times, raise the temperature to 30 °C, react for 6 hours, then raise the temperature to 40 °C, react for 1 hour. Filter the reaction solution, wash the filter cake with tetrahydrofuran, combine the filtrates, and concentrate under reduced pressure to obtain an oily compound J·hydrochloride (containing 14.6 g of compound J·HCl), which can be used directly in the next reaction.

[0543] 1H NMR (400MHz, CDCl3) δ10.64(br,1H),9.98(br,1H),8.34(s,1H),7.20(d,J=3.7Hz,1H),6.62(d,J= 3.7Hz,1H),6.14(s,2H),4.86(br,1H),3.57(br,2H),3.36(s,3H),3.29(br,2H)2.53(br,1H),2.2 9(t,J=7.8Hz,2H),2.18(br,1H),1.75(d,J=10.6Hz,1H),1.53-1.58(m,2H),1.19-1.26(m,9H),1.06(d,J=6.8Hz,3H),0.86(t,J=6.8Hz,3H),0.70((t,J=7.1Hz,3H).(MS+ESI): m / z: calculated value: 430.2 for [C 24 H 40 ClN5O2-HCl+H] + Measured value: 430.2 (100%), [M-HCl+H+] + )

[0544] Cl - Content (AgNO3 aq.): Calculated value: 7.8%, Measured value: 5.0%.

[0545] Based on the 1:1 ratio of characteristic hydrogen 6.14 (s, 2H) of j and characteristic hydrogen 10.64 (br, 1H) of HCl, and the combined chloride ion content of 5%, j·hydrochloride is a single-molecule salt.

[0546] Example 5: Preparation of Formula I·D-DTTA (Route 1)

[0547] Under a nitrogen atmosphere, cyanoacetic acid (4.0 g), HATU (13.2 g), DIPEA (10.8 g), and dichloromethane (73.0 g) were added to a flask. The mixture was cooled to -15 to -20 °C, and then a dichloromethane solution of compound j hydrochloride (containing 13.0 g dichloromethane and 14.6 g compound j HCl; prepared in Example 4) was added. The mixture was heated to 20–25 °C and stirred for 1–2 hours. The organic phase was washed with H2O (50 g x 3), 5% citric acid aqueous solution (12 w x 3 (12 times the weight of j hydrochloride; washed three times)), NaHCO3 aqueous solution (5 w x 1, 2.5 w x 1), and H2O (10 w x 1, 5 w x 1). The resulting solution (dichloromethane solution of Formula I) was concentrated under reduced pressure to obtain an oily substance.

[0548] Add 80.0 g of methyl tert-butyl ether to the oily substance at 30–40 °C, stir until dissolved, then add 12.3 g of D-(+)-di-p-methylbenzoyl tartaric acid, and stir the mixture at 35–40 °C to obtain a clear solution. Cool the solution to 30–35 °C, and continue stirring at 35–40 °C for 16–24 hours. Filter the mixture, and wash the filter cake with a mixed solvent of methyl tert-butyl ether and n-heptane to obtain 104.5 g of wet product (formula I·D-DTTA). Add 45.0 g of ethanol and 45.0 g of H2O to the wet product, and stir for 16–24 hours. Filter the mixture, and wash the filter cake with a mixed solvent of ethanol and H2O to obtain the wet product (formula I·D-DTTA wet product). Melting point of compound I·D-DTTA: 136.0–139.0 °C.

[0549] (MS+ESI): m / z: calculated value: 497.3 for [(C 47 H 58 N6O 11 -C20H 18 O8)+H] + Measured value: 497.4 (100%), [MC] 20 H 18 O8+H] + )

[0550] Place the ground I·D-DTTA sample onto the single-element silicon sample tray, and use a glass slide to make the sample level with the tray surface. Place the prepared sample tray on the instrument's sample stage, and select an appropriate method for data acquisition and processing.

[0551] Upon testing, the obtained solid crystal was found to be the I·D-DTTA crystal form described in this invention, and its X-ray powder diffraction pattern is shown in Figure 4. Its X-ray powder diffraction data are shown in Table 1.

[0552] When differential scanning calorimetry (DSC) is performed, the crystal form of the present invention, I·D-DTTA, begins to show an endothermic peak when heated to around 127.5°C, and its DSC diagram is shown in Figure 11.

[0553] When thermogravimetric analysis was performed, the crystal form of the I·D-DTTA of the present invention was heated to 120°C, and the sample showed a weight loss of 0.04%, as shown in Figure 12.

[0554] Table 1

[0555] Example 6: Preparation of the crystal form of compound I (Route 1)

[0556] Dichloromethane (20 w; 20 times the weight of the wet product of Formula I·D-DTTA) was added to the wet product of Formula I·D-DTTA obtained in Example 5, and the mixture was stirred until dissolved. A solution containing sodium bicarbonate (0.88 w) and purified water (9.12 w) was added to the reaction vessel, stirred, and allowed to stand for phase separation. The organic phase was washed with citric acid aqueous solution (citric acid 0.55 w, purified water 9.45 w), sodium bicarbonate aqueous solution (sodium bicarbonate 0.44 w, purified water 4.56 w), and purified water (5.0 w). The resulting solution was concentrated under reduced pressure to obtain an oily substance, which is the compound of Formula I.

[0557] Methyl tert-butyl ether (3w) was added to the oily substance, and the mixture was heated at 30–40 °C to dissolve it. Then, n-heptane (3w) was slowly added dropwise, and the mixture was stirred at room temperature to induce crystallization. The temperature was then lowered to 15 °C, and the mixture was stirred for 4 hours. The mixture was filtered, and the filter cake was washed with a mixed solvent of methyl tert-butyl ether and n-heptane (10g, 1w / 1w) to obtain 5.4g of the crystalline form of compound I. The melting point of the crystalline form of compound I is 80.5–86.0 °C.

[0558] NMR data of compound I: 1 H NMR (400MHz, CDCl3) δ8.33-8.35(m,1H),7.17(dd,J=13.6Hz,J=3.8Hz,1H),6.55(dd,J=4.6 Hz,J=3.6Hz,1H),6.15(s,1H),6.16(s,1H),5.10-5.13(m,1H),4.06(dd,J=13.2Hz,J=4.2Hz 1H),3.74-3.85(m,1H),3.58-3.62(m,1H)3.44-3.50(m,1H),3.52-3.54(m,2H),3. 36-3.40(m,3H),2.44-2.55(m,1H),2.30(t,J=8.1Hz,2H),1.85-1.99(m,1H),1.67 -1.78(m,1H), 1.53-1.58(m,2H), 1.17-1.24(m,9H), 1.09(dd,J=12.3Hz,J=7.1Hz,3H), 0.86(t,J=7.1Hz,3H), 0.79(t,J=7.1Hz,3H). (MS+ESI): m / z: calculated value: 497.3 for [C 27 H 40 N6O3+H] + Measured value: 497.3 (100%, [M+H]) + ).

[0559] Example 7: Preparation of compound j·dichloromethane hydrochloride solution (Route 1)

[0560] Compound g-1·D-DTTA (196.2 g) was added to tetrahydrofuran (764.7 g) and stirred until dissolved. A mixed aqueous solution of sodium bicarbonate and sodium chloride was added (a mixed solution was prepared by adding sodium bicarbonate (36.0 g) to a semi-saturated aqueous solution of sodium chloride (100.0 g)). A solid precipitated out and was dissolved in water (360.0 g). The mixture was allowed to stand and separate into layers. The organic phase was washed three times with a mixed aqueous solution of sodium bicarbonate and sodium chloride, allowed to stand and separate into layers, and anhydrous sodium sulfate (60.0 g) was added to the organic phase. The mixture was filtered, and the filter cake was washed with tetrahydrofuran. Silica gel (60.0 g) was added to the filtrate, and the temperature was lowered to 0–5 °C and maintained for 0.5–1 hour. The mixture was filtered again, washed with tetrahydrofuran, and anhydrous sodium sulfate (120.0 g) was added to the filtrate. The temperature was adjusted to 5–10 °C and maintained for 4 hours. The filter cake was filtered and washed with tetrahydrofuran to obtain a tetrahydrofuran solution of compound g-1.

[0561] 10% palladium on carbon (7.64 g) was added to a tetrahydrofuran solution (407.8 g) of compound g-1. The mixture was purged with hydrogen three times, heated to 40°C, and stirred for 22 hours. The mixture was then purged with hydrogen three more times, heated to 50°C, and stirred for 7 hours. The mixture was then cooled to 40°C and stirred for 2 days. After cooling to room temperature, the mixture was filtered and washed with tetrahydrofuran (90.0 g). The resulting filtrate was distilled under reduced pressure, rinsing twice with tetrahydrofuran until no more droplets flowed out. The solution was then dissolved in dichloromethane (189.0 g) to obtain a dichloromethane solution of compound j·HCl (purity: 81.30%), which was directly used in the next reaction. The NMR data of compound j·HCl were the same as in Example 4.

[0562] Example 8: Preparation of compound j·hexafluorophosphate hydrochloride (route 2)

[0563] Compound g-1·D-DTTA (26.7 g) was added to THF (175.0 g) and stirred until dissolved. The organic solution was washed twice with a half-saturated sodium chloride solution (90.9 g) containing sodium bicarbonate (3.75 g) and twice with a half-saturated sodium chloride solution (29.1 g). The mixture was allowed to stand and separate into layers. Silica gel (6.3 g) was added to the organic phase, and the mixture was cooled to 0–5 °C and filtered. The filter cake was washed with tetrahydrofuran (6.7 g). Water (4.0 g) and 10% palladium on carbon (1.5 g) were added to the filtrate to replace the hydrogen gas. The mixture was heated to 30–38 °C and stirred for 8–10 hours. The mixture was then filtered, and the filtrate was retained for use.

[0564] The filtrate was distilled under reduced pressure, dissolved in dichloromethane (45.0 g), washed with saturated sodium chloride aqueous solution (10.0 g), and allowed to stand to separate into layers. The lower organic phase was dissolved in hexafluorophosphate (1.65 g), distilled under reduced pressure until no droplets remained, then toluene (34.2 g) was added and distilled under reduced pressure until no droplets flowed out. Toluene (11.7 g) was then added, the temperature was raised to 35–45 °C, and n-heptane (68.6 g) was added dropwise. The temperature was lowered to 20–30 °C, and the mixture was stirred overnight. The mixture was filtered, washed with n-heptane, and the wet product was dried to give a white solid compound j·HCl·HPF6 (6.73 g, yield: 78.28%, purity: 97.79%). The melting point of compound j·HCl·HPF6 is 63.5–84.0 °C.

[0565] NMR of compound j·HCl·HPF6: 1 H NMR (400MHz, DMSO-d6) δ9.62(d,J=10.7Hz,1H),9.43(s,1H),8.38(s,1H),7.50(d,J=3.9Hz,1H),6.85(d,J=3.8Hz,1 H),6.17(s,2H),5.12(dt,J=12.2,4.2Hz,1H),3.64(q,J=11.2Hz,1H),3.33(d,J=12.2Hz,1H),3.27(s,3H),3.15(d, J=12.6Hz,1H),3.07–2.91(m,1H),2.42(dq,J=12.4,4.3,3.8Hz,1H),2.27(t,J=7.6Hz,2H),2.23–2.10(m,1H),1.66 (dd,J=14.5,3.0Hz,1H),1.43(td,J=8.0,4.3Hz,2H),1.29–1.01(m,12H),0.81(t,J=7.0Hz,3H),0.76–0.67(m,3H).

[0566] (MS+ESI): m / z: calculated value: 430.3 for [C 24 H 39 N5O2﹒ HCl﹒ nHPF6-HCl-nHPF6+H] + Measured value: 430.4 (100%), [M-HCl-nHPF6+H + ).

[0567] When differential scanning calorimetry (DSC) was performed, an endothermic peak appeared in j·HCl·HPF6 when heated to around 64°C, another endothermic peak appeared at 116°C, and yet another endothermic peak appeared at 234°C. The DSC chromatogram is shown in Figure 9. When thermogravimetric analysis (TGA) was performed, the j·HCl·HPF6 crystal form exhibited a mass loss gradient of approximately 0.59% when heated from 30°C to 120°C. The TGA chromatogram is shown in Figure 10.

[0568] Example 9: Preparation of the crystal form of formula I·D-DTTA (Route 2)

[0569] Add 1.68 g of purified cyanoacetic acid to 33.5 g of dichloromethane, cool to -10 to 0 °C, add 5.70 g of HATU and 3.89 g of DIPEA, and stir for 15 to 30 minutes. Maintain the temperature at -10 to 0 °C, add dropwise a dichloromethane solution (33.5 g) of the previously prepared compound j·HCl·HPF6 (6.7 g) to the reaction mixture, followed by 2.28 g of DIPEA. After the addition is complete, raise the temperature to 20 to 30 °C and stir for 5 hours. Add 67 g of semi-saturated sodium bicarbonate solution, stir for 30 minutes, let stand overnight, and allow the layers to separate. Wash the organic layer sequentially with a semi-saturated sodium bicarbonate aqueous solution once, water three times, citric acid three times, saturated sodium bicarbonate twice, and water once. Allow the layers to separate, add 0.24 g of mercaptosilica gel and 1.34 g of silica gel to the organic phase, and stir overnight. The mixture was filtered, the filter cake was washed with dichloromethane, and the filtrates were combined. The mixture was then distilled under reduced pressure at below 40°C. Methyl tert-butyl ether (20.1 g) was added and stirred until dissolved. Distillation under reduced pressure continued until no more liquid dripped out. The concentrate was compound I. NMR data were the same as in Example 6.

[0570] The concentrate was dissolved in 35.5 g of methyl tert-butyl ether by stirring. At 35–40 °C, 4.36 g of D-DTTA was added and stirred until dissolved. The solution was cooled to 30–35 °C, and seed crystals of formula I·D-DTTA were added. The mixture was stirred overnight at 30–35 °C. The solution was cooled to 25–30 °C, filtered, and the filter cake was washed twice with a mixed solution of methyl tert-butyl ether and n-heptane to obtain the crystalline form of compound I·D-DTTA. The melting point of compound I·D-DTTA is 136.0–139.0 °C.

[0571] (MS+ESI): m / z: calculated value: 497.3 for [(C 47 H 58 N6O 11 -C20H 18 O8)+H] + Measured value: 497.4 (100%), [MC] 20 H 18 O8+H]+ ).

[0572] Preparation of I·D-DTTA seed crystals:

[0573] The compound of formula I (6.50 g) prepared as before was added to methyl tert-butyl ether (52.0 g), and the temperature was raised to 40 °C. The reaction solution was completely dissolved, and D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA) (5.06 g) was added. The reaction liquid was stirred until dissolved, the heating was turned off, and the reaction system was allowed to cool naturally to 28 °C. Stirring was continued for 16 hours, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed three times with (methyl tert-butyl ether: n-heptane = 1:1, 6.6 g), dried, and I·D-DTTA seed crystals (13.10 g, yield: 100%, purity: 99.17%) were obtained.

[0574] Example 10: Preparation of the crystal form of compound I (routes 1 & 2)

[0575] The formula I·D-DTTA prepared in Example 9 above was added to a single-necked flask, along with ethanol (33.5 g) and water (67 g). The mixture was stirred and heated to 30–35 °C overnight. The mixture was then cooled to 25–30 °C and stirred for 7 hours. After filtration, the filter cake was added to a mixed solution of ethanol (33.5 g) and water (67 g), and the mixture was heated to 30–35 °C overnight. The mixture was cooled to 25–30°C, filtered, and the filter cake was washed with a mixture of ethanol and water. The filter cake was then added to dichloromethane (134.0 g) and stirred until dissolved. A saturated sodium bicarbonate aqueous solution (67.0 g) was added, stirred, and allowed to stand for separation. The organic phase was washed once with 5% citric acid, once with saturated sodium bicarbonate, and once with water. The organic phase was then distilled under reduced pressure, and methyl tert-butyl ether (67.0 g) was added and stirred until dissolved. Silica gel was added, and the mixture was stirred overnight at 35–40°C. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated under reduced pressure until no more droplets flowed out, thus preparing compound I.

[0576] Add 20.1 g of methyl tert-butyl ether to the residue, maintain the temperature at 35–40 °C, stir until dissolved, add 10.05 g of n-heptane dropwise, add the crystal form of compound I as a seed crystal to the mixture, and stir overnight at 35–40 °C. Cool to 25–30 °C, stir for 5 hours, filter, wash the filter cake twice with a mixed solution of methyl tert-butyl ether and n-heptane, and dry the filter cake by nitrogen purging to obtain the crystal form of compound I (2.38 g, yield: 38.56%, purity: 99.83%).

[0577] The melting point of compound I is 80.5–86.0 °C.

[0578] NMR data for Formula I: 1H NMR (400MHz, CDCl3) δ8.33-8.35(m,1H),7.17(dd,J=13.6Hz,J=3.8Hz,1H),6.55(dd,J=4.6 Hz,J=3.6Hz,1H),6.15(s,1H),6.16(s,1H),5.10-5.13(m,1H),4.06(dd,J=13.2Hz,J=4.2Hz 1H),3.74-3.85(m,1H),3.58-3.62(m,1H)3.44-3.50(m,1H),3.52-3.54(m ,2H),3.36-3.40(m,3H),2.44-2.55(m,1H),2.30(t,J=8.1Hz,2H),1.85-1 .99(m,1H),1.67-1.78(m,1H),1.53-1.58(m,2H),1.17-1.24(m,9H),1.09 (dd, J=12.3Hz, J=7.1Hz, 3H), 0.86 (t, J=7.1Hz, 3H), 0.79 (t, J=7.1Hz, 3H).

[0579] (MS+ESI): m / z: calculated value: 497.3 for [C 27 H 40 N6O3+H] + Measured value: 497.3 (100%, [M+H]) + ).

[0580] Preparation method of seed crystals of compound I:

[0581] Prepared according to the method in Example 6.

[0582] Example 11: Purification of Formula I compounds (routes 1 & 2)

[0583] The crystalline form (5.4 g) of the compound of formula I obtained in Example 6 was dissolved in methyl tert-butyl ether (19.98 g) at 35–40 °C, and then n-heptane (7.40 g) was slowly added to the reaction solution. The mixture was cooled to 30–35 °C, and the crystalline form of the compound of formula I obtained in Example 6 was added as a seed crystal. The mixture was stirred at 30–35 °C for 16–24 hours. The mixture was cooled to 25–30 °C and stirred for 4–8 hours. The mixture was filtered, and the filter cake was washed with a mixed solvent of methyl tert-butyl ether and heptane. The wet cake was dried under vacuum at 45 °C to obtain the compound of formula I (4.26 g, yield: 78.9%, purity: 99.26%). The XRPD diagram is shown in Figure 1; the TGA diagram is shown in Figure 2; and the DSC diagram is shown in Figure 3. The XRPD analysis confirmed that the compound of formula I of this invention was the crystalline form.

[0584] X-ray powder diffraction analysis revealed that the obtained solid crystals conformed to the crystal form of Formula I compound described in this invention, and its X-ray powder diffraction pattern is shown in Figure 1. The X-ray powder diffraction data are shown in Table 2.

[0585] When thermogravimetric analysis was performed, the crystal form I of the present invention was heated to 120°C, and the sample showed a weight loss of 0.03%, as shown in Figure 2.

[0586] When differential scanning calorimetry (DSC) is performed, the crystal form of compound I begins to show an endothermic peak when heated to around 86°C, and its TGA curve is shown in Figure 2.

[0587] Table 2

[0588] Comparative Example 1: Similar to Example 3, but the corresponding raw material was replaced with tofacitinib, as shown in Table 3:

[0589] Table 3

[0590] Tofacitinib and the compound hardly react, so compound I is not obtained.

[0591] Example 12: Preparation of compound E·D-DTTA

[0592] Compound cB: Synthesis: As shown in Example 1, feed aB (1g), b (0.8 g), sodium bicarbonate (1.45 g), Bu4NHSO4 (0.19 g), to give compound cB (1.61 g, yield: 100%, purity: 96.11%).

[0593] GCMS(+EI): m / z: calculated value: 191.1 [C] 11 H 21 ClO2-C2H5] .+ Measured value: 191.1 (100%, [M-C2H5]) .+ )

[0594] Compound g-1-B Synthesis: Compound f-1 (7.69 g) was added to anhydrous THF (30 mL) under a nitrogen atmosphere and cooled to 0-5 °C. 60% sodium hydride (0.38 g) was added in portions, and the mixture was stirred at 0-5 °C for 1 hour. Compound cB (1.61 g) was slowly added dropwise, and the mixture was stirred at 0-5 °C for 0.5–1 hour. Water (25 mL) was added to the reaction mixture, and the aqueous phase was extracted three times with ethyl acetate (25 mL). The organic phases were combined and washed with water (25 mL) and saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was then subjected to high-performance liquid chromatography (HPLC) to prepare g-1-B (3 g).

[0595] (MS+ESI): m / z: calculated value: 554.3, 556.3 for [C 51 H 62 ClN5O 10 -C 20 H 18 O8+H] + Measured values: 554.4, 556.3 (100%), [MC] 20 H 18 O8+H] + ).

[0596] compound jB·HCl Synthesis: As shown in Example 4, g-1-B (3g), tetrahydrofuran (30mL), and 10% palladium on carbon (0.51g) were fed under a hydrogen atmosphere to obtain compound jB·HCl (2.3g, yield: 91.3%, purity: 97.09%).

[0597] (MS+ESI): m / z: calculated value: 430.2 for [C 24 H 40 ClN5O2-HCl+H] + Measured value: 430.2 (100%), [M-HCl+H+] + )

[0598] Synthesis of compound E As shown in Example 5, 2.13 g of JB·HCl, 0.62 g of purified cyanoacetic acid, 2.61 g of HATU, 1.17 g of DIEA, and 40 mL of dichloromethane were added to obtain compound E (1.13 g).

[0599] (MS+ESI): m / z: calculated value: 497.3 for [C 27 H 40 N6O3+H] +Measured value: 497.3 (100%, [M+H]) + )

[0600] Synthesis of compound E·D-DTTA: As shown in Example 5, E (1.13 g), methyl tert-butyl ether (8 mL), and DTTA (0.88 g) were added and stirred at 35–40 °C to obtain a clear solution. The solution was cooled to 30–35 °C and stirred at 35–40 °C for 16–24 hours. The mixture was filtered, and the filter cake was washed with a mixed solvent of methyl tert-butyl ether and n-heptane to obtain 104.5 g of wet product (formula I·D-DTTA), yielding compound E·D-DTTA (2.0 g, yield: 100%, purity: 99.53%).

[0601] NMR data of compound E·D-DTTA: 1 H NMR (400MHz, CDCl3) δ13.84(br,2H),8.20-8.21(m,1H),7.91(d,J=8.1Hz,4H),7.41(d,J=3.7Hz,4H),7.31( d,J=3.7Hz,1H),6.69(d,J=3.3Hz,1H),6.13(s,2H),5.83(s,2H),4.86(br,1H),3.98-4.17(m,2H),3.62-3.9 3(m,2H)3.54-3.66(m,2H),3.27(s,3H),2.441(s,6H),2.34-2.37(m,1H),2.26(t,J=7.6Hz,2H),1.58-1.86 (m,2H),1.41-1.46(m,2H),1.11-1.27(m,9H),1.00(d,J=10.0Hz,3H),0.79-0.83(m,3H),0.71-0.75(m,3H).

[0602] (MS+ESI): m / z: calculated value: 497.3 for [(C 47 H 58 N6O 11 -C 20 H 18 O8)+H] + Measured value: 497.4 (100%), [MC] 20 H 18 O8+H] + ).

[0603] Example 13: Stability test of the crystal form of the compound shown in Formula I

[0604] 13.1 The stability of the crystal form of Compound I of the present invention was tested. The crystal form of Compound I was placed in a constant temperature and humidity chamber at 40±2℃ and 75±5% relative humidity for 6 months, and samples were taken at 0, 1, 2, 3 and 6 months to analyze its stability. The results are shown in Figure 5. XRPD identification results show that the crystal form did not change after 6 months of placement under accelerated conditions, indicating that the crystal form has good stability under accelerated conditions.

[0605] 13.2 The crystal form of the compound of formula I of the present invention was placed in a cold storage at a temperature of 5±3℃ for 12 months, and samples were taken to analyze its long-term stability. The results are shown in Figure 6. XRPD identification results show that the crystal form did not change after 12 months of long-term storage, indicating that the crystal form has good long-term stability.

[0606] 13.3 The crystal form of compound I of the present invention was placed in a constant temperature and humidity chamber at a temperature of 25±2℃ and a relative humidity of 60±5% for 24 months, and samples were taken for analysis of its long-term high humidity stability. The results showed that the crystal form did not change after being placed under high humidity conditions for 24 months, indicating that the crystal form has good long-term high humidity stability.

[0607] Placement conditions: Temperature 25±2℃, relative humidity 60±5%

[0608] 13.4 The stability of the crystal form of compound I of the present invention was tested. The crystal form of compound I was placed in an oven at a temperature of 50±2℃ and 80±2℃ for 7 days, and samples were taken at 0 hours, 4 hours, 24 hours, 48 ​​hours and 7 days to analyze its stability.

[0609] Placement conditions: Temperature 50±2℃, 80±2℃.

[0610] The above results indicate that the crystal form of compound I of the present invention has excellent high-temperature, long-term high-humidity stability and long-term stability.

[0611] Example 14: g-1 D-DTTA Stability Test

[0612] The g-1D-DTTA samples were placed in a 45℃ oven to examine their stability at 0 hours, 24 hours, 6 hours, and 7 days, as shown in Table 4.

[0613] Table 4

[0614] g-1D-DTTA was stable after being placed at 45℃ for 7 days.

[0615] Long-term stability of g-1D-DTTA:

[0616] Storage conditions: 2-8℃, sealed and protected from light; Test intervals: 0, 3, 6, and 12 (months) to examine long-term stability, as shown in Table 5:

[0617] Table 5

[0618] The above results indicate that the g-1D-DTTA compound crystal form of the present invention has excellent high-temperature and long-term stability.

[0619] Example 15: Stability test of compound J·hexafluorophosphate hydrochloride

[0620] The stability of J·hexafluorophosphate hydrochloride samples was investigated in a 55℃ oven for 0 hours, 18 hours, 24 hours, and 42 hours, as shown in Table 6.

[0621] Table 6

[0622] J·hexafluorophosphate hydrochloride is stable after being placed at 55℃ for 42 hours.

[0623] The mass of J·HCl·HPF6 was not affected by temperature after 48 hours at 25 and 55℃, as shown in Table 7.

[0624] Table 7

[0625] The wet product of j·HCl·HPF6 was stored at 35-45℃ for 7 days. The residual solvent met the specifications, the material was stable, and the 7-day storage period did not affect the quality of j·HCl·HPF6, as shown in Table 8.

[0626] Table 8

[0627] Long-term stability of compound j·HCl·HPF6:

[0628] Placement conditions: Stored in an environment of ≤40℃ and ≤65%RH; Test intervals: 0, 1, 3, and 6 (months) to examine stability, as shown in Table 9:

[0629] Table 9

[0630] Stable for 6 months under storage conditions of ≤40℃ and ≤65%RH.

[0631] Example 16: Salt formation screening of compound g-1:

[0632] Compound g-1 can form D-DTTA salt and hydrochloride. Direct quenching of the g-1 reaction solution with hydrochloric acid does not readily precipitate g-1 hydrochloride, but quenching with D-DTTA will precipitate g-1·D-DTTA salt. See Table 10:

[0633] Table 10

[0634] The stability of g-1 hydrochloride is shown in Table 11:

[0635] Table 11

[0636] Example 16-1: Compound f-1 (27g) was added to anhydrous THF (238g) under a nitrogen atmosphere and cooled to approximately 0°C. 60% sodium hydride (3.8g) was added in portions, and the mixture was stirred at 0-5°C for 0.5 hours. Compound c (21.3g) was slowly added dropwise, and stirring continued at 0-5°C for approximately 1 hour. Acetic acid (5g) was added dropwise at approximately 0°C to quench the reaction. 4% NaHCO3 solution (140ml) was added, stirred, and allowed to stand for separation. The organic layer was concentrated to dryness, and n-heptane (200ml) and 4% NaHCO3 solution (140ml) were added. The mixture was stirred, allowed to stand, and allowed to separate. Silica gel (13g) was added to the organic layer, and the mixture was stirred at room temperature. The mixture was filtered, and a sample of the filtrate was analyzed by HPLC; the purity was 97.86%.

[0637] 28.20 g of D-DTTA was dissolved in a mixed solvent of MTBE / THF (150 mL), and the solution was added dropwise to the above filtrate. A solid precipitated out. The solid was filtered, washed with n-heptane, and dried to obtain a white solid compound g-1·D-DTTA (52.48 g, yield 76.41%, purity 98.56%).

[0638] Example 16-2: Compound f-1 (44.01 g) was added to anhydrous THF (387.73 g) under a nitrogen atmosphere and cooled to approximately 0°C. 60% sodium hydride (6.16 g) was added in portions, and the mixture was stirred at 0-5°C for 0.5 hours. Compound c (31.25 g) was slowly added dropwise, and stirring continued at 0-5°C for approximately 1 hour. At approximately 0°C, a 5% HCl / MTBE solution (approximately 8.6 g) was added dropwise to adjust the pH of the reaction system to approximately 7, yielding approximately 442.2 g of the quenched reaction solution. Approximately 44 g of this solution was taken, and a 15% HCl / MTBE solution (approximately 2.89 g, 1 eq) was added dropwise at approximately 0°C. The mixture was stirred overnight under controlled temperature, and no solid precipitation occurred. Half of this mixed solution was taken and distilled successively with isopropanol and MTBE to obtain a yellow oily substance. Add MTBE (30g), stir at around 0°C for 5.5 hours, a solid precipitates out, filter and dry to obtain a white solid compound g-1 hydrochloride (1.41g, yield 40%, purity 97.45%).

[0639] Example 17: Salt formation screening of compound j:

[0640] A DCM solution (48.24 g, containing 8 g monomer, purity 94.39%) of compound j hydrochloride prepared as described in Example 7 was added to a saturated NaHCO3 aqueous solution (40 g) and dichloromethane (40 g). The mixture was extracted and separated. The organic layer was concentrated to dryness (purity 92.71%, indicating a risk of degradation of the free base of compound j). MTBE (40 g) was added to dissolve the residue, and the solution was divided into multiple portions for salt formation studies. See Table 13. The monomer is compound j.

[0641] Example 17-1: Take 14g of compound j MTBE solution (containing about 2g of monomer), add cyanoacetic acid MTBE solution (2eq, 0.79g cyanoacetic acid dissolved in 5g MTBE), stir, and no solid precipitation is observed;

[0642] Example 17-2: Take 14g of compound j MTBE solution (containing approximately 2g of monomer), add 2.26g of 15% HCl*MTBE solution, stir, and no solid precipitation is observed;

[0643] Example 17-3: Take 14g of compound j MTBE solution (containing about 2g of monomer), add 1.52g of 60% hexafluorophosphate aqueous solution, stir, and no solid precipitation is observed;

[0644] Example 17-4: Compound j hydrochloride DCM solution (12.06 g, containing about 1.7 g monomer) was dried under nitrogen, 10 g MTBE was added to dissolve it, and 60% hexafluorophosphate (1.02 g, 0.9 eq) was added dropwise. It precipitated as an oil, dried under nitrogen, and 20 g n-heptane was added to slurry to obtain a solid. The solid was obtained by filtration and compound j HCl hexafluorophosphate (purity 95.03%) was obtained.

[0645] Example 17-5: When 11.04 g of DCM solution of compound j hydrochloride (containing approximately 1.6 g of monomer) was added, 0.51 g of HOAt (1.0 eq) was added. The solid precipitated was HOAt, indicating that HOAt cannot form a salt with compound j.

[0646] Example 17-6: A DCM solution of compound j hydrochloride (15.4 g, containing approximately 2.2 g of monomer) was prepared, and HOBt (0.58 g, 1.0 eq) was added. The solid that precipitated was HOBt, indicating that HOBt cannot form a salt with compound j.

[0647] Table 13

[0648] Example 18: Salt formation screening of compound I:

[0649] Compound I and various acids were pre-dissolved in solvents. The corresponding acid solutions (1 mL / g) were slowly added dropwise to the previously prepared free alkaline solution (5 mL / g) of Compound I. The mixture was magnetically stirred at room temperature until homogeneous, and then stirred overnight. The precipitation of solids was observed. The compound can form salts and precipitate solids in MTBE solvent.

[0650] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

Claims

1. A crystal form of a compound of formula I: Its features are, The crystal form has the following X-ray powder diffraction characteristic peaks: 6.876°±0.3°, 20.599°±0.3°, 24.878°±0.3°, 13.947°±0.3°, 11.129°±0.3°, 12.507°±0.3°, and 19.465°±0.3°.

2. A crystal form of the D-(+)-di-p-methylbenzoyl tartrate of the compound represented by Formula I, i.e., the crystal form of Formula I·D-DTTA, 3. A method for preparing a compound of Formula I, characterized in that, Includes the following steps: Step (1) involves reacting compound g to obtain compound j or its salt; In step (2), compound j or its salt undergoes a condensation reaction with cyanoacetic acid to obtain the compound shown in formula I; X is selected from hydrogen and halogens.

4. The preparation method according to claim 3, characterized in that, The compound of formula g is prepared by the following steps: In step (Y1), in the presence of a base, compound c and compound f react to give compound g. Wherein, X is selected from hydrogen and halogens; Alternatively, the compound of formula g can be prepared by the following steps: In step (X1), under the action of a base, compound d and compound c react to obtain compound k. In step (X2), under the action of a base, compound k reacts with compound e to give compound g. X is selected from hydrogen and halogens.

5. The preparation method according to claim 4, characterized in that, The method further includes the following steps: Step (XY1) involves the compound of formula g forming a salt with an acid to obtain a salt of compound of formula g. Step (XY2) involves the release of the salt of compound g to obtain compound g.

6. The preparation method according to claim 3, characterized in that, Step (1) includes the following steps: Add hexafluorophosphate (HPF6) to the compound of formula j obtained by reacting with the compound of formula g, or the hydrohalate thereof, to form a salt, thereby obtaining the hexafluorophosphate of compound j or the hexafluorophosphate of hydrohalate of compound j.

7. The preparation method according to claim 4, characterized in that, The compound of formula c is prepared by the following method: Compound a reacts with compound b to give compound c.

8. The method as described in claim 3, characterized in that, The method further includes the following steps: Step (3) The compound of formula I reacts with an acid to form a salt, thus obtaining a salt of the compound of formula I; Step (4) releases the salt of compound I to obtain compound I.

9. The preparation method according to claim 8, characterized in that, The acid is hydrochloric acid, formic acid, sulfuric acid, methanesulfonic acid, hexafluorophosphate, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogens on the phenyl group being replaced by a group selected from the group consisting of: deuterium, C1-C3 alkyl, C1-C3 alkoxy, cyano, hydroxyl, and halogen; preferably, the acid is hydrochloric acid, substituted or unsubstituted benzoyl tartaric acid or its isomers, or combinations thereof, wherein the substitution refers to one or more hydrogens on the phenyl group being replaced by a group selected from the group consisting of: C1-C3 alkyl, hydroxyl, and halogen; more preferably, the acid is D-(+)-di-p-methylbenzoyl tartaric acid (D-DTTA), L-(-)-di-p-methylbenzoyl tartaric acid (L-DTTA), or combinations thereof.

10. An intermediate compound, characterized in that, The compound has a structure selected from the group consisting of:

11. A method for preparing a compound of formula g, characterized in that, It includes the following steps: in a solvent and in the presence of a base, compound c and compound f react to prepare compound g; Where X is hydrogen or halogen.

12. The method for preparing compound g according to claim 11, characterized in that, It satisfies one or more of the following conditions: (1) The halogen is fluorine, chlorine, bromine or iodine; preferably chlorine; (2) X is hydrogen or chlorine; (3) The solvent is an organic solvent, such as an ether solvent and / or an amide solvent; the ether solvent may be tetrahydrofuran or methyl tert-butyl ether; for example, anhydrous tetrahydrofuran or aqueous tetrahydrofuran; the amide solvent may be N,N-dimethylformamide; (4) The base is an inorganic base; for example, an alkali metal carbonate or an alkali metal hydride; the alkali metal carbonate may be potassium carbonate; the alkali metal hydride may be sodium hydride; for example, 60% sodium hydride; (5) The molar ratio of compound f to compound c is 1:(1.0-4.0); for example, 1:1.3 or 1:3; (6) The molar ratio of the compound of formula f to the base of formula f is 1:(1.0-4.0); for example, 1:1.3 or 1:3; (7) The molar ratio of the compound of formula f to the solvent is 0.1-0.5 mmol / g; or, for example, 0.31 mmol / g or 0.1 mmol / g; (8) The temperature of the reaction is -5℃ to 60℃; for example, -5℃ to 5℃ or 40 to 60℃; or for example, 0 to 5℃ or 50℃; (9) The reaction time is 0.5-28 h; for example, 0.5-1 h or 24 h; The preparation method of compound g described in (10) further includes the following post-processing steps: extraction, washing, drying, filtration, concentration, and separation by silica gel column chromatography; Alternatively, quench, separate, concentrate, separate, add silica gel and stir to obtain filtrate.

13. The method for preparing compound g according to claim 12, characterized in that, It satisfies one or more of the following conditions: (1) The compound of formula c is Or a molar ratio of 1:1 (2) The compound of formula f is (3) The compound of formula g is the compound of formula g. The molar ratio is 1:1 Or a molar ratio of 1:1 (4) When X is a halogen, the base is an alkali metal hydride as described above; the solvent may be an ether solvent as described above. (5) When X is H, the base is an alkali metal carbonate as described above; the solvent may be an amide solvent as described above; (6) When the base is an alkali metal hydride; the reaction temperature is -5℃ to 5℃; for example, 0 to 5℃; (7) When the base is an alkali metal carbonate; the temperature of the reaction is 40-60°C; for example, 50°C.

14. The method for preparing compound g according to claim 13, characterized in that, The preparation method of compound g further includes the following steps: in a solvent, in the presence of an alkali metal bicarbonate and a phase transfer catalyst, compound a and compound b react to prepare compound c. Preferably, the preparation method of the compound of formula c satisfies one or more of the following conditions: (1) The solvent is an organic solvent and / or water; the organic solvent may be an alkane solvent; for example, dichloromethane; (2) The alkali metal bicarbonate is sodium bicarbonate; (3) The phase transfer catalyst is a quaternary ammonium salt phase transfer catalyst; For example, Bu4NHSO4; (4) The molar ratio of compound a to compound b is 1:(1-3); for example, 1:1.

2. (5) The molar ratio of the compound of formula a to the alkali metal bicarbonate is 1:(1-5); for example, 1:3.3; (6) The molar ratio of the compound of formula a to the phase transfer catalyst is 1:(0.04-0.10); for example, 1:0.08; (7) The molar mass ratio of the compound of formula a to the solvent is 0.1-0.4 mmol / g; for example, 0.25 mmol / g; (8) The mass ratio of water to organic solvent is 1:(1-2); for example, 1:1.33; (9) The reaction temperature is 0-30℃; for example, 10-15℃; (10) The reaction time is 1-8 hours; for example, 3-5 hours. The compound of formula a described in (11) is Or a molar ratio of 1:1 15. A method for preparing a compound of formula g·DTTA, characterized in that, It includes the following steps: reacting compound g and compound DTTA in a solvent to prepare compound g·DTTA; Wherein, X is defined as described in claim 11 or 12.

16. The method for preparing the compound of formula g·DTTA as described in claim 15, characterized in that, It satisfies one or more of the following conditions: (1) The compound of formula g is the compound of formula g. The molar ratio is 1:1 Or a molar ratio of 1:1 (2) The DTTA compound is Or a molar ratio of 1:1 (3) The compound of formula g·DTTA is The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 Or a molar ratio of 1:1 (4) The solvent is an organic solvent and / or water; the organic solvent is an ether solvent and / or an amide solvent; the ether solvent and the amide solvent are independently as described in claim 12; preferably, the solvent is an organic solvent and water; (5) The mass ratio of the organic solvent to water is 1:(0.2-0.8); for example, 1:0.5; (6) The molar ratio of the compound of formula g to the compound of formula DTTA is 1:(1.0-2.0); for example, 1:1.3; (7) The molar mass ratio of the compound of formula g to the solvent is 0.05-0.3 mmol / g; for example, 0.1 mmol / g; (8) The reaction temperature is 15-35℃; for example, 20-25℃; The method for preparing the compound of formula g·DTTA as described in (9) further includes a method for preparing compound g; the method for preparing the compound of formula g is independently described in any one of claims 11-14.

17. The method for preparing the compound of formula g·DTTA as described in claim 16, characterized in that, Includes the following steps: Step 1: In a solvent and in the presence of a base, compound c and compound f react to obtain a reaction solution; Step 2: Mix the reaction solution from Step 1, the DTTA compound of formula g, and the solvent; react to obtain the DTTA compound of formula g. The operation and conditions of the reaction in step 1 are independently as described in the method for preparing compound g according to any one of claims 11-13; Preferably, the preparation method of the compound of formula g·DTTA satisfies one or more of the following conditions: (1) The solvent is water; (2) The molar ratio of compound f in step 1 to compound DTTA in step 2 is 1:(1.0-2.0); for example, 1:1.3 or 1:1; (3) The molar ratio of compound f in step 1 to solvent in step 2 is 0.1-0.3 mmol / g; for example, 0.15 mmol / g; (4) The reaction temperature in step 2 is 15-35℃; for example, 20-25℃. The preparation method of the compound of formula g·DTTA described in (5) includes the following post-processing steps: filtration, washing the filter cake, and drying.

18. A method for preparing a compound of formula j·HCl·HPF6, characterized in that, It includes the following steps: in a solvent; the compound of formula j·HCl reacts with hexafluorophosphoric acid to prepare the compound of formula j·HCl·HPF6; 19. The method for preparing the compound of formula j·HCl·HPF6 as described in claim 18, characterized in that, It satisfies one or more of the following conditions: (1) The solvent is an organic solvent; for example, selected from one or more of alkane solvents, benzene solvents and ether solvents; for example, "alkane solvents and benzene solvents" or "benzene solvents and ether solvents"; the alkane solvent may be dichloromethane and / or n-heptane; the benzene solvent may be toluene; the ether solvent may be tetrahydrofuran or methyl tert-butyl ether; for example, anhydrous tetrahydrofuran; (2) The hexafluorophosphate exists in the form of an aqueous solution; for example, a 60% aqueous solution of hexafluorophosphate; (3) The molar ratio of the compound of formula j·HCl to hexafluorophosphoric acid is 1:(0.1-2.0); for example, 1:0.4, 1:0.9 or 1:1.0; (4) The molar mass ratio of the compound of formula j·HCl to the solvent is 0.1-0.8 mmol / g; for example, it is 0.2 mmol / g; (5) The mass ratio of the alkane solvent to the benzene solvent is 1:(1.5-4); for example, 1:2.5; (6) The mass ratio of dichloromethane to n-heptane is 1:(1.2-2); for example, 1:1.5; (7) The reaction temperature is 10-40℃; for example, 20-30℃; (8) The compound of formula j·HCl is Or a molar ratio of 1:1 The compound of formula j·HCl·HPF6 described in (9) is Or a molar ratio of 1:1 20. The method for preparing the compound of formula j·HCl·HPF6 as described in claim 19, characterized in that, The preparation method of the compound of formula j·HCl·HPF6 further includes the following steps: in a solvent, in the presence of a reducing agent and a catalyst, the compound of formula g-1 is reacted to prepare the compound of formula j HCl. Preferably, the method for preparing the HCl compound of formula j satisfies one or more of the following conditions: (1) The solvent is an organic solvent and / or water; the organic solvent may be an ether solvent; for example, it may be tetrahydrofuran; (2) The reducing agent is a conventional reducing agent for this type of reaction in the art; for example, hydrogen gas; (3) The catalyst is a palladium-on-carbon catalyst; for example, 10% palladium on carbon; (4) The molar ratio of the compound of formula g-1 to the reducing agent is 1:(2-5); for example, 1:2 or 1:2.5; (5) The molar ratio of the compound of formula g-1 to the catalyst is 1:(0.01-1); for example, 1:0.1 or 1:0.2; (6) The reaction temperature is 30-60℃; for example, 30-38℃, 30-40℃ or 40-50℃; (7) The reaction time is 1 hour, 55 hours or 8-10 hours; The compound of formula g-1 described in (8) is Or a molar ratio of 1:1 21. The method for preparing the compound of formula j·HCl·HPF6 as described in claim 20, characterized in that, The preparation method of the compound of formula j·HCl further includes the following steps: in a solvent, in the presence of a base, the compound of formula g-1·D-DTTA is prepared to obtain the compound of formula g-1; Preferably, the preparation method of the compound of formula g-1 satisfies one or more of the following conditions: (1) The compound of formula g-1·D-DTTA is The molar ratio is 1:1 Or a molar ratio of 1:1 (2) The solvent is an organic solvent; for example, an ether solvent as described above. (3) The mass-to-volume ratio of the compound of formula g-1 to the solvent is 0.05-0.5 g / mL; for example, 0.089 g / mL, 0.136 g / mL or 0.228 g / mL; (4) The mass ratio of the compound of formula g-1 to sodium bicarbonate is 2-10; for example, 4.73, 5.45 or 7.12; (5) The alkali is an alkali metal carbonate or an alkali metal bicarbonate; for example, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate; and for example, sodium bicarbonate; the sodium bicarbonate may exist in the form of an aqueous solution of sodium bicarbonate; (6) The reaction further includes the addition of sodium chloride; the sodium chloride may be in the form of an aqueous solution of sodium chloride; for example, a semi-saturated aqueous solution of sodium chloride or a saturated aqueous solution of sodium chloride; (7) The preparation method of the compound of formula g-1 further includes adding silica gel; The temperature of the reaction described in (8) is -5℃ to 5℃; or for example, 0℃ to 5℃.

22. The method for preparing the compound of formula j·HCl·HPF6 as described in claim 21, characterized in that, The preparation method of the compound of formula j·HCl·HPF6 includes the following steps: Step 1: In a solvent, in the presence of sodium bicarbonate and sodium chloride, the compound of formula g-1·D-DTTA reacts to obtain a reaction solution; Step 2: Mix the reaction solution from Step 1, the reducing agent, the catalyst, and the compound of formula g-1, and allow them to react to obtain the reaction solution; Step 3: Mix the reaction solution, solvent, compound of formula j·HCl and hexafluorophosphate from step 2 to react and obtain compound of formula j·HCl·HPF6; The operation and conditions of step 1 are independently as described in the preparation method of compound g-1; Preferably, the preparation of the compound of formula j·HCl·HPF6 satisfies one or more of the following conditions: (1) The solvent in step 2 also includes water; (2) In step 3, the solvent is an organic solvent, such as benzene-based solvents and / or alkane-based solvents. (3) The molar ratio of the g-1·D-DTTA compound in step 1 to the catalyst in step 2 is 1:(0.01-1); for example, 1:0.1 or 1:0.2; (4) The molar ratio of the g-1·D-DTTA compound in step 1 to the reducing agent in step 2 is 1:(2-5); for example, 1:2 or 1:2.5; (5) The molar ratio of the g-1·D-DTTA compound in step 1 to the hexafluorophosphate in step 3 is 1:(0.1-2.0); or for example, 1:0.4, 1:0.9 or 1:1.0; (6) When a solvent is present in step 2; the molar mass ratio of the compound of formula g-1·D-DTTA in step 1 to the solvent in step 2 is 3-10 mmol / g; for example, 7.1 mmol / g; (7) The molar mass ratio of the g-1·D-DTTA compound in step 1 to the solvent in step 3 is 0.1-1 mmol / g; for example, 0.25 mmol / g; (8) In step 2, the reaction temperature is 30-60℃; for example, 30-38℃, 30-40℃ or 40-50℃. In step 3 of (9), the temperature of the reaction is 10-40°C; for example, 20-30°C.

23. A method for preparing the crystal form of ID-DTTA as described in claim 2, characterized in that, It includes the following steps: in a solvent, the compound of formula I reacts with the compound of formula D-DTTA to prepare the crystal form of formula I·D-DTTA; 24. The method for preparing the crystal form of formula ID-DTTA as described in claim 23, characterized in that, It satisfies one or more of the following conditions: (1) The solvent is an organic solvent; for example, an ether solvent; the ether solvent may be tetrahydrofuran or methyl tert-butyl ether; for example, methyl tert-butyl ether; (2) The molar ratio of the compound of formula I to the solvent is 0.05-0.3 mmol / g; for example, 0.1 mmol / g or 0.25 mmol / g; (3) The molar ratio of the compound of formula I to the compound of formula DTTA is 1:(1.0-2.0); or for example, 1:1.3 or 1:1; (4) The reaction temperature is 15-60℃; for example, 30-35℃, 35-40℃, 20-25℃ or 28℃; (5) The reaction time is 6-24 hours; for example, 12 hours or 16 hours. (6) The method for preparing the crystal form of the compound of formula I·D-DTTA includes the following post-processing steps: filtration and washing of the filter cake; the alcohol solvent can be ethanol; the ether solvent can be methyl tert-butyl ether; the alkane solvent can be n-heptane; the washing is, for example, rinsing; the number of washing times is, for example, 2 times; (7) The compound of formula I is Or a molar ratio of 1:1 (8) The ID-DTTA formula is Or molar ratio is 25. A method for preparing the crystal form of the compound of formula I as described in claim 1, characterized in that, It includes the following steps: after mixing the positive solvent mixture and the antisolvent of compound I, crystallization is performed to prepare the crystal form of compound I; Preferably, the method for preparing the crystal form of the compound of formula I satisfies one or two of the following conditions: (1) The solvent is an ether solvent; the ether solvent is tetrahydrofuran or methyl tert-butyl ether; (2) In the method for preparing the crystal form of the compound of formula I, the antisolvent is an alkane solvent; the alkane solvent is n-heptane.

26. A compound as shown below: For example, The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 The molar ratio is 1:1 Or a molar ratio of 1:1

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