Methods for preparing solid forms of BET bromodomain inhibitors

Abstract

The present invention relates to solid crystalline forms of compound (I), such as form VII, including pharmaceutical compositions thereof and methods for preparing crystalline compound (I) form VII. Compound (I) modulates or inhibits the activity of BET bromodomain-containing proteins and is useful for treating diseases such as cancer, inflammatory diseases and cardiovascular diseases.

Description

Field of the Invention

[0001] The present disclosure relates to a solid form of Compound I (1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine), which regulates or inhibits the activity of a BET bromodomain-containing protein, including a method for preparing the same, an intermediate for preparing the same, and a pharmaceutical composition thereof, wherein Compound I is suitable for treating diseases such as cancer. Background Art

[0002] Therapeutic agents that modulate or inhibit the activity of BET bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, and BRDT) have the potential to cure, treat, or improve the lives of patients suffering from diseases such as cancer, autoimmunity, and cardiovascular disease. In particular, BET bromodomain modulators or inhibitors have the potential to treat B acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer, or neuroblastoma, among others. Compounds useful for treating such diseases and conditions are disclosed in PCT Publication No. WO 2015 / 002754, the disclosure of which is incorporated herein by reference in its entirety.

[0003] There is an urgent need for compounds including solid forms of derivatives of benzimidazoles with high purity. In addition to effectiveness, the compounds also exhibit improved stability, solubility, and pharmacokinetic and pharmacodynamic profiles that are beneficial for treating diseases modulated by bromodomain-containing BET proteins, and importantly, can be efficiently prepared on a large scale to facilitate clinical and commercial use. Summary of the invention

[0004] Compound I is known to modulate or inhibit BET activity and is described in WO 2015 / 002754. Compound I has the following formula:

[0005]

[0006] The present disclosure provides solid forms of Compound 1, as well as methods for preparing the disclosed solid forms of Compound 1, intermediates used in their preparation, pharmaceutical compositions comprising crystalline forms of Compound 1, and methods of using such forms and pharmaceutical compositions to treat diseases mediated by BET proteins. The details of one or more embodiments are set forth in the following description. Other features, objectives, and advantages will be apparent from the description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1The X-ray powder diffraction pattern (XRPD) of Compound 1 Form VII is shown.

[0008] Figure 2 A differential scanning calorimeter (DSC) curve of Compound 1 Form VII is shown.

[0009] Figure 3 Thermogravimetric analysis (TGA) of Compound 1 Form VII is shown.

[0010] Figure 4 The infrared spectrum (IR) of Compound 1 Form VII is shown. DETAILED DESCRIPTION

[0011] The present disclosure provides a method for preparing a compound I suitable for increasing the ratio and large-scale preparation. The method for preparing compound I is described in WO 2015 / 002754, which is incorporated herein by reference in its entirety, and in particular the description of compound I and its synthesis. Compared to the synthesis described in WO 2015 / 002754, the method provided herein has certain advantages suitable for the scale-up of the preferred polymorphic form (Form VII) of compound I. For example, the method described herein uses less harmful reagents, lower reaction temperatures, more suitable reagents for scale-up, simplified post-processing procedures, and eliminates the purification by column chromatography to streamline the separation of intermediates. All these factors make the preparation method superior to existing methods in terms of efficiency and quality, reduce environmental footprint and reduce costs.

[0012] In some embodiments, the method for preparing compound I comprises starting materials A and G and intermediates B, C, D, E and F:

[0013]

[0014] In some embodiments, the method of preparing compound B comprises compound A (step 1):

[0015]

[0016] and reacting with benzaldehyde in the presence of an acid. In some embodiments, the acid is acetic acid.

[0017] In some embodiments, step 1 is carried out in the presence of a solvent. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. Using methanol or ethanol as a solvent in step 1 provides more efficient post-processing and separation by eliminating the need for column chromatography.

[0018] In some embodiments of step 1, NaHCO 3 solution is added to the reaction mixture after the reaction is completed to precipitate the product, which simplifies the isolation and purification of compound B.

[0019] In some embodiments of step 1, compound A and benzaldehyde are used in a molar ratio of 1:1.

[0020] In some embodiments, step 1 is performed at a reduced temperature, and in some embodiments, the reaction temperature is between 0°C and 5°C, or below 10°C, or below 20°C.

[0021] In some embodiments, the method of preparing compound C comprises compound B (step 2):

[0022]

[0023] React with NaCNBH3 or NaBH4 in a solvent. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol or ethanol.

[0024] In some embodiments, the solvent is ethanol, so that the loading of NaCNBH3 or NaBH4 is reduced to 0.6 molar equivalents relative to compound B, thereby making the process more environmentally friendly and reducing overall costs.

[0025] In some embodiments, the loading of NaCNBH3 or NaBH4 is equal to or less than one equivalent relative to compound B, for example, less than 0.9 equivalents, or less than 0.75 equivalents, or equal to or less than 0.6 equivalents relative to compound B.

[0026] In some embodiments of step 2, post-processing and isolation are performed by adding HCl solution to quench the reaction, followed by adding water to precipitate the product (Compound C) with high purity (+95%), thereby simplifying the post-processing and isolation methods. In some embodiments, other reagents may be used to quench the reaction, such as water or acetic acid.

[0027] In some embodiments, step 2 is performed at 10°C to 40°C, or 15°C to 20°C, or 20°C to 25°C.

[0028] In some embodiments, the method of preparing compound D comprises compound C (step 3):

[0029]

[0030] and

[0031]

[0032] The reaction is carried out in the presence of a transition metal catalyst and a base, wherein the transition catalyst is a palladium catalyst.

[0033] In some embodiments, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphinyl})palladium (PD-132) or tetrakis(tri(o-tolyl)phosphine)palladium(0).

[0034] In some embodiments, the palladium catalyst is Pd(PPh3)4.

[0035] In some embodiments, the base is CsF. In some embodiments, the base is an alkali metal carbonate. In some embodiments, the base is K2CO3. In some embodiments, the base is an alkali metal phosphate. In some embodiments, the base is K3PO4.

[0036] The use of K3PO4 is advantageous over K2CO3 because K3PO4 is well dispersed in the reactor and thus results in a reaction with fewer by-products and a higher purity of the product (compound D).

[0037] In some embodiments, the reaction is carried out in a solvent mixture comprising 1,4-dioxane and water.

[0038] In some embodiments, the reaction is carried out at an elevated temperature, such as 80°C to 100°C, or 90°C to 100°C, or 90°C to 95°C.

[0039] In some embodiments, the method of preparing compound E comprises compound D (step 4):

[0040]

[0041] React with carbonyldiimidazole (CDI) in a solvent.

[0042] In some embodiments, the solvent is an aprotic solvent. In some embodiments, the solvent is 1,4-dioxane, DMSO or DMF.

[0043] The advantage of using DMSO is that it is a safer (level 3) and more environmentally friendly solvent. The use of DMSO also allows the development of a simplified isolation procedure, which involves precipitating the product (Compound E) by adding water to the reaction mixture. This eliminates lengthy post-processing methods (including the use of chromatography) and thus provides Compound E in an efficient manner.

[0044] In some embodiments, CDI in a solvent is added portionwise to reduce heat release during addition to the reaction mixture.

[0045] In some embodiments, the reaction is carried out at an elevated temperature, for example 20°C to 70°C, or 30°C to 40°C, or 40°C to 65°C, or 55°C to 60°C.

[0046] In some embodiments, the method of preparing compound F comprises compound E (step 5):

[0047]

[0048] React with a chlorinating agent in the presence of a base.

[0049] In some embodiments, the chlorinating agent is phosphorus oxychloride (POCl3).

[0050] In some embodiments, POCl 3 is used in excess (2 to 30 molar equivalents, or 4 to 7 equivalents, or 5 to 15 equivalents, or 7 to 10 equivalents relative to Compound E).

[0051] In some embodiments, the base is an amine base.

[0052] In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the amine base is trimethylamine or N,N-dimethylaniline.

[0053] In some embodiments, DIPEA is used in excess (1.01 to 10 molar equivalents, or 1.01 to 3 equivalents, or 5 to 10 equivalents relative to Compound E).

[0054] In some embodiments, 4 to 5 molar equivalents, or 8 to 9 molar equivalents of POCl3 are used relative to compound E, and 1.0 to 1.1 molar equivalents, or 2.5 molar equivalents of DIPEA are used relative to compound E to reduce the formation of unwanted by-products and simplify the purification method of compound E.

[0055] In some embodiments, step 5 is performed at an elevated temperature, such as 95°C to 100°C or 80°C to 100°C.

[0056] In some embodiments, step 5 further comprises co-distilling the crude reaction mixture with ethyl acetate. This is an efficient method for removing excess POCl3 from the reaction mixture and subsequently quenching the reaction with NaHCO3 solution.

[0057] In some embodiments, the product (Compound F) is isolated by crystallization from a mixture of ethyl acetate and a non-polar co-solvent. In some embodiments, the non-polar co-solvent is hexane, heptane, or toluene.

[0058] In some embodiments, the product (Compound F) is isolated by crystallization from an ethyl acetate / n-heptane mixture.

[0059] In some embodiments, the method of preparing Compound I comprises compound F (step 6):

[0060]

[0061] Reacts with methylamine.

[0062] In some embodiments, methylamine 2M in THF is used.

[0063] In some embodiments, the reaction is carried out at 20° C. to 30° C. This temperature avoids volatilization of methylamine and pressure buildup.

[0064] In some embodiments, post-reaction treatment includes dissolving the crude product in an aqueous HCl solution (e.g., 7N HCl) and washing with a non-polar solvent. In some embodiments, the non-polar solvent is dichloromethane, which effectively removes the remaining impurities from the previous step. Subsequently, the crude product is neutralized with an aqueous NaOH solution and the product is isolated.

[0065] In some embodiments, the desired form of Compound I (Form VII) is obtained by crystallization from ethanol (EtOH) and methyl tert-butyl ether (MTBE).

[0066] In some embodiments, to remove any remaining HCl, the dried Compound 1 can be dissolved in ethanol, treated with a solution of sodium hydroxide in ethanol, followed by the addition of treated water to precipitate the product.

[0067] In some embodiments, Compound 1 Form VII is used as seed for crystallization to ensure formation of the desired polymorph.

[0068] In some embodiments, precipitation is performed by: (1) cooling an ethanol solution of Compound I, (2) adding seed crystals of Compound I Form VII, (3) stirring the mixture for about 10 hours, (4) further cooling the mixture and adding MTBE, (5) stirring for about 3 to 5 hours to precipitate Compound I Form VII.

[0069] In some embodiments, MBTE may be added followed by the addition of seeds of Compound I Form VII.

[0070] Disclosed herein is a method for preparing a crystalline solid form of Compound I. Crystalline forms of the same compound typically have different properties, including hygroscopicity, solubility, and stability. Polymorphs with high melting points typically have good thermodynamic stability, which is beneficial for extending the shelf life of formulations containing solid forms of the compound. Polymorphs with lower melting points are typically less stable thermodynamically, but are beneficial for increasing water solubility, which typically translates into increased bioavailability of the compound. Polymorphs with poor hygroscopicity are typically more stable to heat and moisture and resistant to degradation during storage. Anhydrous polymorphs are typically advantageous because they can be consistently prepared with no or less variation in composition due to variations in solvent and water content.

[0071] Compound I can be obtained in a solid crystalline form (referred to as Form VII). Form VII is an anhydrate. Form VII (a polymorph of Compound I) is characterized by its XRPD and other data. Form VII of Compound I is characterized by, for example, using Cu-K α The X-ray powder diffraction pattern (XRPD) measured on a diffractometer using a radiation tube comprises a peak expressed in 2θ at 16.5°±0.2°θ.

[0072] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured on a diffractometer using a radiation tube comprises one or more peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, wherein each peak is ±0.2°θ.

[0073] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured on a radiation tube diffractometer comprises three or more peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, wherein each peak is ±0.2°θ.

[0074] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured on a radiation tube diffractometer comprises six or more peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, wherein each peak is ±0.2°θ.

[0075] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured on a radiation tube diffractometer comprises ten or more peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, wherein each peak is ±0.2°θ.

[0076] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured on a radiant tube diffractometer comprises peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, wherein each peak is ±0.2°θ.

[0077] In some embodiments, Form VII of Compound I is characterized as follows: α The X-ray powder diffraction pattern (XRPD) measured by a radiation tube on a diffractometer is basically as follows Figure 1 as shown in .

[0078] In some embodiments, Form VII of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at a temperature of about 205 °C.

[0079] In some embodiments, Form VII of Compound I is characterized by a differential scanning calorimetry (DSC) thermogram substantially as follows: Figure 2 as shown in .

[0080] In some embodiments, Form VII of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram substantially as follows: Figure 3 as shown in .

[0081] In some embodiments, Form VII of Compound I is characterized by an infrared (IR) spectrum comprising a peak at approximately 3066 cm -1 and 1600cm -1 IR band.

[0082] In some embodiments, Form VII of Compound I is characterized by an infrared (IR) spectrum substantially as follows: Figure 4 as shown in .

[0083] Also disclosed herein are intermediates useful for synthesizing BET bromodomain inhibitors, such as compound B:

[0084]

[0085] and compound C:

[0086]

[0087] In one embodiment, disclosed herein is a method for preparing a therapeutic agent (Compound I) that modulates or inhibits the activity of a BET bromodomain-containing protein (e.g., BRD2, BRD3, BRD4, and BRDT), which has the potential to cure, treat, or improve the lives of patients suffering from diseases mediated by bromodomain-containing proteins (e.g., certain cancers, inflammatory diseases, and cardiovascular diseases).

[0088] One embodiment is directed to a method of treating a disease mediated at least in part by a BET bromodomain-containing protein in an individual in need thereof, the method comprising administering a therapeutically effective amount of Compound I in crystalline Form VII.

[0089] In one embodiment, the disease is selected from cancer, inflammatory disease and cardiovascular disease.

[0090] In one embodiment, the disease is cancer, including B acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer and neuroblastoma.

[0091] In one embodiment, the disease is prostate cancer.

[0092] In one embodiment, the disease is castration-resistant prostate cancer.

[0093] In one embodiment, the disease is metastatic castration-resistant prostate cancer.

[0094] In one embodiment, the disease is breast cancer.

[0095] In one embodiment, the disease is triple negative breast cancer.

[0096] In one embodiment, the disease is estrogen receptor positive breast cancer.

[0097] In one embodiment, the subject is a human.

[0098] When treating a disease mediated at least in part by a BET bromodomain-containing protein in an individual in need thereof, the individual may benefit from a combination drug therapy. For example, one or more forms of Compound 1 described herein may be combined with one or more therapeutic agents in a single composition or in separately administered compositions that may be administered simultaneously, sequentially, or according to a prescribed treatment regimen.

[0099] In one embodiment, the forms of Compound 1 described herein can be administered sequentially with one or more additional therapeutic agents. Sequentially means that one or more forms of Compound 1 and one or more additional therapeutic agents are administered with a time interval of a few seconds (e.g., 15 seconds, 30 seconds, 45 seconds, 60 seconds or less), several minutes (e.g., 1 minute, 2 minutes, 5 minutes or less, 10 minutes or less, 15 minutes or less), 1 to 8 hours, 1 to 7 days, or 1 to 4 weeks. When administered sequentially, one or more forms of Compound 1 described herein and the additional therapeutic agent can be administered in two or more administrations and contained in separate compositions or dosage forms, which can be contained in the same package or in different packages.

[0100] In one embodiment, one or more forms of Compound 1 described herein may be combined with one or more therapeutic agents for the treatment of cancer.

[0101] In one embodiment, Compound I in Form VII described herein may be combined with one or more therapeutic agents for the treatment of cancer.

[0102] In one embodiment, Compound I in Form VII described herein may be combined with a therapeutic agent selected from the group consisting of an androgen receptor antagonist, an androgen synthesis inhibitor, an aromatase inhibitor, a selective estrogen receptor modulator, a selective estrogen down-regulator, a poly ADP ribose polymerase (PARP) inhibitor, or an immunotherapeutic agent.

[0103] In one embodiment, Compound I in Form VII described herein can be combined with a therapeutic agent selected from Abiraterone (Zytiga), Enzalutamide (Xtandi), Apalutamide (ARN-509, Erleada), Darolutamide, Fulvestrant, Exemestane, Talazoparib, Olaperib, Veliparib, Rucaparib, Talazoparib, Niraparib, Pembrolizumab, Nivolumab, Durvalumab, and Rituximab.

[0104] A list of exemplary embodiments includes:

[0105] 1. A solid form of a compound having the formula:

[0106]

[0107] Wherein the solid form is crystalline.

[0108] 2. The solid form according to embodiment 1, which is an anhydrate.

[0109] 3. The solid form of embodiment 1, wherein the solid form is Form VII.

[0110] 4. A solid form as described in embodiment 3, such as using Cu-K α The radiation tube has three or more characteristic XRPD peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5° as measured on a diffractometer, wherein each peak is ±0.2°θ.

[0111] 5. A solid form as described in embodiment 3, such as using Cu-K α The radiation tube has six or more characteristic XRPD peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5° as measured on a diffractometer, wherein each peak is ±0.2°θ.

[0112] 6. A solid form as described in any one of embodiments 1 to 3, which has a substantially similar Figure 1 XRPD pattern shown in .

[0113] 7. The solid form of any one of embodiments 1 to 6, having a DSC thermogram with an endothermic peak at a temperature of about 205°C.

[0114] 8. A solid form as described in any one of embodiments 1 to 6, which has a substantially similar Figure 2 DSC temperature record diagram shown in .

[0115] 9. A solid form as described in any one of embodiments 1 to 7, having a substantially similar Figure 3 TGA temperature record shown in .

[0116] 10. A pharmaceutical composition comprising the solid form of any one of embodiments 1 to 9 and at least one pharmaceutically acceptable carrier.

[0117] 11. A method of treating cancer comprising administering a therapeutically effective amount of the solid form of any one of embodiments 1 to 9 or the pharmaceutical composition of embodiment 10 to an individual in need of such treatment.

[0118] 12. The method of embodiment 11, wherein the cancer is B acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, prostate cancer, ovarian cancer or neuroblastoma.

[0119] 13. The method of embodiment 12, wherein the cancer is prostate cancer.

[0120] 14. The method of embodiment 12, wherein the cancer is castration-resistant prostate cancer.

[0121] 15. The method of embodiment 12, wherein the cancer is metastatic castration-resistant prostate cancer.

[0122] 16. The method of embodiment 12, wherein the cancer is breast cancer.

[0123] 17. The method of embodiment 12, wherein the cancer is triple-negative breast cancer.

[0124] 18. The method of embodiment 12, wherein the cancer is estrogen receptor positive breast cancer.

[0125] 19. A method of treating an inflammatory disease comprising administering a therapeutically effective amount of the solid form of any one of embodiments 1 to 9 or the pharmaceutical composition of embodiment 10 to a patient in need of such treatment.

[0126] 20. A method of treating cardiovascular disease, the method comprising administering a therapeutically effective amount of the solid form of any one of embodiments 1 to 9 or the pharmaceutical composition of embodiment 10 to a patient in need of such treatment.

[0127] 21. The method of embodiment 11, wherein the individual is a human.

[0128] 22. A method for preparing Form VII of Compound I:

[0129]

[0130] The method comprises precipitating Form VII from a solution comprising Compound I and one or more solvents.

[0131] 23. The method of embodiment 22, wherein the solvent is ethanol, tert-butyl methyl ether (MTBE) or a mixture thereof.

[0132] 24. The method of embodiment 22, wherein the precipitation is performed by:

[0133] (1) cooling the ethanol solution of Compound I;

[0134] (2) adding seed crystals of Compound 1 Form VII to the solution;

[0135] (3) stirring the mixture for about 10 hours;

[0136] (4) further cooling the mixture and adding MTBE; and

[0137] (5) Stirring for about 3 to 5 hours to precipitate Compound I Form VII.

[0138] 25. The method of embodiment 24, wherein MTBE is added before adding the seed crystals of Compound I Form VII to the mixture.

[0139] 26. A method for preparing compound I

[0140]

[0141] The method comprises steps (a) to (d):

[0142] (a)

[0143]

[0144] With compound G:

[0145]

[0146] The reaction produces compound D:

[0147]

[0148] (b) Compound D:

[0149]

[0150] Reaction with the first reagent produces compound E:

[0151]

[0152] (c) Compound E:

[0153]

[0154] Reaction with chlorinating agent produces compound F:

[0155]

[0156] (d) Compound F:

[0157]

[0158] Reacts with methylamine.

[0159] 27. The method of embodiment 26, wherein step (a) is carried out in the presence of a transition metal catalyst and a base.

[0160] 28. The method of embodiment 27, wherein the transition metal catalyst is a palladium catalyst.

[0161] 29. A method as described in embodiment 28, wherein the palladium catalyst is Pd(PPh3)4.

[0162] 30. The method of embodiment 27, wherein the base is an alkali metal carbonate.

[0163] 31. The method of embodiment 27, wherein the base is K3PO4.

[0164] 32. The method of embodiment 26, wherein the first reagent in step (b) is carbonyldiimidazole (CDI), and step (b) is performed in a solvent.

[0165] 33. The method of embodiment 32, wherein the solvent is an aprotic solvent.

[0166] 34. The method of embodiment 32, wherein the solvent is DMSO.

[0167] 35. The method of embodiment 32, wherein step (b) comprises adding water to the reaction mixture and precipitating compound E.

[0168] 36. The method of embodiment 26, wherein step (c) is performed in the presence of a base.

[0169] 37. A method as described in embodiment 36, wherein the chlorinating agent is phosphorus oxychloride (POCl3).

[0170] 38. The method of embodiment 36, wherein the base is N,N-diisopropylethylamine (DIPEA).

[0171] 39. The method of embodiment 36, wherein 4 to 5 or 8 to 9 molar equivalents of POCl3 and 1.0 to 1.1 or 2.5 molar equivalents of DIPEA are used relative to compound E.

[0172] 40. The method of embodiment 36, further comprising co-distillation with ethyl acetate followed by quenching the reaction with NaHCO3 solution.

[0173] 41. The method of embodiment 36, wherein compound F is isolated by crystallization from an ethyl acetate / n-heptane mixture.

[0174] 42. The method of embodiment 26, wherein step (d) is carried out using 2M methylamine in THF.

[0175] 43. The method of embodiment 26, wherein step (d) is performed at 20°C to 30°C.

[0176] 44. The method of embodiment 26, wherein step (d) further comprises a post-reaction treatment comprising dissolving the crude product in aqueous HCl and washing with a non-polar solvent, followed by neutralization with aqueous NaOH.

[0177] 45. The method of embodiment 26, wherein step (d) further comprises removing any remaining HCl comprising dissolving the dried material in ethanol, treating with a solution of sodium hydroxide in ethanol, and then adding water to precipitate the product.

[0178] 46. ​​The method of embodiment 26, wherein compound C is prepared by

[0179] (e) Compound B:

[0180]

[0181] React with NaBH4 in a solvent.

[0182] 47. The method of embodiment 46, wherein the solvent is alcohol.

[0183] 48. A method as described in embodiment 46, wherein the solvent is ethanol.

[0184] 49. The method of embodiment 46, wherein 0.6 molar equivalents of NaBH4 are used relative to compound B.

[0185] 50. The method of embodiment 46, further comprising post-treatment and separation, wherein the post-treatment and separation comprises adding HCl solution to quench the reaction, followed by adding water to precipitate compound C.

[0186] 51. The method of embodiment 46, wherein compound B is prepared by:

[0187] Compound A:

[0188]

[0189] React with benzaldehyde in the presence of acid.

[0190] 52. The method of embodiment 51, wherein the acid is acetic acid.

[0191] 53. The method of embodiment 51, further comprising a solvent, wherein the solvent is methanol.

[0192] 54. The method of embodiment 51 further comprises adding a NaHCO3 solution to the reaction mixture after the reaction is completed to precipitate compound B.

[0193] Example

[0194] General Methods: FT-IR of Compound I was obtained on a Nicolet 380 FT-IR spectrophotometer. TGA analysis was performed on a TA Q5000 Instruments Thermogravimetric Analyzer. DSC analysis was performed on a TAQ2000 Instruments Differential Scanning Calorimeter (30°C to 300°C at 10°C / min). XRPD pattern of Compound I was obtained on a Bruker Instruments D8 Advanced Diffractometer or similar instrument, primarily using the following settings: 40 KV, 40 mA, K α =1.5406A(Cu-K α Radiation tube), scan range 4 to 40° 2θ, 15 rpm, 10° / min. NMR experiments were recorded on a Bruker AV400 MHz spectrometer.

[0195] Example 1: 5-Bromo-N 3 Synthesis of -(phenylmethylene)pyridine-2,3-diamine (Compound B)

[0196]

[0197] In the reactor, compound A (12.47 kg) was dissolved in methanol (100 kg) and acetic acid (2.3 kg). The solution was cooled to 0°C to 5°C and stirred for 0.5 to 1 hour, and benzaldehyde (56.4 g) was added dropwise over 2 hours. Once the reaction was complete (5 to 10 hours), water (53 kg) was added over 2 hours, and NaHCO solution (7% in water) was added dropwise over 2 hours, keeping low temperature (0°C to 5°C). The mixture was stirred for 3 hours. The solid was filtered out and washed with methanol / water (1: 1), then dried to obtain compound B with a yield of 94% and a purity of +99% (by HPLC). 1 H-NMR(DMSO-d6): δ8.75(1H),8.04(2H),7.93(1H),7.65(1H),7.50-7.60(3H).

[0198] Example 2: N 3 -Synthesis of Benzyl-5-Bromopyridine-2,3-diamine (Compound C)

[0199]

[0200] Compound B (17.1kg) was dissolved in ethanol (140kg) and NaBH4 (1.4kg) was added portionwise, keeping the temperature between 15°C and 25°C. The reaction mixture was stirred for 8 to 15 hours until the reaction was completed by HPLC monitoring. HCl solution (2N, 12kg) was added, the pH was adjusted to 6 to 7, and then water (350kg) was added dropwise over 5 hours, keeping the temperature between 15°C and 25°C. The mixture was stirred for 1 to 5 hours, filtered and washed with an ethanol / water mixture (1:1 ratio, 50kg). After the solid was dried at about 60°C for 15 to 20 hours, compound C (yield: 14.35kg (83%), purity: 99%) was obtained. 1 H-NMR (DMSO-d6): δ7.2-7.4(6H), 6.55(1H), 5.70-5.83(3H), 4.30(2H).

[0201] Example 3: N 3 Synthesis of Benzyl-5-(3,5-dimethyl-1,2-oxazol-4-yl)pyridine-2,3-diamine (Compound D)

[0202]

[0203] Compound C (14.2kg), compound G (14.8kg) and tripotassium phosphate trihydrate (22.0kg) are mixed, followed by addition of 1,4-dioxane (145kg) and water (28kg), and stirred for 1 to 2 hours. The resulting mixture is fully purged with nitrogen. Tetrakis (triphenylphosphine) palladium (0) (2.9kg) is added, and the solution is fully purged with nitrogen, and heated to 90°C to 95°C until the ratio of compound C to compound D measured by HPLC is no more than 1% (16 to 20 hours). After cooling to 20°C to 30°C, the reaction mixture is filtered, the solid is washed with 1,4-dioxane (25kg), the aqueous phase is removed, and the organic phase is concentrated. Water (96kg) is added dropwise at 40°C to 45°C, the mixture is cooled to 20°C to 25°C, and the mixture is stirred for 1 to 2 hours until the amount of the remaining compound D in the mother liquor is no more than 0.5%. Compound D was separated by filtration and washed with 1,4-dioxane / water (1:2 ratio, 25kg) and tert-butyl methyl ether (27kg) in sequence. At 40°C to 45°C, the wet cake was mixed in dichloromethane (658kg) until all solids dissolved and silica gel (7.0kg) was added. After stirring for 0.5 to 1 hour, the mixture was cooled to 20°C to 25°C, filtered, washed with dichloromethane (85kg), and then concentrated. At 35°C to 40°C, the mixture was cooled and tert-butyl methyl ether (56kg) was added dropwise. The reactor was cooled to 5°C to 10°C and stirred for 2 to 3 hours. The product was separated by filtration, washed with methyl tert-butyl ether and dried until dichloromethane, tert-butyl methyl ether and moisture content did not exceed 0.5%, to obtain compound D (yield: 9.7kg (65%), purity: 99%). 1 H-NMR (DMSO-d6): δ 7.30-7.45 (4H), 7.20-7.25 (2H), 6.35 (1H), 5.65-5.80 (3H), 4.30-4.40 (2H), 2.15 (3H), 1.95 (3H). Alternatively, the wet cake obtained after washing with 1,4-dioxane / water and MTBE in sequence can be purified using ethanol (5 volumes) slurry at 30° C. to 40° C. for 1 to 3 hours, followed by drying until the moisture content does not exceed 0.5% and the ethanol content does not exceed 0.5%.

[0204] Example 4: Synthesis of 1-benzyl-6-(3,5-dimethyl-1,2-oxazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-one (Compound E)

[0205]

[0206] Carbonyl diimidazole solid (8.4kg) is added (CDI can be added in portions) to a stirred mixture of compound D (10.0kg) and dimethyl sulfoxide (35kg). The mixture is heated to 55°C to 60°C for 1 to 3 hours or 35°C to 40°C until the ratio of compound D to compound E is NMT 0.5%. The mixture is cooled to 35°C to 40°C and water is added over 4 hours. The resulting mixture is stirred at ambient temperature for 3 hours. The product is separated by filtration and washed with water. Before using heating and vacuum drying, dimethyl sulfoxide is tested to be NMT 0.5%. When the moisture content is NMT 0.5%, drying is complete. Compound E (yield: 9.8kg (94%), purity: 99.9%) is obtained. 1 H-NMR(DMSO-d6): δ11.85(1H),7.90(1H),7.20-7.45(6H),5.05(2H),3.57(3H),2.35(3H),2.15(3H).

[0207] Example 5: Synthesis of 4-[1-benzyl-2-chloro-1H-imidazo[4,5-b]pyridin-6-yl]-3,5-dimethyl-1,2-oxazole (Compound F)

[0208]

[0209] Compound E (9.6kg) is mixed with phosphorus oxychloride (40kg), and then treated dropwise with diisopropylethylamine (DIPEA) (9.8kg) at 50°C. The resulting mixture is heated to 95°C to 100°C for 60 to 70 hours. After the reaction is complete, the mixture is concentrated and then cooled. Ethyl acetate is added and the mixture is concentrated 3 times under vacuum, co-distilled with ethyl acetate. Ethyl acetate (EtOAc) (114kg) is added to the concentrate, the mixture is cooled to ambient temperature, and then slowly added to sodium bicarbonate aqueous solution (7%), keeping the mixture between 15°C and 25°C. The organic phase is separated and the organic layer is washed twice with sodium bicarbonate aqueous solution (7%) and then with water. The organic phase is concentrated, ethyl acetate (288kg) is added, and the mixture is concentrated to ensure that the moisture content does not exceed 0.2%. The ethyl acetate containing the mixture is decolorized with carbon (CUNO, containing 1.2kg activated carbon). The mixture is concentrated and n-heptane (23kg) is added. The product is separated by filtration and dried under vacuum. When the residual moisture, ethyl acetate and n-heptane did not exceed 0.5%, the drying was completed to obtain compound F (4.95 kg, 46%, purity: 95%). 1H-NMR(MeOH-d4): δ8.40(1H),7.90(1H),7.25-7.45(5H),5.65(2H),2.37(3H),2.22(3H).

[0210] Example 6: 1-Benzyl-6-(3,5-dimethyl-1,2-oxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine (Compound I)

[0211]

[0212] Compound F (4.54 kg) was mixed with methylamine in tetrahydrofuran (THF) (31.9 kg, 2 M) and stirred at ambient temperature until the ratio of Compound F to Compound I was NMT 0.1% as measured by HPLC. After the reaction was complete, the mixture was concentrated under vacuum, water (34 kg) was added dropwise to maintain ambient temperature, stirred for 1 to 1.5 hours, and the product was isolated by filtration. The filter cake was washed with water. The wet filter cake was placed in a reactor and water (17 kg) was added, and hydrochloric acid (36 kg, 35%) was added and stirred for 2 hours to dissolve the solid. The resulting solution was washed twice with dichloromethane to remove impurities. The aqueous solution was neutralized by adding sodium hydroxide solution (14.5 kg, 15%) dropwise over 1.5 hours, and stirred for 5 hours. Compound I was isolated by filtration, washed with water and dried under vacuum. To remove any remaining hydrochloric acid, the dried material may be dissolved in ethanol (13.4 kg), treated with a solution of sodium hydroxide in ethanol (0.2 kg NaOH in 4 kg ethanol), and stirred for 1 hour, followed by the addition of water (70 kg) to precipitate the product. Compound I is isolated by filtration, washed with water and dried. Compound I may be further purified by slurry in hot water if necessary.

[0213] Dry compound I is dissolved in ethanol (16.2kg), and the resulting solution is filtered into a clean room. The ethanol solution is dried in an azeotropic manner with pure ethanol. The resulting mixture is heated to dissolve the product and concentrated. The mixture is heated to dissolve any solids with reflux and slowly cooled with inoculation (Compound I Form VII). At 50°C to 60°C, the mixture is stirred for 10 hours. XRPD represents Form VII. The mixture is further cooled to 45°C to 50°C, and stirred for 3 hours at 45°C to 50°C, and the solid XRPD indicates that it is Form VII. At 45°C to 50°C, tert-butyl methyl ether (MTBE) (26kg) is added dropwise for at least 4 hours and stirred for 1 hour at 45°C to 50°C. The mixture is cooled to 20°C to 30°C for 3 hours and stirred for 2 hours at 20°C to 30°C. Filter the solid and rinse with MTBE and dry to obtain Compound I Form VII (2.82kg, 63%, purity>99%). 1 H-NMR (DMSO-d6): δ7.96 (d, 1H, J = 2.0Hz), 7.42 (d, 1H, J = 2.0Hz), 7.37 (q, 1H, J = 4.2Hz), 7.32 (m, 2H), 7.2 6(m,1H),7.24(m,2H),5.30(s,2H),3.00(d,3H,4.5Hz),2.34(s,3H),2.16(s,3H).13C-NMR(DMSO-d6):d 164.8, 158.4, 157.7, 156.0, 141.1, 136.4, 128.6 (2C), 127.5, 127.4, 127.2 (2C), 115.8, 114.2 (2C), 44.5, 29.3, 11.2, 10.3). Alternatively, MTBE can be added and then seed crystals of Compound I Form VII can be added to the mixture.

Claims

1. A method for preparing compound I The method comprises steps (a) to (d): (a) With compound G: The reaction produces compound D: wherein step (a) is carried out in the presence of Pd(PPh3)4 and K3PO4 and at a temperature of 80°C to 100°C; (b) Compound D: Reaction with carbonyldiimidazole (CDI) produces compound E: wherein step (b) is carried out in DMSO and at a temperature of 30°C to 70°C; (c) Compound E: Reaction with chlorinating agent produces compound F: (d) Compound F: Reaction with methylamine produces compound I.

2. A method for preparing crystalline Compound I Form VII, The method comprises steps (a) to (e): (a) With compound G: The reaction produces compound D: (b) Compound D: Reaction with the first reagent produces compound E: (c) Compound E: Reaction with chlorinating agent produces compound F: (d) Compound F: reacting with methylamine to produce compound I; and (e) precipitating crystalline Compound I Form VII from a solution comprising Compound I and ethanol, tert-butyl methyl ether (MTBE), or a mixture thereof, wherein the precipitate is precipitated using Cu-K α The crystalline Compound I Form VII has three or more characteristic XRPD peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, as measured on a 400 nm radiation tube diffractometer, wherein each peak is ±0.2°θ.

3. The method according to claim 2, wherein the precipitation is carried out by: (1) cooling the ethanol solution of Compound I; (2) adding seed crystals of Compound 1 Form VII to the solution; (3) stirring the mixture for 10 hours; (4) further cooling the mixture and adding MTBE; and (5) Stirring for 3 to 5 hours to precipitate Compound I Form VII.

4. The method according to claim 2 or 3, wherein the Cu-K α The crystalline Compound I Form VII has six or more characteristic XRPD peaks expressed in 2θ at 7.2, 10.3, 11.2, 12.0, 13.8, 13.9, 15.2, 15.6, 16.5, 17.3, 20.7, 20.9, 21.6 and 22.5°, as measured on a 400 nm radiation tube diffractometer, wherein each peak is ±0.2°θ.

5. The method of claim 2 or 3, wherein the crystalline Compound 1 Form VII has an XRPD pattern as shown in Figure 1.

6. The method of claim 2 or 3, wherein the crystalline Compound I Form VII has a DSC thermogram with an endothermic peak at a temperature of 205°C.

7. The method of claim 2 or 3, wherein the crystalline Compound 1 Form VII has a DSC thermogram as shown in Figure 2.

8. The method of claim 2 or 3, wherein the crystalline Compound 1 Form VII has a TGA thermogram as shown in Figure 3.

9. The method according to claim 2 or 3, wherein step (a) is carried out in the presence of a transition metal catalyst and a base.

10. The method according to claim 9, wherein the transition metal catalyst is a palladium catalyst.

11. The method of claim 10, wherein the palladium catalyst is Pd(PPh3)4.

12. The process of claim 9, wherein the base is an alkali metal carbonate.

13. The method of claim 9, wherein the base is K3PO4.

14. The method according to claim 2 or 3, wherein the first reagent in step (b) is carbonyldiimidazole (CDI), and step (b) is performed in a solvent.

15. The method of claim 14, wherein the solvent is an aprotic solvent.

16. The method of claim 14, wherein the solvent is DMSO.

17. The method of claim 14, wherein step (b) comprises adding water to the reaction mixture and causing compound E to precipitate.

18. The process according to any one of claims 1 to 3, wherein step (c) is performed in the presence of a base.

19. The method of claim 18, wherein the chlorinating agent is phosphorus oxychloride (POCl3).

20. The method of claim 18, wherein the base is N,N-diisopropylethylamine (DIPEA).

21. The method of claim 18, wherein 8 to 9 molar equivalents of POCl3 and 2.5 molar equivalents of DIPEA are used relative to compound E.

22. The method of claim 18, further comprising co-distilling with ethyl acetate followed by quenching the reaction with NaHCO3 solution.

23. The process of claim 18, wherein compound F is isolated by crystallization from an ethyl acetate / n-heptane mixture.

24. The process according to any one of claims 1 to 3, wherein step (d) is carried out using methylamine 2M in THF.

25. The method of any one of claims 1-3, wherein step (d) is performed at 20°C to 30°C.

26. The process according to any one of claims 1-3, wherein step (d) further comprises a post-reaction treatment comprising dissolving the crude product in aqueous HCl and washing with a non-polar solvent, followed by neutralization with aqueous NaOH.

27. The process of any one of claims 1-3, wherein step (d) further comprises removing any remaining HCl comprising dissolving the dried material in ethanol, treating with a solution of sodium hydroxide in ethanol, followed by addition of water to precipitate the product.

28. The method according to any one of claims 1 to 3, wherein compound C is prepared by (f) Compound B: React with NaBH4 in a solvent.

29. The method of claim 28, wherein the solvent is an alcohol.

30. The method of claim 28, wherein the solvent is ethanol.

31. The method of claim 28, wherein 0.6 molar equivalents of NaBH4 are used relative to compound B.

32. The method of claim 28, further comprising post-treatment and separation, the post-treatment and separation comprising adding HCl solution to quench the reaction, followed by adding water to precipitate compound C.

33. The method of claim 28, wherein compound B is prepared by: (g) Compound A: React with benzaldehyde in the presence of acid.

34. The method of claim 33, wherein the acid is acetic acid.

35. The method of claim 33, further comprising a solvent, wherein the solvent is methanol.

36. The method of claim 33, further comprising adding a NaHCO3 solution to the reaction mixture after the reaction is completed to precipitate compound B.

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