Synthetic methods and intermediates for producing compounds for treating KIT- and PDGFRA-mediated diseases

Abstract

The present disclosure provides methods and intermediates for producing Compound A, or a pharmaceutical salt thereof and / or a solvate thereof, which are useful as methods and intermediates for manufacturing compounds for treating diseases and conditions associated with mutant KIT and PDGFRA. JPEG2024508329000030.jpg7265

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 155,947, filed March 3, 2021. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002]

[0002] The present disclosure relates to synthetic intermediates and methods for producing novel pyrrolotriazine compounds that are useful as selective inhibitors of activated KIT and PDGFRA mutant protein kinases. Inhibitors of KIT and PDGFRA mutant protein kinases are useful, for example, in producing pharmaceutical compositions, such as for the treatment of chronic disorders. The KIT receptor belongs to the class III receptor tyrosine kinase family, which also includes the structurally related protein PDGFRA. Normally, stem cell factor binds to KIT and activates it by inducing dimerization and autophosphorylation, which induces the initiation of downstream signaling. However, in some tumor types, somatic activating mutations in KIT promote ligand-independent constitutive oncogenic activity, including tumor types such as acute myeloid leukemia, melanoma, intercranial germ cell tumors, mediastinal B-cell lymphoma, seminoma, and gastrointestinal stromal tumors. Mutant KIT is also known to play a role in mast cell activation, which is common and likely essential for maintenance. Unregulated mast cell activation occurs when mast cells are pathologically overproduced or when their activation is out of balance to the extent that it is perceived as threatening homeostasis. Mast cell activation syndrome refers to a group of disorders with diverse causes that present with transient multi-tissue symptoms as a result of mast cell mediator release. Mastocytosis is one type of mast cell activation syndrome. The compounds of the present disclosure are useful for treating mastocytosis. The World Health Organization (WHO) classifies mastocytosis into seven different categories: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), mastocytosis with associated hematological neoplasms (SM-AHN), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and mast cell sarcoma.

[0003]

[0003] The compounds produced by the methods disclosed herein may be useful for treating mast cell disorders. Mast cell disorders include mast cell activation syndrome (MCAS) and hereditary alpha tryptasia (HAT). Other mast cell disorders include mast cell mediated asthma, anaphylaxis (including idiopathic, IgE mediated, and non-IgE mediated), urticaria (including idiopathic and chronic), atopic dermatitis, edema (angioedema), irritable bowel syndrome, mast cell gastroenteritis, mast cell colitis, pruritus, chronic pruritus, pruritus associated with chronic renal failure, and conditions associated with mast cells in the heart, blood vessels, intestine, brain, kidney, liver, pancreas, muscle, bone, and skin.

[0004]

[0004] The compounds produced by the methods described in this disclosure are also capable of inhibiting wild-type KIT. The compounds described in this disclosure may be useful for treating mast cell disorders associated with wild-type KIT.

[0005]

[0005] U.S. Patent No. 10,829,493, the entire teachings of which are incorporated herein by reference, discloses the compound shown below (hereinafter "Compound A") for the safe and effective treatment of chronic disorders such as ISMs and SSMs, as well as other diseases mediated by mutant KIT or PDGFRA, which has highly selective and potent activity against mutant KIT and PDGFRA kinases.

[0006] [ka] Summary of the Invention [Problem to be solved by the invention]

[0007]

[0006] It is an object of the present disclosure to provide novel synthetic intermediates and methods for preparing compound A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008]

[0007] Thus, the compounds produced by the methods described herein and from the intermediates described herein provide treatments with desirable efficacy, safety, and pharmaceutical properties for the treatment of KIT- and PDGFRA-mediated diseases. More specifically, compound A produced by the synthetic route described herein exhibits a number of beneficial properties, including reduced levels of brain penetrance, while maintaining efficacy and other desirable pharmaceutical properties, compared to other known pyrrolotriazine compounds with mutant KIT and PDGFRA inhibitory activity.

[0009]

[0008] It has now been found that the use of a phosphonium activating agent for the preparation of compound A in the coupling of 6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol with (tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate) enables a superior process than the use of other coupling agents which result in slow and / or incomplete reactions as well as undesirable side reactions (Example 3).

[0010]

[0009] The present disclosure provides a method for preparing Compound A. Additionally, the present disclosure provides an intermediate in the preparation of Compound A. A first embodiment is a compound A:

[0011] [ka]

[0012] The present invention relates to a method for preparing a

[0011] The above method comprises reacting a compound of formula (I-1):

[0013] [ka]

[0014] or a pharma- ceutically acceptable acid salt thereof; Formula (II-1):

[0015] [ka]

[0016] (In the formula, R 1 and R 2 are each independently selected from H and an amine protecting group) with a second compound or a pharma- ceutically acceptable acid salt thereof, and cleaving the amine protecting group, if present. An "amine protecting group" is a chemical moiety that forms a bond with an amine functional group in a molecule to render the amine functional group inert to the conditions of a subsequent reaction. After completion of the subsequent reaction, the amine protecting group is removed or cleaved to restore the amine group to its original reactivity. Exemplary protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety. When R is an amine protecting group, suitable examples include, but are not limited to, Boc(C(O)OC(CH3)3) or S(=O)C(CH3)3.

[0017] In a second embodiment, the method is as described in the first embodiment, wherein the amine protecting group is absent, i.e., the second compound (II-1) is R 1 is H and R 2 is H.

[0018] In a third embodiment, the method is as described in the first embodiment, wherein R 2 is H and R 1 is S(=O)C(CH3)3. In a fourth embodiment, the method is as described in the first embodiment, wherein R 2 is C(O)OC(CH3)3, and R 1 is S(=O)C(CH3)3. In a fifth embodiment, the method is as described in the third or fourth embodiment, wherein the amine protecting group is removed using an acid to obtain the second compound (II-1) in its deprotected form, i.e., R 1 and R 2 is H. In some embodiments, the amine protecting group is removed using an acidic solvent. In some embodiments, the amine protecting group is removed using acidic methanol.

[0019] In a sixth embodiment, the method is as described in the first, second, third, fourth, or fifth embodiment, wherein the reaction is mediated by an agent that activates an aromatic hydroxyl group in the first compound (I-1) for nucleophilic substitution. An agent that activates an aromatic hydroxyl group is an agent that, in the presence of the agent, renders the aromatic hydroxyl group more susceptible to displacement by a nucleophile than in the absence of the agent. For example, activation occurs by an agent that reacts with the hydroxyl group and converts it into a functional group that is more readily displaced by a nucleophile than the hydroxyl group. Examples of agents that activate aromatic hydroxyl groups include carbodiimides, phosphonium salts, aminium salts, uranium / aminium salts, fluoroformamidinium coupling agents, organophosphorus reagents, and triazine coupling reagents.

[0020]

[0016] In a seventh embodiment, the method is as described in the sixth embodiment, where the agent is a phosphonium salt.

[0017] In an eighth embodiment, the method is as described in the seventh embodiment. Among the eight activating agents tested, a phosphonium agent provided the fastest conversion and the highest yield with the lowest level of by-product formation in the reaction. Examples of phosphonium agents include (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), 2-(benzotriazol-1-yloxy)-1,3-dimethyl-2-pyrrolidin-1-yl-1,3-diazaphosphoridinium hexafluorophosphate (BOP ... MP), (7-azabenzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (AOP), (7-azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP).

[0021]

[0018] In a ninth embodiment, the method is as described in the sixth, seventh, or eighth embodiment, where the agent is PyBOP or PyClOP. In one aspect, the agent is PyBOP. In another aspect, the agent is PyClOP. The agents PyBOP and PyClOP are added to give higher yields and higher purity products than other phosphonium agents, and release less heat. PyClOP has the added advantage of high reactivity and safety, avoiding the release of toxic HMPA.

[0022] In a tenth embodiment, the method is as described in the sixth, seventh, eighth, or ninth embodiment, wherein the agent that activates aromatic hydroxyl groups is present in a molar excess relative to the number of moles of the first compound (I-1), for example, a molar excess of 1.3 to 1.8. "Molar excess" refers to the number of moles of the agent present in the reaction divided by the number of moles of the first compound (I-1) present in the reaction. In some embodiments, the agent is present in a molar excess of 1.3 to 1.7, a molar excess of 1.3 to 1.6, a molar excess of 1.3 to 1.5, a molar excess of 1.4 to 1.5, or a molar excess of 1.4 to 1.6. In some embodiments, the agent is present in a molar excess of 1.3, a molar excess of 1.4, a molar excess of 1.5, a molar excess of 1.6, a molar excess of 1.7, or a molar excess of 1.8.

[0023] In an eleventh embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, wherein the reaction occurs in the presence of a non-nucleophilic base. The non-nucleophilic base is a sterically hindered basic molecule that is poorly nucleophilic. In some embodiments, the non-nucleophilic base is an amine non-nucleophilic base. In some embodiments, the amine non-nucleophilic base is selected from the group consisting of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), and triethylamine (TEA). In some embodiments, the amine non-nucleophilic base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU). In other embodiments, the amine non-nucleophilic base is triethylamine (TEA).

[0024] In a twelfth embodiment, the method is as described in the eleventh embodiment, wherein the non-nucleophilic amine base is DBU and the agent that activates aromatic hydroxyl groups is PyBOP. PyBOP was tested in combination with five non-nucleophilic amine bases, and the combination of PyBOP / DBU provided the fastest conversion rate and the highest yield with fewer impurities.

[0025]

[0022] In a thirteenth embodiment, the method is as described in the eleventh embodiment, where the non-nucleophilic amine base is TEA and the agent activating aromatic hydroxyl groups is PyClOP. PyClOP was tested with DBU and TEA. The PyClOP / TEA combination resulted in a cleaner reaction profile and better control of key impurities (Example 4). Furthermore, the reaction by-product of TEA has low solubility in the reaction mixture using acetonitrile as the solvent, which provides the advantage of easy isolation of the product by crystallization.

[0026] In a fourteenth embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, wherein the second compound is a pharma- ceutically acceptable acid salt of the compound of formula (II-1). Examples of pharma- ceutically acceptable acid salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, and the like.

[0027] In a fifteenth embodiment, the method is as described in the fourteenth embodiment, wherein the pharma- ceutically acceptable acid salt of the compound of formula (II-1) is an HCl salt.Compared to some other salts tested, the HCl salt of formula (II-1) provides higher yields, faster conversions, and less impurities than other salts tested, for example, the HCl salt contains 3.5 moles of HCl per mole of compound (II-1).

[0028]

[0025] In a sixteenth embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment, wherein the second compound is a free base of the compound of formula (II-1).

[0029] In a seventeenth embodiment, the method is as described in the fourteenth, fifteenth, or sixteenth embodiments, wherein the amine non-nucleophilic base is present in a molar excess relative to the moles of the first compound (I-1), for example, a molar excess of 5.0 to 12.0. In some examples, the amine non-nucleophilic base is present in a molar excess of 5.0 to 6.5, a molar excess of 5.0 to 6.0, a molar excess of 9.0 to 10.5, or a molar excess of 9.0 to 10.0 relative to the moles of the first compound (I-1). In some embodiments, the amine non-nucleophilic base is present in a 5.5 molar excess, a 6.0 molar excess, a 6.5 molar excess, a 7.0 molar excess, a 8.5 molar excess, a 9.0 molar excess, a 9.5 molar excess, a 10.0 molar excess, a 10.5 molar excess, or a 12.0 molar excess relative to the moles of the first compound (I-1). In one embodiment, the agent that activates aromatic hydroxyl groups is PyBOP, the non-nucleophilic amine base is DBU, and the DBU is used in a 5.3-5.7 molar excess (e.g., a 5.5 molar excess) relative to the first compound (I-1). This amount of DBU allows for fast, nearly quantitative conversion under mild conditions in high yield with minimal impurities. In one embodiment, the agent activating the aromatic hydroxyl group is PyClOP and the non-nucleophilic amine base is TEA, where TEA is used in a molar excess of 10.3-10.7 or 11.8-12.2 (e.g., a molar excess of 10.5 or 12.0) relative to the first compound (I-1). This amount of TEA also allows for fast, nearly quantitative conversion in high yield with minimal impurities. PyClOP is used in a molar excess of 1.5-1.7 (e.g., a molar excess of 1.6) relative to the first compound (I-1).

[0030] In an eighteenth embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment, wherein the first compound (I-1) and the second compound (II-1) are dissolved in a first solvent to form a solution. A suitable solvent can be readily selected by one skilled in the art of organic synthesis. A suitable solvent does not substantially react with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, and does not substantially interfere with the reaction. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Examples of suitable first solvents include acetonitrile (CH3CN), dimethylformamide (DMF), ethanol / water mixture, 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), dichloroethane (DCE), dioxane, and dimethylaminopyridine (DMAP). In one embodiment, the first solvent is acetonitrile (CH3CN). The use of acetonitrile as the first solvent provides a homogeneous reaction mixture and also allows the direct isolation of compound A by crystallization from the reaction mixture by adding water as an anti-solvent. Most of the reaction by-products remain dissolved in the acetonitrile-water mother liquor, while compound A, which has low solubility, crystallizes out of the solution.

[0031] In a nineteenth embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment, wherein the reaction is carried out at a temperature of 15-100° C. In some examples, the reaction is carried out at 20-50° C., 30-40° C., 15-25° C., 25-35° C., 45-55° C., 55-65° C., 65-75° C., 75-85° C., 80-90° C., or 90-100° C. In another aspect, when the activating agent is PyBOP and the base is DBU, the temperature is between 20-30° C. (e.g., room temperature, e.g., 25±3° C.). In another embodiment, when the activating agent is PyClOP and the base is TEA, the temperature is between 80 and 90° C. (eg, 85° C.).

[0032] In a twentieth embodiment, the method is as described in the eighteenth or nineteenth embodiment, wherein the agent is added to a solution of the first compound (I-1) and the second compound (II-1) dissolved in a first solvent. In some embodiments, the agent is added over a period of time ranging from 5 to 120 minutes. In some examples, the agent is added over a period of time ranging from 10 to 100 minutes, 20 to 80 minutes, 30 to 60 minutes, 5 to 30 minutes, 30 to 60 minutes, 60 to 90 minutes, or 90 to 120 minutes. In some examples, in order to obtain consistent and reproducible results for large-scale production of compound A, the agent must be added to the solution of the first compound (I-1) and the second compound (II-1). In one embodiment, when the agent is PyBOP, the agent must be added to the solution.

[0033] In a twenty-first embodiment, the method is as described in the eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiments, wherein the non-nucleophilic amine base is added prior to the addition of the first solvent. In some examples, following removal of the amine protecting group in acidic methanol, TEA is added prior to the addition of CH3CN. If TEA is not added prior to the addition of CH3CN, problems such as crust formation in the reaction vessel and significant formation of impurities arise.

[0034] [ka]

[0035] In a twenty-second embodiment, the method is as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment, wherein activated carbon is added. The addition of activated carbon improves the purity and color of the resulting compound A.

[0036]

[0032] A twenty-third embodiment is a compound of formula (I-1):

[0037] [ka]

[0038] or a pharma- ceutically acceptable salt thereof. The phrase "pharma- ceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the bounds of medical good sense, without undue toxicity, irritation, allergic response, or other abnormalities or complications, and commensurate with a reasonable benefit / risk ratio. Representative pharma- ceutically acceptable salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate, and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19).

[0039] A twenty-fourth embodiment is a compound A:

[0040] [ka]

[0041] 1. A method for purifying converting compound A into an acid salt; removing impurities from the acid salt; basifying the acid salt to prepare purified compound A; The method includes:

[0042]

[0034] In a twenty-fifth embodiment, the method is as described in the twenty-fourth embodiment, wherein compound A is converted to a phosphate by reacting compound A with phosphoric acid.

[0043]

[0035] In a twenty-sixth embodiment, the method is as described in the twenty-fourth or twenty-fifth embodiment, wherein compound A is converted to an acid salt by dissolving compound A in an aqueous solution and adding at least one equivalent of an acid.

[0044] In a twenty-seventh embodiment, the method is as described in the twenty-sixth embodiment, wherein impurities are removed from the acid salt by washing the aqueous solution with an organic solvent that is immiscible with the aqueous solution. In certain embodiments, the organic solvent is 2-methyltetrahydrofuran.

[0045]

[0037] In a twenty-seventh embodiment, the method is as described in the twenty-fourth, twenty-fifth, and twenty-sixth embodiments, wherein impurities are removed from the acid salt using activated carbon.

[0046] In a twenty-eighth embodiment, the method is as described in the twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiments, wherein the aqueous solution is basified with an aqueous base to precipitate compound A. In certain embodiments, the aqueous base is an aqueous hydroxide, such as sodium hydroxide.

[0047]

[0039] In a twenty-ninth embodiment, the method is as described in the twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment, wherein compound A is a compound produced by a method according to any one of the first to twenty-second embodiments disclosed herein.

[0048]

[0040] The present disclosure is illustrated by the following examples, which are not intended to be limiting in any way. EXAMPLES

[0049] Synthetic Preparation Example 1A Preparation of intermediate (I-1) using DTBPF Preparation 1A: 6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (I-1)

[0050] [ka]

[0051]

[0042] Synthesis of 6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (I-1): (Ia) (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol) (5 kg) and (Ib) (6-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol) (11.1 kg, 2 equivalents) were mixed and stirred in N-methyl-2-pyrrolidone (NMP) (20 L) at 20-30°C. To this mixture was added palladium(II) acetate (105 g, 0.02 equiv.), 1,1'(di-tert-butylphosphino)ferrocene (222 g, 0.02 equiv.), and 50%-w / w aqueous potassium phosphate (K3PO4) (60 kg, 6 equiv.). The reaction solution was heated at 105-115°C. After 2 hours, the reaction solution was cooled to 60-80°C and transferred to a second vessel containing a mixture of N-acetyl-L-cysteine ​​(760 g, 0.20 equiv.) and ethylenediaminetetraacetic acid disodium salt dihydrate (780 g, 0.09 equiv.) in water (42 kg). The resulting mixture was stirred at 45-55°C for 30 minutes, then allowed to settle for 30 minutes to allow separation and the aqueous phase was removed. The resulting organic layer was diluted with water (50 kg) and the pH was adjusted to 6.3-7.5 with aqueous hydrochloric acid. After addition of seeds (10 g) at 45-55°C, crystals were observed and the mixture was cooled to 5-15°C. The solid crystals were isolated by filtration and washed with water (3 x 15 kg) followed by isopropyl alcohol (4 x 12 kg). The solid was dried at 60°C to give 4.3 kg in 75% yield and 99.1%-w / w purity.

[0052] Example 1B Preparation of intermediate product (I-1) Preparation 1B: 6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol (I-1)

[0053] [ka]

[0054] A reaction vessel was charged with N-methyl-2-pyrrolidone (NMP) (52.7 L), (Ib) (10.55 kg, 1.0 equiv.), (Ia) (23.5 kg, 2.0 equiv.), tetra-N-butylammonium bromide (n-Bu4NBr, also referred to as "TBAB") (636 g, 0.04 equiv.), palladium(II) acetate (Pd(OAc)2) (221.2 g, 0.02 equiv.), and 1,1'-bis(ferrocenediyl-bis(diphenylphosphine (dppf)) (548 g, 0.02 equiv.) and degassed with N2. Then, tripotassium phosphate (K3PO4) (62.8 kg, degassed with N2) was added. A solution of (Ib, 6.0 equiv.) in water (63 L) was added and the batch was heated to reflux at about 110° C. After 2 hours of reflux, the reaction solution was sampled for conversion of (Ib) to (I-1) (IPC conversion: 99.4%; target ≧95% conversion). The batch was then cooled to about 59° C. and water (105.5 L) was added. The batch was cooled to about 29° C. and filtered through a pad of Celite® (7 kg) followed by a water rinse (21.1 L×2). The mixture was stirred at 15-30° C. for 2 hours and then cooled to about 59° C. for 2 hours. After filtration, the mixture was ... The product was precipitated from the filtrate by adding a solution of HCl (46.5 kg, 8.5 equiv.) to pH 6-7. The slurry was cooled to 5-15°C and allowed to stand for 3 days, then cooled to (-)5-5°C and allowed to stand for 2 hours before isolation. The (I-1) product was isolated by filtration, washed with water (31.7 L x 2) pre-cooled to (-)5-5°C, and deliquored.

[0055] The (I-1) wet cake was added to a reaction vessel and triturated with water (105.5 L) at 60-65°C for a minimum of 1 hour, then cooled to 20-25°C. (I-1) was isolated by filtration, washed with water (21.1 L x 2) at 15-25°C, and deliquored. Samples were analyzed for residual pinacol (0.02%) and (Ib) (0.1%). The wet cake was dried at 60°C using a vacuum oven for about 4.5 days to give 9.41 kg of the title compound in 78% yield and 99.8% purity.

[0056] Example 1C Alternative preparation of intermediate (I-1)

[0057] [ka]

[0058] A reaction vessel was charged with NMP (1200 mL), (Ia) (667.5 g, 1.0 equiv), (Ib) (300 g, 2.0 equiv), dppf (15.5 g, 0.02 equiv), and Pd(OAc)2 (6.3 g, 0.02 equiv). The mixture was degassed with N2. To the same reaction vessel was added a degassed aqueous solution (1872 mL) of K3PO4 (1785 g, 6.0 equiv). The mixture was heated to 75° C. and stirred for 2 h, cooled to ambient temperature with stirring overnight, then heated to 110° C. and stirred for 3 h (IPC by HPLC showed 97.8% conversion). The mixture was cooled to 20-25°C, followed by the addition of water (3000 mL), EDTA tetrasodium salt hydrate (52.5 g, 0.09 equiv.), and N-acetylcysteine ​​(45.8 g, 0.2 equiv.). The mixture was stirred for 3 hours and the organic layer was separated from the aqueous layer. The organic layer was heated to 45-55°C. Concentrated HCl (10.6 N, 285 mL) was added to adjust the pH to 6.84. Compound (I-1) seeds (1.5 g, 0.5% w / w) were added to the mixture at about 50°C, followed by the mixture being cooled to 5-15°C and stirred for 1.5 hours. The slurry was filtered and the wet cake was placed in a reaction vessel followed by the addition of water (3000 mL). The slurry was filtered again and the wet cake was placed in a reaction vessel followed by the addition of i-PrOH (3000 mL). The slurry was filtered and washed with i-PrOH (900 mL x 2). The wet cake was dried under reduced pressure at 50°C to give 189 g of compound (I-1) as a solid in 55% yield, 98.6% HPLC purity, and 97.8 wt% by quantitative NMR assay.

[0059] Example 2 Timing of triethylamine addition Example 2A Preparation of compound A from intermediate (I-1) using PyClOP and TEA Preparation 2A: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)1H-pyrazol-1-yl)ethan-1-ol (Compound A)

[0060] [ka]

[0061] Compound (Ic) may be prepared according to the procedures disclosed in International Publication Nos. WO2020 / 210293 and WO2020 / 210669, the entire teachings of which are incorporated herein by reference. (Ic) A mixture of (tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate) (27.2 kg, 1.10 eq.) and hydrogen chloride (8.8 kg, 4.95 eq.) was stirred in methanol (239 L) at 35-45° C. for 2 hours. At this point, the reaction solution was refluxed under reduced pressure for 2 hours and then cooled to 20-30° C. The methanol solvent was replaced with acetonitrile via a solvent exchange. Specifically, the methanol solution was transferred to a vessel containing acetonitrile (168 L) and the mixture was distilled at 70-85° C. while maintaining the volume by adding additional acetonitrile. After cooling to 15-25° C., triethylamine (TEA) (71 L, 10.5 equiv.) was added and after 30 min, the solid by-product was removed by filtration. To the remaining solution was added acetonitrile (48 L), (I-1) (6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-ol) (12 kg, 1 equiv.), and chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP, 33 kg, 1.6 equiv.). The reaction solution was heated at 70-85° C. for 4 hours, then cooled to 55-65° C. and seeded with Compound A free base. After cooling to 0-10°C over 5 hours and maintaining for 15 hours, the solid product was isolated by filtration. The filter cake was washed with acetonitrile (37 kg) and water (5 x 48 kg). After drying, 15.0 kg of compound A was isolated in 58% yield and 96.6% purity.

[0062] Example 2B Preparation of compound A from intermediate (I-1) by adding TEA before the addition of CH3CN Preparation 2B: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)1H-pyrazol-1-yl)ethan-1-ol (Compound A)

[0063] [ka]

[0064]

[0050] Methanol (136 mL), (Ic) (22.7 g, 1.10 equiv.) were charged to reaction vessel R1 at 15-25°C. Hydrogen chloride gas (7.36 g, 4.95 equiv.) was then charged to R1 at 15-45°C. The resulting mixture was stirred at 35-45°C for at least 2 hours until the in-process control (IPC) indicated the completion of the reaction. Methanol (50 mL) was then charged to R1, followed by removal of about 50 mL of methanol by distillation at 35-45°C under reduced pressure. Triethylamine (TEA, 28.4 mL, 5 equiv.) was added to R1 at 25-45°C and adjusted to pH ≥ 8 before the addition of CH3CN. The mixture in R1 was distilled at 60-85°C under atmospheric pressure, removing about 30 mL of methanol distillate. The distillation was continued at atmospheric pressure with a parallel feed of acetonitrile (about 300 mL) and a constant volume was maintained by removing about 300 mL of distillate. Then about another 40 mL of distillate was removed at 75-85°C. A second charge of TEA (38.9 mL, 7 equiv.) was charged to R1 at 70-85°C. The mixture was cooled to 15-25°C and filtered (filtrate collected in reaction vessel R2). Acetonitrile (10 mL) was charged to R1 and rinsed into R2 through a polish filter.

[0065]

[0051] In R2 at 15-30°C, (I-1) (10.0 g, 1.00 equiv.) and PyClOP (27.5 g, 1.60 equiv.) were charged. Acetonitrile (10 mL) was added to rinse the dosing system. The mixture in R2 was heated at 70-85°C and stirred for at least 4 hours until IPC indicated completion of the reaction. The reaction mixture was cooled to 55-65°C, followed by compound A seed crystals (0.17 g) at 50-60°C and stirred for at least 15 minutes. The mixture in R2 was cooled to 0-10°C for at least 5 hours and stirred at 0-10°C for at least 1 hour. The resulting suspension was filtered. The wet cake was washed successively with acetonitrile (40 mL) and deionized water (40 mL × 2), and then dried at 45-55 °C under reduced pressure to give 16.6 g of Compound A free base as a solid in 77% yield and 98.9% HPLC purity.

[0066] [Table 1]

[0067] Example 2C Preparation of Compound A from Intermediate (I-1) Using PyBOP and DBU Preparation 2C: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)1H-pyrazol-1-yl)ethan-1-ol (Compound A)

[0068] [ka]

[0069] A reaction vessel (R1) was charged with acetonitrile (CH3CN, 40 L), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (22 kg, 5.5 equiv.), and the DBU transfer line was rinsed with CH3CN (13 L) which was added to the reaction vessel. (II-2) (11.16 kg, 1.1 equiv.) was added to the reaction vessel followed by (I-1) (6.78 kg, 95 wt % assay, 1 equiv.) added to R1. In a second reaction vessel (R2), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (17.8 kg, 1.30 equiv.) was dissolved in CH3CN (32 L) and added slowly in batches to R1 while maintaining the temperature at 15-35°C. R2 was rinsed with CH3CN (6.5 L) and the rinse was added to R1. The batch was stirred at 15-35°C for 15-30 min, then the reaction mixture was sampled for reaction completion IPC (97.7% of (I-1) converted to compound A). CPW charcoal (0.64 kg, 10 wt%) was added to a second reaction vessel (R2) and the batch in R1 was transferred to the charcoal reaction vessel R2. The slurry was stirred at 25°C for 14.5 h and then filtered through an in-line filter (3M Zeta-Plus HT). R2 and the in-line filter were rinsed with CH3CN (6.5 L x 2) and the rinse was sent to R1. The deliquored wet cake was dried in a vacuum oven at 50°C for >90 h to give 11.43 kg of crude compound A free base as a solid in 83% yield and 98.5% purity.

[0070] Example 2D Alternative preparation of compound A from intermediate (I-1) using PyBOP and DBU followed by recrystallization

[0071] [ka]

[0072] Reaction vessel R1 was charged with DBU (98.6 g, 5.5 equiv), CH3CN (240 mL), (II-2) (54.6 g, 70.6 wt% assay in free base, 1.1 equiv) at 20-32°C. (I-1) (30 g, 95 wt% assay, 1 equiv) was then added to R1. A separate reaction vessel R2 was charged with PyBOP (79.0 g, 1.30 equiv) and CH3CN (150 mL), which was then slowly added to R1 at 25-32°C. The reaction mixture in R1 was stirred at the same temperature until the reaction was judged complete by IPC (98.5% conversion in 0.5 h). The reaction vessel was charged with CPW charcoal (3 g, 10 wt%). The slurry was stirred at 20-25°C for 1 h and then filtered. R1 and the in-line filter were rinsed with CH3CN (30 mL x 2). The filtrate in a separate reaction vessel R3 was seeded with compound A (0.3 g, 1 wt%) followed by water (855 mL) at 18-20 °C for 1 h. The slurry was stirred at the same temperature for 18 h and then filtered. The wet cake was washed with water (120 mL x 2) and then dried to obtain 54.7 g of compound A. Compound A obtained from the procedure just described was further purified. Reaction vessel R1 was charged with water (514 mL), 2-methyltetrahydrofuran (2-MeTHF) (271 mL), and compound A (30 g). Then, 85% phosphoric acid (H3PO4) (7.2 g, 76.3 wt%, 1.1 equiv.) was added to the above solution of compound A. The mixture was stirred for 0.5 h and then filtered into a separate reaction vessel R2. The aqueous layer was separated from the organic layer. The aqueous layer was washed with 2-MeTHF (136 mL x 2). CPW charcoal (3 g, 10% w / w) was added to the reaction vessel containing the aqueous layer, followed by filtration and washing with water (30 mL). Isopropanol (i-PrOH) (120 mL) was added to the reaction vessel containing the filtrate, followed by a 18.2% w / w solution prepared from 30% sodium hydroxide (NaOH) (7.77 g) and water (39.3 mL). The mixture was seeded with compound A (0.3 g, 1 wt%), followed by the remainder of the NaOH solution. The resulting slurry was stirred at ambient temperature for 1 hour, filtered, and then washed with water (90 mL).The wet cake was dried at 50° C. under reduced pressure to give 24 g of compound A as a solid in 77% yield, 99.7% HPLC purity, and 98.1 wt % by quantitative NMR assay. Recrystallization of compound A helped to remove significant impurities and increased the purity of compound A (Table 2).

[0073] [Table 2]

[0074] [ka]

[0075] Example 3 Examination of coupling agents and conditions for the preparation of compound A

[0076] [ka]

[0077]

[0055] Several different coupling agents, bases, and solvents were investigated for the preparation of compound A. It was found herein that a specific phosphonium reagent is necessary for the successful coupling of I-1 and II-1 to produce compound A. All other coupling agents investigated did not afford compound A. More specifically, the results of the conditions investigated for the coupling of the first compound (I-1) with the second compound (II-1) (Method A: II-1 as 3.5×HCl salt form (Table 2) and Method B: II-1 as free base (Table 3)) are described below. The experiment was carried out as follows: (I-1) (1.0 g, 1.0 equivalent), amide coupling reagent (1.5 equivalent), and solvent (15 mL) were placed in a flask (R1) at room temperature. In a separate flask (R2), (II-2 3.5×HCl salt, Method A; II-1 free base, Method B) (1.2 equiv.), base, and solvent (15 mL) were mixed at room temperature. The contents of R2 were added to R1, stirred (at room temperature using Method A, at target temperature using Method B) and monitored by HPLC. Preferably, only PyBOP in acetonitrile afforded the desired compound A.

[0078] [Table 3]

[0079] [Table 4-1]

[0080] [Table 4-2]

[0081] Example 4 Using TEA in combination with PyClOP and PyBOP Several bases such as DIPEA, DMAP, DABCO, N-methylmorpholine, and potassium carbonate were tried for the coupling of the first compound (I-1) and the second compound (II-1) with only limited success. When DABCO, N-methylmorpholine, and potassium carbonate were used at 50° C., only trace amounts of the desired product, compound A, were observed. DMAP and DIPEA showed low conversion of a / a I-1 at 50° C., approximately 40%, and 1) problems were encountered with DIPEA in acetronitrile due to the biphasic nature of the reaction mixture and its oily nature after the addition of water, which made the isolation of compound A difficult. TEA and DBU were both identified as suitable non-nucleophilic bases for the coupling reaction in combination with PyClOP and PyBOP.

[0082] TEA was finally found to be the non-nucleophilic base that gave the best results with PyClOP. TEA has the advantage of being miscible with acetonitrile. Precipitation of TEA hydrochloride during the reaction offers the advantage that it can be easily removed by filtration before crystallization of the product. The combination of PyClOP and TEA results in a cleaner reaction profile and better control of critical impurities (Table 4).

[0083] [Table 5]

[0084] [ka]

Claims

1. Compound A: 【Chemistry 1】 A method for preparing To form compound A, a compound of formula (I-1): 【Chemistry 2】 or a pharma- ceutically acceptable acid salt thereof; Formula (II-1): 【Chemistry 3】 (In the formula, R １ and R ２ are each independently selected from H and an amine protecting group), or a pharma- ceutically acceptable acid salt thereof; The R １ and R ２ When an amine protecting group is present, R １ and R ２ cleaving the amine protecting group; The method includes:

2. R ２ is H, and R １ S(=O)C(CH ３ ) ３ or R2 is C(O)OC(CH3)3 and R1 is S(=O)C(CH3)3.

3. The method of claim 1 or 2, wherein the reaction is mediated by an agent that activates an aromatic hydroxyl group in the first compound (I-1) for nucleophilic substitution.

4. The drug is (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP), 2-(benzotriazol-1-yloxy)-1,3-dimethyl-2-pyrrolidin-1-yl-1,3-diazaphosphoridinium hexafluorophosphate (BOMP), (7-azabenzoxazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 4. The method of claim 3, wherein the aryloxy group is selected from the group consisting of (7-azabenzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (AOP), (7-azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP).

5. 5. The method of claim 4, wherein the agent is (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or the agent is chlorotripyrrolidinophosphonium hexafluorophosphate (PyClOP).

6. The method of any one of claims 1 to 5, comprising reacting in the presence of a non-nucleophilic base.

7. The method of claim 6 , wherein the non-nucleophilic base is an amine non-nucleophilic base.

8. 8. The method of claim 7, wherein the amine non-nucleophilic base is 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) or the amine non-nucleophilic base is triethylamine (TEA).

9. the second compound is a pharma- ceutically acceptable acid salt of a compound of formula (II-1); wherein the pharma- ceutically acceptable acid salt is an HCl salt, or wherein the second compound is a free base of the compound of formula (II-1): The method according to any one of claims 1 to 8.

10. The method of any one of claims 1 to 9, wherein the first compound (I-1) and the second compound (II-1) are dissolved in a first solvent to form a solution.

11. The first solvent is acetonitrile (CH ３ CN), dimethylformamide (DMF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), dichloroethane (DCE), dioxane, and dimethylaminopyridine (DMAP).

12. The process according to any one of claims 1 to 11, wherein the reaction is carried out at a temperature of from 15 to 100°C.

13. 13. The method of claim 12, wherein the temperature is 20-30°C when PyBOP is the activating agent and the non-nucleophilic base is DBU, or 80-90°C when PyClOP is the activating agent and the non-nucleophilic base is TEA.

14. Formula (I-1): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

15. Compound A: 【Chemistry 5】 1. A method for purifying converting compound A into an acid salt; removing impurities from the acid salt; basifying the acid salt to prepare purified Compound A. The method includes:

16. Compound A is converted to a phosphate by reacting the compound A with phosphoric acid; Here, compound A is converted to a phosphate salt by dissolving compound A in an aqueous solution and adding at least one equivalent of phosphoric acid; wherein impurities are removed from the phosphate by washing the aqueous solution with an organic solvent that is immiscible with the aqueous solution; and wherein the aqueous solution is basified with an aqueous base to precipitate compound A; The method of claim 15.

17. The method of claim 16, wherein the organic solvent is 2-methyltetrahydrofuran.

18. The method of claim 15, wherein the impurities are removed from the acid salt using activated carbon.

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