Method of preparing pralsetinib

Abstract

This article provides, in part, compounds and compositions that can be used to prepare pralsetinib. It also provides methods for preparing pralsetinib.

Description

Prior Technology

[0001] Targeting oncogenic driver kinases with specially tailored inhibitors has transformed the management of various hematologic malignancies and solid tumors. Receptor tyrosine kinase rearrangement (RET) during transfection is an oncogenic driver activated in various cancers, including non-small cell lung cancer (NSCLC), medullary thyroid carcinoma (MTC), and papillary thyroid carcinoma (PTC). Oncogenic RET alterations promote ligand-independent constitutive RET kinase activation, which drives tumorigenesis (e.g., RET fusions are observed in 10-20% of PTC, 1-2% of NSCLC, and many other cancer subtypes).

[0002] Pralsetinib is a potent and selective RET inhibitor designed to overcome limitations by efficiently and selectively targeting oncogenic RET alterations, including the most common RET fusions and certain RET activating mutations. Pralsetinib is also known as (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanemethylamine, and has the following chemical structure: (X).

[0003] Clinical trials are underway, namely NCT03037385 entitled "Phase 1 / 2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW)" and NCT04222972 entitled "AcceleRET Lung Study of Pralsetinib for 1L RET Fusion-positive, Metastatic NSCLC".

[0004] In patent publication WO2017 / 079140, pralatinib is disclosed as one of a variety of RET inhibitor compounds. Successful commercialization of a new therapeutic agent requires an efficient process for its preparation in high yield and purity. Therefore, the industry still needs a more efficient and suitable process for large-scale manufacturing of pralatinib. Summary of the Invention

[0005] In a single-state sample, this disclosure provides a compound of formula (I): [] (I), Or its salt.

[0006] Compound (I) is the same as compound (Ia): (Ia), Or its salt.

[0007] Compound (I) is the same as compound (Ib): (Ib), Or its salt.

[0008] In another state, this disclosure provides a compound of formula (II): (II), Or its salt.

[0009] Compound (II) is the same as compound (IIa): (IIa), Or its salt.

[0010] Compound (II) is a compound of formula (IIb): (IIb), Or its salt.

[0011] This disclosure partially provides for compounds of formula (III): (III), Or its salt.

[0012] Compound (III) is the same as compound (IIIa): (IIIa), Or its salt.

[0013] Compound (III) is a compound of formula (IIIb): (IIIb), Or its salt.

[0014] This article also provides isomer mixtures of cis and trans isomers of compounds of formula (III) or their salts: (III), The cis isomer is a compound of formula (IIIa) or a salt thereof: (IIIa), Furthermore, the trans isomer is a compound of formula (IIIb) or a salt thereof: (IIIb), The ratio of the cis isomer to the trans isomer is greater than or equal to approximately 4:1.

[0015] This article provides in part the compounds of formula (IVa): (IVa), Or its salts or tautomers.

[0016] This article also provides compounds of formula (IVb): (IVb), Or its salts or tautomers.

[0017] This disclosure also provides isomer mixtures of cis and trans isomers of the compound of formula (IV) or its salts: (IV), The cis isomer is a compound of formula (IVa) or a salt thereof: (IVa), Furthermore, the trans isomer is a compound of formula (IVb) or a salt thereof: (IVb), The ratio of the cis isomer to the trans isomer is greater than or equal to approximately 4:1.

[0018] In another state, this disclosure provides a compound of formula (V-1): (V-1), or its salt, wherein R is an activating group.

[0019] In some embodiments, the compound of formula (V-1) is the compound of formula (V): (V), Or its salt.

[0020] Compound of formula (V) is the same as compound of formula (Va): (Va), Or its salt.

[0021] Compound of formula (V) is the same as compound of formula (Vb): (Vb), Or its salt.

[0022] This article also provides isomer mixtures of cis and trans isomers of compounds of formula (V) or their salts: (V), The cis isomer is a compound of formula (Va) or a salt thereof: (Va), Furthermore, the trans isomer is a compound of formula (Vb) or a salt thereof: (Vb), The ratio of the cis isomer to the trans isomer is greater than or equal to approximately 4:1.

[0023] This document partially provides for compositions comprising a compound of formula (VI) or a salt thereof: (VI), The composition substantially does not contain compounds of formula (VIa): (VIa), Or its salt.

[0024] This disclosure also provides compositions comprising a compound of formula (VII) or a salt thereof: (VII), The composition substantially does not contain compounds of formula (VIIa): (VIIa), Or its salt.

[0025] In another embodiment, this document provides a process for preparing compositions comprising mixtures of cis and trans isomers of a compound containing form (IV) or its salts or tautomers: (IV), This process includes: (a) To make a compound of formula (II) or a salt thereof: (II), The ammonium source reacts in the presence of a solvent to produce a compound of formula (III): (III), or its salt; and (b) Reacting a compound of formula (III) with an alkyl acetate to produce a composition comprising a mixture of a cis isomer and a trans isomer of a compound of formula (IV), wherein the cis isomer is of formula (IVa): (IVa), Or the amount of its salt is greater than that of the trans isomer (IVb): (IVb) Or its salt.

[0026] This disclosure partially provides a process for preparing a composition comprising a mixture of cis and trans isomers of a compound of formula (III) or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is increased: (III), The cis isomer is a compound of formula (IIIa) or a salt thereof: (IIIa), Furthermore, the trans isomer is a compound of formula (IIIb) or a salt thereof: (IIIb), The process involves using a compound of formula (II) or a salt thereof: (II), The mixture reacts with an ammonium source in the presence of a solvent to produce a composition comprising a mixture of cis isomers and trans isomers of a compound of formula (III), wherein the ratio of the cis isomer to the trans isomer is increased.

[0027] This article partially provides the preparation process for compound (X) or its salts: (X), The process includes the following steps: (a) To make a compound of formula (II) or a salt thereof: (II), The compound reacts with an ammonium source (e.g., NH3 or NH4Cl) in the presence of a solvent to produce a compound of formula (III): (III), or its salt; (b) Reacting a compound of formula (III) or a salt thereof with an alkyl acetic acid ester to produce an isomer mixture of a compound of formula (IV) or a salt thereof: (IV), In this isomer mixture of compounds of formula (IV), the cis isomer of formula (IVa) is: (IVa), The amount is greater than that of the trans isomer (IVb): (IVb), or its salt; (c) Purify the isomer mixture of compound (IV) to obtain compound (IVa); (d) Reacting the compound of formula (IVa) or its salt with an activator to provide the compound of formula (V-1a): (V-1a), or its salt; (e) Reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI): (VI); or its salt; (f) Reacting the compound of formula (VI) or its salt with a base to provide the compound of formula (VII): (VII), or its salt; (g) React the compound of formula (VII) or its salt with the compound of formula (VIII) or its salt: (VIII), This provides a compound of formula (X) or a salt thereof.

[0028] This article also partially provides the preparation process for compound (X) or its salts: (X), The process includes the following steps: (a) To make a compound of formula (IVa) or a salt thereof: (IVa), It reacts with an activator to provide a compound of formula (V-1a): (V-1a), or its salt; (b) Reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI): (VI), or its salt; (c) Reacting the compound of formula (VI) or its salt with a base to provide the compound of formula (VII): (VII), or its salt; and (d) Reacting a compound of formula (VII) or a salt thereof with a compound of formula (VIII) or a salt thereof: (VIII), This provides a salt of compound (X).

[0029] This article also provides a process for preparing a mixture of cis and trans isomers of a composition comprising (X), wherein the majority of the composition is in the cis isomer configuration. (X), The process includes: Make the compound of formula (VII) or its salt: (VII), Reaction with compounds of formula (VIII) or their salts: (VIII), This provides a composition comprising a mixture of cis and trans isomers of the compound of formula (X), wherein the majority of the composition is in the cis isomer configuration.

[0030] This article partially provides geometric isomer mixtures of inclusion (X) compounds: (X), It is prepared using a process as described herein, wherein the cis:trans molar ratio of the geometric isomer mixture is about 4:1 to about 99:1. Implementation

[0031] []

[0032] This disclosure partially provides novel compounds and compositions that can be used to prepare pralatinib. It also provides a process for preparing pralatinib that results in higher stereoselectivity and yield, and is therefore more suitable for large-scale manufacturing processes compared to known methods. Definitions

[0033] "alkyl" refers to a monovalent group of a saturated straight-chain or branched hydrocarbon, such as a straight-chain or branched group with 1-12, 1-10 or 1-6 carbon atoms, referred to in this article as C1-C12 alkyl, C1-C10 alkyl and C1-C6 alkyl, respectively. Exemplary alkyl groups include (but are not limited to) methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tributyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0034] Certain compounds disclosed herein may exist in specific geometric or stereoisomeric forms. This disclosure considers all such compounds that fall within the scope of this disclosure, including cis and trans isomers, R- and S- mirror isomers, non-mirror image isomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof.

[0035] Geometric isomers may also exist in the compounds disclosed herein. This disclosure covers various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a ring (e.g., a carbocyclic ring). The arrangement of substituents around a ring (e.g., a carbocyclic ring) is specified as "cis" or "trans". The term "cis" indicates that the substituents are on the same side of the ring plane, and the term "trans" indicates that the substituents are on opposite sides of the ring plane. If two substituents are present on a carbon atom of the ring, these substituents are ranked according to the Cahn-Ingold Prelog priority rule (the priority of the atom / group is assigned based on the atomic number of the atom. The higher the atomic number, the higher the priority). A mixture of compounds with substituents arranged on the same and opposite sides of the ring plane may be specified as "cis / trans".

[0036] As used herein, “geometric isomer mixture” refers to a mixture of cis and trans isomers of the compounds disclosed herein.

[0037] Unless otherwise indicated, when a compound is named or illustrated by an unspecified stereochemical structure, it should be understood that it represents all possible stereoisomers of the compound (e.g., all cis and trans isomers).

[0038] The compounds described herein may also contain atomic isotopes in non-natural proportions at one or more of the atoms constituting such compounds. For example, the compounds may be radiolabeled with radioactive isotopes such as deuterium (2H), tritium (3H), carbon-13 (13C), or carbon-14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be included within the scope of this disclosure. Furthermore, all tautomerisms of the compounds described herein are intended to be included within the scope of this disclosure.

[0039] The compounds disclosed herein can be used in free base form or as salts. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, glucono-p-ethyl, lactobionate, and laurylsulfonate, and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0040] The term "tautomer" refers to a compound that is an interchangeable form of a particular compound structure, differing in the substitution of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H).

[0041] The term "activator" refers to an agent that increases the tendency of molecules to undergo a specific chemical reaction.

[0042] Unless otherwise indicated, all numerical values ​​used in this specification and the claims to represent amounts of ingredients, reaction conditions, data points (e.g., geometric isomer ratios, temperatures, angles, etc.) should be understood to be modified by the term "about" in all cases. Therefore, unless indicated otherwise, the numerical parameters described in this specification and the appended claims are approximate values, which may vary depending on the desired properties sought to be obtained in this disclosure.

[0043] Unless otherwise indicated, all numerical ratios used in this document to describe heterogeneous mixtures should be understood as mole ratios. Compounds and Compositions

[0044] In a single-state sample, this disclosure provides a compound of formula (I): [] (I), Or its salt.

[0045] Compound (I) is the same as compound (Ia): (Ia), Or its salt.

[0046] Compound (I) is the same as compound (Ib): (Ib), Or its salt.

[0047] In another state, this disclosure provides a compound of formula (II): (II), Or its salt.

[0048] Compound (II) is the same as compound (IIa): (IIa), Or its salt.

[0049] Compound (II) is a compound of formula (IIb): (IIb), Or its salt.

[0050] This disclosure partially provides for compounds of formula (III): (III), Or its salt.

[0051] Compound (III) is the same as compound (IIIa): (IIIa), Or its salt.

[0052] Compound (III) is a compound of formula (IIIb): (IIIb), Or its salt.

[0053] This article also provides isomer mixtures of cis and trans isomers of compounds of formula (III) or their salts: (III), The cis isomer is a compound of formula (IIIa) or a salt thereof: (IIIa), Furthermore, the trans isomer is a compound of formula (IIIb) or a salt thereof: (IIIb), The ratio of the cis isomer to the trans isomer is greater than or equal to about 4:1, greater than or equal to about 5:1, greater than or equal to about 6:1, greater than or equal to about 7:1, greater than or equal to about 8:1, greater than or equal to about 9:1, greater than or equal to about 3:1, greater than or equal to about 2:1, greater than or equal to about 75:25, greater than or equal to about 7:3, greater than or equal to about 85:15, greater than or equal to about 65:35, or greater than or equal to about 3:2.

[0054] This article provides in part the compounds of formula (IV): (IV), Or its salt.

[0055] Compounds of formula (IV) are compounds of formula (IVa): (IVa), Or its salt.

[0056] Compound (IV) is the same as compound (IVb): (IVb), Or its salt.

[0057] This disclosure also provides isomer mixtures of cis and trans isomers of the compound of formula (IV) or its salts: (IV), The cis isomer is a compound of formula (IVa): (IVa), Furthermore, the trans isomer is a compound of formula (IVb) or a salt thereof: (IVb), The ratio of the cis isomer to the trans isomer is greater than or equal to about 4:1, greater than or equal to about 5:1, greater than or equal to about 6:1, greater than or equal to about 7:1, greater than or equal to about 8:1, greater than or equal to about 9:1, greater than or equal to about 3:1, greater than or equal to about 2:1, greater than or equal to about 75:25, greater than or equal to about 7:3, greater than or equal to about 85:15, greater than or equal to about 65:35, or greater than or equal to about 3:2.

[0058] In another state, this disclosure provides a compound of formula (V-1): (V-1), or its salt, wherein R is an activating group.

[0059] In some embodiments, the activating group is a chemical group introduced by activating an alcohol to carry out a substitution reaction. In some embodiments, R is selected from the group consisting of: -Cl, -O-methanesulfonyl, -O-p-toluenesulfonyl, phosphite, chlorosulfite, and trifluoromethanesulfonate.

[0060] In some embodiments, the compound of formula (V-1) is the compound of formula (V-1a): (V-1a), or its salt, wherein R is an activating group.

[0061] In other embodiments, the compound of formula (V-1) is the compound of formula (V-1b): (V-1b), or its salt, wherein R is an activating group.

[0062] In some embodiments, the compound of formula (V-1) is the compound of formula (V): (V), Or its salt.

[0063] Compound of formula (V) is the same as compound of formula (Va): (Va), Or its salt.

[0064] Compound of formula (V) is the same as compound of formula (Vb): (Vb), Or its salt.

[0065] This article also provides isomer mixtures of cis and trans isomers of compounds of formula (V) or their salts: (V), The cis isomer is a compound of formula (Va) or a salt thereof: (Va), Furthermore, the trans isomer is a compound of formula (Vb) or a salt thereof: (Vb), The ratio of the cis isomer to the trans isomer is greater than or equal to about 4:1, greater than or equal to about 5:1, greater than or equal to about 6:1, greater than or equal to about 7:1, greater than or equal to about 8:1, greater than or equal to about 9:1, greater than or equal to about 3:1, greater than or equal to about 2:1, greater than or equal to about 75:25, greater than or equal to about 7:3, greater than or equal to about 85:15, greater than or equal to about 65:35, or greater than or equal to about 3:2.

[0066] This document partially provides for compositions comprising a compound of formula (VI) or a salt thereof: (VI), The composition substantially does not contain compounds of formula (VIa): (VIa), Or its salt.

[0067] In some embodiments, when the ratio of compound (VI) or a salt thereof to compound (VIa) or a salt thereof is greater than or equal to about 9:1, greater than or equal to about 91:9, greater than or equal to about 92:8, greater than or equal to about 93:7, greater than or equal to about 94:6, greater than or equal to about 95:5, greater than or equal to about 96:4, greater than or equal to about 97:3, greater than or equal to about 99:3, or greater than or equal to about 99:1, the composition is substantially free of compound (VIa) or a salt thereof.

[0068] In other embodiments, HPLC was used to detect the ratio of compound (VI) or a salt thereof to compound (VIa) or a salt thereof.

[0069] In some embodiments, the composition contains less than 10%, 5%, 1%, 0.5% or 0.1% of a compound of formula (VIa) or a salt thereof by weight of the compound of formula (VI) or a salt thereof.

[0070] This disclosure also provides compositions comprising a compound of formula (VII) or a salt thereof: (VII), The composition substantially does not contain compounds of formula (VIIa): (VIIa), Or its salt.

[0071] In some embodiments, the ratio of the compound of formula (VII) or a salt thereof to the compound of formula (VIIa) or a salt thereof is greater than or equal to about 9:1, greater than or equal to about 91:9, greater than or equal to about 92:8, greater than or equal to about 93:7, greater than or equal to about 94:6, greater than or equal to about 95:5, greater than or equal to about 96:4, greater than or equal to about 97:3, greater than or equal to about 99:3, or greater than or equal to about 99:1. Preparation process of compounds

[0072] In another embodiment, this document provides a process for preparing compositions comprising mixtures of cis and trans isomers of a compound containing form (IV) or its salts or tautomers: (IV), This process includes: (a) To make a compound of formula (II) or a salt thereof: (II), The ammonium source reacts in the presence of a solvent to produce a compound of formula (III): (III), or its salt; and (b) Reacting a compound of formula (III) with an alkyl acetate to produce a composition comprising a mixture of a cis isomer and a trans isomer of a compound of formula (IV), wherein the cis isomer is of formula (IVa): (IVa), Or the amount of its salt is greater than that of the trans isomer (IVb): (IVb) Or its salt.

[0073] This disclosure partially provides a process for preparing a composition comprising a mixture of cis and trans isomers of a compound of formula (III) or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is increased: (III), The cis isomer is a compound of formula (IIIa) or a salt thereof: (IIIa), Furthermore, the trans isomer is a compound of formula (IIIb) or a salt thereof: (IIIb), The process involves using a compound of formula (II) or a salt thereof: (II), The mixture reacts with an ammonium source in the presence of a solvent to produce a composition comprising a mixture of cis isomers and trans isomers of a compound of formula (III), wherein the ratio of the cis isomer to the trans isomer is increased.

[0074] This article partially provides the preparation process for compound (X) or its salts: (X), The process includes the following steps: (a) To make a compound of formula (II) or a salt thereof: (II), The ammonium source reacts in the presence of a solvent to produce a compound of formula (III): (III), or its salt; (b) Reacting compound (III) with an alkyl acetate to produce an isomer mixture of compound (IV) or its salt: (IV), In this isomer mixture of compounds of formula (IV), the cis isomer of formula (IVa) is: (IVa), Or the amount of its salt is greater than that of the trans isomer (IVb): (IVb), or its salt; (c) Purify the isomer mixture of the compound of formula (IV) or its salt to obtain the compound of formula (IVa) or its salt; (d) Reacting the compound of formula (IVa) or its salt with an activator to provide the compound of formula (V-1a): (V-1a), Or its salt, wherein R is an activating group; (e) Reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI): (VI); or its salt; (f) Reacting the compound of formula (VI) or its salt with a base to provide the compound of formula (VII): (VII), or its salt; (g) React the compound of formula (VII) or its salt with the compound of formula (VIII) or its salt: (VIII), This provides a compound of formula (X) or a salt thereof.

[0075] It will be understood that, in some embodiments, the reaction of one compound with another may be carried out in the presence of a solvent or additional solvent, or even any solvent described herein or associated with a particular reaction step. For example, the solvents considered may include suitable solvents used, for example, for each step of the process or method considered. In some embodiments, R is selected from the group consisting of: -Cl, -O-methanesulfonyl, -O-p-toluenesulfonyl, phosphite, chlorosulfite, and trifluoromethanesulfonate. In some embodiments, R is -Cl or -OMs.

[0076] In some embodiments, the activator is a methanesulfonate base and R is -OMs.

[0077] This article also provides the preparation process for compound (VIII) or its salts: , The process includes the following steps: (a) To make a compound or its salt represented by the following formula: , Reaction with (R)-2-methyl-2-propanesulfinamide between -15°C and -25°C yields a compound represented by the following formula: , or its salt; and (b) React the compound provided in step (a) with an acid to provide the compound of formula (VIII) or a salt thereof.

[0078] This article also partially provides the preparation process for compound (X) or its salts: (X), The process includes the following steps: (a) To make a compound of formula (IVa) or a salt thereof: (IVa), It reacts with an activator to provide a compound of formula (V-1a): (V-1a), Or its salt, wherein R is an activating group; (b) Reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI): (VI), or its salt; (c) Reacting the compound of formula (VI) or its salt with a base to provide the compound of formula (VII): (VII), or its salt; and (d) Reacting a compound of formula (VII) or a salt thereof with a compound of formula (VIII) or a salt thereof: (VIII), This provides a salt of compound (X).

[0079] In some embodiments, R is selected from the group consisting of: -Cl, -O-methanesulfonyl, -O-p-toluenesulfonyl, phosphite, chlorosulfite, and trifluoromethanesulfonate. In some embodiments, R is -Cl or -OMs. In some embodiments, the activator is a methanesulfonyl agent and R is -OMs.

[0080] In some embodiments, the final step of the process further includes reacting a salt of compound (X) with a base to provide compound (X). For example, in some embodiments, the salt of compound (X) is a hydrochloride salt.

[0081] The ratio of the cis isomer to the trans isomer of compound (III) may be about 4:1, at least 4:1, greater than or equal to about 4:1, about 75:25, at least 75:25, or greater than or equal to about 75:25. The ratio of the cis isomer to the trans isomer of compound (IV) may be about 4:1, at least 4:1, greater than or equal to about 4:1, about 75:25, at least 75:25, or greater than or equal to about 75:25.

[0082] In some embodiments, the reaction of the compound of formula (II) or a pharmaceutically acceptable salt thereof with an ammonium source (such as in one of the steps (a) set forth herein) further comprises heating the solvent (e.g., heating to reflux), for example, step (a) further comprises heating the solvent to about 30°C or about 40°C or higher, for example, to about 50°C or higher, for example, about 55°C or higher, about 60°C or higher, about 65°C or higher, for example, about 70°C or higher. In any of the embodiments herein that include a method of reacting the compound of formula (II) with an ammonium source in the presence of a solvent, the solvent is a polar solvent in which the ammonium source is soluble, such as a polar protic solvent or a polar aprotic solvent or a mixture thereof. In some embodiments, the solvent comprises a C1-C4 alkyl alcohol or a mixture of alcohols. In some embodiments, the solvent is methanol, or ethanol, or propanol, or butanol, or dioxane or a combination thereof. In some embodiments, the ammonium source is ammonia or ammonium chloride. In some embodiments, the solvent is methanol and the ammonium source is ammonia. In some embodiments that may include any of the foregoing embodiments, the compound of formula (II) reacts with an ammonium source in the presence of a solvent at a temperature of at least 30°C, at least 40°C, at least 50°C, at least 60°C, at least 70°C, at least 80°C, between 30°C and 100°C, between 40°C and 90°C, between 50°C and 80°C, between 60°C and 80°C, or between about 60°C and about 70°C. In some embodiments, the reaction mixture is heated to reflux. In some embodiments, the reaction mixture is heated to between about 50°C and 80°C, and the solvent is a C1-C4 alkyl alcohol or a mixture of alcohols, and the ammonium source is ammonia. In some embodiments, the solvent is methanol, the ammonium source is ammonia, and the reaction mixture is heated to reflux at standard pressure (e.g., about 65°C). In other embodiments, an ammonium salt, such as ammonium chloride, is used.

[0083] In other embodiments, the process further includes heating the solvent to about 30°C or higher, about 40°C or higher, about 50°C or higher, such as about 55°C or higher, about 60°C or higher, about 65°C or higher, such as about 70°C or higher, or for example, heating the solvent to reflux.

[0084] In some embodiments, the solvent is a polar organic solvent. For example, the solvent is an alcohol, such as methanol, ethanol, or isopropanol. In other embodiments, the solvent is a polar protic solvent, such as an alcohol or a mixture of alcohols. In other embodiments, the solvent is a polar aprotic solvent, such as dioxane.

[0085] The alkyl acetone under consideration can be methyl acetone. The alkyl acetone under consideration can be ethyl acetone.

[0086] In some embodiments, the ammonium source is a reagent that introduces a -NH₂ group. In some embodiments, the ammonium source is NH₃ or NH₄Cl. In some embodiments, the ammonium source provides NH₄⁺ to the reaction mixture, which is added to the reaction mixture, for example, in the form of an ammonium salt or ammonia. In some embodiments, the solvent is a solvent in which the ammonium source is soluble, such as a combination of C₁-C₄ alkyl alcohols and ammonia, such as methanol, or ethanol, or propanol or butanol. Dioxane may also be used in some embodiments.

[0087] In other embodiments, the methanesulfonate agent is a reagent that introduces a methanesulfonate group.

[0088] Methyl sulfonate base can be methyl sulfonate chloride.

[0089] In some embodiments, the base is a metal hydroxide, such as sodium hydroxide.

[0090] This article also provides a process for preparing compositions comprising a mixture of cis and trans isomers of a compound of formula (X), with the majority being cis isomers. (X), The process includes: Make the compound of formula (VII) or its salt: (VII), Reaction with compounds of formula (VIII) or their salts: (VIII), This provides a composition comprising a mixture of cis and trans isomers of the compound containing formula (X), with the majority being in the cis isomer configuration.

[0091] In some embodiments, the cis:trans molar ratio of the composition, which is mostly in the configuration of the cis isomer, is about 4:1 to about 99:1, about 5:1 to about 99:1, about 6:1 to about 99:1, about 7:1 to about 99:1, or about 8:1 to about 99:1.

[0092] In some embodiments, increasing the temperature of the reaction between the compound of formula (II) and the ammonium source increases the cis:trans molar ratio in the resulting mixture of compounds of formula (III) (i.e., the amount of compound (IIIa) is greater than that of compound (IIIb)). In some embodiments, the ratio is about 4:1 to about 99:1, about 5:1 to about 99:1, about 6:1 to about 99:1, about 7:1 to about 99:1, or about 8:1 to about 99:1. In some embodiments, performing the same reaction at room temperature (e.g., about 20°C) produces cis:trans isomers in a 1:1 ratio; while heating the reactants to, for example, reflux (e.g., between 60°C and 70°C, or about 65°C) produces cis:trans isomers in a ratio greater than 8:2. This increased cis:trans ratio can be carried over to the next step of the synthetic pathway to produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof, in which a larger cis:trans ratio is present (i.e., a larger amount of compound of formula (IVa) compared to formula (IVb)). In some embodiments, the cis:trans ratio is about 4:1 to about 99:1, about 5:1 to about 99:1, about 6:1 to about 99:1, about 7:1 to about 99:1, or about 8:1 to about 99:1. This is particularly advantageous because the cis isomer can be isolated and further used in the synthetic pathway to produce the desired compound of formula (X), thereby reducing the amount of discarded trans compound of formula (IV) (i.e., formula (IVb)). Therefore, in the method provided herein, heating the reaction mixture comprising a compound of formula (II) or a salt thereof, an ammonium source, and a solvent to a temperature of at least about 40°C, at least about 50°C, at least about 60°C, or at least about 70°C (such as 50°C to 80°C or 60°C to 70°C) causes an unexpected and advantageous shift in the cis:trans ratio of the resulting compound of formula (III) or a salt thereof (e.g., more cis isomers than trans isomers), which improves the efficiency of the synthesis of compounds of formulas (IIIa) and (X) or their salts. In some embodiments, the solvent used in the reaction of the compound of formula (II) or its salt is a polar protic solvent or a polar aprotic solvent or a mixture thereof. In some embodiments, the solvent comprises a C1-C4 alkyl alcohol or a mixture of alcohols. In some embodiments, the solvent is methanol, or ethanol, or propanol, or butanol, or dioxane or a combination thereof. In some embodiments, the ammonium source is ammonia or ammonium chloride. In some embodiments, the solvent is methanol and the ammonium source is ammonia. In some embodiments, the solvent is a C1-C4 alkyl alcohol (such as methanol), the ammonium source is ammonia or ammonium chloride, and the solvent is heated to reflux (e.g., 60°C to 70°C or higher, depending on the solvent).

[0093] In other embodiments, the cis:trans molar ratio of the composition, which is mostly of the cis isomer configuration, is about 97:3 to about 99:3, about 9:1 to about 99:1, about 9:1 to about 99:3, about 9:1 to about 97:3, about 95:5 to about 99:3, about 95:5 to about 97:3, greater than or equal to about 9:1, greater than or equal to about 91:9, greater than or equal to about 92:8, greater than or equal to about 93:7, greater than or equal to about 94:6, greater than or equal to about 95:5, greater than or equal to about 96:4, greater than or equal to about 97:3, greater than or equal to about 99:3, greater than or equal to about 99:1, or, for example, about 8:2 or greater of the cis:trans molar ratio.

[0094] In some embodiments, the process further includes a process for preparing a compound of formula (VII) or a salt thereof, which includes: (a) To make a compound of formula (IVa) or a salt thereof: (IVa), It reacts with an activator to provide a compound of formula (V-1a): (V-1a), Or its salt, wherein R is an activating group; (b) Reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI): (VI); or its salt; (c) Reacting the compound of formula (VI) or a salt thereof with a base to provide the compound of formula (VII) or a salt thereof.

[0095] In some embodiments, R is selected from the group consisting of: -Cl, -O-methanesulfonyl, -O-p-toluenesulfonyl, phosphite, chlorosulfite, and trifluoromethanesulfonate. In some embodiments, R is -Cl or -OMs. In other embodiments, R is -OMs. In some embodiments, the activator is a methanesulfonyl agent (e.g., MsCl).

[0096] This article partially provides geometric isomeric mixtures of inclusion (X) compounds prepared using the disclosed process: (X), The cis:trans molar ratio of the mixture of geometric isomers is approximately 4:1 to approximately 99:1.

[0097] In some embodiments, the cis:trans molar ratio of the geometric isomer mixture is about 4:1 to about 99:1, about 5:1 to about 99:1, about 6:1 to about 99:1, about 7:1 to about 99:1, or about 8:1 to about 99:1.

[0098] In other embodiments, the cis:trans molar ratio of the geometric isomer mixture is about 90:10 to about 99:1, greater than or equal to about 9:1, greater than or equal to about 91:9, greater than or equal to about 92:8, greater than or equal to about 93:7, greater than or equal to about 94:6, greater than or equal to about 95:5, greater than or equal to about 96:4, greater than or equal to about 97:3, greater than or equal to about 99:3, or greater than or equal to about 99:1.

[0099] In some embodiments, the cis:trans molar ratio of the geometric isomer mixture is about 90:3 to about 99:3. Pharmaceutical Composition

[0100] This document also provides pharmaceutical compositions comprising pralatinib or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients or carriers. The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refer to any pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, involved in carrying or transporting any target composition or its components. Each excipient or carrier must be "acceptable" in the sense of being compatible with the target composition and its components and not harming the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, etc. Seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in pharmaceutical formulations.

[0101] Pharmaceutically acceptable excipients may include citric acid, hydroxypropyl methylcellulose (HPMC), magnesium stearate, microcrystalline cellulose (MCC), pregelatinized starch and sodium bicarbonate, colorants (e.g., brilliant blue FCF), hydroxypropyl methylcellulose or titanium dioxide.

[0102] The compositions disclosed herein can be administered orally, non-enterically, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable cartridge. As used herein, "non-enteric" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions disclosed herein are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions disclosed herein may be an aqueous or oily suspension. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in this art. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, non-enteric acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that may be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are often used as solvents or suspension media.

[0103] For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, can also be used to prepare injectable formulations, similar to pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially in their polyoxyethylated form). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. For formulation purposes, other commonly used surfactants, such as Tween and Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used.

[0104] The oral-administered composition can be prepared into any suitable dosage form, such as capsules, sugar-coated tablets, granules, powders, or tablets. In a particular embodiment, the dosage form is capsules. In some embodiments, the capsule size is 0. In other embodiments, the capsule size is 00. In some embodiments, the capsule size is 1.

[0105] In one state, the composition as described herein contains about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of pralatinib or a pharmaceutically acceptable salt thereof. In one state, the composition as described herein contains about 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 200 mg, 300 mg, or 400 mg of pralatinib or a pharmaceutically acceptable salt thereof.

[0106] The pharmaceutically acceptable compositions disclosed herein can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets intended for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0107] Alternatively, the pharmaceutically acceptable compositions disclosed herein may be administered in suppository form for rectal administration. These compositions can be prepared by mixing the agent with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0108] The pharmaceutically acceptable compositions disclosed herein can also be administered topically, particularly when the therapeutic target includes areas or organs that can be easily reached by topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily prepared. Topical application to the lower intestine can be achieved using rectal suppository formulations (see above) or suitable enema formulations. Topical-percutaneous patches can also be used.

[0109] For topical application, a pharmaceutically acceptable composition may be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds disclosed herein include (but are not limited to) mineral oil, liquid paraffin, leucocele, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, a pharmaceutically acceptable composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oil, dehydrated sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0110] The pharmaceutically acceptable compositions disclosed herein can also be administered via nasal aerosol or inhalation. These compositions are prepared according to techniques well known in pharmaceutical compounding and can be prepared into solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers (to enhance bioavailability), fluorocarbons and / or other conventional solubilizers or dispersants.

[0111] The amount of the compound disclosed herein, which can be combined with a carrier material to produce a single dosage form, will vary depending on the host being treated and the specific administration method. [Treatment methods] []

[0112] Praltinib or the compound of formula (X) can be used to treat cancers with RET alterations. Therefore, this disclosure also provides a method for treating cancers with RET alterations, comprising administering a therapeutically effective amount of the composition disclosed herein to a patient in need. Another embodiment of this disclosure relates to a method for treating a patient with RET-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective amount of the composition disclosed herein to a patient in need. In a specific case, the patient is a RET-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) detected by an FDA-approved test. Another embodiment of this disclosure relates to a method for treating a patient with RET-mutant-positive locally advanced or metastatic medullary thyroid carcinoma (MTC), comprising administering a therapeutically effective amount of the composition disclosed herein to a patient in need. In a specific case, the patient is 12 years of age or older. Another embodiment of this disclosure relates to a method for treating patients with RET fusion-positive locally advanced or metastatic thyroid cancer who require systemic therapy and have no satisfactory alternative treatment options, comprising administering a therapeutically effective dose of the composition disclosed herein to the patient in need. In a particular case, the patient is 12 years of age or older.

[0113] As used herein, the terms “individual” or “patient” refer to an organism for which treatment is desired by the methods of this disclosure. Such organisms include (but are not limited to) mammals (e.g., rats, apes, horses, cattle, pigs, dogs, cats, and the like), and in some embodiments include humans. In a particular case, the patient or individual has or is suspected of having a disease or condition associated with abnormal RET manifestations (i.e., increased RET activity caused by RET signaling) or biological activity. Specifically, the disease or condition is cancer. Many cancers are associated with abnormal RET manifestations (Kato et al., Clin. Cancer Res. 23(8): 1988-97 (2017)). Non-limiting examples of "cancer" as used herein include lung cancer, head and neck cancer, gastrointestinal cancer, breast cancer, skin cancer, genitourinary cancer, gynecological cancer, hematologic malignancies, central nervous system (CNS) cancer, peripheral nervous system cancer, endometrial cancer, colorectal cancer, bone cancer, sarcoma, spitzoid neoplasm, adenosquamous carcinoma, pheochromocytoma (PCC), hepatocellular carcinoma, multiple endocrine neoplasms (MEN2A and MEN2B), and inflammatory myofibroblastic tumor. For other examples, see Nature Reviews Cancer 14: 173-86 (2014).

[0114] "Treatment" in the context of a disease or condition refers to the improvement of at least one symptom of that disease or condition. When used in conjunction with a disease (such as cancer), these terms mean one or more of the following: inhibiting cancer growth, causing cancer to shrink by weight or volume, prolonging the patient's expected survival time, inhibiting tumor growth, reducing tumor mass, reducing the size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonging survival, prolonging progression-free survival, prolonging time to progression, and / or improving quality of life.

[0115] The term "therapeutic effect" refers to a beneficial local or systemic effect in animals, particularly mammals, and more particularly humans, caused by administration of the compound or composition of this disclosure. The phrase "therapeutic effective amount" means the amount of the compound or composition of this disclosure that is effective in treating a disease or ailment caused by RET overexpression or abnormal RET biological activity at a reasonable benefit / risk ratio. The therapeutic effective amount of this substance will vary depending on the individual being treated and the symptoms of the disease, the individual's weight and age, the severity of the disease, the method of administration, and so on, and can be readily determined by a person skilled in the art. [Example] []

[0116] The following examples are intended to be illustrative and not to be limiting in any way.

[0117] The compounds (including their salts) disclosed herein can be prepared using known organic synthetic techniques and can be synthesized according to any of a number of possible synthetic routes, such as those described in the following synthetic schemes and examples. The following schemes are intended to provide general guidance for the preparation of the compounds disclosed herein. Those skilled in this art will understand that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare the various compounds disclosed herein. [4-] [Cyano] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [3)] [Synthesis] [] [synthesis] [A] [synthesis] [A] [,step] [1. 8-] [Methoxy] [-1,4-] [Dioxane snail] [[4.5]] [Decane] [-8-] [Methyl formate] [(] [Compound] [1a)] [Synthesis] []

[0118] Methanol (22.60 kg) was added to the reactor, and the internal temperature was set between 20°C and 35°C. 1,4-Dioxaspiro[4.5]dec-8-one (1.90 kg) and potassium carbonate (13.50 kg) were added to the reactor while maintaining the temperature range. After the addition was complete, the mixture was heated to 35°C to 40°C. While maintaining the temperature at 35°C to 40°C, tribromomethane (4.94 kg) was added dropwise to the mixture at a rate of 2 to 4 kg / h. The mixture was stirred at 35°C to 40°C to allow the reaction to proceed. After 4 h, the reaction mixture was monitored by GC every 1 to 4 h until the area % of 1,4-dioxaspiro[4.5]dec-8-one was ≤1%. The reaction mixture was cooled to 20°C to 30°C. The mixture was filtered through a filter funnel, and the filter cake was washed with methanol (3.04 kg). The filtrate was concentrated under reduced pressure (P ≤ -0.08 MPa) at T ≤ 50 °C until 1–2 volumes remained. The temperature was maintained at 20 °C–35 °C, and ethyl acetate (8.60 kg) and purified water (15.20 kg) were added to the reactor. The temperature was maintained at 15 °C–30 °C, and the mixture was stirred for 15–30 min and allowed to settle for 15–30 min, followed by separation. The organic phase was concentrated under reduced pressure (P ≤ -0.08 MPa) at T ≤ 50 °C until 1–2 volumes remained. 2.86 kg of a pale yellow oil was obtained, with a corrected yield of approximately 70% and a GC purity of 92%. [Analysis Method:] [] [Column:] HP-5, 30 m length × 0.32 mm ID × 0.25 μm membrane [Carrier gas:] helium [flow] 1.9 ml / min [Running Time] 22.5 min [Temperature Program] Maintain 50℃ for 2 minutes; increase to 260℃ at a rate of 20℃ / min and hold for 10 minutes. [Inlet Temperature] 250℃ [Temperature Detection] 300℃ [Duration of stay:] [] Dwell time, min RRT Chemical name area,% 7.74 0.77 Starting materials 1% 9.73 0.97 Eliminate impurities 5% 10.07 1.00 8-Methoxy-1,4-dioxaspiro[4.5]decane-8-carboxylic acid methyl ester 92% [synthesis] [A] [,step] [twenty one-] [Methoxy] [-4-] [Side-oxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [2a)] [Synthesis] []

[0119] Maintain the temperature between 10°C and 25°C, and add the compound to the reactor. [1a] (Combining a batch (2.86 kg) containing 1.96 kg of compound 1a with another batch (2.62 kg) containing 1.94 kg of compound 1a), and starting the stirrer. Maintaining the temperature at 10°C–25°C, a 1 M hydrochloric acid solution prepared from concentrated hydrochloric acid (4.60 kg) in purified water (43.12 kg) was added dropwise at the rate determined by the actual temperature. The mixture was stirred at 10°C–25°C to allow the reaction to proceed. After 4 h, the reaction mixture was monitored by GC every 2–6 h until the compound was fully incorporated. [1a] until the area % is ≤5%. Maintain the temperature at 10℃~25℃, add dichloromethane (10.34 kg) to the mixture, and allow the mixture to settle for 10~15 min, then separate. Extract the aqueous phase with dichloromethane (5.19 kg) at 10℃~25℃, stir the mixture for 10~30 min, and allow it to settle for 10~15 min, then separate. Combine the organic phases. Concentrate the combined organic phases at T≤40℃ under reduced pressure (P≤-0.08 MPa) until 1~2 volumes (relative to the compound) remain. [1a]) Maintain the temperature at 10°C–25°C, add tetrahydrofuran (3.47 kg) to the reactor and start the stirrer. Maintain the temperature at 10°C–25°C, add dropwise a 1 M hydrochloric acid solution prepared from concentrated hydrochloric acid (2.07 kg) in purified water (21.46 kg), at a rate determined by the actual temperature. Allow the reaction mixture to react at 10°C–25°C for 4 h, then monitor the reaction mixture every 2–6 h by GC until the compound is obtained. [1a] area % ≤ 1.0%. Maintaining the temperature at 10°C–25°C, add dichloromethane (10.34 kg) to the mixture and allow it to settle for 10–15 min, then separate. Extract the aqueous phase with dichloromethane (5.19 kg) at 10°C–25°C, stir the mixture for 10–30 min, allow it to settle for 10–15 min, then separate. Combine the organic phases. Add anhydrous sodium sulfate (1.95 kg) to the organic phase, and then filter the mixture using a 10 L filter flask. Wash the filter cake with dichloromethane (1.95 kg). Sample the filter cake for purity analysis by GC. Concentrate the mixture under reduced pressure (P ≤ -0.08 MPa) at T ≤ 40°C until a volume of 0.5–1 remains (essentially no distillate relative to compound 2a). 3.40 kg (corrected to 2.58 kg) of light brown oily substance was obtained with a yield of 81.98% and a GC purity of 97%. [, , ] [Analysis Method:] [] [Column:] HP-5, 30 m length × 0.32 mm ID × 0.25 μm membrane [Carrier gas:] helium [flow] 1.9 ml / min [Running Time] 22.5 min [Temperature Program] Maintain 50℃ for 2 minutes; increase to 260℃ at a rate of 20℃ / min and hold for 10 minutes. [Inlet Temperature] 250℃ [Temperature Detection] 300℃ [Duration of stay:] [] Dwell time, min RRT Chemical name 7.67 0.80 Eliminate impurities 1.17 8.06 1.00 compound [2a] 97.16 9.44 1.16 compound [1a] 0.41 [synthesis] [A] [,step] [3.4-] [Cyano] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [3)] [Synthesis] [] []

[0120] Add tetrahydrofuran (20.25 kg) to the reactor. Maintain the temperature at 0°C–25°C while adding the compound to the reactor. [2a] (1.97 kg, corrected to 1.50 kg), followed by the addition of TosMIC (2.04 kg) and stirring. The mixture was cooled to -5°C to 0°C. While maintaining the temperature at -5°C to 0°C, a solution of potassium terbutoxide (2.18 kg) in terbutanol (7.26 kg) and tetrahydrofuran (3.45 kg) was added dropwise to the mixture, with the addition rate determined by temperature control. The mixture was reacted at -5°C to 0°C for 2 h, followed by a rise to 5°C to 10°C. After 1 h, samples of the mixture were taken every 1 to 3 h for analysis until the compounds were analyzed. [2a] The area % ≤1% and the intermediate ≤1% after 14.4 min (RRT=1.52) were maintained at -5℃ to 15℃. A solution of sodium chloride (1.65 kg) in purified water (15.00 kg) was added dropwise to the mixture, and the actual addition rate was determined according to the temperature control. The mixture was stirred for 10 to 15 min and allowed to settle for 10 to 15 min, and then separated. The aqueous phase was extracted with ethyl acetate (5.41 kg), the mixture was stirred for 10 to 15 min and allowed to settle for 10 to 15 min, and then separated. The aqueous phase was extracted twice with ethyl acetate (5.40 kg + 2.70 kg), the mixture was stirred for 15 to 30 min and allowed to settle for 15 to 30 min, and then separated. The organic phases were combined. The organic phase was concentrated under reduced pressure (P≤-0.08 MPa) at T≤45℃ until 2 to 4 L remained. Silicone (0.75 kg) was added to the mixture and stirred by rotary evaporation until homogeneous, then the mixture was concentrated to dryness. The mixture was loaded into a pre-loaded chromatography column, and sodium chloride (0.75 kg) was added to the surface and leveled. The column was then dissolved in a solution of the prepared ethyl acetate (3.00 kg) in n-heptane (60.03 kg). The purity of the precipitate was sampled every 10 L until the entire product was washed. The mixture was concentrated under reduced pressure (P ≤ -0.08 MPa) at T ≤ 45 °C until a solid precipitated with no significant solvent residue. The solid was transferred to a tray and then dried by purging with nitrogen. Approximately 700 g of white powder solid was obtained, with a corrected yield of approximately 50% and a GC purity of 98%–99%. [, , ] [Analysis Method:] [] [Column:] HP-5, 30 m length × 0.32 mm ID × 0.25 μm membrane [Carrier gas:] helium [flow] 1.9 ml / min [Running Time] 22.5 min [Temperature Program] Maintain 50℃ for 2 minutes; increase to 260℃ at a rate of 20℃ / min and hold for 10 minutes. [Inlet Temperature] 250℃ [Temperature Detection] 300℃ [Duration of stay:] [] Dwell time, min RRT Chemical name 8.08 0.85 Eliminate impurities <0.05% 8.68 0.91 Compound 2a <0.05% 9.49 1.00 Compound 3 (main) 54.12 9.38 0.98 Compound 3 (minor) 43.35 14.27 1.52 intermediate <0.05%

[0121] The major and minor isomers of compound 3 are cis and trans isomers. However, the stereochemistry of the major and minor isomers is not assigned. [4-] [Cyano] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [3)] [Synthesis] [] [synthesis] [B] [] [synthesis] [B] [,step] [1.8-] [Methoxy] [-1,4-] [Dioxane snail] [[4.5]] [Decane] [-8-] [Methyl formate] [(] [Compound] [1a)] [Synthesis] []

[0122] Methanol (15 V) and K₂CO₃ (8 eq.) were placed in a container at 20 °C. Cyclohexanedione monoethylene glycol acetal (200.0 g, 1.0 eq) was added to the mixture. The slurry was then heated to 35 °C–40 °C. Bromoform (1.6 eq) was added dropwise to the reactants at 35 °C–40 °C. The reaction was maintained at 35 °C–40 °C for 20 hours or until the starting material was completely converted. After the cyclohexanedione monoethylene glycol acetal was completely consumed, the reactants were filtered and concentrated to 2 volumes. Water and ethyl acetate were added to the separated crude organic layer. The organic layer was distilled to obtain a crude product as an oil. Yield of crude product: 76%, purity: 92.07% (GC method) [test] [content] [(%) bromoform 1.00 Cyclohexanedione monoethylene glycol acetal 0.22 compound [1a] 92.07 Eliminate impurities 4.79 Dimethoxy impurities ND [synthesis] [B] [,step] [2.1-] [Methoxy] [-4-] [Side-oxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [2a)] [Synthesis]

[0123] The crude compound was prepared at 25℃-30℃. [1a] (500 g) was treated with an aqueous solution of HCl (1 N 15 V) in THF (2 V) for 16 hours or until the starting material was used up. The reactants were extracted with DCM. The organic layer was completely distilled. An aqueous solution of HCl (1 N 5 V) was added, followed by THF (1 V), and the treatment was continued until the compound was obtained. [1a] Use until finished. Extract the reactants with DCM. Wash the organic layer with 5% NaHCO3, filter and concentrate to obtain the crude product. Yield of crude product: 71.7%, purity: 94.90% (GC method). [test] [content] [(%) bromoform 1.06 compound [2a] 94.9 compound [1a] 0.32 impurities 2.39 [synthesis] [B] [,step] [3.4-] [Cyano] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [3)] [Synthesis] []

[0124] Compounds under nitrogen conditions [2a] (100 g, 1.0 eq) was added to a dry RBF, followed by the addition of TosMIC reagent (1.3 eq) and dimethoxyethane (18 V). Potassium terbutoxide (2.4 eq) and terbutanol (6.25 V) were mixed in another RBF to form a suspension / slurry. The slurry / suspension was slowly added to the reactants at -3°C to 0°C. The reaction was maintained at 0°C for 1–2 hours, followed by 5 hours at 25°C–30°C. After the reaction was complete, brine was added to the reactants and the mixture was extracted with DME. Yield of crude product: 41% [4-] [Cyano] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [3)] [Synthesis] [] [synthesis] [C] [] [synthesis] [C] [,step] [1. 1,4-] [Dioxane snail] [[4.5]] [Decane] [-8-] [Formonitrile] [(] [Compound] [1b)] [The synthesis of...] []

[0125] A solution of potassium tert-butoxide (13.6 kg, 121.2 mol, 2.4 eq.) in tBuOH (50 L) and DME (25 L) was added to a suspension of 1,4-dioxaspiro[4,5]dec-8-one (8.0 kg, 51.2 mol, 1.0 eq.) and p-toluenesulfonylmethylisocyanate (13.0 kg, 66.6 mol, 1.3 eq.) in DME (150 L) at -3 °C to 0 °C. The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 2 h. The reaction mixture was then heated to room temperature and stirred for 5 h. Brine (100 kg) was added and the mixture was extracted with DME (25 L). The combined organic phases were concentrated under reduced pressure. The residue was distilled (100 °C–120 °C, 5 mm Hg) to give an oily compound. [1](5.6 kg, 66%). [synthesis] [C] [,step] [twenty four-] [Side-oxycyclohexane] [-1-] [Formonitrile] [(2b)] [The synthesis of...] []

[0126] To the compound at room temperature [1b] HCl (1 N, 10 V) was added to a solution of (3.0 kg, 17.9 mol) in THF (6 L, 2 V). The reaction mixture was stirred overnight at room temperature. The reaction solution was extracted with DCM (3 × 3 L). All crude compounds were then processed. [2b] (Contains some compounds) [1b]) The mixture was concentrated and then treated again with HCl (1 N, 5 V) and THF (3 L, 1 V). The resulting mixture was stirred at room temperature for 4 h and extracted with DCM (3 × 3 L). The combined organic phases were washed with 5% NaHCO3 (5 L) and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a compound as a yellow oil. [2b](1.7 kg, 78%). [synthesis] [C] [,step] [3. 4-] [Cyano] [-1-] [Methyl methoxycyclohexaneformate] [(3)] [。] []

[0127] At 0℃, the compound [2b] K₂CO₃ (13.5 kg, 97.6 mol, 8.0 eq.) was added in portions to a solution of (1.5 kg, 12.2 mol, 1.0 eq.) and (4.6 kg, 36.6 mol, 1.5 eq.) in MeOH (22.5 L, 15 V). The reaction mixture was stirred at 0 °C for 3 h, followed by stirring at room temperature for 3 d. The salt was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (12 L, 8 V) and extracted with EtOAc (7.5 L × 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude compound as a solid. [3] (2.0 kg, 74% yield). The mass spectra were analyzed by atmospheric pressure chemical ionization (APCI) in positive ion mode and the measured mass (m / z) 198.1121 was consistent with the theoretical [M+H]+ mass (m / z) 198.1125. 1H data (Main isomers) 13C data (Main isomers) 1H data (minor isomers) 13C data (minor isomers) - 122.01 - 121.66 2.58–2.42 (m, 0.6H) 27.16 2.92-2.81 (m, 0.4H) 26.37 1.99–1.42 (m, 2.4H) 24.52 1.99–1.42 (m, 1.6H) 23.68 2.16-2.00 (m, 1.2H);1.99-1.42 (m, 1.2H) 30.01 2.16-2.00 (m, 0.8H);1.99-1.42 (m, 0.8H) 28.13 - 77.97 - 77.54 3.24 (s, 1.7H) 51.84 3.22 (s, 1.3H) 51.84 - 173.80 - 173.42 3.75 (s, 1.7H) 52.33 3.77 (s, 1.3H) 52.31 [4-(] [Imine] [(] [Methoxy] [)] [methyl] [)-1-] [Methoxycyclohexane] [-1-] [Methyl Formate Hydrochloride] [(] [Compound] [4)] [Synthesis] [] [synthesis] [A.] []

[0128] compound [3] (50 g, 1.0 eq) was placed in a dry round-bottom flask (RBF) and methanol (5 V) was added. Acetyl chloride (5 V) was added dropwise to the RBF at 0-5 °C. The reaction was maintained until the starting material was exhausted. Diisopropyl ether was added to the reaction mixture and stirred for 1 h. The suspension was filtered and dried to obtain the compound. [4]. Compounds [4] It is used in the next step without further purification.

[0129] Alternatively, compound 3 can be dissolved in a solvent or solvent mixture (e.g., isopropyl ether, methanol), and HCl gas can be bubbled through the solvent to generate compound 4. [synthesis] [B.] []

[0130] At 0℃, the compound [3] AcCl (1.2 kg, 15.2 mol, 1.5 eq.) was added dropwise to a solution of MeOH (810 g, 25.3 mol, 2.5 eq.). The reaction mixture was stirred at room temperature for 2 days. Then iPr₂O (6 L) was added and stirred for 1 h. The solid was collected by filtration to obtain the compound as a solid. [4] (approximately 2.4 kg). [synthesis] [C.] []

[0131] Add methanol (1.109 kg, 4 volumes) to the reactor. Maintain the temperature at 0°C–25°C and add the compound to the reactor. [3] (0.352 kg, 1.0 eq.) and a stirred reactor. The mixture was cooled to -5°C to 0°C in an ice bath. While maintaining the temperature at 0°C to 5°C, acetyl chloride (0.838 kg, 6.0 eq.) was added dropwise to the mixture, with the addition rate determined according to temperature control. The mixture was slowly heated to room temperature with stirring. After 10 h, samples of the mixture were taken every 1 to 3 h for analysis until the compounds were analyzed. [3] The area percentage was ≤1%. The mixture was concentrated to approximately 1 volume under reduced pressure (P≤-0.08 MPa) at T≤30°C. Then, methanol was exchanged with 3*2 volumes of methyl tributyl ether (MTBE). 2 volumes of MTBE were added to the mixture and stirred at 0°C~5°C for 2 h. The mixture was filtered and the wet filter cake was washed with 1 volume of pre-cooled MTBE. The solid was transferred to a tray and then dried by purging with nitrogen. After 12 h, approximately 315 g of off-white powder solid was obtained, with a crude yield of approximately 68% and a GC purity of 96%.

[0132] Analysis of compounds in positive ion mode using atmospheric pressure chemical ionization (APCI) by mass spectrometry [4]. Mass spectrometry showed that the measured mass (m / z) 230.1393 was consistent with the theoretical [M+H]+ mass (m / z) 230.1387. [Analysis Method:] [] [Column:] HP-5, 30 m length × 0.32 mm ID × 0.25 μm membrane [Carrier gas:] helium [flow] 1.9 ml / min [Running Time] 22.5 min [Temperature Program] Maintain 50℃ for 2 minutes; increase to 260℃ at a rate of 20℃ / min and hold for 10 minutes. [Inlet Temperature] 250℃ [Temperature Detection] 300℃ 1H data a (Main isomers) 13C data b (Main isomers) 1H data a (minor isomers) 13C data b (minor isomers) - 173.98 - 172.71 2.40–2.29 (m, 0.7H) 40.99 3.08-3.02 (m, 0.3H) 40.34 1.96–1.39 (m, 2.8H) 23.44 1.96–1.39 (m, 1.2H) 25.47 2.18-1.97 (m, 1.4H);1.96-1.39 (m, 1.4H) 29.96 2.18-1.97 (m, 0.6H);1.96-1.39 (m, 0.6H) 31.03 - 78.83 - 77.37 3.25 (s, 2.0H) 51.94 3.22 (s, 1.0H) 51.88 - 182.26 - 182.29 3.74 (s, 2.0H) 52.36 3.80 (s, 1.0H) 52.43 4.31 (s, 2.1H) 60.98 4.31 (s, 0.9H) 61.11 12.47 (s, 0.7H);11.66 (s, 0.7H) - 12.47 (s, 0.3H) ;11.66 (s, 0.3H) - [4-] [Methamidophos] [-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [5)] [and] [4-(4-)] [Hydroxy] [-6-] [Methylpyrimidine] [-2-] [base] [)-1-] [Methoxycyclohexane] [-1-] [Methyl formate] [(] [Compound] [6)] [Synthesis] [] [] [Compound] [5] [,synthesis] [A] []

[0133] compound [4](from 135 g compound) [3] The starting material was placed in a dry RBF and methanol (2 V) was added. The mixture was cooled to 0-5 °C and methanol-ammonia (10 V) was added. The reaction was maintained at 25-30 °C until the compound was obtained. [4] Continue heating until completely exhausted. Heating causes cis:trans isomerization to further convert the compound to cis-. [5] Progress. The reactants were completely distilled and exchanged twice with methanol to obtain a grayish-white solid (approximately 2:1 cis: trans). [Compound] [5] [,synthesis] [B]

[0134] 7 N NH3 / MeOH (1.48 kg, 10 eq) was added to the reactor at 0℃-25℃. The compound was added to the reactor while maintaining the temperature at 0℃-25℃. [4] (0.35 kg, crude product). The mixture was slowly heated to 20-30°C with stirring. After 10 h, samples of the mixture were taken every 1-3 h for analysis until the compounds were analyzed. [4] The area percentage was ≤5%. The mixture was heated to 55°C to 60°C for 1 to 2 h and samples were taken to monitor the cis:trans ratio. The typical cis:trans ratio was 80:20 to 85:15. The mixture was concentrated to about 1 volume under reduced pressure (P ≤ -0.08 MPa) at T ≤ 30°C. Then, a solvent exchange of methanol and 3*2 volumes of heptane was performed. An additional 2 volumes of heptane were added to the mixture and stirring was continued at 0°C to 5°C for 2 h. The mixture was filtered and the wet filter cake was washed with 1 volume of pre-cooled heptane. The solid was transferred to a tray and dried by purging with nitrogen. A grayish-white powder solid was obtained with a crude yield of about 100% and an HPLC-CAD purity of 92%. [, , ] [Analysis Method:] [] [IPC] [:] [HPLC-CAD] [Column:] Atlantis T3, 4.6*150 mm, 3.0 um [Column temperature:] 40℃ [flow] 1.0 ml / min [Injection Volume] 5 ul [Moving Phase] A: 0.1% FA in water B: 0.1% FA in ACN [Gradient Table] T(min) 0.0 9.0 12.0 12.1 18.0 B% 0 95 95 0 0 [CAD] [Detection] Data collection rate: 10 Hz Filter: 1.0 [Running Time] 18.0 min [, Cis , ] [, : , ] [, trans , ] [Ratio:] [HPLC-UV] [Column:] Atlantis T3, 4.6*150 mm, 3.0 um [Column temperature:] 20℃ [flow] 1.0 ml / min [Injection Volume] 5 ul [Moving Phase] A: 0.1% FA in water B: 0.1% FA in ACN [Gradient Table] T(min) 0.0 9.0 12.0 12.1 18.0 B% 0 95 95 0 0 [Detection] 210 nm [Running Time] 18.0 min [Compound] [6] [,synthesis] [A.] []

[0135] Methanol (1.14 kg, 4 vol) and a compound were added to the reactor. [5] (360 g, 1.0 eq). Methyl acetate (0.21 kg, 1.1 eq) and K₂CO₃ (0.81 kg, 3.5 eq) were added to the reactor at room temperature. The mixture was rapidly heated to 65°C–68°C. After 1–2 h, samples of the mixture were taken every 0.5–1 h for analysis until the compounds were analyzed. [5] The area % was ≤2%. After IPC, the mixture was rapidly cooled to room temperature. The reaction mixture was filtered, and the wet filter cake was washed with 2 volumes of MeOH and 2 volumes of DCM. The filtrate and washing solvent were combined. The combined organic matter was evaporated to 0.5 to 1 volume under vacuum (P ≤ -0.08 MPa) at a temperature below T ≤ 45°C, and then H2O (5 V) was added to dilute the mixture. The solution was adjusted to pH = 5 with HCl (2 N), and then 5 volumes of DCM were added to dissolve it. The mixture was allowed to settle for 10 to 15 min, and the layers were separated. The aqueous phase was extracted with 2 volumes of DCM. The organic matter was combined and then washed with 8 volumes of saturated NaHCO3 solution. The phases were separated. The organic layer was washed with 8 volumes of water, and the layers were separated. The organic layer was concentrated to 1 to 2 volumes under reduced pressure (P ≤ -0.08 MPa) at a temperature below T ≤ 50°C. Then, the solvent was exchanged from DCM to EtOAc using 2*4 volumes of EA. Add 4 volumes of EA to the mixture. Heat the mixture to 55°C–60°C and maintain for 2 hours. Cool the mixture to 0°C–5°C and stir for 2 hours. Filter the mixture and dry it to provide the compound. [6]. This produces 250 g of a white solid compound. [6]. 250 g of a grayish-white crude compound with a purity of 99% and a cis:trans ratio of 75:25 was obtained. The crude compound was added to the reactor. [6] and 10 volumes of EA (based on crude weight). The mixture was heated to 55°C–60°C and stirred for 2 h. The mixture was cooled to 0°C–5°C for 2 h. The mixture was filtered and washed with pre-cooled EA. The filter cake was dried under vacuum at 45°C–50°C until KF ≤0.5% and EA residue ≤0.2%. About 152 g of white powder solid was obtained, with a corrected yield of about 32% (after 3 steps) and a purity of 100% by HPLC. According to the release method, the product ratio was 97:3 cis:trans. [Analysis Method:] [] [IPC] [:] [HPLC-CAD] [Column:] Atlantis T3, 4.6*150 mm, 3.0 um [Column temperature:] 40℃ [flow] 1.0 ml / min [Injection Volume] 5 ul [Moving Phase] A: 0.1% FA in water B: 0.1% FA in ACN [Gradient Table] T(min) 0.0 9.0 12.0 12.1 18.0 B% 0 95 95 0 0 [CAD] [Detection] Data collection rate: 10 Hz Filter: 1.0 [Running Time] 18.0 min [Release Method:] [] [Column:] YMC-Pack pro-C18, 3 μm particle size, 4.6 mm * 150 mm [Column temperature:] 30℃ [flow] 1.0 ml / min [Injection Volume] 5 ul [Moving Phase] A: 100% ACN B: 100% Water [Gradient Table] T(min) 0 25 30 B% 95 15 95 A% 5 85 95 [Detection] 235 nm [Running Time] 30 min [Compound] [6] [,synthesis] [B.] []

[0136] To compounds [5] 9.0 mol of methyl 3-sideoxybutyrate (1.1 kg, 9.9 mol, 1.1 eq.) and NaOMe / MeOH (30%, 3.6 L) were added to a solution of MeOH (approximately 7.4 L), and the reaction mixture was refluxed overnight. The solvent was removed under reduced pressure, and the residue was diluted with water (12 L, 5 V). The solution was adjusted to pH 5 with HCl (2 N), and the solid was collected by filtration. It was then dissolved in DCM (12 L) and washed with NaHCO3 (saturated) (16 L) and H2O (16 L). The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the compound. [6](>95:5 cis: trans). The compound was obtained by grinding from EtOAc (800 mL) into a white solid. [6](710 g, 20.8%, after 4 steps). [, 1 , ] [H NMR](400 MHz, CDCl 3): δ 12.78 (s, or 1H), 6.16 (s, 1H), 3.77 (s, 3H), 3.30 (s, 3H), 2.64-2.67 (m, 1H), 2.31 (s, 3H), 2.14-2.18 (m, 2H), 1.80-1.98 (m, 6H).

[0137] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry [6] (Theoretical m / z 280.1423). ESI-MS shows the main measured mass (m / z) 281.1504 and the compound [6] The form [M+H] +(m / z) 281.1496 is consistent. The measured mass (m / z) 344.1609 is consistent with [M+H 2O+2Na] +(m / z) 344.1319. 1H data 13C data 12.15 (s, 1H) - - 162.54 5.99 (s, 1H) 110.03 - 164.23 2.14 (s, 3H) 23.42 - 185.04 2.60–2.51 (m, 1H) 41.16 1.82-1.52 (m, 4H) 24.59 2.02 (dt, J= 11.2, 2.5 Hz, 2H);1.82-1.52 (m, 2H) 30.26 - 77.48 3.13 (s, 3H) 51.16 - 173.98 3.67 (s, 3H) 51.85 [(1s,4s)-1-] [Methoxy] [-4-(4-)] [methyl] [-6-((] [Methylsulfonyl] [)] [Oxygen group] [)] [Pyrimidine] [-2-] [base] [)] Cyclohexane [-1-] [Methyl formate] [(] [Compound] [7)] [Synthesis] [] []

[0138] compound [7] The intermediate system is achieved by making the compound [6] The compound was prepared by reacting (1.00 kg ± 1%) with methanesulfonyl chloride (0.31 L ± 1%, 1.1 equivalents) and triethylamine (0.60 L ± 1%, 1.2 equivalents) in tetrahydrofuran (4.50 L ± 5%) at a temperature between 0°C and 10°C. [7] Non-separated intermediate (>97:3 cis:trans). This intermediate is not purified before proceeding to the next reaction.

[0139] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry [7] (Theoretical m / z 358.1199). ESI-MS shows the main measured mass (m / z) 359.1284 and the compound [7] The form [M+H]+(m / z) 359.1271 is consistent. The measured mass (m / z) 381.1136 is consistent with [M+Na]+(m / z) 381.1096. The measured mass (m / z) 344.1595 is consistent with [M+H-CH3]+(m / z) 344.1042. The measured mass (m / z) 281.1505 is consistent with [M-SO3CH3+H2O]+(m / z) 281.1496. 1H data 13C data 3.58 (s, 3H) 41.83 - 164.63 6.78 (s, 1H) 107.93 - 171.33 2.56 (s, 3H) 24.31 - 173.77 2.93 (tt, J= 10.4, 5.1 Hz, 1H) 45.42 2.11-1.97 (m, 1H);1.97-1.83 (m, 3H) 25.88 2.22-2.11 (m, 2H);1.97-1.83 (m, 1H);1.83-1.76 (m, 1H) 31.05 - 78.42 3.27 (s, 3H) 51.88 - 174.95 3.77 (s, 3H) 52.23 [(1s,4s)-1-] [Methoxy] [-4-(4-)] [methyl] [-6-((5-] [methyl] [-1H-] [Pyrazole] [-3-] [base] [)] [Amine] [)] [Pyrimidine] [-2-] [base] [)] Cyclohexane [-1-] [Methyl formate] [(] [Compound] [8)] [Synthesis] []

[0140] Next, 5-methyl-3-pyrazolamine (0.52 kg ± 1%, 1.5 equivalents) was added to the reaction mixture, followed by washing with tetrahydrofuran (1.00 L ± 5%), and the reaction mixture was heated to reflux temperature to form the compound. [8] Non-isolated intermediate. This intermediate is used without further purification. cis:trans ratio and input compound [6] The ratio is the same, with a ratio of >97:3 (cis: trans).

[0141] 5-Methyl-3-pyrazolamine can be synthesized from 3-aminocrotonitrile, hydrazine and water by a method similar to that disclosed in CN107980784, WO2014147640, US8,08,066, CN104844567 and CN108341782.

[0142] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry [8] (Theoretical m / z 359.1957). ESI-MS shows the main measured mass (m / z) 360.2035 with the compound. [8] The form [M+H] +(m / z) 360.2030 is consistent. 1H data 13C data 2.31 (s, 3H) 11.75 - 138.17 9.96 (s, 1H) - - 148.09 6.08 (s, 1H) 95.62 7.46 (s, 1H) - - 160.06 6.70 (s, 1H) 101.82 - 166.32 2.36 (s, 3H) 24.33 - 172.84 2.75 (tt, J= 10.9, 4.5 Hz, 1H) 46.09 2.07-1.97 (m, 1H);1.97-1.78 (m, 3H) 26.16 2.22-2.09 (m, 2H);1.97-1.78 (m, 1H);1.78-1.72 (m, 1H) 31.33 - 78.78 3.29 (s, 3H) 51.90 - 175.34 3.76 (s, 3H) 52.21 [(1s,4s)-1-] [Methoxy] [-4-(4-)] [methyl] [-6-((5-] [methyl] [-1H-] [Pyrazole] [-3-] [base] [)] [Amine] [)] [Pyrimidine] [-2-] [base] [)] Cyclohexane [-1-] [Formic acid] [(] [Compound] [9)] [Synthesis] []

[0143] In compounds [8] After the reaction was complete, the reaction mixture was cooled to a temperature between 30°C and 25°C, and a solution of previously prepared deionized water (9.00 L ± 5%) and 50% w / w sodium hydroxide (1.34 Kg ± 1%, 4.7 equivalents) was added to the reaction mixture to form the compound. [9] The reaction mixture was stirred at a temperature between 30°C and 25°C until the reaction was complete, and tetrahydrofuran (5.50 L ± 5%) was added at a rate not exceeding 4.44 Kg / (h·Kg) while maintaining the temperature between 30°C and 25°C. The suspension was cooled to a temperature between 25°C and 15°C at a cooling rate not exceeding 6°C / h. The suspension was stirred at a temperature between 15°C and 25°C for not less than 4 hours and not more than 10 hours. The suspension was filtered, and the wet filter cake was washed with deionized water (2.00 L ± 5%) at a temperature between 15°C and 25°C, and washed twice with acetone (2.00 L ± 5%) at the same temperature. The wet solids were dried under vacuum at a temperature not exceeding 40°C until the water content by KF was less than or equal to 17% w / w and the triethylamine content by GC was less than 5000 ppm. The yield was 65%-85% in 3 steps.

[0144] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry [9] (Theoretical m / z 345.1801). ESI-MS showed the main measured mass (m / z) 346.1876 with the compound. [9] The form [M+H]+ (m / z) 346.1874 is consistent. The gaseous ions observed at 208.0395 m / z are consistent with the fragmentation at the pyrimidine ring, which produces the proposed protonated fragments and water (m / z) 208.1193. 1H data 13C data 2.20 (s, 3H) 10.79 - 138.50 12.23 (or s, 1H) - - 148.37 6.16 (s, 1H) 95.28 9.52 (s, 1H) - - 159.82 6.86 (s, 1H) 101.61 - 164.51 2.24 (s, 3H) 23.76 - 171.92 2.61 (tt, J= 11.3, 3.8 Hz, 1H) 45.40 1.91-1.77 (m, 2H);1.77-1.67 (m, 2H) 25.81 2.06-1.91 (m, 2H);1.77-1.67 (m, 1H);1.67-1.61 (m, 1H) 30.56 - 77.47 3.18 (s, 3H) 50.95 - 175.56 12.23 (br s, 1H) - [4-] [fluorine] [-1H-] [Pyrazole Hydrochloride] [(] [Compound] [16)] [Synthesis] [] [synthesis] [A.]

[0145] [Compound]

[11] [Synthesis]: Makes

[10] A mixture of 200 g (1.0 equivalent) methanesulfonyl chloride (1.1 equivalent) in ethyl acetate (3.0 relative volumes) was cooled to 0-5°C, and then triethylamine (1.2 equivalent) was added between 0-20°C. After the addition was complete, the reaction mixture was stirred at 20-30°C until the reaction was complete. Water (3.0 relative volumes) was added to the resulting mixture, and the phases were separated. The aqueous layer was then extracted with ethyl acetate (1.0 relative volume), and the combined organic layers were washed with water (2.0 relative volumes) and then concentrated under vacuum at 40-45°C. The pure compound was obtained in excellent yield (93%) when the EtOAc content (94.9% area, EtOAc 4.8% area) was taken into account.

[11] . The compound

[11] A mixture of 294 g (1.0 equivalent) and morpholine (4.0 equivalent) was heated to 130-135 °C until the reaction was complete. The resulting mixture was cooled to 90 °C, and water (1.0 relative volume) was added. The reactants were further cooled to 20-30 °C, and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 × 1.0 relative volumes). The organic layer was laminated and washed with water (2 × 1.0 relative volumes), and then concentrated under vacuum at 40-45 °C. When considering the EtOAc content (94.8% area, EtOAc 4.7% area), this produced pure 2 in excellent yield (91%).

[0146] [Compound]

[12] [Synthesis:] Methyl methanesulfonate (1.1 equivalents) was heated to 130°C-135°C, and then added dropwise.

[11] (1.71 kg, 1.0 equivalent). After the addition was complete, the reaction mixture was cooled to 100-105°C and stirred at this temperature until the reaction was complete. Then, the reaction mixture was cooled to about 85°C and isopropanol (IPA) (1.5 relative volumes) was added. The mixture was then cooled to 0-5°C and stirred for 30 min. The resulting precipitate was filtered and the solid was washed with IPA (0.5 relative volumes) and then dried under vacuum at 45-50°C. A total of 2.34 kg (88%) of off-white solid was obtained.

[0147] [Compound]

[13] [and]

[14] [The synthesis:] will

[12] A solution of 1.0 equivalent of sodium hydroxide dissolved in water (1.0 relative volume) was heated to 50°C–60°C, followed by the addition of sodium hydroxide (10 M, 1.15 equivalents). The mixture was then stirred at this temperature until the reaction was complete. The mixture was then cooled to 20°C–30°C and filtered through diatomaceous earth. The diatomaceous earth pad was washed with water (0.2 relative volume), and the resulting aqueous solution was added directly to a mixture of morpholine (1.0 equivalent) and TEA (2.0 equivalent) heated at 70°C–80°C. The mixture was then stirred at this temperature until the reaction was complete. The reaction mixture was then cooled to 20°C–30°C and diluted with DCM (2.0 relative volume). The phases were separated, and the aqueous layer was extracted with DCM (2 × 2.0 relative volumes). The combined organic layers were washed with a saturated potassium carbonate solution (1.0 relative volume) and then concentrated under vacuum at 40°C–45°C. Next, toluene (2.0 relative volumes) was added and distillation was restarted to remove 1.0 relative volume of toluene. The resulting slurry was cooled to 0-5°C and filtered. The solid was washed with toluene (0.2 relative volumes) and dried under vacuum at 45-50°C. A total of 1.28 kg (78%) brown solid was obtained. HPLC purity: 98.3% area. GC purity: 99.4% area at room temperature for 21.4 min.

[0148] [Compound]

[15] [Synthesis:] (Z)-2-fluoro-3-morpholinyl-propan-2-enal (compound) dissolved in water (2.4 L, 2.0 relative volumes)

[14] 1.2 kg, 7.5 mol, 1.0 equivalent) of hydrazine dihydrochloride (870 g, 8.3 mol, 1.1 equivalent) was added. The material was heated to 50℃-55℃ and stirred for 2 h. At this time, HPLC showed that the remaining compound had an area of ​​0.13%.

[14] . The reactants were then cooled to 20-30°C and alkalized to pH 9-11 using an aqueous sodium carbonate solution (20%, w / w). The mixture was then diluted with ethyl acetate (3.6 L, 3 relative volumes) and filtered through diatomaceous earth. The mixture was extracted with ethyl acetate (2 × 3.6 L, 2 × 3 relative volumes), and the combined organic phases were concentrated under vacuum at 40°C. Yield: 1.17 kg (1.10 kg, 85%, adjusted for EtOAc content).

[0149] [Compound]

[16] [Synthesis:] The compound was synthesized at 20℃-30℃.

[15] The residue (1.1 kg, 12.8 mol, 1.0 equivalent) was added to a mixture of MTBE (2.2 L, 2.0 relative volumes) with ethanol-HCl (2.3 kg, 30% w / w, 1.5 equivalents). The reaction mixture was then stirred at this temperature for 2 h, cooled, and stirred at 0-5 °C for 1 h. The resulting slurry was filtered, and the filter cake was washed with MTBE (1.1 L, 1.0 relative volume) and then dried at 45-50 °C. Yield: 1.2 kg (77%). 1H data 19F data 7.74 (d, 2H) -181.64 - - 12.93 (s, 2H) - [4-] [fluorine] [-1H-] [Pyrazole Hydrochloride] [(] [Compound] [16)] [Synthesis] [] [synthesis] [B.] []

[0150] Selectfluor (0.25 eq) was added to a solution of 1H-pyrazole (1.0 eq, 20 g) in ACN (5 volumes), and the mixture was stirred and heated to 80-85°C for the reaction, with monitoring of the SM limit (22 area%, HPLC). After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (EA), filtered on a wet silicone mat, and the filter cake was washed with EA. The filtrate was distilled to obtain a crude product, which was dissolved in EA. The organic layer was washed with HCl (1 M) and distilled to obtain the crude material. The crude solid was dissolved in EA, and the organic layer was washed with 0.5 M HCl, dried over Na₂SO₄, and evaporated. The mixture was redissolved in EA, and the organic layer was washed with 0.5 M HCl, followed by brine. Finally, the organic layer was dried over Na₂SO₄ and evaporated to obtain the compound.

[16] (F-pyrazole), with a purity of 94.6% by HPLC, yielded 3.4 g of the desired product.

[0151] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry

[16] (Theoretical m / z 86.0280). ESI-MS showed the main quantified mass (m / z) at 87.03576, consistent with the compound.

[16] The form [M+H] +(m / z) 87.03530 is consistent. 1H data 13C data 7.70 (d, J HF = 4.5 Hz, 2H) 120.18 (d, J = 21.0 Hz) - 149.51 (d, J = 239.9 Hz) 11.66 (s, 2H) - [1-(6-)] [Clopyridine] [-3-] [base] [)] [Second] [-1-] [ketone] [(] [Compound] [17)] [and] [1-(6-(4-] [fluorine] [-1H-] [Pyrazole] [-1-] [base] [)] [Pyridine] [-3-] [base] [)] [Second] [-1-] [ketone] [(] [Compound] [18)] [The synthesis of...] []

[0152] [1-(6-)] [Clopyridine] [-3-] [base] [)] [Second] [-1-] [Ketone compounds]

[17] [。] Isopropyl magnesium chloride (2 M, 18 mL, 1.4 eq, 36 mmol) was added to a solution of 5-bromo-2-chloropyridine (5.0 g, 1 eq, 26 mmol) in anhydrous toluene (15 mL) at -5 °C for 45 min. The reaction mixture was stirred overnight at room temperature.

[0153] In a second flask, acetic anhydride (2.9 mL, 1.2 eq, 31 mmol) was diluted with anhydrous toluene (15 mL), and the solution was cooled to -5 °C. Grignard solution was added to the second flask after 15 min, while maintaining the temperature between -5 °C and 0 °C. The reaction mixture was stirred at this temperature for 2 h.

[0154] The reactants were then quenched with 50 mL of saturated ammonium chloride aqueous solution, and the phases were separated. The aqueous phase was extracted twice with 50 mL of toluene. The combined organic layers were washed with water and brine, dried over Na₂SO₄, and... [Concentration] yielded 4.0 g of a pale yellow solid compound.

[17]

[0155] The material is used in the next step without purification.

[0156] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry

[17] (Theoretical single isotopic mass 155.0138 amu). ESI-MS shows the main measured mass (m / z) as 156.

[2106] With compounds

[17] The form [M+H]+ is consistent, and its single isotopic mass is 156.02107 amu. 1H data 13C data - 196.28 2.62 (s, 3H) 27.01 - 131.37 8.29 (dd, J=8.3, 2.5 Hz, 1H) 138.99 7.67 (dd, J=8.3, 0.8 Hz, 1H) 124.48 - 154.06 8.94 (dd, J=2.5, 0.7 Hz, 1H) 150.25 [1-(6-(4-] [fluorine] [-1H-] [Pyrazole] [-1-] [base] [)] [Pyridine] [-3-] [base] [)] [Second] [-1-] [ketone] [(] [Compound] [18)] [The synthesis of...] []

[0157] In a 25 mL flask equipped with a condenser, the compound was... [16 (]4-fluoro-1H-pyrazole hydrochloride, 500 mg, 1 eq, 4.0 mmol), compound

[17] (890 mg, 1.4 eq, 5.7 mmol) and potassium carbonate (1.18 g, 2.1 eq, 8.6 mmol) were dissolved in NMP (5 mL). The reaction mixture was stirred at 85 °C for 19 h. After the reaction was complete, the mixture was cooled and 15 mL of water was added. The precipitate formed was filtered through a P4 filter and washed with 4 mL of water. The residue was dried under vacuum. To remove minor impurities, the solid was dissolved in DCM and treated with charcoal. After stirring at room temperature for 30 min, the solution was filtered through diatomaceous earth and concentrated to give a compound as a light brown solid.

[18] , with a yield of 86% and good purity.

[0158] Analysis of compounds using electrospray ionization (ESI) positive ion mode by mass spectrometry

[18] (theoretical m / z 205.0651). The compounds were also analyzed by mass spectrometry using both electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) techniques.

[18] Both techniques are in negative ion mode. ESI-MS positive ion mode shows the measured mass (m / z) 206.0724 and the compound.

[18] The form [M+H]+ (m / z) 206.0735 is consistent. The ESI-MS negative ion mode shows the measured mass (m / z) 206.0 as consistent with the compound.

[18] The form [M+H] -(m / z) 206.0735 is consistent. 1H data 13C data - 195.98 2.64 (s, 3H) 26.87 - 130.47 8.45 (dd, J = 8.6, 2.3 Hz, 1H) 139.16 8.07-7.96 (m, 2H) 111.02 (d, J = 1.6 Hz) - 152.78 9.01 (d, J = 2.3 Hz, 1H) 149.36 8.77 (d, J HF = 4.5 Hz, 1H) 114.00 (d, J = 29.3 Hz) - 151.00 (d, J = 247.6 Hz) 8.07-7.96 (m, 2H) 131.59 (d, J = 15.1 Hz) [(R)-N-((S)-1-(6-(4-)] [fluorine] [-1H-] [Pyrazole] [-1-] [base] [)] [Pyridine] [-3-] [base] [)] [Ethyl] [)-2-] [Methylpropane] [-2-] [sulfinamide] [(] [Compound] [20)] [Synthesis] [] []

[0159] Compounds are prepared by the following methods

[20] : to make the compound

[18] The compound was prepared by reacting (R)-(+)-2-methyl-2-propane-2-sulfinamide (1.18 Kg ± 2%, 2.00 equivalence) in tetrahydrofuran (7.00 L ± 5%) in the presence of titanium isopropoxide (IV) (2.77 Kg ± 2%, 2.00 equivalence) at a temperature between 70 °C and 80 °C.

[19] Non-separated intermediate. The reaction mixture was cooled to a temperature between -15°C and -25°C, and an L-Selectride solution (6.94 kg ± 2%, 1.60 equivalents, toluene) was added while maintaining the temperature to obtain the compound.

[20] . Heptane can be added to toluene to cause compound 20 to precipitate from solution.

[0160] Analyzing compounds in positive ion mode using electrospray ionization (ESI) by mass spectrometry

[20] (Theoretical mass 310.1264 AMU). ESI-MS shows the measured mass (m / z) as 311.1332 and the compound.

[20] The form [M+H] +(m / z) 311.1342 is consistent. 1H data 13C data 5.54 (d, J = 5.4 Hz, 1H) - 4.52 (dq, J= 6.32, 6.32 Hz, 1H) 52.24 1.51 (d, J = 6.7 Hz, 3H) 24.20 - 138.67 7.96 (dd, J = 8.6, 2.3 Hz, 1H) 137.86 7.93 - 7.83 (m, 2H) 111.02 (d, J = 1.5 Hz) - 149.71 8.43 (d, J = 2.2 Hz, 1H) 146.69 8.66 (dd, J HF= 4.5 Hz, J HH= 0.9 Hz, 1H) 113.31 (d, J = 29.2 Hz) - 150.59 (d, J = 246.7 Hz) 7.93 - 7.83 (m, 2H) 129.90 (d, J = 14.7 Hz) - 55.09 1.10 (s, 9H) 22.59 [Compound] [twenty one] [Synthesis] []

[0161] The compound is prepared by the following methods

[21] : At a temperature between 15°C and 25°C, the compound was...

[20] (1.00 kg ± 2%) was added in portions over a period of not less than 1 hour to a solution of HCl (0.55 L ± 5%) in acetone (8.00 L ± 5%) (or THF could be used instead of acetone). The mixture was rinsed with acetone (2.00 L ± 5%) while maintaining a temperature between 15°C and 25°C. The reaction mixture was stirred until the UPLC compound was obtained.

[20] content relative to compound

[21] The area should be less than or equal to 1%. At the end of the reaction, filter the mixture and adjust it to the previously prepared solution. The reactor and solids were washed with acetone (2.00 L ± 5%) at a temperature between 15°C and 25°C. The wet solids were dried under vacuum and nitrogen purging at a temperature not exceeding 60°C until the water content was less than or equal to 0.5% w / w by Karl Fischer and the acetone content was less than 5000 ppm by GC. The yield was 85%–100%. The compounds were analyzed by electrospray ionization (ESI) in positive ion mode by mass spectrometry.

[21] (Theoretical m / z 206.0968, free amine). ESI-MS showed the measured mass (m / z) as 207.1047, consistent with the compound.

[21] The form [M+H] +(m / z) 207.1041 is consistent. 1H data 13C data 8.75 (s, 3H) - 4.54 (q, J = 6.8 Hz, 1H) 47.33 1.58 (d, J = 6.8 Hz, 3H) 20.11 - 133.35 8.20 (dd, J = 8.6, 2.3 Hz, 1H) 138.34 8.00-7.91 (m, 2H) 111.14 (d, J = 1.5 Hz) - 150.55 8.63 (d, J = 2.3 Hz, 1H) 147.51 8.72 (d, J HF = 4.5 Hz, 1H) 113.60 (d, J = 29.2 Hz) - 150.75 (d, J = 247.2 Hz) 8.00-7.91 (m, 2H) 130.46 (d, J = 14.8 Hz) [Praltinib hydrochloride] [(] [Compound] [twenty two)] [Synthesis] []

[0162] Compounds are prepared by the following methods

[22] : The compound was placed over a period not exceeding 60 minutes.

[21] A solution of (0.73 kg ± 2%, 1.1 eq) in deionized water (103835, 5.0 L ± 5%) / NMM (N-methylmorpholine) (1.5 L ± 2%) was added to the previously prepared solution. [Compound] [9] (1.00 kg ± 2%, 1.0 eq) and CDMT (103593, 0.63 kg ± 2, 1.31 eq) were suspended in THF (100960, 5.0 L ± 5%) / deionized water (103835, 1.0 L ± 5%), and the temperature was maintained between 3°C and 17°C. The reaction mixture was stirred at a temperature between 9°C and 17°C until the compounds were analyzed by HPLC. [9] or compounds

[21] The content was reduced to or equal to 0.5% of the area. When the reaction was complete, the mixture was cooled to 8°C-2°C and quenched with HCl (1.2 L ± 5%), maintaining the temperature below 15°C. After adding about half the amount of HCl, the mixture crystallized into agglomerates of needle-like particles. Then anhydrous ethanol (6.0 L ± 5%) was added, and the resulting suspension was heated to reflux. The mixture was distilled at atmospheric pressure until the final volume was 21 L ± 5% or 5 L ± 5% of the solvent was distilled off. The jacket temperature used was usually below 93°C, and the mixture temperature was usually between 74°C and 81°C. The mixture was cooled to a temperature below 70°C. Ethanol (5.0 L ± 5%) and isopropanol (6.0 L ± 5%) were added. The suspension was heated to reflux temperature and stirred for 2 hours. The resulting suspension was slowly cooled to 25°C-20°C. The solid was separated by filtration and washed twice with a mixture of anhydrous ethanol (1.0 L ± 5%), deionized water (1.0 L ± 5%), and isopropanol (1.0 L ± 5%). The wet solid sample was collected for IPC analysis by HPLC. The solid was vacuum dried at 50°C or below until the water content was ≤3.0% w / w by Karl Fischer process. Further purification may be required.

[0163] The purification procedure consisted of the following steps: The wet solid was suspended in isopropanol (6.0 L ± 5%), anhydrous ethanol (5.0 L ± 5%), and deionized water (5.0 L ± 5%). The suspension was heated to a temperature between 70°C and 75°C over 1 to 2 hours, and stirred for 1 to 3 hours within the same temperature range. The suspension was then cooled to a temperature between 38°C and 42°C over 1 to 2 hours. It was then heated to a temperature between 70°C and 75°C over 1 to 2 hours, and stirred for 1 to 3 hours within the same temperature range. The resulting suspension was cooled to a temperature between 20°C and 25°C over 3.5 to 4.5 hours, and stirred for 1.5 to 3.5 hours within the same temperature range. The solid was separated by filtration and washed twice with a mixture of ethanol (1.0 L ± 5%), isopropanol (1.0 L ± 5%), and deionized water (1.0 L ± 5%). The wet solid sample was collected for IPC analysis by HPLC. The solid was vacuum dried at a temperature below or equal to 50°C until the water content was below or equal to 3.0% w / w by the Karl Fischer method. The dried solid sample was collected for analysis by HPLC.

[0164] The measured mass (m / z) 534.2740 is consistent with the theoretical mass (m / z 534.2736) and exhibits the expected isotopic distribution of [MH]+ ions. Based on high-resolution MS data, the calculated... The molecular formula is C27H33FN9O2, which is consistent with the molecular formula of the protonated molecular ion of pralatinib. Location 1H data COSY HSQC HMBC 13C data 1 2.20 (s, 3H) - 1 2, 4, 5 10.71 2 - - - - 138.16 3 11.89 (s, 1H) - - 2、4、5 - 4 - - - - 148.72 5 6.20 (s, 1H) - 5 - 95.32 6 9.51 (s, 1H) - - - - 7 - - - - 159.78 8 6.85 (s, 1H) - 8 - 101.65 9 - - - - 164.33 10 2.23 (s, 3H) - 10 8、9 23.82 11 - - - - 172.02 12 2.57 (tt, J=10.8, 5.2 Hz, 1H) 13、14 12 11、13、14 45.56 13、14 1.77-1.67 (m, 2H);1.88-1.77 (m, 2H) 12、15、16 13、14 11、13-16 25.94、25.98 15、16 1.67-1.57 (m, 1H);1.77-1.67 (m, 1H);1.95-1.88 (m, 1H);2.01-1.95 (m, 1H) 13-16 15、16 13-17、19 30.03、30.97 17 - - - - 78.62 18 3.13 (s, 3H) - 18 17 50.81 19 - - - - 173.47 20 8.47 (d, J=8.3 Hz, 1H) 21 - 19、21、22 - 21 5.05 (dq, J=7.2 Hz, 1H) 20、22 21 19、22、23、24、27 45.41 22 1.46 (d, J=7.1 Hz, 3H) 21 22 21、23 21.58 23 - - - - 138.88 24 7.99 (dd, J=8.5, 2.3 Hz, 1H) 25、27 24 21、26、27 137.36 25 7.87 (dd, J=8.4, 0.8 Hz, 1H) 24 25 23、26 111.04 (d, J C-F=1.5 Hz) 26 - - - - 149.49 27 8.43 (d, J=2.3 Hz, 1H) 24 27 21、23-26 146.19 28 8.67 (dd, J H-F=4.6 & J H-H=0.9 Hz, 1H) 30 28 29、30 113.35 (d, J C-F=29.2 Hz) 29 - - - - 150.59 (d, JCF=246.7 Hz) 30 7.90 (dd, J HF=4.3 & J HH=0.9 Hz, 1H) 28 30 28, 29 129.85 (d, JCF=14.6 Hz) [Praltinib] [(] [Compound] [twenty three)] [Synthesis] [] []

[0165] The sodium hydroxide solution, previously prepared using deionized water (5.0 L ± 5%, 5.0 Kg ± 5%) and sodium hydroxide (50% w / w) (0.55 L ± 5%, 0.84 Kg ± 5%), was added to the compound within a period of not less than 15 minutes.

[22] Pralatinib was prepared in a suspension of dichloromethane (12.0 L ± 5% 15.94 Kg ± 5%) (1.00 Kg ± 2% - analytical standard). The feeding system was rinsed with deionized water (1.0 L ± 5% 1.0 Kg ± 5%) and the rinse solution was added to the main solution. The mixture was heated to a temperature between 35°C and 45°C and stirred at this temperature for at least 2 hours. The pH of the mixture was verified. If the pH was below 12, more sodium hydroxide solution was added, with a concentration similar to that of sodium hydroxide. [Previously] the same as prepared, until the pH is satisfied. Confirm that a clear two-phase mixture is obtained. If solids are present in the mixture, stir the mixture at a temperature between 35°C and 45°C for at least 2 hours. Separate the phases for at least 30 minutes. Store the obtained organic phase 1 (bottom phase) (lower phase, containing product). Keep aqueous phase 1 (upper phase) in the same reactor. If solids are present, maintain them in the aqueous phase. Add dichloromethane (5.0 L ± 5% 6.64 Kg ± 5%) to aqueous phase 1 and stir for at least 30 minutes, maintaining the temperature between 25°C and 35°C. Separate the phases for at least 30 minutes. Combine the obtained organic phase (organic phase 2, lower phase) with the previous organic phase (organic phase 1), and if solids are present, maintain them together with the organic phase. Discard aqueous phase 2 (upper phase). Add deionized water (6.0 L ± 5% 6.0 Kg ± 5%) to the combined organic phases, maintaining the temperature between 25°C and 35°C, and then stir for at least 30 minutes. Allow the phases to separate for at least 30 minutes. Maintain the rag layer and organic phase 3 (lower phase), and discard aqueous phase 3 (upper phase). Wash organic phase 3 again with deionized water (103835; 6.0 L ± 5% 6.0 Kg ± 5%) and stir for at least 30 minutes. Allow the phases to separate for at least 30 minutes. Transfer the obtained organic phase 4 (lower phase) to a reactor for distillation. Distill organic phase 4 at atmospheric pressure until the final volume is 4.0 L ± 5%. Distillation is expected to occur at a temperature between 38°C and 40°C. Add acetone (9.0 L ± 5% 7.1 Kg ± 5%) and deionized water (1.0 L ± 5% 1.0 Kg ± 5%), and distill the mixture at atmospheric pressure until the final volume is 8.0 L ± 5%. Distillation is carried out at a temperature between 51°C and 57°C. Add acetone (9.0 L ± 5% 7.1 Kg ± 5%) and deionized water (1.0 L ± 5% 1.0 Kg ± 5%) again, and distill the mixture again at atmospheric pressure until the final volume is 8.0 L ± 5%. This distillation is carried out at a temperature between 51°C and 60°C. Add acetone (9.0 L ± 5% 7.1 Kg ± 5%) and deionized water (1.0 L ± 5% 1.0 Kg ± 5%) again. Adjust the temperature between 40°C and 30°C, and filter the mixture through a filter with a porosity of less than 1 micrometer. The previous reactor and transfer lines were flushed with a mixture of acetone (3.0 L ± 5% 2.4 Kg ± 5%) and deionized water (0.2 L ± 5% 0.2 Kg ± 5%).Distill the mixture at atmospheric pressure until the final volume is 8.0 L ± 5%. This distillation takes place at a temperature between 52°C and 62°C. Cool the mixture to a temperature between 50°C and 55°C. Take a sample to determine the water content using the Karl Fischer method. Calculate the amount of deionized water and acetone to be added using the water content value (% w / w, used to one decimal place) determined by Karl Fischer volumetric titration. Calculation of acetone addition = 6.32 × [KF % (w / w) / 100] = XX Kg Calculation of deionized water addition = 3.50 - [8 × [KF % (w / w]) / 100]] = YY Kg

[0166] Note: According to the equation, water should not be added for water content higher than 43.7% (w / w) obtained by the Kal-Fischer process.

[0167] After adjusting the acetone and water, the mixture is preferably cooled to a temperature between 35°C and 45°C at a rate of 5°C / h, and then (0.005 kg ± 5%) or a compound is added.

[23] (0.005 Kg ± 5%) seed crystals were added, and [Next] Rinse the feeding system with a mixture of deionized water (0.06 kg ± 5% + 0.06 L ± 5%) and acetone (0.011 kg ± 5% + 0.014 L ± 5%). Adjust the temperature to between 40°C and 45°C and stir for at least 30 minutes within the same temperature range. Alternatively, the seed crystals can be added directly to the mixture, and the feeding system can be rinsed with a mixture of deionized water and acetone. After 3 to 5 hours, add deionized water (10.5 L ± 5% + 10.5 kg ± 5%), maintaining the temperature between 40°C and 45°C. After 2 to 3 hours, heat the resulting suspension to reflux temperature and stir for 2 to 3 hours at reflux temperature. The reflux temperature is expected to be approximately 68°C. After 5 to 6 hours, cool the suspension to a temperature between 25°C and 15°C and stir for 5 to 6 hours within the same temperature range. The solids were separated by filtration and washed with a mixture of acetone (0.7 L ± 5% 0.6 Kg ± 5%) previously filtered through a filter with a porosity of less than 1 micrometer and deionized water (1.3 L ± 5% 1.3 Kg ± 5%). The solids were vacuum dried at a temperature below or equal to 50°C until the water content was below or equal to 4.0% (w / w) by the Karl Fischer process. The yield was approximately 97%.

[0168] The measured mass (m / z) 534.2740 is consistent with the theoretical mass (m / z 534.2736) and exhibits the expected isotopic distribution of [MH]+ ions. Based on high-resolution MS data, the... The molecular formula of [Calculation] is C 27H 33FN 9O 2, which is consistent with the molecular formula of the protonated molecular ion of praltinib. Location 1H data COSY HSQC HMBC 13C data 1 2.20 (s, 3H) - 1 2, 4, 5 10.71 2 - - - - 138.16 3 11.89 (s, 1H) - - 2, 4, 5 - 4 - - - - 148.72 5 6.20 (s, 1H) - 5 - 95.32 6 9.51 (s, 1H) - - - - 7 - - - - 159.78 8 6.85 (s, 1H) - 8 - 101.65 9 - - - - 164.33 10 2.23 (s, 3H) - 10 8、9 23.82 11 - - - - 172.02 12 2.57 (tt, J=10.8, 5.2 Hz, 1H) 13、14 12 11、13、14 45.56 13、14 1.77-1.67 (m, 2H);1.88-1.77 (m, 2H) 12、15、16 13、14 11、13-16 25.94、25.98 15、16 1.67-1.57 (m, 1H);1.77-1.67 (m, 1H);1.95-1.88 (m, 1H);2.01-1.95 (m, 1H) 13-16 15、16 13-17、19 30.03、30.97 17 - - - - 78.62 18 3.13 (s, 3H) - 18 17 50.81 19 - - - - 173.47 20 8.47 (d, J=8.3 Hz, 1H) 21 - 19、21、22 - 21 5.05 (dq, J=7.2 Hz, 1H) 20、22 21 19、22、23、24、27 45.41 22 1.46 (d, J=7.1 Hz, 3H) 21 22 21、23 21.58 23 - - - - 138.88 24 7.99 (dd, J=8.5, 2.3 Hz, 1H) 25、27 24 21、26、27 137.36 25 7.87 (dd, J=8.4, 0.8 Hz, 1H) 24 25 23、26 111.04 (d, J C-F=1.5 Hz) 26 - - - - 149.49 27 8.43 (d, J=2.3 Hz, 1H) 24 27 21、23-26 146.19 28 8.67 (dd, J H-F=4.6 & J H-H=0.9 Hz, 1H) 30 28 29、30 113.35 (d, J C-F=29.2 Hz) 29 - - - - 150.59 (d, J C-F=246.7 Hz) 30 7.90 (dd, J H-F=4.3 & J H-H=0.9 Hz, 1H) 28 30 28、29 129.85 (d, J C-F=14.6 Hz)

Claims

1. A compound of formula (I) or a salt thereof, 2. The compound of claim 1 or a salt thereof, wherein the compound is a compound of formula (Ia):

2. Or its salt.

3. A compound of claim 1 or a salt thereof, wherein the compound is a compound of formula (Ib):

3. Or its salt.

4. A compound of formula (II) or a salt thereof, 5. A compound or salt thereof as claimed in claim 4, wherein the compound is a compound of formula (IIa):

5. Or its salt.

6. A compound or salt thereof as claimed in claim 4, wherein the compound is a compound of formula (IIb):

6. Or its salt.

7. A compound of formula (III) or a salt thereof, 8. The compound of claim 7 or a salt thereof, wherein the compound is a compound of formula (IIIa):

8. or its salts.

9. The compound of claim 7 or a salt thereof, wherein the compound is a compound of formula (IIIb):

9. or its salts.

10. An isomeric mixture of a compound of formula (III) or a salt thereof, comprising a cis isomer and a trans isomer.

10. Wherein the cis isomer is a compound of formula (IIIa) or a salt thereof:

10. And the trans isomer is a compound of formula (IIIb) or a salt thereof:

10. The ratio of the cis isomer to the trans isomer is greater than or equal to 4:

1.

11. A compound of formula (IVa) or a salt thereof, 12. A compound of formula (IVb) or a salt thereof, 13. An isomer mixture of a compound of formula (IV) or a salt thereof, comprising its cis and trans isomers.

13. The cis isomer is a compound of formula (IVa):

13. And the trans isomer is a compound of formula (IVb) or a salt thereof:

13. The ratio of the cis isomer to the trans isomer is greater than or equal to 4:

1.

14. A compound of formula V or a salt thereof, 15. A compound of formula (Va) or a salt thereof, 16. The compound of claim 14 or a salt thereof, wherein the compound is a compound of formula (Vb):

16. Or its salt.

17. An isomer mixture of a compound of formula (V) or a salt thereof, comprising its cis and trans isomers.

17. Wherein the cis isomer is a compound of formula (Va) or a salt thereof:

17. And the trans isomer is a compound of formula (Vb) or a salt thereof:

17. The ratio of the cis isomer to the trans isomer is greater than or equal to 4:

1.

18. A composition comprising a VI compound or a salt thereof, 18. The composition substantially does not contain compounds of formula (VIa):

18. or its salt.

19. The composition of claim 18, wherein the ratio of the compound of formula (VI) or a salt thereof to the compound of formula (VIa) or a salt thereof is greater than or equal to 97:

3.

20. The composition of claim 18 or 19, wherein HPLC is used to detect the ratio of the compound of formula (VI) or a salt thereof to the compound of formula (VIa) or a salt thereof.

21. The composition of claim 18 or 19, wherein the composition comprises less than 0.1% by weight of a compound of formula (VIa) or a salt thereof.

22. A composition comprising a compound of formula (VII) or a salt thereof, 22. The composition substantially does not contain compounds of formula (VIIa):

22. Or its salt.

23. The composition of claim 22, wherein the ratio of the compound of formula (VII) or a salt thereof to the compound of formula (VIIa) or a salt thereof is greater than or equal to 97:

3.

24. A method for preparing a composition comprising a mixture of cis isomers and trans isomers of a compound containing form (IV) or a salt thereof.

24. The method comprises: (a) making a compound of formula (II) or a salt thereof:

24. Reaction with an ammonium source in the presence of a solvent, thereby producing a compound of formula (III):

24. or a salt thereof; and (b) reacting a compound of formula (III) with an alkyl acetate to produce a composition comprising a mixture of cis and trans isomers of a compound of formula (IV), wherein the cis isomer is of formula (IVa):

24. Or the amount of its salt is greater than that of the trans isomer (IVb):

24. or its salt.

25. A method for preparing a composition comprising a mixture of a cis isomer and a trans isomer of a compound of formula (III) or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is increased:

25. The cis isomer is a compound of formula (IIIa) or a salt thereof:

25. And the trans isomer is a compound of formula (IIIb) or a salt thereof:

25. The method includes making a compound of formula (II) or a salt thereof:

25. A composition comprising a mixture of a cis isomer and a trans isomer of a compound of formula (III) or a salt thereof, wherein the ratio of the cis isomer to the trans isomer is increased.

26. A method for preparing a compound of formula (X) or a salt thereof, 26. The method comprises the following steps: (a) making a compound of formula (II) or a salt thereof:

26. Reaction with an ammonium source in the presence of a solvent, thereby producing a compound of formula (III):

26. or its salt; (b) Reacting compound (III) with an alkyl acetate to produce an isomer mixture of compound (IV) or its salt:

26. In the isomer mixture of the compound of formula (IV), the cis isomer of formula (IVa) is:

26. Or the amount of its salt is greater than that of the trans isomer (IVb):

26. or its salt; (c) Purifying the isomer mixture of the compound of formula (IV) or its salt to obtain the compound of formula (IVa) or its salt; (d) Reacting the compound of formula (IVa) or its salt with an activator to provide the compound of formula (V-1a):

26. or a salt thereof, wherein R is an activating group selected from the group consisting of -Cl, -O-methanesulfonyl (-OMs), -O-p-toluenesulfonyl, phosphites, chlorosulfites and trifluoromethanesulfonates; (e) reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI):

26. or a salt thereof; (f) reacting the compound of formula (VI) or a salt thereof with a base to provide the compound of formula (VII):

26. or a salt thereof; (g) to react the compound of formula (VII) or a salt thereof with the compound of formula (VIII) or a salt thereof:

26. thereby providing a compound of formula (X) or a salt thereof.

27. A method for preparing a compound of formula (X) or a salt thereof, 27. The method comprises the following steps: (a) making a compound of formula (IVa) or a salt thereof:

27. Reaction with an activator to provide a compound of formula (V-1a):

27. or a salt thereof, wherein R is an activating group selected from the group consisting of -Cl, -O-methanesulfonyl (-OMs), -O-p-toluenesulfonyl, phosphites, chlorosulfites and trifluoromethanesulfonates; (b) reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI):

27. or a salt thereof; (c) reacting the compound of formula (VI) or a salt thereof with a base to provide the compound of formula (VII):

27. or a salt thereof; and (d) to react a compound of formula (VII) or a salt thereof with a compound of formula (VIII) or a salt thereof:

27. This provides a salt of compound (X).

28. The method of claim 26 or 27, wherein the final step of the method further comprises reacting a salt of compound (X) with a base, thereby providing compound (X).

29. The method of claim 28, wherein the salt of the compound of formula (X) is an HCl salt.

30. The method of any one of claims 24 to 26, wherein the ratio of the cis isomer to the trans isomer of the compound of formula (III) is at least 4:

1.

31. The method of claim 24 or 26, wherein the ratio of the cis isomer to the trans isomer of the compound of formula (IV) is at least 4:

1.

32. The method of claim 24 or 26, wherein step (a) further comprises heating the solvent.

33. The method of claim 25, further comprising heating the solvent to reflux.

34. The method of claim 24 or 26, wherein step (a) further comprises heating the solvent to 40°C or higher, or to 50°C or higher.

35. The method of claim 25, further comprising heating the solvent to 50°C or higher.

36. The method of any one of claims 24 to 27, wherein the solvent is a polar organic solvent.

37. The method of any one of claims 24 to 27, wherein the solvent is an alcohol.

38. The method of any one of claims 24 to 27, wherein the solvent is methanol.

39. The method of claim 24 or 26, wherein the alkyl acetate is methyl acetate.

40. The method of any one of claims 26 to 27, wherein the activator is a methanesulfonate base or methanesulfonate chloride, and R is -OMs.

41. The method of any one of claims 26 to 27, wherein the base is a metal hydroxide.

42. The method of claim 41, wherein the metal hydroxide is sodium hydroxide.

43. The method of claim 26, wherein the ammonium source is NH3 or NH4Cl.

44. A method for preparing a composition comprising a mixture of cis and trans isomers of a compound of formula (X), wherein the majority of the composition is in the cis isomer configuration.

44. The method includes: Make the compound of formula (VII) or its salt:

44. Reaction with compounds of formula (VIII) or their salts:

44. Thereby providing a composition comprising a mixture of cis and trans isomers of the compound of formula (X), wherein the majority of the composition is in the cis isomer configuration.

45. The method of claim 44, wherein the cis:trans molar ratio of the composition, wherein the majority of the composition is in the cis isomer configuration, is from 4:1 to 99:

1.

46. ​​The method of claim 44 or 45, wherein the cis:trans molar ratio of the composition, wherein the majority of the composition is in the cis isomer configuration, is 97:3 to 99:

3.

47. The method of claim 44 or 45, further comprising a method for preparing a compound of formula (VII) or a salt thereof, the method comprising: (a) To make a compound of formula (IVa) or a salt thereof:

47. Reaction with an activator to provide a compound of formula (V-1a):

47. or a salt thereof, wherein R is an activating group selected from the group consisting of -Cl, -O-methanesulfonyl (-OMs), -O-p-toluenesulfonyl, phosphites, chlorosulfites and trifluoromethanesulfonates; (b) reacting the compound of formula (V-1a) or a salt thereof with 5-methyl-3-pyrazolamine to provide the compound of formula (VI):

47. or its salt; (c) Reacting the compound of formula (VI) or a salt thereof with a base to provide the compound of formula (VII) or a salt thereof.

48. The method of claim 47, wherein the activator is a methanesulfonate base and R is -OMs.